Team Shelby's Research Corner

America Becoming Diabetes Nation

2008-11-04T06:03:00.000-08:00

The media was full of stories recently about the nearly doubling in the number of Americans with diabetes in the past decade. (Here's an Associated Press Report)

More than 90% of those cases are Type 2 Diabetes, which is directly linked to the poor diet and exercise habits of many Americans. We are literally eating ourselves to death. The old school lunch paradigm of providing cheap high carb food to poor children is piling up on the cheap McDonald's, Jack in the Box and other fast food junk they are eating at home. Regular soda has so much sugar in it that each can is like eating a candy bar.

At Team Shebly, we focus on Type I Diabetes because of the unmitigated cruelty it's seeming randomness and incurability visits on families and the patients for life. Type 2 Diabetes is largely preventable: eat less, move more. It's not rocket science, and the vast number who get it because they aren't willing to sacrifice and discipline themselves are obscuring those who have Type 2 as a complication from more serious health problems.

This is a perfect example of why Liz's work at our children's elementary school is so important. She teaches Jr. Jazzercise to the entire student body of some 600 children once a week. From kindergarten through 5th grade, they come to the multipurpose room with their teachers in bunches of about four classes each for a 30-minute dance-based workout tailored to their age-appropriate abilities. This program is funded entirely by the Parent Teacher Organization with no funding from the local school district. It helps fulfill the expanded district mandate that teachers, schooled in academic education of our children, engage them in additional minutes of physical activity each week.

Liz's work not only gets the kids moving in an organized way to popular music they know and love, but also shows them that there are more ways to move and stay fit than organized sports, at which many children are not adept or inclined. She teaches them about various muscle groups, how the body works together and how what they eat impacts how they feel.

This is particularly important for the 4th and 5th graders who don't receive a set physical education program, but are tested on their ability to achieve various physical fitness standards. How crazy is this: The school district provides a physical education teacher for first through 3rd graders. The PE requirement for 4th and 5th graders is up to their regular classroom teacher. But the 5th graders are tested near the end of the school year on their ability to reach various state-mandated physical fitness standards. Without the PTO funding Jr. Jazzercise, these kids would be totally set up to fail. That's why Liz has added a second 30-minute session a week for the 5th graders focusing on core strength training. Last year, the teachers reported that our school saw huge improvements in the physical fitness testing of our 5th grade, and that our school was among the best in the entire district.

All of this ties back to Type 2 Diabetes. A lot of these kids eat late dinners of greasy fast food provided by parents who are commuting long distances, can't afford home-cooked meals or are trying to cram too much into their schedules to pay attention to healthy eating habits. Kids spend lots of time watching TV, playing on computers, text messaging their friends. Predators have made neighborhoods unsafe for children to ride their bikes or skate after school. Urban designers put high-speed four-lane roads through neighborhoods and use narrow sidewalks as the "safe route to school."

Everything has an impact. Learn about Type 2 Diabetes and how to protect yourself and your family from this disease. I can't imagine why anyone would choose to live with the chronic threat to their future that my daughter faces through no fault of her own.

>>The CDC report on soaring Type 2 rates>>

>>Market Watch report: Moving more staves off Type 2>>

Artificial Pancreas Work Progresses in Human Trials

2008-10-28T05:57:00.000-07:00

The University of Virginia has announced very positive results from their first round human trials of a closed loop artificial pancreas developed solely through a computer simulation model rather than the traditional animal trials.

This is key for two main reasons:

The five patients that received the system that automatically monitors their blood glucose levels and adjusts it based upon a prescribed insulin delivery regime responded very well. Great news for people like Shelby who someday hope to manage their Type I Diabetes with this type of device.
The Food and Drug Administration accepted the computer simulation in approving the human trials without requiring years of animal testing first. This has tons of implications both for the animals involved (a long-standing ethical issue in all medical research) but also in terms of cost of research and the speed with which laboratory hypotheses can be proven and converted into beneficial tools for patients.

>> READ THE FULL RELEASE HERE>>

Developing a 'closed loop' system, also called an artificial pancreas, is sort of the holy grail in the management of Type I Diabetes.

It would eliminate the need for painful finger prick blood glucose testing.
It also would eliminate the specter of dangerous overnight low blood glucose episodes, which can be particularly dangerous for patients who live by themselves.
It allows blood glucose levels to be dialed in much more precisely within a 'normal' range thereby delaying or preventing devastating side impact of diabetes, such as liver and kidney damage, blindness and circulatory problems.

This research was funded in major part by the Juvenile Diabetes Research Foundation and coordinated globally by the Artificial Pancreas Consortium.

Green Tea May Delay Type I Onset

2008-10-28T05:33:00.001-07:00

The University of Georgia School of Dentistry discovered a correlation between an antioxidant present in green tea and the delayed onset of Type I Diabetes in mice genetically prone to the disease. The discovery came while researchers were studying primarily another autoimmune disease - Sjogren's Syndrome, which affects the function of salvatory glands.

>>READ THE FULL PRESS RELEASE HERE>>

The research is interesting and heartening, particularly because the green tea antioxidant EGCGwas introduced to the mice diluted in water, as it would commonly be administered by drinking tea. It's also important because now we have knowledge about a commonly occurring compound that appears to have a positive impact on a disease that is very difficult to prevent and currently impossible to cure.

However, with several approaches to delaying the onset of Type I Diabetes, the study requires knowledge that the subject is prone to the disease. This is the conundrum for researchers: how do you find human test subjects to move the research to the next level, or how do you apply it when you can't reliably predict natural onset of Type I Diabetes.

Researchers have identified genetic markers that indicate a predisposition to develop Type I Diabetes, but not everyone with it eventually develops the disease. Applying or even testing prophylactic treatments requires a fairly wide scale screening process of potential subjects, namely infants. The double blind nature of scientific experimentation also means that some children will develop the disease while in the study, but how do you weed out those who never run into the unknown environmental links believed to trigger the genetic cascade into Type I Diabetes?

Thank you to the researchers at the University of Georgia for this important work. It's another link in the ongoing work into discovering how natural compound can protect the human body from going haywire. But EGCG is not a cure-all that will wipe out Type I by itself. Stay tuned for more research in to the applications of this new knowledge.

Continuous Glucose Monitors Proven Effective

2008-09-19T16:11:00.000-07:00

Continuous glucose monitoring is effective in controlling blood sugar levels, according to a new study from the University of Colorado Denver published this month in the New England Journal of Medicine.

The findings, from a study involving test subjects from 8 years old to 72 years old with Type I Diabetes, indicate that monitoring blood sugar through an insulin-pump like device on a continual basis provides much more accurate information and allows better insulin dosing.

While this has been the expectation of this new technology and the early indications from animal and developmental testing, this study was the first broad human study to prove the effectiveness of this technology. The study was funded by the Juvenile Diabetes Research Foundation.

The positive results were most pronounced among adults over 25 years old and among children ages 8 to 14. Researchers noted that those age groups tend to treat their diabetes more intensely than do young adults between the ages of 15 and 24. This finding is very consistent with other indications of slack attention to diabetes care among young adults who are transitioning from parent-supervised care to self-care.

Once proven safe and effective, continuous glucose monitoring systems will become part of the usual treatment protocol (much as insulin pumps have in recent years), and be more likely to be covered by durable medical device provisions of most health care policies.

Proving the monitoring is reliable and effective also is a key step in the production of a 'closed loop' insulin delivery system in which a continuous glucose monitor is coupled with an insulin pump to both monitor glucose levels and deliver insulin automatically, in what researchers call an 'artificial pancreas.' (The Artificial Pancreas Center at Stanford University is spearheading global work in this area.)

Here are the key links for this article:

Abstract of New England Journal of Medicine article (link may expire)
Barbara Davis Center for Childhood Diabetes @ University of Colorado, Denver
CBS4 Denver report on findings
9NEWS Denver report on findings
ABC 7 Denver report on findings

'Chicago Project' working toward a cure

2008-09-17T06:15:00.000-07:00

Came across an interesting group from the University of Illinois that is working as "The Chicago Project" to bring top scientists from around the world together on the idea of speeding up the reliability of islet cell transplantation.

This idea has been around for a while, but there have been a number of challenges:

sufficient supplies
long-term anti-rejection therapy
long-term study results

Here's the basic concept: Islet cells inside the pancreas create insulin, which is a hormone essential to the absorption of glucose from the blood stream into the body's cells where it can be used to energy. In diabetes, islet cells are either destroyed altogether or impaired such that they can't effectively produce the insulin the patient needs. In islet cell transplantation, you inject new, functioning islet cells into the patient. In early tests, the transplanted cells took and started making insulin, but there were complications.

The Chicago Project has linked many top researchers in the world to collaborate on solving the myriad complications with islet cell transplantation in the drive to make this a functional cure for diabetes.

We've added a Chicago Project link in the right-hand column. We'll check back with them from time to time and keep you posted.

High blood sugar impairs blood flow to heart in diabetics

2005-10-14T16:37:00.000-07:00

Press Release from the Washington University in St. Louis School of Medicine

By Gwen Ericson

Oct. 5, 2005 — Normally, when the heart pumps harder, the blood vessels that feed it open wider to bring the heart more fuel. But in people with diabetes this function often is impaired.

Poorly controlled blood glucose levels in type I diabetes can have a negative effect on blood flow to the heart.

In the heart muscle of type 1 diabetics, high blood glucose is a significant contributor to poorly opening vessels, or poor vasodilation, according to a study by researchers at Washington University School of Medicine in St. Louis. Even administration of high levels of insulin, which usually enhances vasodilation, can't counteract the negative effect of high glucose on the heart.

"It's known that diabetes can lead to a reduced capacity for dilation of blood vessels and that this contributes to increased plaque buildup and heart disease," says senior author Robert J. Gropler, M.D., professor of radiology, medicine and biomedical engineering and director of the Cardiovascular Imaging Laboratory at the Mallinckrodt Institute of Radiology at the School of Medicine.

"Since it is typical for type 1 diabetics to periodically experience insulin deficits or increased blood glucose, we systematically isolated the effect of insulin and glucose to see which had a greater effect on dilation of blood vessels in these patients."

The researchers measured the capacity of heart blood vessels to dilate in 20 patients with type 1 diabetes using positron emission tomography (PET) imaging. Other than their diabetes, the patients had no physical conditions, such as coronary disease, hypertension or high cholesterol, that would contribute to impaired vasodilation. Eighty percent of the patients were women, and their average age was 44.

The team used the drug adenosine to encourage dilation of the blood vessels of the heart, and at the same time they maintained constant insulin and glucose levels in the patients using an intravenous system.

The researchers found that in response to adenosine, patients maintained at high insulin and normal glucose levels increased the rate of blood flow in the heart about four fold. But patients maintained at high insulin and high glucose increased their heart blood flow rate only about two fold.

"We know that insulin has beneficial effects on vasodilation," Gropler says. "But in the second group of patients, we saw that a high level of insulin could not overcome the inhibition of vasodilation caused by a high level of glucose."

The study demonstrates the detrimental effect of high glucose levels on heart function and highlights the importance for diabetic patients of keeping their blood glucose within the normal range.

"It can be very challenging for diabetic patients to maintain normal blood sugar," says co-author Janet B. McGill, M.D., associate professor of medicine. "But this study provides yet another reason to push for tight control of glucose levels. If instituted early enough, tight glycemic control may potentially reduce heart problems in diabetic patients."

The study's authors note that high blood glucose reduces production of nitrous oxide, a substance that contributes to vasodilation, and increases production of hormones that constrict blood vessels. It also increases oxidative stress in tissues of the body by altering cellular energy metabolism.

"The heart has become an organ of primary concern for endocrinologists and people with diabetes," McGill says. "And although physicians previously were concerned with the risk of coronary artery disease in diabetics, it appears we must also consider the impact of high blood glucose on energy metabolism in the heart."

Robert Gropler and his colleagues are now conducting a study of metabolic changes that occur in type 2 diabetes.

"We are focusing on blood fat levels in this next study," Gropler says. "We want to see if drugs that reduce blood fat levels and thus decrease fat delivery to the heart will have beneficial effects on the metabolism of heart muscle as well as blood flow and heart function."

For this study, the research team is recruiting patients over the age of 18 with type 2 diabetes and without known coronary disease. Each volunteer will receive a full physical exam, including a battery of tests to assess cardiac function, and will be followed up for four to six months on a study medicine. Those interested in participating in the study should call 314-362-8604.

--------------------------------------------------------------------------------
Srinivasan M, Herrero P, McGill JB, Bennik J, Heere B, Lesniak D, Davila-Roman VG, Gropler RJ. The effects of plasma insulin and glucose on myocardial blood flow in patients with type I diabetes mellitus. Journal of the American College of Cardiology 2005 July 5;46(1):42-48.
Funding from the National Institutes of Health and the Barnes-Jewish Hospital Foundation supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
--------------------------------------------------------------------------------

Bill would let schools give emergency diabetes injection

2005-09-22T17:38:00.000-07:00

From the Salt Lake City Tribune // Sept. 22, 2005
By Carey Hamilton // The Salt Lake Tribune

What is Glucagon?

Glucagon is a hormone, available by prescription. It is used to treat people with diabetes when their blood glucose levels drop dangerously low and they cannot swallow food or liquid - they may be having a seizure or losing consciousness. It comes in an emergency kit and is administered by injection.

Natalie Rodgers fears school policies could prevent her 6-year-old daughter and other diabetic children from receiving a lifesaving injection.

The Kearns woman has enlisted the help of state Sen. Patrice Arent, D-Holladay, who is sponsoring a bill that would allow trained adults to administer glucagon to children who take insulin and are losing consciousness. Glucagon is a hormone that raises blood sugar levels, staving off diabetic comas and even death.

Rodgers, Arent and health experts believe trained volunteers at Utah schools should be able to give the injections, which do not need to go in a vein. But students are currently forbidden from bringing almost all medications to school, with the exception of asthma inhalers.

"The thing that's great about it is it's hard to do wrong," said Rodgers, who spoke at an Education Interim Committee at the Capitol on Thursday. "There's no risk of overdose; it's a hormone that your body stores naturally. If you gave it to someone who doesn't have diabetes, it wouldn't hurt them."

People who have diabetes do not produce or properly use insulin, a hormone needed to convert sugar, starches and other food into energy. While the cause of diabetes is unknown, experts believe genetics and environmental factors, such as obesity and lack of exercise, play roles.
Nationwide, more than 18 million people - including a growing number of children - have diabetes, and many are unaware they have it. In Utah, about 4,000 children and teens under 20 - roughly .37 percent of all Utah youth - have diabetes, according to the Utah Department of Health. In 1991, the number of youth with diabetes was 1,800.

Rodgers' daughter, Andrea, was diagnosed with Type I diabetes in 2003 at the young age of 3.

"I have friends who have used glucagon on their children," Rodgers said. "We kindly refer to it as the Heimlich maneuver for diabetics. Normally, I wouldn't let my child go anywhere where she doesn't have glucagon available. It's a lifesaver for her."

Mary Murray, an endocrinologist and director of the diabetes program at Primary Children's Medical Center, beseeched the committee to endorse the legislation, which it did unanimously. Lawmakers will consider the bill when the legislative session begins in January.

Murray has treated patients who could have been helped by glucagon.

"Glucagon is safe and easy to administer," she said. "It can be given to a normal individual by accident, and the worst that will happen is nausea or vomiting."

Under the bill, children would get a prescription for the emergency kit from their doctors and carry it with them in their backpacks. School personnel trained in administering the medication would be shielded from lawsuits or criminal charges if they gave the injections in good faith.

"I don't want to have a situation where we have kids die when we can save them," Arent said.

Type 1 diabetes link to bone loss

2005-09-21T09:32:00.000-07:00

From AustralianDoctor.com.au // Sept. 21, 2005
By Jill Stein

ALMOST half of adults with type 1 diabetes have low bone mineral density, according to a study reported at the European Association for the Study of Diabetes meeting held in Athens last week.

Rheumatologist Dr Heather McDonald-Blumer and colleagues from the University of Toronto in Canada presented results of a bone mineral density (BMD) assessment in adult type 1 diabetes patients from a large community diabetes practice.

Among 130 people who completed a BMD assessment, 40% had a T score of less than -1.0 in at least one of three measured sites (femoral neck, total hip and lumbar spine).

"In other words, their T scores were in the low bone mass or osteoporotic range," Dr McDonald-Blumer said.

Men were affected more than women, with 46% of male type 1 diabetic patients showing low BMD compared with 34% of women, a trend especially apparent in the quartile with the lowest BMD.

"Overall, a disproportionate number of young male patients had low BMD scores," Dr McDonald-Blumer said.

While low BMD was more common in older age groups, it was also high among younger patients (11 of 30 patients aged 20-34).

In this population, BMD values did not correlate directly with age, BMI, age of onset of diabetes, duration of diabetes, the presence of micro- or macrovascular complications or the presence of traditional osteoporosis risk factors, Dr McDonald-Blumer said.

She said the results suggested undefined mechanisms were likely to be responsible for low bone mass in this population and further research was needed in the broader type 1 diabetic population.

Patients who were pregnant, seeking pregnancy or who had secondary causes of osteoporosis, or those with low BMD using anti-resorptive medications, were excluded from the study.

FDA approves new continuous glucose monitor

2005-09-16T04:26:00.000-07:00

Many people we talk to ask about the future of a continuos glucose monitoring system that will eliminate the need for the numerous daily fingerpricks. Here's the latest on one company's efforts.

From the Sept. 2005 JDRF Research Frontline Newsletter

Diabetes product providers continue to develop and refine diabetes management devices that could ultimately represent the component parts of an artificial pancreas. In August, the Food and Drug Administration (FDA) approved the Guardian RT Continuous Glucose Monitoring System, a blood sugar monitor that works both as a round-the-clock tracking device, recording a patient's blood glucose for up to three days, and as an alarm, sounding when blood sugar changes precipitously.

Patients wearing the beeper-sized, wireless monitor can get realtime glucose readings every five minutes, and also track how diet, exercise, and medication are affecting their blood sugar levels.

"Continuous monitors represent where diabetes selfmanagement is heading," says JDRF Scientific Program Manager Aaron Kowalski, who has type 1 diabetes.

Manufactured by Medtronic, Inc., the Guardian RT uses a sensor inserted in the abdomen just under the skin. The sensor transmits information to the monitor and records up to 288 readings a day. These data can be downloaded onto a PC to view trends in the individual's blood glucose activity. It also alerts users to high or low blood glucose levels. After three days, the sensor must be replaced.

While the manufacturer continues to evaluate training, education, and reimbursement fees, the Guardian RT is being sold only in selected U.S. cities. It requires a physician's prescription.

Currently, the only other continuous glucose monitors approved for use by the FDA are Medtronic's CGMS System Gold, an earlier model similar to the Guardian RT, and the GlucoWatch G2 Biographer, a wristwatch-like device manufactured by Cygnus.

Clinical trials show continuous monitors are effective, but at this point in their development they don't work well enough to replace conventional fingerstick glucose meters. As a result, the FDA requires that continuous monitors, including the Guardian RT, be used to complement fingerstick testing and give patients additional information about glucose level trends.

But taking a longer view, continuous monitors represent an important step toward an artificial pancreas, which would sense glucose levels and dispense appropriate amounts of insulin automatically.

"Technology will probably be reoriented around identifying trends and taking measures to prevent extreme highs or lows," says Dr. Kowalski. "Ultimately, it may be more important to know which way your glucose levels are heading than what your exact reading may be."

Antibiotic may slow or prevent diabetic retinopathy

2005-09-16T04:25:00.000-07:00

From the Sept. 2005 edition of JDRF Research Frontline Newsletter

JDRF-funded researchers at Penn State University have found that an antibiotic used to treat acne may slow or prevent diabetic retinopathy, the most common eye-related complication of diabetes and the leading cause of adult blindness in the U.S. The drug, minocycline, has proved effective in diabetic rats and could begin tests in humans soon.

"We think minocycline could enter clinical trials relatively quickly, given that it is already FDA-approved for another use." said Thomas Gardner, M.D., director of the JDRF Center for Mechanisms and Intervention of Diabetic Retinopathy at Penn State University Hershey Medical Center, where the study was conducted.

The researchers found that minocycline reduces by half the damage caused by diabetes to certain nerve cells, microglia, in the retina. Normally, microglia act as the cleanup crew for the nervous system, disposing of damaged cells by releasing toxins and engulfing them. In the presence of diabetes, microglia in the retinas become activated inappropriately - researchers were unsure how - and release toxins that kill healthy nerve cells critical for normal vision. Treatment with minocycline blocks this activation and the ensuing nerve cell death that leads to retinopathy.

Previous studies have shown that the changes diabetes causes in the body lead to increased production of cytokines, or proteins that cause inflammation of the nerves. The Penn State study, led by Kyle Krady, Ph.D., and published in the May issue of Diabetes, goes a step further to show that in early diabetes, elevated levels of cytokines activate the microglia, setting off destruction of retinal nerve cells.

After confirming that diabetic rats had high cytokine levels, Dr. Krady treated the animals with minocycline and found that it reduced cytokine levels and inflammation. Since nerve cell damage also decreased from the drug, the study draws a strong link between elevated cytokine levels and nerve cell death, suggesting how retinal cells may be damaged or changed by diabetes.

"These results confirm that diabetes causes an early increase in the _expression of inflammatory mediators within the retina, and that minocycline reduces this inflammatory component," said study co-author Steve Levison, Ph.D, professor of neural and behavioral sciences at Penn State College of Medicine.

Dr. Gardner said the Center's data will be introduced as a candidate for therapeutic development to the Diabetic Retinopathy Clinical Research Network, a collaborative network between the JDRF and the National Eye Institute at the National Institutes of Health.

"This is an exciting new development that has great potential for the treatment of this devastating complication," said Antony Horton Ph.D., JDRF Program Director for Diabetes Complications.

Identification of minocycline's potential is the latest payoff from the JDRF Center's unconventional approach to studying diabetic retinopathy, which traditionally has been regarded as a blood vessel disease that damages capillaries supplying blood to the retina.

Researchers at the Penn State Center think retinopathy may also - or even primarily - result from changes in the retinal cells. When researchers can identify and completely understand the sequence of these early retinal changes in various cell types, the information could help medical research intervene earlier in the
course of the disorder.

Adult cells reprogrammed to embryonic state

2005-09-16T04:21:00.000-07:00

From the Sept. 2005 JDRF Research Frontline

Researchers at Harvard report they have developed a method for creating therapeutic stem cells by fusing adult cells with embryonic stem cells. This fusion appears to reprogram the adult cell, resetting it to a state that resembles the embryonic stem cell. From that point, it might be coaxed to develop into specialized cells that could be used therapeutically in people.

This technique could be used to create replacement cells that are genetically identical to the donor of the adult cell. In addition, it may permit scientists to derive new human embryonic stem cell lines without the need to use human embryos. The research was led by Kevin Eggan, Ph.D., working with Douglas Melton, Ph.D. JDRF support enabled the research, which is reported in the August 26 issue of the journal Science.

"This research, while interesting and provocative, is still in the earliest stage of development and needs to be confirmed by other groups before we begin to understand its long-range impact," said JDRF Chief Scientific Officer Robert Goldstein, M.D. "It presents another possibility for scientists to explore and demonstrates once again the importance of stem cell research. But it would be a mistake to abandon other areas of diabetes research in general, and embryonic stem cell research in particular, because of this preliminary finding."

Currently, human embryonic stem cells are derived using human embryos either left over from in vitro fertilization procedures or created for research. That process is the major reason why some groups are opposed to embryonic stem cell research.

In the Science study, the researchers combined human skin cells with human embryonic stem cells in the presence of a detergent-like substance that caused the two cell types to fuse. The fused cells were "tetraploid" - meaning they contained the combined chromosomes of both the somatic cells (in this case, skin cells) and the embryonic stem cells, and therefore double the normal amount of DNA as in a human cell.

The fused cells were shown to have the characteristics of embryonic stem cells. They expressed the same genes as embryonic stem cells, even with two kinds of chromosomes (from the adult skin cell, and from the embryonic stem cell). This means that the fused cells must have reprogrammed the skin cell chromosomes so that they expressed the same genes as the embryonic stem cell.

Like stem cells, the fused cells could be grown in culture for long periods. Moreover, these tetraploid cells could be induced to develop into nerve cells, hair follicles, muscle cells, and cells of the stomach lining. This demonstrated the ability of the fused cells to give rise to a variety of different cell types.

Several technological hurdles still remain, with the biggest challenge figuring out a way to eliminate the embryonic stem cell nucleus from the newly created cell so that the fused cell would have a normal number of chromosomes instead of double that amount.

While any therapeutic applications from the new method lie far off, the researchers say that in the short term, it is more likely that the new technique will help to understand how embryonic cells reprogram adult, or "somatic" cells to an embryonic state. But Dr. Eggan told Science he expects that in 10 to 15 years, researchers will be able to use the technique routinely and will no longer need embryos or human eggs to reset adult cells.

"This is another example of how much scientists are learning about human embryonic stem cells in these early years of the research," said Dr. Goldstein.

Obesity: Double diabetes threat?

2005-07-12T09:02:00.000-07:00

The Sacamento Bee // July 11, 2005 04:45 PM

The obesity epidemic appears to be fueling a hybrid type of diabetes that afflicts adults and children and, some believe, may increase the devastating complications of the disease.

Dubbed "double diabetes" by some and "diabetes one-and-a-half" by others, the combination of types 1 and 2 diabetes symptoms confounds doctors attempting to accurately diagnose patients and find the best medicines to treat them.

"We don't really know how prevalent this is," said Dr. Francine Kaufman, head of the Center for Diabetes and Endocrinology at Childrens Hospital Los Angeles. "We are just at the vista of realizing it's out there and trying to determine how do we get an understanding of it."

Even Kaufman, former president of the American Diabetes Association and author of the book "Diabesity" -- about the obesity epidemic and related rise in type 2 diabetes -- does not always recognize the double diabetes cases.

Her patient, Cameron Stark, had classic symptoms of type 2 diabetes. Then 14, the girl's thirst was unquenchable. She was losing weight rapidly because her body wasn't absorbing necessary nutrients. She was vomiting. She felt tired all the time, one day falling sound asleep on the marble floor of her home.

At just a little under 5 feet tall, about 200 pounds and with a family history of the disease, Stark appeared a prime candidate for the diagnosis.

A blood sugar test confirmed it. She was given insulin to control the high sugar levels in her blood, and the Sherman Oaks teen joined the growing cadre of children diagnosed with what used to be called "adult onset" and is now known as type 2 diabetes.

One month later, another test on Stark revealed telltale signs of the far more rare variation of the disease known as "juvenile diabetes" and more commonly called type 1 diabetes.

"It was a whole different ballgame from that day forward," said Cameron's mother, Shelley Stark.

Now 15, Stark's daughter appears to be part of an emerging population with a complex set of symptoms that may require multiple medications as well as strict adherence to a healthy diet and regular exercise.

Obesity long has been associated with type 2 diabetes, a condition in which the body doesn't use insulin efficiently. Increasingly, people with type 1 diabetes -- in which the body does not produce sufficient insulin -- are becoming obese and showing signs of type 2.T

o understand how the two types of diabetes may overlap, it helps to look at the diseases separately.

Type 1 diabetes is defined as an autoimmune disorder in which the body starts attacking the "beta" cells in the pancreas that produce insulin, the hormone that escorts sugar into the body's cells for energy production. When the cells stop working, they no longer produce insulin and glucose builds up in the blood, starving the body's organs of fuel.

The causes of type 1 are not entirely understood, although genetics, viral infections and trauma to the pancreas can affect development of the disease. Type 1 diabetics must be treated with insulin shots.

In type 2 diabetes, the body produces insufficient insulin to meet increased needs for the hormones that occur because of insulin resistance, a condition in which the cells don't make efficient use of insulin.

Research has proven that, in many cases, type 2 diabetes can be controlled with a healthy diet and regular exercise. Many type 2 diabetics, however, require drugs, including insulin, to maintain healthy blood sugar levels.

For each type of diabetes, complications can vary in severity but are generally the same, ranging from heart disease, stroke and kidney disease to blindness, nerve damage, foot problems and skin disorders.

Although they don't agree on how the process works or which name to use to describe it, clinicians and researchers are finding evidence of both diseases simultaneously in the same patients. The rise in obesity is seen as a leading culprit.

In one study, for example, researchers at the University of Washington found that a majority of children with type 2 diabetes also had signs of type 1 diabetes in the form of antibodies and T-cells, immune system markers that respond to cell damage.

"There is some indication that obesity, by putting more stress on the beta cells, may in fact make the cells more susceptible to immune attack," said Dr. Jerry P. Palmer, who is head of endocrinology and metabolism at the VA Puget Sound Health Care System.

For her part, Stark gets four to six injections of insulin every day, in amounts that have dropped gradually in recent weeks.

Her mother said she now shops for low-carb, sugar-free foods. "I am learning to read labels," she said. "I check everything now.

Regular exercise also has become part of the teen's daily routine.

"I work out with a trainer two days a week," she said. "We do kickboxing, tae kwon do, yoga and core work. I learned very quickly what I had to do with my life and to take care of myself to stay healthy."

UCSF sets pace on stem cells

2005-07-12T08:48:00.000-07:00

>>Related story on Diabetes work here>>

Contra Costa Times // Tues, July 12, 2005

By Betsy Mason // CONTRA COSTA TIMES
SAN FRANCISCO - In 1981, UC San Francisco biologist Gail Martin isolated some remarkable cells from a mouse embryo. She named them "stem cells" because nearly every type of cell seemed to stem from them.

The discovery laid the groundwork for a whole new area of research. Nearly two decades later, a University of Wisconsin scientist adapted Martin's technique to human embryos.

The jump to human cells stoked a growing ethical controversy that led the Bush administration in 2001 to back away from funding work involving human embryonic stem cells, save for a few pre-existing stem cell lines. That decision threatened to hobble U.S. research and give the rest of the world an edge.

UCSF took matters into its own hands and has raised $13 million in private funds, including $5 million from Intel Corp. chairman Andy Grove, to establish a stem cell biology program and a separate facility to derive new embryonic stem cell lines. Today, UCSF is still a world leader and pioneer in stem cell research.

More than 60 scientists at UCSF are exploring the cells' potential to treat diseases and conditions such as diabetes and stroke. This work is supported by continued dedication to nuts-and-bolts basic cell science critical to enabling new discoveries.

"We cover quite a bit of the territory that is going to be required to bring cell-based therapies to our patients," said Arnold Kriegstein, head of UCSF's stem cell program.

Now with the help of Prop. 71, California's 10-year, $3-billion stem cell initiative, UC's premier medical research institution is poised to capitalize on its assets in a huge way.

One of UCSF's greatest strengths, and one that sets it apart from most research institutions, is its human embryonic stem cell program, co-directed by Susan Fisher and Renee Reijo Pera. One of just two centers in the country that derived federally approved embryonic stem cell lines, UCSF has distributed these cells worldwide.

Now, UCSF scientists are deriving new human embryonic stem cell lines that could be critical to research and future therapies. These lines cannot be used in studies supported by federal funding, but Prop. 71 may help scientists bring the new lines into their labs.

Reijo Pera is also interested in understanding how human embryos develop with an eye toward understanding birth defects. Her work could benefit women who use in vitro fertilization by reducing problematic multiple births.

"If you can understand what a good embryo is, that's a huge battle that's been won," said Reijo Pera. "We don't have to then put two or three embryos back in a woman; we can put one good embryo."

Much has been made of stem cells' potential to treat brain disorders such as Parkinson's disease. Realizing that potential is likely to be more than a decade away, said Kriegstein, but a recent discovery is a major step forward.

Not long ago, scientists believed adult brains couldn't make new neurons. Fortunately, that idea was wrong. Last year, UCSF neuroscientist Arturo Alvarez-Buylla led a team that discovered newborn neurons in the fluid-filled cavity of adult brains called the subventricular zone.

The team also found a sheet of common, star-shaped brain cells known as astrocytes in the same zone. These cells were traditionally thought to simply support neurons, the brain cells that do the actual work of thinking, feeling and directing movement. But when grown in a petri dish, the astrocytes produced neurons and are the likely source of the new neurons the team discovered. One day, the discovery could help restore brain function to people with diseases like Parkinson's.

Other studies have shown that stem cells found in bone marrow and the bloodstream can help hearts function better after a heart attack. UCSF cardiologist Yerem Yeghiazarians is trying to find out how this works.

"Getting from the stem cells all the way to how we improve heart muscle, there's a huge step in between," he said. "Nobody really knows exactly how this happens."

He hopes understanding the process could lead to better treatments for millions of Americans who suffer from heart disease or heart failure.

UCSF scientists are also studying adult stem cells in other areas of the body such as the pancreas. Michael German hopes to be able to harness these cells to help people with diabetes. And Rik Derynck is studying the possibility of convincing adult stem cells on their way to becoming fat cells to grow into bone or muscle cells instead, which could help conditions like osteoporosis.

Readily available therapies are years and maybe decades away, said Kriegstein. "But we are hopeful that the Prop. 71 funds will help accelerate all of this progress and make some of these hopes a reality."

Betsy Mason covers science. Reach her at 925-847-2158 or bmason@cctimes.com.

Envisioning a cure for diabetes

2005-07-12T07:51:00.000-07:00

Contra Costa Times // Tue, July 12, 2005

By Betsy Mason

Diabetes is one of the most promising targets of stem cell research. People with this disease have problems with insulin, a hormone in the pancreas that regulates blood sugar levels. Patients have poorly functioning or too few insulin-producing cells, known as beta cells.

"We think that ultimately the way to cure people with diabetes, or at least many patients with diabetes, is to replace those cells," said Michael German of the UC San Francisco Diabetes Center.

Several clinics worldwide, including UCSF, already do this by transplanting beta cells from cadavers into diabetes patients.

"The problem is, at present we don't have nearly enough cells to do this," German said.
There are more than 150 million people with diabetes and more than a half million new cases each year in the United States alone. But fewer than 5,000 pancreases are available for donation yearly, he said.

"If we had an unlimited supply of these cells, we could treat everybody with diabetes," German said.

He hopes stem cells can help generate that supply.

In normal human development, some stem cells eventually become beta cells. The cells face a series of decisions that lead them down the path to becoming insulin-producing cells or another cell type. To become a beta cell, they must first decide to become part of the gastrointestinal tract, and eventually part of the pancreas, and then part of the pancreas area that contains specialized cells, including beta cells. Finally they must decide to become a beta cell.

German is working on how to coax embryonic stem cells along this path.

"The programs by which those decisions are controlled at a molecular level is what my laboratory has been focused on," he said. "The idea is that if we knew the genes and the signaling pathways that control each of these decisions that we could in fact take embryonic stem cells and drive them specifically to make these decisions and end up as beta cells."

He and other scientists have already identified some genes along the pathway in mice, and there is good evidence that the same pathway exists in humans.

European Researchers Find Drug That Preserves Beta Cell Function in Type 1 Diabetes Patients

2005-06-27T17:39:00.000-07:00

From Medical News Today // June 27, 2005

The Juvenile Diabetes Research Foundation (JDRF), the world's leading charitable funder of research into type 1 diabetes and its complications, announced today that JDRF-funded researchers in Europe have shown that short-term treatment with an anti-CD3 antibody (ChAglyCD3) can preserve residual beta cell function and decreases the insulin need for at least 18 months in people with recent-onset type 1 diabetes. This finding, reported in the June 23 issue of the New England Journal of Medicine, represents an important step towards finding ways to prevent and stop type 1 diabetes by altering the clinical course of the disease.

The Phase II clinical trial involved 80 newly diagnosed patients, was conducted in collaboration with a team of clinicians and researchers from France, Belgium, Germany and England* and was led by Lucienne Chatenoud, M.D., Ph.D. of the Hopital Necker in Paris. Dr. Bart Keymeulen (in Brussels) was the clinical coordinator for the trial, which was one of the projects undertaken by the JDRF Center for Beta Cell Therapy in Europe, directed by Daniel Pipeleers, M.D., Ph.D.

The team found that patients who received the antibody over the course of six days immediately following their diagnosis continued to produce their own insulin and needed less supplemental insulin to maintain normal blood glucose levels, as compared with patients who received a placebo. This benefit was apparent at 6, 12 and 18 months after the treatment, suggesting that the protective effect is lasting -- although for how long is not yet known. Moreover, side effects were minor and short-lived including flu and mono-like symptoms.

"These exciting results provide enormous hope that we can preserve residual beta cell function by modulating the autoimmune attack and in fact change the clinical course of type 1 diabetes," said JDRF Executive Vice President for Research Richard Insel, M.D. "There is no other current treatment that can actually change the clinical course once the disease has begun. This study shows we are on the right track, and opens the door for researchers to target this treatment specifically to individuals who would receive the most benefit."

This clinical trial extends a JDRF study using a similar antibody -- published in 2002 -- by Kevan Herold, M.D., of Columbia University College of Physicians and Surgeons, and Jeffrey Bluestone, Ph.D., director of the JDRF Center for Islet Transplantation at University of California, San Francisco/University of Minnesota.

The European study takes the Bluestone/Herold study -- and anti-CD3 research overall -- a step further by involving a much larger group of patients and recording how much residual beta cell function each patient had at the beginning of treatment. This allowed the researchers to track and compare ChAglyCD3's effect on patients who had high and low residual beta cell function initially to see how well the drug worked with patients in both categories. The research team observed that ChAglyCD3's protective effect was more pronounced in patients who had higher beta cell function at the time they received the drug. Interventions that can preserve endogenous insulin production are expected to result in better metabolic control of diabetes, and thus delay, or reduce the risk of diabetes-related complications such as eye, nerve and kidney disease.

As stated by Dr. Chatenoud, "A tremendous amount of work was put into this study, and I am thrilled with the outcome. The team of clinicians and their colleagues who dedicated themselves to this effort are to be commended for their work. These include Dr. Bart Keymeulen and Dr. Chantal Mathieu in Belgium and Dr. Anette Ziegler in Germany, as well as the Belgian Diabetes Registry, all of whom made it possible to recruit the patients. And I would be remiss for not mentioning that the international collaboration within the JDRF Center allowed the researchers to proceed in an efficient manner."

"JDRF made this possible" said Dr. Pipeleers. "We can now inform patients that a step has been made towards stopping the disease but we will also have to explain why more work is needed before a treatment will be routinely available for clinical practice."

About Anti-CD3

Anti-CD3 antibodies such as ChAglyCD3 and hOKT3g1 (ala-ala) are engineered to block the function of CD3 cells, immune T cells that orchestrate the destruction of islets. The antibodies prevent "activation" of the T cells after they have identified their target, disarming them once they are poised to attack.

The ChAglyCD3 drug that was used in the European study is a humanized, non-mitogenic anti-CD3 antibody, a new type of agent showing promise for this kind of intervention. This antibody was conceived and manufactured by Drs. Herman Waldman and Geoff Hale in Oxford, England.

About JDRF

JDRF (http://www.jdrf.org) was founded in 1970 by the parents of children with juvenile diabetes -- a disease that strikes children suddenly, makes them insulin dependent for life, and carries the constant threat of devastating complications. Since inception, JDRF has provided more than $800 million to diabetes research worldwide. More than 80 percent of JDRF' expenditures directly support research and education about research. JDRF's mission is constant: to find a cure for diabetes and its complications through the support of research.

-- The coauthors are: Bart Keymeulen, Evy Vandemeulebroucke, Frans Gorus, Pieter De Pauw, Denis Pierard, Ilse Weets, Daniel Pipeleers from the VUB-Academic Hospital and Brussels Free University-VUB in Brussels, Belgium; Chantal Mathieu from the UZ Gasthuisberg, Katholieke Universiteit Leuven -- KUL in Leuven, Belgium; Christophe De Block from the University Hospital Antwerp-UIA in Antwerp, Belgium; Michel Goldman, Liliane Schandene and Laurent Crenier from Hopital Erasme, Universite Libre de Bruxelles -- ULB in Brussels, Belgium; Anette Ziegler and Markus Walter from the Hospital Munchen-Schwabing in Munich, Germany; Leonard Kaufman, from Brussels Free University-VUB in Brussels, Belgium; Geoff Hale, Pru Bird, Eleanor Berrie, Mark Frewin, and Herman Waldmann, from the Sir William Dunn School of Pathology in Oxford, England; Lucienne Chatenoud, Sophie Candon and Jean-Francois Bach from Hopital Necker-Enfants Malades, INSERM U580 in Paris, France and Jean-Marie Seigneurin from the CHU Michallon in Grenoble, France. The Belgian Diabetes Registry includes over 200 diabetologists, pediatricians and researchers from all Belgian universities and over 100 non-university hospitals.

The Juvenile Diabetes Research Foundation; New England Journal of Medicine
http://www.jdrf.org

New gene shows way for autoimmune disease

2005-06-13T22:14:00.000-07:00

From the Australian National University // May 26, 2005

A new gene suspected to contribute to autoimmune diseases such as type 1 diabetes and lupus — a condition in which the body’s own immune system attacks organs such as the kidneys and skin — has been discovered by ANU immunologists.

The researchers found that a mutation in the gene, which they have named Roquin, causes the body’s infection fighters — T-cells — to attack their own tissue; the realisation opening the way to explore treatments that target the mutation.

Studies of the gene are underway in patients with lupus — which affects one in 700 women of childbearing age — and type 1 diabetes to determine whether the same or similar mutations observed in laboratory mice are present in humans.

“This could reveal other abnormalities that underpin autoimmunity, and open up opportunities for developing specific treatments and drugs,” said lead researcher Dr Carola Vinuesa, from the John Curtin School of Medical Research (JCSMR) at ANU.

The discovery of Roquin was revealed in the latest edition of Nature magazine.

The researchers mirrored the spontaneous genetic variation that occurs naturally during population growth by introducing random changes in the mouse genome, generating novel models of autoimmune disease. After identifying signs of lupus, they worked backwards to find the altered gene responsible for the condition.

“Before this study, the existence and function of Roquin was not known. However, we now know that in the immune system of mammals, the protein Roquin usually suppresses the activity of forbidden T-cells that bind to parts of the body.

“We found that a single mutation in Roquin causes these T-cells to be abnormally activated, and results in autoimmunity affecting many different parts of the body,” Dr Vinuesa said.

Autoimmune disease occurs when the immune system is activated to mount a response against normal tissue in the body, treating it as if it were a germ and damaging and destroying the tissue. For example, in type 1 diabetes, an immune response is mounted against the insulin-secreting cells of the pancreas; in lupus, virtually any part of the body can be attacked by the immune system.

According to Professor Christopher Goodnow, the Head of the Immunogenomics Laboratory at JCSMR and Director of the Australian Phenomics Facility, the discovery hinged upon identifying a single letter change in the DNA code of Roquin.

“It’s one very small part of the genome that has proven a very big breakthrough. That single nucleotide change reduces the function of an autoimmunity gene and protein that was hithertoentirely unknown.

According to Professor Goodnow, the characteristics of the Roquin protein suggest that it might repress immune cells by silencing the communication channel between genes and cell functions.

“Roquin stops T-cells from displaying a stimulatory receptor, ICOS, that may cause the cells to attack normal body tissues. Therefore this gene seems critical in protecting us from autoimmunity — but it only takes the mutation of one letter in that gene to cripple its function and lead to autoimmune disease.

“This finding immediately opens up research into testing the function of Roquin, examining variants that may explain autoimmune disease and working towards discovering drugs that might increase or decrease the activity of the newly-realised process.”

The discovery was part of a research program into autoimmune diseases by the John Curtin School of Medical Research, the Australian Phenomics Facility, the ANU Medical School and Oxford University, Professor Goodnow said.

“The specific work described stems from a Wellcome Trust Programme between ANU and Oxford University, and its intersection with a separate Juvenile Diabetes Research Foundation and National Health and Medical Research Council special program in diabetes.

“These represent ambitious efforts to pioneer a new way to connect genes with immune system control mechanisms in diseases such as systemic lupus erythematosus and type 1 diabetes.”

New Textbook Is Leading Source for Advances in Diabetes Care

2005-06-10T23:08:00.000-07:00

Newswise — Joslin Diabetes Center, the world's leading authority in diabetes research, care and education, has published the fourteenth edition of Joslin Diabetes Mellitus, providing the medical profession with valuable new insights on diabetes research and treatments. With the first 5,000 copies selling in less than two months, the book is now in its second printing - demonstrating an enthusiastic market for this comprehensive guide.

"Dramatic advances in the laboratory and the clinic are revolutionizing our understanding and the care of diabetes," said C. Ronald Kahn, M.D., President and Director of Joslin Diabetes Center, the Mary K. Iacocca Professor of Medicine at Harvard Medical School (HMS) and one of the book's six senior editors. "It's critical for both researchers and healthcare professionals to keep pace, particularly as diabetes is growing at epidemic proportions and research advances are coming quickly."

Tailored to primary care and specialty practitioners, the 1,209-page book, published by Lippincott Williams & Wilkins of Philadelphia, harnesses the expertise of more than 125 diabetes authorities worldwide. Significantly expanding the previous edition, the current book contains 70 chapters. Beginning with the history of diabetes and the pioneering work of Elliott P. Joslin, M.D., founder of Joslin Diabetes Center, the father of modern day diabetes care and author of the first edition (published in 1916), the new textbook contains eight main sections, each designed to help healthcare practitioners and researchers solidify their understanding of diabetes and treatment of the disease.

In addition to serving as a comprehensive overview for endocrinologists and diabetes specialists, the new Joslin textbook is an important tool for primary care physicians, nurses and educators. "With millions of people with diabetes or at risk for developing the disease, primary caregivers are a critical part of the healthcare team, and this book provides them with an excellent tool," said Editor Gordon C. Weir, M.D., Head of Joslin's Section on Islet Transplantation and Cell Biology and HMS Professor of Medicine. "The more primary caregivers know about diabetes, the more they can do for their patients."

"Many of the advances in the research lab have been translated into the clinical practices outlined in this book," said Joslin Diabetes Mellitus Editor George L. King, M.D., Director of Research, Head of the Section on Vascular Cell Biology at Joslin and HMS Professor of Medicine.

"The textbook covers a wide spectrum of topics, ranging from the basic mechanisms of islet development and function, hormone action and regulation of metabolism, to the epidemiology and genetics of diabetes, the role of obesity, insulin therapy and oral agents, diabetes in minorities, nutrition and exercise, and the behavioral and psychological issues related to diabetes," said Editor Alan M. Jacobson, M.D., Senior Vice President of Joslin's Strategic Initiatives Division, Director of Behavioral and Mental Health, and HMS Professor of Psychiatry.

Included in the textbook are the following recent findings regarding the basic science of diabetes and its clinical care:

The biology of insulin function, including how it stimulates events inside cells to produce energy.
The role of fat cells-once considered dormant storage sites-which is thought to include secretion of a protein that regulates body tissues, such as brain cells and blood vessels.
An additional role for islet cells, which, in addition to secreting insulin, produce proteins that enhance insulin activity-a discovery that may lead to new drugs for treating diabetes.
Further insight into how high glucose levels cause eye and kidney damage, leading to possible ways to prevent these complications.
Promising new treatments for type 1 diabetes, including transplantation of islet cells.
Emerging new classes of drugs to treat type 2 diabetes, such as medications that target a nuclear molecule called PPAR-gamma, which promotes insulin sensitivity.

Other editors include Alan C. Moses, M.D., former Chief Medical Officer at Joslin and HMS Professor of Medicine; and Robert J. Smith, M.D., Director of Medicine at the Hallett Center for Diabetes and Endocrinology, Professor of Medicine at Brown Medical School, Providence, R.I.

The fourteenth edition of Joslin Diabetes Mellitus can be purchased online through the Joslin Store at or by calling toll-free (within the U.S.) 1-800-344-4501 or outside the U.S. at 1-508-583-3240.

About Diabetes

An estimated 18 million Americans have type 2 diabetes; about one-third of those don't even know they have it. Type 2 diabetes, traditionally considered a disease of middle-aged and older adults, is occurring more frequently in younger people due to increasing obesity and sedentary lifestyle. Diabetes can lead to many serious complications, including heart disease, stroke, nerve damage, kidney failure and blindness. Over 41 million Americans are believed to have pre-diabetes, or risk factors that will lead to type 2 diabetes if left untreated. Approximately 1 million people in the U.S. have type 1 diabetes, which is associated with the body's failure to produce insulin, a hormone necessary for the body to convert glucose into energy. Insulin is required treatment for people with type 1.

About Joslin Diabetes Center

Joslin Diabetes Center, dedicated to conquering diabetes in all of its forms, is the global leader in diabetes research, care and education. Founded in 1898, Joslin is an independent nonprofit institution affiliated with Harvard Medical School. Joslin research is a team of more than 300 people at the forefront of discovery aimed at preventing and curing diabetes. Joslin Clinic, affiliated with Beth Israel Deaconess Medical Center in Boston, the nationwide network of Joslin Affiliated Programs, and the hundreds of Joslin educational programs offered each year for clinicians, researchers and patients, enable Joslin to develop, implement and share innovations that immeasurably improve the lives of people with diabetes. As a nonprofit, Joslin benefits from the generosity of donors in advancing its mission. For more information on Joslin, call 1-800-JOSLIN-1 or visit http://www.joslin.org.

Insulin Pump Therapy in Young Children

2005-06-10T22:57:00.000-07:00

From Diabetes Care, American Diabetes Association, Inc. via Medscape

A Randomized Controlled Trial of Insulin Pump Therapy in Young Children With Type 1 Diabetes

By Larry A. Fox, MD; Lisa M. Buckloh, PHD; Shiela D. Smith, RN; Tim Wysocki, PHD; Nelly Mauras, MD

Abstract and Introduction

Objective: This study assesses the effects of insulin pump therapy on diabetes control and family life in children 1–6 years old with type 1 diabetes.

Research Design and Methods: Twenty-six children with type 1 diabetes for ≥6 months were randomly assigned to current therapy (two or three shots per day using NPH insulin and rapid-acting analog) or continuous subcutaneous insulin infusion (CSII) for 6 months. After 6 months, current therapy subjects were offered CSII.

Changes in HbA1c, mean blood glucose (MBG), hypoglycemia frequency, diabetes-related quality of life (QOL), and parental adjustment were recorded.

Results: Eleven subjects from each group completed the trial (age 46.3 ± 3.2 months [means ± SE]). At baseline, there were no differences between groups in HbA1c, MBG, age, sex, diabetes duration, or parental QOL. Mean HbA1c, MBG, and parental QOL were similar between groups at 6 months. Mean HbA1c and MBG did not change from baseline to 6 months in either group. The frequency of severe hypoglycemia, ketoacidosis, or hospitalization was similar between groups at any time period.

Subjects on CSII had more fasting and predinner mild/moderate hypoglycemia at 1 and 6 months. Diabetes-related QOL improved in CSII fathers from baseline to 6 months. Psychological distress increased in current therapy mothers from baseline to 6 months. All subjects continued CSII after study completion.

Conclusions: CSII is safe and well tolerated in young children with diabetes and may have positive effects on QOL. CSII did not improve diabetes control when compared with injections, despite more mild/moderate hypoglycemia. The benefits and realistic expectations of CSII should be thoroughly examined before starting this therapy in very young children.

Introduction

The Diabetes Control and Complications Trial clearly demonstrated the benefits of good blood glucose control.[1,2] However, achieving the necessary good control is not easy and is especially challenging in infants and toddlers with type 1 diabetes. Several factors contribute to the difficulty in managing diabetes in these young children, including unpredictable insulin absorption,[3,4] variable eating patterns and activity, increased sensitivity to small amounts of insulin, parental fear of hypoglycemia,[5,6] and difficulty in treating hypoglycemia because of their refusal to eat or drink. These problems can lead to widely fluctuating blood glucose levels or frequent hypoglycemia, which could have adverse developmental effects.[7,8] Thus, a better way to provide insulin therapy to toddlers and young children with diabetes is desirable.

Insulin pump therapy (continuous subcutaneous insulin infusion [CSII]) is an attractive way of treating patients with diabetes,[9] but there are limited data comparing insulin injection therapy with CSII in toddlers and preschool-aged children with type 1 diabetes.[10-12] Furthermore, although there is an extensive body of literature concerning the complex psychological factors and family management of diabetes,[13,14] there are few data assessing these quality of life (QOL) issues in this young population. We therefore designed this study to determine whether the use of CSII in young children improves diabetes control, decreases the frequency of hypoglycemia, and improves the family's QOL.

Research Design and Methods

After institutional review board approval, children between the ages of 12 and 72 months with type 1 diabetes for at least 6 months were recruited for the study between January 2001 and September 2003. Parental informed consent was obtained, and enrolled subjects were randomly assigned to either continue their current insulin regimen (current therapy group) (consisting of two or three injections per day of NPH insulin and a rapid-acting analog) or receive CSII (using the Medtronic MiniMed 508; Medtronic, Northridge, CA). Insulin pumps and supplies were provided at no charge to all study participants for the duration of the trial. Families randomly assigned to CSII underwent proper pump education over the next 2–4 weeks before starting CSII.

Blood glucose levels were monitored at home at least four times per day in both treatment groups. Blood glucose records were analyzed to assess frequency of mild, moderate, and severe hypoglycemia and to obtain mean blood glucose (MBG) (averages of all blood sugar levels for 1 month before baseline, before 1-, 3-, and 6-month visits in both groups, and before 9- and 12-month visits in CT). In addition to the endocrine physicians, a dedicated diabetes educator was available for all education and follow-up needs of the study subjects. HbA1c was measured at 3-month intervals using a Bayer DCA 2000+ (Tarrytown, NY), which is certified by the National Glycohemoglobin Standardization Program and displays Diabetes Control and Complications Trial equivalent results. Patients randomly assigned to current therapy were offered CSII 6 months after randomization.

Family dynamics and QOL were assessed at baseline before randomization and at 6 months using several validated questionnaires: the Impact on Family Scale, a measure of perceived effects of the disease and its treatment on family function[15]; the Brief Symptom Inventory, a measure of parental psychological adjustment and psychopathology[16]; the Parenting Stress Index, a measure of the degree of stress experienced by parents regarding the child with diabetes[17]; and the Pediatric Diabetes Quality of Life Scale, designed for this study to retrieve parental perceptions of the degree to which the child's current diabetes regimen has positive or negative effects on certain specific dimensions of child behavior and parent-child interactions surrounding diabetes.
Statistical Analysis

Statistical evaluation was performed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL). Data are expressed as means ± SE. A 2 × 4 factorial ANOVA with repeated measures on one factor (two groups of subjects and four time periods of baseline, 1, 3, and 6 months) was used to test for differences in HbA1c and MBG. Paired Student's t tests were used to test for differences between baseline and 3- and 6-month HbA1c. χ2 analyses were used to compare the frequency of hypoglycemia between groups. Unpaired t tests were used for between-group analyses of other baseline characteristics. The psychological measures were analyzed using separate independent sample t tests to compare current therapy with CSII. ANOVA with baseline as a covariate was used to analyze the differences between the two groups at 6 months to control for differences in baseline values between the two groups. Paired-sample t tests were used to compare maternal and paternal scores on all measures at baseline and at 6 months and to compare psychological functioning from baseline to 6 months in CSII and current therapy. P < 0.05 was considered significant.

Results

Thirteen children were randomly assigned to each group ( Table 1 ). Two patients dropped out of the CSII group before starting pump therapy because the children refused to wear the pump. One subject dropped out of the current therapy group immediately after randomly assigned because the family did not want to wait for pump therapy. One current therapy subject was lost to follow-up before the 6-month visit. Therefore, 11 subjects completed 6 months in each treatment group. Eight of the 11 subjects who completed current therapy also completed 6 months of pump therapy.

At baseline ( Table 1 ), there were no differences between CSII and current therapy groups in HbA1c, MBG, age, race, duration of diabetes, number of injections per day, total daily insulin dose, or socioeconomic status.

Mean HbA1c values were similar between CSII and current therapy groups at baseline (7.43 ± 0.48 vs. 7.57 ± 0.27, CSII vs. current therapy), 3 months (7.20 ± 0.29 vs. 7.46 ± 0.22), and 6 months (7.24 ± 0.31 vs. 7.46 ± 0.18) (Fig. 1). There was no group effect ( P = 0.59) or interaction effect for group and time period ( P = 0.94). There was no significant change in HbA1c in either group from baseline to 3 months ( P = 0.475 for CSII; P = 0.509 for current therapy) or 6 months ( P = 0.58 for CSII; P = 0.60 for current therapy). HbA1c did not change in the current therapy subjects after starting CSII ( P = 0.848 comparing current therapy at 12 and 6 months).

Figure 1. HbA1c (means ± SE) results for the 6-month study period in current therapy (CT) (– – –) and CSII (——) groups. Number of subjects are indicated for each group. Repeated- measures ANOVA revealed no significant differences for baseline, 3 months, and 6 months between groups ( P = 0.537). There was no group effect ( P = 0.592) nor time period effect ( P = 0.935).

MBG analysis (repeated-measures ANOVA) revealed no significant differences between time periods (baseline, 1 month, 3 months, and 6 months; P = 0.964) or between groups ( P = 0.308), nor was there a time period by group interaction ( P = 0.533). Comparison of MBG from the current therapy subjects after starting pump therapy with the CSII group revealed no significant differences for mean glucose by time ( P = 0.578), between groups ( P = 0.406), or for a time by group interaction ( P = 0.230). Comparison of MBG values in the current therapy group while receiving pump therapy with the current therapy group while receiving injections revealed no significant differences in MBG by time ( P = 0.135), by type of therapy ( P = 0.576), or for a time by therapy type interaction ( P = 0.682).

The frequency of mild/moderate hypoglycemia (defined as blood glucose <80 for this age-group) was similar at baseline between the two treatment groups before meals and at bedtime (Fig. 2). However, CSII subjects experienced more hypoglycemia before breakfast at 1 month but not afterward and more hypoglycemia before dinner at 3 months and 6 months (Fig. 2). These differences were present at 1 month even if mild/moderate hypoglycemia was defined as blood glucose level <70, <60, or <50. As shown in Fig. 2, CSII subjects also experienced more mild/moderate hypoglycemia at breakfast at 6 months if low blood glucose was defined as <70 or <60. Furthermore, after adjusting for multiple comparisons with a significance level set at P < 0.004, the amount of hypoglycemia was still significantly more in the CSII group at these time periods ( P < 0.001). There were no differences between current therapy and CSII groups at any time period throughout the study when hypoglycemia was defined as blood glucose level <40.

Figure 2. Frequency of hypoglycemia. The number of episodes of mild/moderate hypoglycemia for each treatment group at the different meals or at bedtime, depending on how hypoglycemia was defined, is shown. CSII/current therapy pairs with significant differences using χ2 analysis are highlighted, and P values are provided.

We also compared the frequency of hypoglycemia in current therapy subjects after starting pump therapy (6–12 months) with when they were receiving injections (0–6 months). Subjects had more frequent mild/moderate hypoglycemia while receiving pump therapy than with injections at breakfast, whether the definition of hypoglycemia was defined as blood glucose level <80 (number of recorded episodes = 50 CSII vs. 16 current therapy; P < 0.01), <70 (36 vs. 11; P < 0.01), <60 (24 vs. 3; P = 0.001), or <50 (7 vs. 0; P < 0.03). There were no differences between current therapy subjects receiving injections versus pump therapy at any time period throughout the study when hypoglycemia was defined as blood glucose level <40.

One current therapy patient had a severely low blood glucose level within 1 month after randomization. There were no severe hypoglycemic events for patients enrolled in the CSII group, although one patient initially enrolled in the current therapy group had two severe low blood glucose readings after starting pump therapy. One subject in the CSII group was admitted for diabetic ketoacidosis ~2 months after starting pump therapy. One current therapy subject had three hospitalizations for diabetic ketoacidosis within 2 months after starting pump therapy because of a failure to follow sick-day management protocol while using the pump.

Mothers in the current therapy group reported a greater impact of diabetes on the family than did mothers in the CSII group at baseline ( P = 0.04), but there were no differences between the mothers in the two groups at 6 months when controlling for the baseline differences. Fathers in the CT group reported more psychological distress than did fathers in the CSII group at baseline ( P = 0.05), but there were no significant differences between the two groups at 6 months when correcting for these baseline differences. There were no differences between groups for mothers or fathers on the Pediatric Diabetes QOL scale at any time period. However, fathers in the CSII group reported significantly more positive QOL changes for themselves from baseline to 6 months ( P = 0.03). Mothers in the CT group reported more parenting stress than did mothers in the CSII group at baseline ( P = 0.05). The differences in maternal parenting stress did not remain significant at 6 months. No differences were found between mothers and fathers for any of the psychological measures at baseline or 6 months.

There were no significant problems with the placement and care of infusion sites in these young children, and no subjects experienced site infections. All subjects who completed 6 months of current therapy ( n = 11) began CSII after the 6-month study period, including two who started CSII outside of the study. All subjects treated with CSII have continued this therapy after study completion.
Conclusions

Our data indicate that CSII is safe and well tolerated in this population, consistent with three recent reports in this age-group.[10-12] In our study, however, CSII did not result in improved diabetes control when compared with insulin injections, similar to the study by DiMeglio et al.[11] and the more recent paper by Wilson et al.[12] but in contrast to two other studies.[10,18] In the study by Litton et al.[10] comparing CSII with multiple daily injections in toddlers between 20 and 58 months of age, HbA1c levels decreased after using CSII for an average of 13 months. There are several reasons for the difference in results; one is difference in study design. Their study was not a randomized trial; each patient served as his or her own control, and it included only nine subjects. A second potential reason is difference in patient selection. It is possible that insulin pump therapy did not lower the average HbA1c in our subjects because it was already low at baseline (7.5 ± 0.3% for all subjects); the subjects reported by Litton et al.[10] had a higher HbA1c at baseline (9.5 ± 0.4%). Safely lowering an already low HbA1c may not be better achieved with insulin pump therapy and may certainly be accompanied by increased hypoglycemia. The low HbA1c in our subjects indicates that some of them may have been in the remission phase, also suggested by the low total insulin daily dose (0.6 ± 0.1 units · kg–1 · day–1 in both groups) at the start of the study. Lastly, although we studied more subjects than those reported by Litton et al.,[10] using the effect size of our population, 40–60 subjects per group would have been needed to demonstrate a significance difference in HbA1c or MBG. This population size would be best evaluated in a large, multicenter trial.

In another recent study,[18] children with type 1 diabetes using insulin pumps were compared with children receiving multiple daily injections (using insulin glargine and insulin aspart), a more intensive regimen than that used in our subjects receiving injections. In that randomized trial, patients receiving CSII had significantly lower HbA1c levels at 16 weeks compared with multiple daily injections. However, subjects were older (>8 years) than in our study, and the duration of CSII therapy was shorter, making direct comparisons difficult.

Fear of hypoglycemia is often a deterrent to good diabetes control.[5,6] Our data do not indicate that the frequency of severe hypoglycemia is affected when using CSII, similar to the results reported by Maniatis et al.[19] and more recently by Wilson et al.[12]. However, CSII subjects in our study experienced more mild/moderate hypoglycemia at certain time periods (most often fasting or before dinner) than subjects receiving injections; that difference persisted even when a lower definition of hypoglycemia was used. It is interesting to note that even though subjects receiving CSII in our study had more frequent fasting hypoglycemia, they did not have frequent hypoglycemia at bedtime. This suggests that CSII may predispose subjects to late-night or early-morning hypoglycemia.

The frequency of hypoglycemia seen in pump subjects is highly variable in published reports. Litton et al.[10] had results similar to ours (i.e., an increase in mild/moderate hypoglycemia with the use of pumps), whereas two other studies[19,20] showed that the frequency of hypoglycemia decreased with the use of CSII in children and adolescents. Our results may reflect the tighter diabetes control as reflected in the lower HbA1c levels in our subjects, indicating that they are more likely to have hypoglycemia. Although the number of children in our study was relatively small, other investigators have studied a comparable number of children, or even less as in the report by Litton et al.[10]. Additionally, only one other study[18] analyzed the data with respect to time of day. Nonetheless, although care should still be taken when interpreting these data, our results are important as they demonstrate that CSII is at least as good as insulin injection therapy in toddlers and preschoolers, and our experimental design using a randomized control arm makes our obser-vations strong. A large-scale randomized trial would best be suited to further assess whether mild/moderate hypoglycemia is more likely with pump therapy in toddlers.

As with injection therapy, the family must adjust to a variety of new tasks with CSII, which can have a psychosocial impact. Wilson et al.[12] reported that diabetes QOL slightly improved in those receiving either treatment (injections or pumps), although only the improvement in the CSII group was significant. They found no difference between the two treatment groups. Our findings are congruent with this report and suggest that CSII does not adversely affect diabetes-related QOL and parental stress/distress when compared with current therapy. On the contrary, fathers in the CSII group reported improved diabetes-related QOL from baseline to 6 months, even though comparisons of those changes over time in the current therapy and CSII groups were not significant. Mothers and fathers reported similar levels of distress and impact on QOL, suggesting that for these families CSII and current therapy did not have differential effects within the family. Caution should be taken when interpreting these analyses given the large number of statistical tests that were performed relative to the small sample size. Lastly, the fact that all subjects continued CSII after study completion is itself an excellent indicator of parent satisfaction. Other studies had also suggested high levels of parental satisfaction with CSII,[10,11] although QOL issues were not formally tested in young children in those studies.

This randomized controlled trial showed that CSII is safe and well tolerated in toddlers and young children with diabetes and is as good as current therapy with two or three daily insulin injections in maintaining good diabetes control. However, CSII did not result in improved diabetes control when compared with injection therapy in that age-group, despite a trend toward increased frequency of mild/moderate hypoglycemia with CSII use. CSII may have some positive effects on QOL. The possible benefits and realistic expectations for diabetes control of CSII need to be thoroughly examined and reviewed with the family before starting this form of therapy in young children. Even though pump therapy may increase the costs associated with diabetes management, other potential benefits must be taken into account when considering this regimen in young children. A description of CSII to parents of children with type 1 diabetes in this age-group must emphasize that this pump therapy may not necessarily improve diabetes control, although it may provide a more precise tool for insulin therapy, avoiding frequent injections in very young children.

Parts of this study were presented in abstract form at the annual meetings of the Pediatric Academic Society, San Francisco, CA, 1–4 May 2004 and the American Diabetes Association, San Francisco, California, 14–18 June 2002.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Table 1. Baseline Characteristics of the Two Treatment Groups

CSII Current therapy P value
n (enrolled/completed) 11/11 12/11
Sex (male/female) 7/4 6/5
Age (months) 47.5 ± 4.8 45.3 ± 4.3 0.29
Duration of diabetes (months) 15.3 ± 3.4 19.7 ± 4.1 0.31
Injections/day 2.5 ± 0.3 2.3 ± 0.1 0.54
Total daily dose (units · kg–1 · day–1) 0.6 ± 0.1 0.6 ± 0.1 0.65
HbA1c (%) 7.4 ± 0.5 7.6 ± 0.3 0.62
MBG (mg/dl) 175 ± 20 182 ± 8 0.96

Data are means ± SE. Baseline data analyses do not include subjects who dropped out immediately after randomization (two CSII and one current therapy).

References

1. DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986, 1993
2. DCCT Research Group: Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr 125:177-188, 1994
3. Hildebrandt P, Birch K, Sestoft L, Volund A: Dose-dependent subcutaneous absorption of porcine, bovine and human NPH insulins. Acta Med Scand 215:69-73, 1984
4. Galloway JA, Spradlin CT, Howey DC, Dupre J: Intrasubject differences in pharmacokinetic and pharmacodynamic responses: immutable problem of present-day treatment? In Diabetes 1985: Proceedings of the International Diabetes Federation . Serrano-Rios M, Lefebvre P, Eds. New York, Elsevier Science, 1986, p. 877-886
5. Marrero DG, Guare JC, Vandagriff JL, Fineberg NS: Fear of hypoglycemia in the parents of children and adolescents with diabetes: maladaptive or healthy response? Diabetes Educ 23:281-286, 1997
6. Cryer PE: Hypoglycemia is the limiting factor in management of diabetes. Diabetes Metab Res Rev 15:42-46, 1999
7. Rovet JF, Ehrlich RM, Hoppe M: Intellectual deficits associated with early-onset of insulin-dependent diabetes mellitus in children. Diabetes Care 10:510-515, 1987
8. Soltesz G, Acsadi G: Association between diabetes, severe hypoglycemia, and electroencephalographic abnormalities. Arch Dis Child 64:992-996, 1989
9. Ahern JA, Boland EA, Doane R: Insulin pump therapy in pediatrics: a therapeutic alternative to safely lower HbA1c levels across all age groups. Pediatr Diabetes 3:10-15, 2002
10. Litton J, Rice A, Friedman N, Oden J, Lee MM, Freemark M: Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. J Pediatr 141:490-495, 2002
11. DiMeglio LA, Pottorff TM, Boyd SR, France L, Fineberg N, Eugster EA: A randomized, controlled study of insulin pump therapy in diabetic preschoolers. J Pediatr 145:380-384, 2004
12. Wilson DW, Buckingham BA, Kunselman EL: A two-center randomized controlled feasibility trial of insulin pump therapy in young children with diabetes. Diabetes Care 28:15-19, 2005
13. Anderson BJ, Laffel L: Behavioral and family aspects of the treatment of children and adolescents with IDDM. In Ellenberg and Rifkin's Diabetes Mellitus . 5th ed. Porte R, Sherwin R, Rifkin H, Eds. Stamford, CT, Appleton & Lange, 1996, p. 811-825
14. Wysocki T, Greco P: Self management of childhood diabetes in family context. In Handbook of Health Behavior Research . Vol. II. Gochman DS, Ed. New York, Plenum Press, 1997, p. 169-187
15. Stein REK, Reissman CK: The development of an impact on family scale: Preliminary findings. Medical Care 18:465-472, 1980
16. DeRogatis A: Brief Symptom Inventory: Scoring and Procedures Manual . Baltimore, Clinical Psychometrics Research, 1977
17. Abidin RR: Parenting Stress Index Manual: Manual and Administration Booklet . Charlottesville, VA, Pediatric Psychology Press, 1983
18. Doyle EA, Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, Tamborlane WV: A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 27:1554-1558, 2004
19. Maniatis AK, Klingensmith GJ, Slover RH, Mowry CJ, Chase HP: Continuous subcutaneous insulin infusion therapy for children and adolescents: an option for routine diabetes care. Pediatrics 107:351-356, 2001
20. Sulli N, Shashaj B: Continuous subcutaneous insulin infusion in children and adolescents with diabetes mellitus: decreased HbA1c with low risk of hypoglycemia. J Pediatr Endocrinol Metab 16:393-399, 2003

Funding Information

This study was funded by the Nemours Research Programs (Jacksonville, FL) and an unrestricted grant from Medtronic MiniMed (Northridge, CA).
Abbreviation Notes

CSII = continuous subcutaneous insulin infusion; MBG = mean blood glucose; QOL = quality of life
Reprint Address

Address correspondence and reprint requests to Larry A. Fox, MD, Nemours Children';s Clinic, NE Florida Pediatric Diabetes Center, 807 Children's Way, Jacksonville, FL 32207. E-mail: lfox@lwpes.org

Larry A. Fox , MD ,1 Lisa M. Buckloh , PHD ,2 Shiela D. Smith , RN ,1 Tim Wysocki , PHD ,2 and Nelly Mauras , MD 1

1 Division of Endocrinology, Nemours Children’s Clinic, Jacksonville, Florida
2 Division of Psychology and Psychiatry, Nemours Children’s Clinic, Jacksonville, Florida

Disclosure: N.M. has received grant support from Medtronic MiniMed.

Univ. of Texas researchers get $2.1 million for development of an alternative to daily injections

2005-06-06T22:43:00.000-07:00

From the Houston Chronicle June 6, 2005

By PATRICK KURP

With the aid of a $2.1 million grant from the National Institutes of Health, a team of researchers at the University of Texas at Austin is developing analternative to daily insulin injections for diabetics.

The group, headed by Nicholas Peppas, a professor of chemical engineering, biomedical engineering and pharmaceutics, is creating an oral means of ingesting insulin, the protein that enables the body to metabolize and use glucose. People withType I diabetes inject insulin directly into their bloodstream.

Apart from the discomfort and inconvenience of the shots, some patients report a buildup of fatty deposits, bruises and scar tissue at the injection site.

"Diabetics are traditionally very compliant patients. If they don't take their insulin, they will get very sick very quickly. But they tell me it can still be uncomfortableto take their injections," Peppas said.

Insulin is a highly unstable substance, readily destroyed by the body, from the enzymes in the mouth and esophagus to acidic gastric juices in the stomach. Peppas and other researchers have already experimented unsuccessfully with insulin sprays and patches.

The NIH-funded work focuses not on insulin itself, but on its delivery system — a tablet or capsule made of polymers, a sort of customized plastic.

The device would be a porous polymer network, woven of methylacrylic acid and polyethylene glycol, to protect the insulin as it passed through the upper digestive tract.

The polymer, called a hydrogel for its water-carrying qualities, would swell once it reaches the basic (high pH) conditions inside the upper small intestine. The capsule or tablet would adhere to that site and the cells of the intestinal lining would absorb the insulin.

From there it would enter the bloodstream.

Studies by Peppas' collaborators in Japan and Philadelphia have found that at least 12.8 percent of the insulin in his polymer delivery system reaches the bloodstreams of test animals. With the NIH money, Peppas team will focus on extending the time the capsule adheres to the upper small intestine.

"We call this a material with a certain intelligence," Peppas said. "The tablet orcapsule must survive the trip through the stomach and must know where tofasten itself in the upper small intestine. We want to make it even smarterso it will stay there even longer."

Peppas expects orally administered insulin to be on the market within five to six years.

Healso expects his research to have implications for the oral treatment of other diseases, including multiple sclerosis and some forms of cancer.

"What we're trying to do is make very, very sophisticated materials that can outsmart the body itself and have a direct impact on the quality of life of our patients,"Peppas said.

For comments on the Health & Medicine page, contact raequel.roberts@chron.com.

RESOURCES

SIGNS OF DISEASE AND POSSIBLE HELP

Symptoms
Some signs include:
• Being very thirsty
• Urinating often
• Feeling very hungry or tired
• Losing weight without trying
• Having sores that heal slowly
• Having dry, itchy skin
• Losing the feeling or having tingling in your feet
• Having blurry eyesight

You may have had one or more of these signs before you found out you had diabetes. Or you may have had no signs at all. A blood test to check your glucose levels will show if you have pre-diabetes or diabetes.

For more information, contact:

• National Diabetes Information Clearinghouse
5 Information Way Bethesda, Md. 20892-3568
Phone: 800-860-8747 Fax: 703-738-4929 E-mail: ndic@info.niddk.nih.gov
Internet: http://www.diabetes.niddk.nih.gov

• National Diabetes Education Program
1Diabetes Way Bethesda, Md. 20814-9692
Phone: 800-438-5383 Fax: 703-738-4929 Internet: http://ndep.nih.gov

Source: National Institutes of Health

A Natural Anti-Oxidant to Prevent Long-Term Complications of Diabetes?

2005-02-20T11:52:00.000-08:00

This article was distributed via email by the Juvenile Diabetes Research Foundation on Feb. 10, 2005. We repost it here for educational purposes only.

The Diabetes Center at UCSF and the UCSF Pediatric Diabetes Program are launching a study to assess the ability of an over-the-counter antioxidant to prevent or delay the long-term complications of type 1 diabetes.

Most people are aware that the long-term effects of diabetes include blindness, kidney failure, and nerve damage. Recently, researchers have discovered that high blood sugar increases the amount of free-radicals in those with diabetes. It is believed that these free-radicals cause retinopathy (eye damage), nephropathy (kidney damage) and neuropathy (nerve damage) by a process called “oxidative stress”.

Researchers at UCSF believe that alpha-lipoic acid, a potent anti-oxidant, could decrease oxidative stress, thereby preventing or delaying the devastating long-term complications of diabetes.

Although alpha-lipoic acid is gaining recognition as an effective treatment for diabetes complications after they have occurred, its ability to prevent or delay these complications has not yet been studied in humans. The UCSF study will be the first to assess if this natural anti-oxidant has a future role in preventing or delaying the long-term complications of type 1 diabetes.

In this study, 30 adolescents with type 1 diabetes will be given alpha-lipoic acid, and 10 adolescents with type 1 diabetes will be given placebo pills. The amount of oxidative stress before and after 3 months of treatment will be compared. If the results are promising, a more extensive study will be launched to further explore if alpha-lipoic acid can successfully prevent or delay eye, kidney, and nerve damage.

The study's principal investigators include: Dr. Stephen Gitelman, Professor of Clinical Pediatrics and Director of the UCSF Pediatric Diabetes Program, and Dr. Eric Huang, Clinical Fellow in the Division of Pediatric Endocrinology.

If you or your child is interested in participating in this study, please contact Dr. Huang by phone – (415)-476-8216, or e-mail huange1@itsa.ucsf.edu

To learn more about diabetes research at UCSF, visit http://m1e.net/c?22835818-iHLZru3hKBFHA%40846840-OD4y7WPERUQ9Y

Diabetes Center at UCSF researchers in national beta cell effort

2005-02-20T11:51:00.000-08:00

This article was distributed by the Diabetes Center at UCSF on Feb. 15, 2005. We repost it here for educational purposes only.

Diabetes Center researchers in national beta cell effort

In keeping with the Diabetes Center’s tradition of collaboration, faculty members Michael German, MD, Matthias Hebrok, PhD, and Didier Stainier, PhD are working in a national consortium with nearly twenty other renowned U.S. scientists to "fast track" the creation of insulin-producing beta cells.

This esteemed group of researchers, known as the Beta Cell Biology Consortium (BCBC), was formed by the National Institutes of Health (NIH) in 2001 to advance the scientific community's understanding of pancreatic islet development and function. It is believed that this knowledge is critical if we are to succeed in converting human stem cells into insulin-producing beta cells.

In addition to sitting on the Consortium’s steering committee, Dr. German heads up the “Molecular Control of Pancreatic Islet Development” program of the BCBC. The program utilizes zebrafish, and human stem cells as model systems. In mouse model systems, the consortium is examining new strategies to rapidly manipulate genes that play essential roles in the development of the pancreas, with the aim to determine exactly what genes play a role in beta cell development and if this knowledge can be used to create new sources of beta cells. Dr. Hebrok’s BCBC project aims to define the role of neuronal guiding molecules during islet formation.

In addition to the Beta Cell Biology Consortium, Diabetes Center researchers are actively involved in a number of other important national and international collaborations, such as Type 1 Diabetes TrialNet and the Type 1 Diabetes Genetics Consortium, as well as being home to the Immune Tolerance Network.

New research into gene-disease relationship

2005-02-20T11:50:00.000-08:00

This we distributed Feb. 15 by the Diabetes Center at UCSF. We repost this very technical but interesting article here for educational purposes only.

Don't shoot the messenger... silence it!

Michael McManus, PhD is exploring new ways to stop bad genes

A new tool that gives researchers the ability to block disease-causing genes is the next wave in biotechnology. If successful, “RNA interference” (known as RNAi) could provide new cures for everything from cancer to HIV to diabetes. Dr. Michael McManus, a world leader in RNAi, recently moved his MIT laboratory to the Diabetes Center at UCSF to focus his groundbreaking research on the problem of diabetes.

--

In the era of the human genome, it is clear that our genes play a vital role in determining our health. Mutations in specific genes, either inherited or caused by environmental damage, are responsible for a wide array of human disease. Subverting these mutated genes and the damage they cause would address disease at its source, providing long-lasting or permanent cures.

But exactly how do you stop a bad gene? There are several ways. For one, you could target the DNA that encodes the bad gene. Known as gene therapy, this technique has met with only limited success. On the other hand, you could target the proteins that precipitate the ill-effects of the bad genes. While this has proven more practical, in many cases, one bad gene can affect the function of many different proteins and so therapies targeted at proteins are often only partially effective.

RNA, the lesser-known cousin of DNA offers a third technique. RNA is an intermediary in the creation of proteins from genes. Single-stranded RNA molecules, known as messenger RNA act as templates for constructing new proteins encoded by the gene. Therefore, shutting down the RNA of a specific gene should do the trick. To date, attempts at targeting RNA with “antisense” pieces of artificial single-stranded RNA that bind and disable the messenger RNA have not been overly successful.

However, in 1998 a new form of RNA was discovered known as “small interfering RNA” or siRNA. These short, single stranded molecules are part of an ancient mechanism for regulating genes that is found in both plants and in animals as diverse as yeast and humans. Each piece of siRNA is specific for a given gene and is capable of stopping its expression, halting the effects of the mutation or overexpression that is causing a disease.

According to Dr. McManus, “siRNA acts like a one-way volume dial on a radio -- quickly turning down the amount of a specific gene that is expressed. We call the process ‘gene silencing’."

Over 300 hundred of these small RNA volume knobs have been discovered. Now called microRNAs, scientists are only beginning to determine which specific genes that each acts upon. According to McManus, however, one microRNA known as miR-375 was recently found to regulate insulin secretion.

“We certainly expect that we will uncover additional control RNAs that relate to both type 1 and type 2 diabetes,” says McManus. “In the meantime, we are working to learn more about how siRNA functions and how we can harness this discovery to develop new therapies.”

Dr. McManus is currently investigating a gene called “Dicer,” which was originally discovered through the Human Genome Project. Dicer is a naturally occurring protein that acts like a pair of scissors to cut double stranded RNA into the siRNAs that regulate gene expression. Without it, gene silencing doesn’t work. So determining exactly how Dicer functions and the pathways that microRNAs use to silence specific genes may lead to new treatments for diseases where gene silencing has broken down. His studies may also offer ways to enhance the "tailored siRNAs" that could be used to treat diseases like diabetes.

Researchers have already tailor-made siRNA that target the gene Phosphatase-1B (PTP-1B), which is involved in insulin resistance.

While this treatment gives the appearance of a "magic bullet", McManus says the biggest challenge so far is finding ways to deliver siRNAs to the cells.

“In organisms such as plants and worms, siRNAs are easily taken up by cells. In mammals, siRNAs need help from chemical carriers,” he says. Many pharmaceutical companies are working day and night to develop chemical treatments intended to deliver the siRNA to the intended target. "RNAi has transformed the way scientists are performing gene function studies and has consumed the biotech industry like wildfire. It was recently given the title of 'Breakthrough of the Year' by Science magazine, and Fortune magazine has heralded it as 'Biotech's Billion-Dollar Breakthrough'." McManus says, "I believe it will revolutionize the way we look at medicine".

“In addition to his work with Dicer, McManus is collaborating with other Diabetes Center scientists like Mike German and Matthias Hebrok. Among other things, they are looking to determine the role of microRNAs in beta cell development.

“There is much research to be done” he says. “I came here because of the fantastic forward-thinking attitude in research and medicine. Look around you, UCSF is a place of tremendous growth and accomplishments. The UCSF Diabetes Center is at the forefront -- it is a place where my research can contribute to the major advances being made in both basic science and the curing of diseases such as diabetes.”

Improving the outlook for simultaneous pancreas-kidney transplants

2005-02-20T11:49:00.001-08:00

This article was posted by the Diabetes Center at UCSF. We repost it here for educational purposes only.

Improving the outlook for simultaneous pancreas-kidney transplants

The body's rejection of transplanted organs and tissues is an unfortunate risk of transplant surgery. Historically, rejection rates in a simultaneous pancreas-kidney (SPK) transplant have been as high as 80% and, in 2001, averaged nearly 20% [1]. What's more, steroid-based immunosuppressive drugs that have been traditionally used to combat rejection are associated with several serious side-effects, including increased risks of osteoporosis and bone and joint problems.

Diabetes Center surgeons Drs. Peter Stock and Chris Freise have been pioneering new methods of immunosuppression for SPK transplants that do not rely upon steroids, with great success.

In a retrospective case review of 40 patients who received a simultaneous pancreas-kidney transplant followed by a steroid-avoiding immunosuppression protocol, the UCSF team reported 95% patient survival 1 year following transplant. Importantly, 87.5% of patients had retained insulin independence for 1 full year after transplantation, indicating their transplanted pancreas was continuing to function, while 92.5% had retained functioning kidney transplants at 1 year.

The study also looked at side effects of this immunosuppression regimen, and found no increased risk of infections or surgical complications. One potential concern with steroid use is abnormal cholesterol levels, and patients on the steroid free regimen required cholesterol lowering drugs only 18% of the time. The use of blood pressure medicines was needed about 50% of the time. Other potential benefits of avoiding steroids include less bone disease, less weight gain, and hopefully fewer cardiovascular problems. These other side effects are being studied by the investigators.

Over the past 15 years, the UCSF Transplant Division has performed nearly 350 pancreas transplants. Most of these have been performed as a simultaneous pancreas and kidney transplant in type 1 diabetic patients who have progressed to end stage kidney failure. Pancreas-kidney transplantation can be a very effective, highly successful treatment for patients with diabetes who are experiencing severe complications including renal failure, severe hypoglycemic unawareness, and debilitating neuropathy. Pancreas-only transplants are now being offered for patients who do not require a kidney transplant, but who have very unpredictable and erratic blood sugar control despite intensive insulin therapy. Success rates for solitary pancreas transplants (as defined by insulin independence) are approximately 90% at 1 year post-transplant.

For more information on the UCSF Kidney and Pancreas Transplantation Program, contact: (415) 353-1551. Or visit Diabetes Center at UCSF

Progress Seen in Transplants for Diabetes

2005-02-20T11:49:00.000-08:00

This article from the New York Times was distributed via e-mail on Feb. 16, 2005 by the JDRF. We post it here for private educational purposes only.

The New York Times
Wednesday, February 16, 2005

By MARY DUENWALD

Doctors may have found a way around a major obstacle in the effort to perfect transplants of islet cells, an experimental treatment for Type 1 diabetes, a severe form that often begins in childhood.

Such transplants usually succeed only if islet cells from the pancreases of two or even three donors are used - a significant drawback, given the scarcity of donor organs. But now, in a trial of eight patients at the University of Minnesota, in Minneapolis, doctors have managed successful transplants of islet cells, which are needed to produce insulin, with the pancreases of single donors.

The use of anti-inflammatory drugs that are normally used to treat arthritis seems to have enabled many more of the transplanted cells to survive, said Dr. Bernhard J. Hering, director of the islet transplant program at the University of Minnesota. Patients were given these drugs before surgery to dampen the inflammation that otherwise destroys as many as half of transplanted islet cells in the first 24 hours, Dr. Hering said.

The doctors also cultured the donated islet cells in the laboratory for two days, rather than transplanting them within hours of isolating them from the donor pancreas. This step appears to give the islet cells greater resilience, Dr. Hering said.

The results of the trial are reported today in The Journal of the American Medical Association.

"This is really a long-awaited development, if it can be reproduced, because it means that the efficiency of islet cells is being increased," said Dr. R. Paul Robertson, scientific director of the Pacific Northwest Research Institute, a diabetes research center in Seattle. Dr. Robertson was not involved in the trial.

Diabetes researchers hope islet-cell transplants, which can be done almost as easily as a blood transfusion, in less than an hour, will one day free many people with Type 1 diabetes from the need to inject themselves with insulin several times a day to control their blood sugar.

But refining the procedure has not been easy. Among the first patients to have successful transplants five years ago, most are using insulin again-though not as much as they needed before their transplants.

Type 1 diabetes, sometimes called juvenile diabetes, occurs when the body's immune system destroys the insulin-producing cells in the pancreas, which are contained in tiny structures called the islets of Langerhans.

An estimated one million people in the United States have Type 1 diabetes.

Although it is possible to transplant the entire pancreas, the risk of death is great enough that the operation is rarely done in people who do not also need a kidney transplant because of diabetes-related kidney failure. Islet-cell transplants are less invasive and less dangerous.

Islet cells, which make up about 2 percent of the pancreas, can be isolated from cadaver pancreases and then transplanted through a catheter into the recipient's liver. They cannot be placed into the pancreas, because that organ is too vulnerable to inflammation.

When islet-cell transplants were first performed in humans, in the 1980's, they were rarely successful. But five years ago, surgeons at the University of Alberta in Edmonton adjusted the combination of immunity-suppressing drugs that are used to prevent rejection of the new cells and achieved successful transplants in eight patients.

Since then, the Edmonton protocol, with some variations, has been used on about 500 patients worldwide, said Dr. James Shapiro, director of the islet-cell transplant program at the University of Alberta, who designed the protocol.

"We've come a long way in a really short time, and I think islet transplantation is here to stay," Dr. Shapiro said. "It's still far from perfect, however."

A total of 73 patients have now received islet-cell transplants in Edmonton, most of whom have had the procedure twice. One year after transplant, 82 percent of patients need no insulin injections. After three years, however, that number falls to about 50 percent, Dr. Shapiro said. But after five years, he said, it appears that only 15 percent will still be independent of insulin.

"It appears that some of the grafts are failing, but it is not a complete failure," Dr. Shapiro said. "Some of the transplanted cells are still producing insulin."
Some of the cells may succumb to the anti-rejection drugs. Or perhaps the autoimmune reaction that caused the patient's diabetes kills them, Dr. Shapiro said.

Last month, working with surgeons in Kyoto, Japan, Dr. Shapiro accomplished the first islet-cell transplant from a living donor. A 27-year-old woman with Type 1 diabetes was given islet cells that had been isolated from half of her mother's pancreas.

Such transplants would expand the supply of donor cells. But some experts are wary of risks to donors.

Federal Govt., JDRF Launch Resource for Diabetic Kidney Disease Gene Studies

2005-01-01T17:02:00.000-08:00

National Institutes of Health press release -- Dec. 28, 2004

The National Institutes of Health (NIH), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC) announced today the availability of the largest single collection of biosamples and data for research on the genetic causes of kidney disease in type 1 diabetes.

The Genetics of Kidneys in Diabetes (GoKinD) collection has nearly 10,000 DNA, serum, plasma and urine samples, plus genetic and clinical data, from more than 1,700 adults with type 1 diabetes in the United States and Canada. Of those, 818 have had diabetes at least 10 years and have developed kidney disease, a common complication of diabetes. The other 893 have had diabetes at least 15 years but do not have kidney disease. Also in the collection are data and samples from 1,096 parents (548 sets).

“GoKinD is a tremendous resource. We’re thrilled about the promise it represents,” said Rebekah Rasooly, Ph.D., who oversees the project for NIH and directs genetics and genomics programs at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). “We fund research all the time, but this kind of project reflects a new way of thinking. GoKinD is a gift that will keep on giving, and we are deeply indebted to the individuals and families who made this invaluable resource possible.”

Researchers can apply for DNA, extensive clinical data and some genetic data from GoKinD at www.gokind.org/access; serum, plasma and urine samples will be made available later. Methods of treatment, insulin doses, complications, smoking history and other data have been documented for all GoKinD participants. Also, DNA has been genotyped for genes well-known to predispose to type 1 diabetes. To protect the privacy of patients and families, researchers do not have access to names and other identifying information.

“This study is of exceptional quality and offers a unique opportunity for genetic research,” said Patricia Mueller, Ph.D., chief of CDC’s diabetes and molecular risk assessment laboratory.

Gathering information and samples of the kind, quality and quantity that individual researchers alone would be unable to collect, GoKinD provides a rich means for learning about the genetics of both kidney disease and type 1 diabetes.

“GoKinD will help us tease out genes linked to kidney disease versus those that are primarily important causes of diabetes itself,” said Concepcion R. Nierras, Ph.D., director of research for JDRF.

Both NIH and JDRF will separately consider requests to fund research on GoKinD data and samples. NIH grant applications are at http://grants.nih.gov, and resources for type 1 diabetes research are listed at www.niddk.nih.gov/fund/diabetesspecialfunds/funding.htm. JDRF grant applications are under the research tab at www.jdrf.org.

Once found, genes for susceptibility to kidney disease can be studied to find out what they do, how they do it and how researchers might intervene to prevent the disease or improve treatment. Studies have already linked several genes to susceptibility to type 1 diabetes, but scientists are confident that more genes exist and that other, as yet unknown, genes increase susceptibility to complications such as kidney disease. (Learn more about genetic factors in diabetes at www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=diabetes.chapter.987.)

“These genes alone don’t explain the complete genetic risk for diabetes, and little is known about genes for kidney disease or other complications. Yet, there is clearly a genetic risk for complications, because they run in families and among certain populations,” said Paul L. Kimmel, M.D., F.A.C.P., a nephrologist working part-time with Rasooly and NIDDK on GoKinD. Kimmel also directs the renal disease and hypertension division at George Washington University Medical Center in Washington, D.C.

Diabetes is the leading cause of kidney failure in the United States. In 2002, treatment of kidney failure cost Medicare and private insurers $25 billion for more than 400,000 people, 40 percent of whom had diabetes. Twenty to 40 percent of people with type 1 diabetes will develop kidney failure by the age of 50, but some develop it before the age of 30.

Type 1 diabetes accounts for up to 10 percent of people diagnosed with diabetes in the United States (up to 1 million people). This form of diabetes usually strikes children and young adults, who need several insulin injections a day or an insulin pump to survive. Insulin, though critical for controlling blood glucose, is no cure. Most people with the disease eventually develop one or more complications, including damage to the heart and blood vessels, eyes, nerves, and kidneys.

NIH, JDRF and CDC collaborated on GoKinD. NIH supported the study through a special fund for type 1 diabetes research established by Congress in 1997 and coordinated by NIDDK. In all, the fund will provide $1.14 billion between fiscal years 1998 and 2008, supplementing funds available for type 1 diabetes research through regular NIH appropriations.

Under JDRF, the Joslin Diabetes Center and the George Washington University (GWU) Biostatistics Center (and its associated clinical centers) each recruited about half the patients and their parents. GWU will also distribute GoKinD data. CDC provided genotyping data for the major type 1 diabetes risk factors, HLA DRB1, DQA1, and DQB1 and the -23 insulin gene single nucleotide polymorphism (SNP). In addition, CDC will distribute samples and conduct research on the collection. Biochemical clinical data were provided by the University of Minnesota.

Investigators and centers that recruited participants and provided clinical and genetic data are:

* Stephen A. Brietzke, Univ. of Missouri
* David Brillon, New York Presbyterian Hospital, Cornell Univ.
* George A. Burghen, Univ. of Tennessee
* George W. Burke, Univ. of Miami
* Patricia Cleary, George Washington Univ. Biostatistics Center
* Suzanne Cordovado and Patricia Mueller, CDC
* Debra Counts, Univ. of Maryland Medical System
* James Desemone, Albany Medical Center
* Steven V. Edelman, Univ. of California San Diego
* Carla Greenbaum, Virginia Mason Research Center
* Richard A.Guthrie, Mid-America Diabetes Associates, P.A.
* Irene Hramiak, St. Joseph's Health Care, Univ. of Western Ontario
* Mark Johnson, Univ. of North Carolina at Chapel Hill
* Lois Jovanovic, Sansum Medical Research Center
* John I. Malone, Univ. of South Florida
* Michael Mauer and Mike Steffes, Univ. of Minnesota
* Michael E. May, Vanderbilt Univ. Medical Center
* Larry Melton, Baylor Univ. Medical Center
* Mark E. Molitch, Northwestern Univ.
* Robert E. Ratner, Med-Star Clinical Research Center
* John Rogus, Adam Smiles and James Warram, Joslin Diabetes Center
* William L. Sivitz, Univ. of Iowa
* Maria Szpiech, Medical Univ. of South Carolina
* Neil H. White, Washington Univ. School of Medicine
* Bernard Zinman, Mount Sinai Hospital, Univ. of Toronto

High Blood Sugar Decreases School Performance

2005-01-01T16:51:00.000-08:00

From Diabetes Today, American Diabetes Association -- Dec. 22, 2004

ALEXANDRIA, Va. -- A temporary rise in blood glucose (sugar) levels in people with both types of diabetes can interfere with their ability to think quickly and solve problems, according to a study in the January issue of Diabetes Care.

Researchers at the University of Virginia Health System (UVHS) found that people who had both type 1 and type 2 diabetes performed poorly on math and verbal tests when they became hyperglycemic, a condition in which blood glucose levels are higher than normal. Symptoms of hyperglycemia include high blood glucose, high levels of sugar in the urine, frequent urination, and increased thirst. Roughly 55 percent of the people in the study showed signs of cognitive slowing or increased errors while hyperglycemic, suggesting that the consequences of hyperglycemia vary among individuals. However, among those whose cognitive performance deteriorated when blood sugar levels rose, the negative effects consistently appeared once levels reached or exceeded a threshold of 15 mmol/l or 270 mg/dl.

Because hypoglycemia (when blood glucose levels are too low) can cause dizziness and an inability to focus, many people consume large amounts of carbohydrates to avoid this state prior to school exams and other cognitive- sensitive tasks. But this study suggests that carbohydrate-loading could be counterproductive, the researchers conclude, because hyperglycemia often occurs after overeating.

"The best way to minimize any negative effects on cognitive functioning is to keep blood glucose levels tightly controlled," said lead researcher Dr. Daniel J. Cox, of the Center for Behavioral Medicine Research at UVHS. "People who have diabetes should pay careful attention to the warning signs of hyperglycemia so that they can quickly take action to treat it."

Treatment for hyperglycemia can include increasing insulin or reducing food intake.

Diabetes Care, published by the American Diabetes Association, is the leading peer-reviewed journal of clinical research into the nation's fifth leading cause of death by disease. Diabetes also is a leading cause of heart disease and stroke, as well as the leading cause of adult blindness, kidney failure and non-traumatic amputations. For more information about diabetes, visit the American Diabetes Association Web site http://www.diabetes.org or call 1-800-DIABETES (1-800-342-2383).

Pregnancy Can Go Well for Women with Diabetes

2005-01-01T16:38:00.000-08:00

From Reuters Health News -- Fri Dec 31, 2004

NEW YORK (Reuters Health) - Women with type 1 diabetes who monitor their blood glucose daily both before and during pregnancy have better outcomes, Danish researchers report.

In the largest study to date of pregnant women with type 1 diabetes, Dr. Dorte M. Jensen of Odense University Hospital and colleagues found that only one-third of women said they monitored their blood sugar levels every day around the time they conceived.

Daily monitoring and good overall control of blood glucose levels were associated with a lower likelihood of infant mortality and birth defects.

The study is published in the medical journal Diabetes Care.

Specifically, the researchers compared rates of pregnancy complications in the general population with rates for 1,218 consecutive pregnancies in 990 women who had type 1 diabetes.

Among the women with diabetes, compared with the general population, the percentage of babies that died soon after birth was higher (3.1 percent vs. 0.75 percent), as was the rate of stillbirths (2.1 percent vs. 0.45 percent) and birth defects (5.0 percent vs. 2.8 percent).

Among the 93 diabetic women who had serious adverse outcomes - meaning babies that died or had malformations - 22 percent monitored their blood glucose daily at conception, compared to 35 percent of the women who had uncomplicated pregnancies.

Also, blood sugar control before and during pregnancy was not as good among the adverse outcome group, on average, and they were less likely to have received pre-conception guidance than the women without seriously affected babies.

In Denmark, where healthcare is free and women with diabetes are entitled to regular visits with diabetes specialists, the researchers note, the low rates of daily monitoring at conception and pre-conception guidance were "disappointing."

"Our data suggest that glycemic control, self-care and education of the patient still need to be improved significantly and that adequate control using daily glucose monitoring in all patients is a crucial step toward reaching the goals of the St. Vincent declaration," Jensen's team concludes.

That 1989 declaration stated that within five years, rates of complications in diabetic pregnancies should be similar to those seen with non-diabetic pregnancy -- a goal that has not been achieved, the researchers note.

Diabetes vaccine to be tested on humans

2004-12-13T18:39:00.000-08:00

From the Guardian Unlimited, London, England

David Batty
Monday December 13, 2004

A vaccine against the most serious type of diabetes will be tested on humans for the first time next year, UK scientists said today.

The clinical trial is due to start in August once scientists have gathered together 18 patients with type 1 diabetes, the life-threatening form of the disease which usually develops during childhood or adolescence.

The researchers, from Bristol University and King's College London, believe the vaccine could prevent the onset of the type 1 diabetes and cure people in the early stages of the disease. If the trial is successful they anticipate a cure could be widely available within a decade.

Diabetes charities said this would be the most significant development in the treatment of the disease since the widespread prescription of insulin began in the 1920s.

There are 300,000 sufferers of type 1 diabetes, which destroys the cells in the pancreas that produce the hormone insulin needed to control blood sugar levels, in the UK. They need daily injections of synthetic insulin for the rest of their lives. Without treatment, glucose builds up in the bloodstream and death is inevitable.

The vaccine involves the injection of a protein, which stops the body destroying the insulin producing cells, known as islets.

The research, led by immunologists Professor Mark Peakman, Dr Colin Dayan and Dr Susan Wong, began four years ago with the identification of the proteins in islets that are attacked by white blood cells in diabetes.

This was followed by the successful inoculation of mice with a protein that stops the white blood cells from attacking the islets. Diabetic animals were protected for the rest of their lives.

The next stage is to conduct a human trial, following 18 patients with type 1 diabetes for 18 months. If successful, this would be followed by a larger scale trial.

Dr Wong, an immunologist at the University of Bristol, said: "In the first instance we will be looking to see an effect in people who already have diabetes. But ultimately the aim would be to prevent those at risk from ever developing the disease."

The research has been funded by the Juvenile Diabetes Research Foundation and Diabetes UK. Georgina Slack, head of research at the charity Diabetes UK, said it appeared to improve the chances of providing a cure for the disease.

She said: "The prospect of finding a way of stopping the body from attacking itself and causing type 1 diabetes is the holy grail of diabetes research. We'll be following any progress with the research into humans very closely."

Researchers target type 1 diabetes prevention

2004-10-10T01:39:00.000-07:00

From the American Medical News, Sept. 27, 2004:

By Victoria Stagg Elliott, AMNews staff

Type 1 diabetes, often viewed as inevitable for those predisposed to it, could one day be as preventable as its well-known relative, type 2.

Such a shift in understanding would be revolutionary. It also would create a need for primary care physicians to take on screening and prevention for type 1 with the same vigor as they currently do for type 2.

For now, though, prevention of type 1 is a proposition of someday, spoken of in terms of "if," not "when." Even so, many experts believe that they now possess important clues that will help them solve the mystery of how to stop it before it starts.

To that end, the National Institute of Diabetes and Digestive and Kidney Diseases in June launched TrialNet, an international network of 18 centers that will study interventions that may prevent development of the disease and improve the prospects for those newly diagnosed with it.

"This will absolutely be in the purview of primary care physicians once we have something that we really think delays or prevents diabetes," said Ellen Leschek, MD, TrialNet's program director. "Even if you're talking about delaying by just two or three years, that's substantial, because every moment that you have diabetes, those are moments that are contributing towards having the long-term effects."

The network is building on the work of the Diabetes Prevention Trial-Type 1, also funded by NIDDK and launched in 1995, which examined the use of low doses of injectable insulin or oral insulin to prevent the development of the disease in those at high risk.

The results, published in the New England Journal of Medicine May 30, 2002, clearly showed that neither intervention worked. In the process, however, researchers learned how to predict who was most likely to progress to type 1 diabetes.

"We can now identify who's at risk for diabetes. It's just a matter of time before we find agents that will actually prevent diabetes," said H. Peter Chase, MD, one of TrialNet's principal investigators and a professor of pediatrics at the University of Colorado Health Sciences Center.

Being able to make this determination allows researchers to target interventions to those who would benefit the most. This testing is also most likely to be the first innovation out of the initial trial and TrialNet to make inroads into clinical practice -- although not just yet.

NIH to Award $75M to Study Islet Transplantation

2004-10-09T23:52:00.000-07:00

Press Release: Oct. 4, 2004

NIH Funds Centers to Study Islet Transplantation

The National Institutes of Health (NIH) announced today that it plans to award about $75 million over five years to five clinical centers and a data coordinating center to conduct studies of islet transplantation in patients with type 1 diabetes. The network includes centers located in Iowa City, Miami, Minneapolis and Philadelphia, as well as in Edmonton, Canada, and Uppsala, Sweden.

The studies will focus on improving the safety and long-term success of methods for transplanting islets, the insulin-producing cells of the pancreas, in people whose own islets have been destroyed by the autoimmune process that characterizes type 1 diabetes. Some studies will focus on improving combined islet and kidney transplants in patients with type 1 diabetes and kidney failure, a common complication of diabetes.

“This award accelerates studies of an experimental approach that could be very promising for some people with severe type 1 diabetes if specific barriers can be overcome,” said Dr. Thomas Eggerman, who oversees the consortium for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Two institutes of the National Institutes of Health (NIH) — the NIDDK and the National Institute of Allergy and Infectious Diseases (NIAID) — sponsor the consortium.

Type 1 diabetes accounts for up to 10 percent of diagnosed cases of diabetes in the United States (up to 1 million people). This form of diabetes usually strikes children and young adults, who need several insulin injections a day or an insulin pump to survive. Insulin, though critical for controlling blood glucose, is no cure. Most people with type 1 diabetes eventually develop one or more complications, including damage to the heart and blood vessels, eyes, nerves, and kidneys.

In islet transplantation, islets are extracted from the pancreas of a deceased donor and infused into a person with difficult-to-control type 1 diabetes though the portal vein of the liver. In successful transplants, the cells lodge in the liver’s small blood vessels and begin producing insulin.

In the 1990’s, islet transplantation rarely succeeded in freeing patients from insulin injections for more than a year. In June 2000, however, a research team led by Dr. James Shapiro at the University of Alberta in Edmonton, Canada, reported sustained insulin independence in seven patients transplanted with islets from two to four donor pancreases. The patients received an immunosuppressive regimen that omitted glucocorticoids, also known as steroids, which were often used to prevent rejection but are now thought to be toxic to islets. In the next few years, researchers participating in the Immune Tolerance Network (ITN), a collaboration of clinical and basic researchers sponsored by the NIAID, NIDDK, and the Juvenile Diabetes Research Foundation International, replicated what became known as the “Edmonton protocol.”

Despite these gains, scientists continue to grapple with several impediments to the wider testing of islet transplantation. One is the scarcity of islets. Only about 6,000 donor pancreases become available each year, and many are used for whole organ transplantation. Posing another obstacle are the potentially serious side effects — such as anemia, nerve damage, meningitis, and vulnerability to infection — of the medications that stop the immune system from rejecting donor islets. Finally, in some transplanted patients, donor islets function well initially, but in time diabetes recurs. Why the islets die is not well understood.

Recent NIH-funded advances may lead to some answers. “Newly developed immune assays are helping us flesh out a more complete picture of the immune events that trigger rejection,” said Dr. Nancy Bridges, who oversees the consortium for NIAID. “Studies are also laying the groundwork for less toxic immunosuppressive agents, which will be tested in upcoming trials. Our ultimate goal is to develop ways to induce tolerance, a state of immune acceptance of the donor tissue or organ.”

Researchers in the newly funded centers will be designing studies to:

* improve the isolation and viability of islets
* reduce complications of the transplant procedure, e.g., bleeding and clotting
* reduce the side effects of immunosuppression
* trace the fate of islets after transplantation and determine why donor islets sometimes fail
* evaluate new ways to safely prevent immune rejection of donor tissues.

Newly designed studies will be submitted for review by the Food and Drug Administration, the NIDDK/NIAID Islet Transplantation Data and Safety Monitoring Board, and local institutional review boards before being offered to patients. Patient enrollment is scheduled to begin in 2005.

The consortium consists of the following principal investigators and centers:
Dr. William Clarke, University of Iowa (Data Coordinating Center)
Iowa City, Iowa

Dr. Camillo Ricordi, University of Miami
Miami, Florida

Dr. Bernhard Hering, University of Minnesota
Minneapolis, Minnesota

Dr. Ali Naji, University of Pennsylvania
Philadelphia, Pennsylvania

Dr. James Shapiro, University of Alberta
Edmonton, Alberta, Canada

Dr. Olle Korsgren, Uppsala University
Uppsala, Sweden

The consortium is supported by a special funding program for type 1 diabetes research, which provides a total of $1.14 billion from fiscal year 1998 through fiscal year 2008 to supplement other funds for type 1 diabetes research made available through the regular NIH appropriations process.

Diabetes doesn't guarantee a shorter life

2004-09-26T23:25:00.000-07:00

Here's a great little story about people with diabetes living into their 80s. It seems that because of their overall awareness of healthful habits, people with diabetes can actually avoid those medical issues that kill the rest of us early.

Published Sunday, Sept. 26, 2004

Growing old with diabetes
By WILLIAM KATES, THE ASSOCIATED PRESS

SYRACUSE, New York -- Day in and day out, for seven decades, brothers Robert and Gerald Cleveland have meticulously managed their blood glucose levels, fending off a disease that typically gives its victims just 20 or 30 years. On Thursday, the world's leading diabetes research centre paid tribute to the Clevelands for their longevity and everyday perseverance.

According to the Boston-based Joslin Diabetes Center, they are the first siblings known to have lived with Type 1 diabetes for 50 years or longer.

DIABETES FOR 79 YEARS

Robert, 84, has lived with Type 1 diabetes for 79 years and, according to the centre's Dr. Hillary Keenan, is the longest known survivor. Gerald, 88, has had diabetes for 72 years.

"It's a minor distraction from a normal person's life. It doesn't have to interfere with any activities," said Robert, who believes he is probably in better overall health today because of his meticulously healthful habits.

Diabetes makes people more prone to heart disease, stroke, high blood pressure, blindness, kidney disease, nervous system disease and amputations.

"You're not handicapped with diabetes," Gerald said. "You just have a special job to do."

A diabetic doesn't produce or properly use insulin, the hormone needed to convert food into energy. The reason why continues to be a mystery, although genetics and factors such as obesity and lack of exercise appear to play roles, according to the American Diabetes Association.

DIABETES KILLED 69,301 IN 2000

Since the Joslin Center began its 50-year medal awards in 1972, more than 2,200 Americans have been identified as living with diabetes for 50-plus years, said Dr. George King, research director at the centre, which has more than 300 doctors and scientists. Eleven patients have lived 75-plus years with diabetes, he said. In 2000, the disease claimed 69,301 lives.

Over that time, Joslin researchers have studied the group to better understand what biological and genetic factors may contribute to a long life with diabetes, Keenan said.

Today, in the United States, there are 18.2 million diabetics, a third of whom aren't aware they have the disease.

Robert, a retired accountant, was diagnosed at age five in 1925 - three years after insulin was invented. He nearly died. Seven years later, Gerald, a former Syracuse school superintendent, was diagnosed at age 16.

Wierd story from Boston

2004-09-26T22:26:00.000-07:00

The Boston Globe carried the following story on Sunday, Sept. 26. Though I didn't find anything scientific about it, I thought it was interesting enough to share.

One quick note for our friends in Boston: You can't catch diabetes. It's not a contagious disease, like say tuberculosis or even AIDS. I'm thinking the school buildling probably isn't the problem here, but that's just my guess. I'll keep you updated on any new developments.

Some suspect school building in student diabetes cases
Mayor asks state to probe possible link

By Maureen Costello, Globe Correspondent | September 26, 2004

The diagnoses of Type 1 diabetes in seven students who attended the Goodyear Elementary School have prompted Woburn officials to ask for the state's help in investigating whether environmental factors in or near the building may have contributed to the children's sickness.

"There is some concern," said Mayor John C. Curran, who last month asked the state's Department of Public Health to investigate a possible link between the diagnoses and the condition of the 77-year-old school, where 231 students attend kindergarten through Grade 5. "I think it's highly unlikely that it's the school, but we're going to check it out. We're just trying to rule everything out."

Nicole St. Peter, a spokeswoman for the state public health department, confirmed that a preliminary assessment of the building was conducted Sept. 2 and final results are expected soon. Families and school officials will receive a copy of the findings.

Coincidentally, a new elementary school opened this month, allowing some families to send their children to another school. Parents Tammie Brinkley, Justine Cromer, and Kristin Ahearn opted out of Goodyear, claiming the physical condition of the building may be responsible for triggering Type 1 diabetes, formerly known as juvenile diabetes, in their boys.

"We were looking for a common denominator, and all information pointed that way," said Brinkley, whose son Tyler, 7, was diagnosed in June, and son Christian, 5, was diagnosed two months later. Christian began kindergarten at the new Malcolm White School this year, but his mother said he spent a week at the Goodyear during a kindergarten readiness program last winter.

Brinkley and Cromer said there is no history of diabetes in their families. But Ahearn said her cousin's son was diagnosed with diabetes six years ago and noted that she, her cousin, and Brinkley grew up in East Woburn. When Ahearn's son Kyle, 13, was diagnosed in January 2003 and her other son, Ethan, 9, was diagnosed in June, she began to think that their neighborhood had something to do with the disease.

But Ahearn said last month's diagnosis of Cromer's child, Nick, 9, undermined that theory. Cromer and her family moved to Woburn from Seattle in July 2003. Cromer said her son began experiencing allergy-like symptoms after entering Goodyear, and became unable to quench his thirst beginning in June. Excessive thirst and frequent urination are typical symptoms of Type 1 diabetes.

"I truly believe it's a complicated combination of the environment and stress," said Cromer.

None of these five students is attending Goodyear this year. The two other students who were diagnosed with diabetes continue to attend the school. School officials would not identify these students.

In Type 1 diabetes, the pancreas produces little or no insulin, which is used to transfer sugar from the blood to fuel the cells. Once diagnosed, the disease means a lifetime of dependency on insulin shots. Complications may include blindness, kidney failure, amputation of lower extremities, and a life expectancy 15 years shorter than average.

The cause is not yet known, but genetics do play a factor, though not in as simple a pattern as inheriting brown eyes, said James H. Warram, an investigator at the Joslin Diabetes Center at Harvard Medical School.

"There is overwhelming evidence, no question, that genetics is suspected, but only about 5 to 10 percent of the people who are susceptible get it," he said. "There is no one trigger, but probably a whole sequence of triggers."

Diet and cold temperatures are two factors that could trigger diabetes, Warram said. He also cited a theory by British researcher Edwin Gale that suggests extremely clean environments could contribute to Type 1 diabetes. "Now, I'm sure these mothers aren't going to want to hear that," said Warram, who added that exposure to many types of bacteria helps develop healthy immune systems.

Warram said the cluster of cases in Woburn ''is definitely higher than average, but it's one of the most common childhood diseases."

On average, the onset of Type 1 diabetes affects one out of 100 people before age 70, and typically three out of 1,000 people are stricken before age 20. Boys, especially teens, are more susceptible, said Warram, who cautioned that the cluster in Woburn may stem from mere chance rather than a common trigger. He said it takes years for the pancreas to break down, so it is unlikely these boys, who must have been genetically predisposed to get the disease, all experienced the same trigger.

Still, Warram said, environment is an important factor. ''The environment is somehow or other getting worse for these kids."

Superintendent of Schools Carl R. Batchelder said that 15 of the city's 4,700 students have Type 1 diabetes, a ratio he likened to the national average. However, he took the parents' concerns seriously and accompanied the state investigator on rounds of the building early this month. School officials also sent a letter about the concern to all Goodyear parents before school opened for the year, Batchelder said.

Batchelder said, besides diabetes, he has seen a rise in a number of other childhood illnesses, such as nut allergies, in his 10 years with the city. This has prompted officials to hire a full-time nurse for every school building.

Youngsters with Type 1 diabetes must have their sugar and insulin levels constantly monitored, and their insulin dosage calculated by the amount of sugar and carbohydrates they eat. ''It's major math, and my youngest couldn't do it," said Ahearn, adding that Ethan must visit the school nurse at least four times a day for monitoring, and Kyle spends his lunch period there.

The children also have to beware of treats and other foods they come across at school, friends' homes, and other locations. Before their diagnoses, Ahearn said, neither child ever visited the nurse.

Islet transplant results compiled

2004-09-09T06:05:00.000-07:00

From the National Institutes of Health:

Centers Report Islet Transplant Results in Patients with Type 1 Diabetes

Sept. 7, 2004 -- Researchers from 12 medical centers in the United States and Canada, who have performed islet transplants in 86 patients with type 1 diabetes, published their results today in the first annual report of the Collaborative Islet Transplant Registry (CITR). The report (www.citregistry.org ) analyzes many factors that can affect the outcome of this experimental procedure for people with severe or complicated type 1 diabetes.

The report provides data on recipient and donor characteristics, pancreas procurement and islet processing, immunosuppressive medications, function of the donated islets, patients’ lab results, and adverse events. “We now have much-needed information on the short-term results of islet transplantation,” said Dr. Thomas Eggerman of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the part of the National Institutes of Health (NIH) that funds the project. “Our goal is to collect data on both short- and long-term outcomes for all patients who receive islet transplants so we can better define the overall risks and benefits of this exciting but still experimental procedure.”

Type 1 diabetes, which affects up to 1 million people in the United States, develops when the body’s immune system destroys the insulin-producing beta cells of the pancreas. This form of diabetes usually strikes children and young adults, who need several insulin injections a day or an insulin pump to survive. Insulin, however, is not a cure, and eventually most people with type 1 diabetes develop one or more complications of the disease, including damage to the heart and blood vessels, eyes, nerves, and kidneys.

In islet transplantation as performed by these centers, insulin-producing cells derived from donor pancreata were infused into patients with difficult-to-control type 1 diabetes though the portal vein of the liver. When successful, the transplanted islets took up residence in the liver’s small blood vessels and began producing insulin.

The 86 recipients, who had type 1 diabetes for an average of 30 years, received a total of 158 infusions of islets extracted from 173 donor pancreata. Twenty-eight patients received one islet infusion, 44 received two, and 14 received three. At 6 months after the last infusion, 61 percent of recipients no longer had to inject insulin. At 1 year after the last transfusion, 58 percent were still insulin independent. Some insulin-independent patients, although not receiving insulin, did have higher-than-normal blood glucose levels. Researchers will continue to monitor patients to see how long they remain insulin independent.

Recipients, 66 percent of whom were women, were an average age of 42 years (range 24 to 64 years) and average weight of 143 lbs. (range 103 to 213 lbs.). Before the procedure, nearly half the recipients were using an insulin pump. Most had recently experienced at least one episode of hypoglycemia, or dangerously low blood glucose, requiring another person’s help. Their average level of hemoglobin A1c (HbA1c), which reflects blood glucose control over the previous 3 months, was 7.7 percent, compared to a normal HbA1c of 6 percent.

HbA1c levels generally improved with each infusion, as did levels of fasting blood glucose and C-peptide, which reflect insulin production. One infusion, though rarely providing enough islets to free a person from the need to inject insulin, alleviated episodes of severely low blood glucose. After the first infusion of islets, only two recipients had a low blood sugar problem requiring the help of another person. None of those who received a single infusion reported a problem with hypoglycemia a year after the procedure.

“Data collection on islet transplantation has been difficult, because most of the 750 islet transplants performed worldwide since 1974 have been done as part of small, single-center pilot trials,” said Dr. Bernhard Hering of the University of Minnesota, who chairs CITR’s scientific advisory committee. “This report is an important collaborative effort to combine data from 12 centers on the risks and successes of islet transplantation and to make the information widely available to patients and investigators.”

From 1990 to 1999, only 8 percent of islet transplants resulted in insulin independence for more than 1 year. In 2000, however, a group of researchers led by Dr. James Shapiro at the University of Alberta in Edmonton, Canada, reported much greater success in patients transplanted with islets from two to four donor pancreata and treated with an immunosuppressive regimen that left out glucocorticoids, now thought to be toxic to islets. In the next few years, other researchers replicated the “Edmonton protocol” pioneered by the Canadian team, and many centers are now using this approach to islet transplantation.

The centers reported 45 serious adverse events but no deaths in the recipients. The 27 percent of events that were classified as life-threatening included those linked to the transplant procedure itself (e.g., infection, bleeding into the chest or abdomen, low hemoglobin, high liver enzymes) and to medications that suppress the immune system (e.g., anemia, nerve damage, meningitis, and low numbers of white blood cells). Most recipients received the same drug regimen used in the Edmonton protocol: daclizumab at induction to prevent the immune system from rejecting the donor islets and sirolimus combined with tacrolimus to maintain immunosuppression.
The CITR’s mission is to expedite progress and promote safety in islet transplantation by collecting analyzing, and communicating data on islet transplantation. NIDDK established the registry in 2001 through a contract awarded to EMMES Corporation in Rockville, Maryland.

In the CITR's first report, 12 islet transplant centers detail the experiences of 86 patients who received at least one islet transplant from 1999 to 2003. Omitted from the report are outcomes for 74 other recipients at these centers and data on about 40 people who received islet transplants in other centers during this time. "We're continuing to receive additional data from the inaugural 12 centers and from new centers joining and contributing data, so future reports will be even more comprehensive," noted Dr. Eggerman.

"The CITR will prove invaluable, not only to investigators, but to all parties with an interest in moving the field forward," added Dr. Brian Flanagan, Scientific Program Manager at the Juvenile Diabetes Research Foundation International (JDRF). Recently, five islet transplant centers in Europe, with JDRF funding, began contributing data to the CITR.

“In addition to collecting data on islet transplant outcomes, the CITR is integrating data from other sources, such as the United Network for Organ Sharing (UNOS) and the Islet Cell Resource Centers. This effort will give us critical information on donor characteristics, organ procurement, islet processing, and other key variables that influence the success of islet transplantation,” said Dr. Camillo Ricordi of the Diabetes Research Institute at the University of Miami, who serves on the CITR’s scientific advisory committee.

The CITR is supported by a special funding program for type 1 diabetes research, which provides a total of $1.14 billion from fiscal year 1998 through fiscal year 2008 to supplement other funds for type 1 diabetes research made available through the regular NIH appropriations process.

Because only about 6,000 donor pancreata become available each year, and many are used for whole organ transplantation, the scarcity of islets poses a major obstacle to wider testing of islet transplantation as a treatment for type 1 diabetes. To improve the potential of cell replacement therapy for type 1 diabetes, NIH-funded research is focusing on understanding the beta cell and its regeneration and on efforts to develop alternative sources of beta cells. Researchers are also working on ways to coax the immune system into accepting donated cells or tissues without suppressing the whole immune system.

JDRF/Harvard launch new research partnership

2004-09-04T09:10:00.000-07:00

August 23, 2004
BOSTON-The Juvenile Diabetes Research Foundation (JDRF) and Harvard Medical School today announced the opening of the JDRF Center for Immunological Tolerance in Type 1 Diabetes at Harvard Medical School, Generously Supported by Marshalls Ten Year Partnership with JDRF.

The Center was developed because advances in the immune tolerance area are critical for finding better treatments, and eventually a cure, for type 1 diabetes. The primary goals of the JDRF Center for Immunological Tolerance at Harvard Medical School are:

* understanding how immunological tolerance breaks down to provoke type 1 diabetes
* learning how to re-establish tolerance in order to prevent or cure type 1 diabetes, in particular via islet transplantation
* providing a framework for integrating basic research and clinical endeavors focused on islet transplantation
* serving as a magnet for research on immunological tolerance in type 1 diabetes at Harvard Medical School and its affiliated hospitals, and in the Boston area more generally
* becoming a reservoir for new technologies and resources to service the worldwide community of type 1 diabetes researchers.

The new Center will be supported by JDRF with a three-year grant of approximately $5 million.

"We are excited about tackling the critical and very complicated area of immune tolerance," says Raphael Dolin, M.D., Dean for Academic and Clinical Programs at Harvard Medical School. "The Center's scientists are dedicated to learning more about immune tolerance and are acutely aware of its potential impact on islet transplantation, which is a very promising strategy for treating and potentially curing diabetes. We are honored to be working with JDRF to help find a cure for type 1 diabetes."

Type 1 diabetes is caused by a breakdown in immunological tolerance. Specifically, type 1 diabetes results when the body attacks its own insulin-producing beta cells. As such, understanding immunological tolerance is a critical objective for type 1 diabetes researchers.

Co-directors Dr. Diane Mathis and Dr. Christophe O. Benoist are heading the JDRF Center for Immunological Tolerance in Type 1 Diabetes at Harvard Medical School and they will oversee a group of ten laboratories from Harvard and its affiliated institutions.

With the development of this Center they are bringing together complementary expertise in immunology, molecular biology and experimental transplantation. Essentially, the Center is a confederation of eight research projects and three supporting cores, constituting a broad-based basic research program on immunological tolerance in type 1 diabetes.

According to Dr. Mathis, "Christophe and I are delighted to have pulled together such an 'All Star' team for this Center. With our team in place we are confident that, in due time, we will elicit an impressive amount of new information about how the immune system breaks down and provokes the onset of type 1 diabetes. Armed with this new knowledge, we will be that much closer to finding ways to prevent and ultimately cure the disease."

Peter Van Etten, President and CEO of JDRF, further emphasized the power of the new Center when he said, "We are confident that the brilliant scientists affiliated with the new JDRF Center for Immunological Tolerance in Type 1 Diabetes at Harvard Medical School will produce very promising results. We always strive to work with the best the science world has to offer, and I¹m confident that these people are at the very top of their field."

"The other half of this impressive story of discovery and strides for a cure belongs to our partners in fundraising," continued Van Etten. "Today I would especially like to recognize Marshalls as an exceptional corporate partner. This new center is generously supported by Marshalls ten year partnership with JDRF, a partnership which began in 1994 when they raised $22,000 for the Walk. Just three years later in 1997, Marshalls was raising $500,000 a year, and by 2000, their annual donations exceeded $1 million. Now, more than 650 stores participate in 42 states and Puerto Rico, selling JDRF paper sneakers and forming Walk teams. Last year, Marshalls raised a phenomenal $1,275,000, and over the past 10 years, their cumulative contributions have exceeded $7.4 million. So, it¹s safe to say that this Center has been blessed with two 'Dream Teams!'"

Harvard Medical School
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Hospital, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.

About JDRF
JDRF was founded in 1970 by the parents of children with juvenile diabetes -- a disease that strikes children suddenly, makes them insulin dependent for life, and carries the constant threat of devastating complications. Since inception, JDRF has provided more than $800 million to diabetes research worldwide. More than 80 percent of JDRF's expenditures directly support research and education about research. JDRF's mission is constant: to find a cure for diabetes and its complications through the support of research.

New technology detects early signs of diabetes

2004-09-04T09:00:00.000-07:00

From the Joslin Diabetes Center:

BOSTON – By the time overt symptoms of type 1 diabetes appear in an individual, destruction of the insulin-producing beta cells of the pancreas has already progressed significantly. However, findings by researchers at Joslin Diabetes Center and Massachusetts General Hospital, published in the Aug. 24 issue of Proceedings of the National Academy of Sciences, show that a powerful new imaging technology gives scientists a glimpse into the earliest stages of the inflammatory process leading to type 1 diabetes in laboratory animals. The new findings one day may be useful for predicting whether and when diabetes will develop in humans.

Type 1 diabetes is an autoimmune disease in which the body’s immune system mistakenly launches an attack on the insulin-producing beta cells of the pancreatic islets. This process may eventually destroy the beta cells, preventing them from producing sufficient insulin, so that high blood-glucose levels—and full-blown diabetes—develop. Early in this process, white blood cells called T-cells invade the islets (an inflammatory condition known as “insulitis”). A very early marker of this inflammation is increased permeability (leaking) of the tiny blood vessels surrounding and within the islets.

Until recently, the only way to track type 1 diabetes in its earliest stages was to measure blood levels of autoantibodies (the immune system’s “guided missiles”) directed against pancreatic islet proteins. Yet, these tests are only an indirect indication of the disease process, and don’t allow researchers to directly follow the progression of disease.

This gap may someday be filled by a new technology that exploits magnetic resonance imaging, commonly known as MRI, to monitor miniscule magnetic nanoparticles leaking from the blood vessels of the pancreas, according to researchers at the Joslin Diabetes Center and Massachusetts General Hospital.

How the technology works
The new imaging technology uses tiny probes called long-circulating magnetofluorescent nanoparticles (CMFN). These particles contain magnetic nanocrystals of iron oxide, which are very easily detected by MRI. After being injected intravenously, CMFN travels throughout the body, including through the tiny blood vessels of the pancreas. If these vessels have started to become permeable as a result of islet inflammation, more CMFN tends to leak out and collect in the surrounding tissue, as can be seen on the MRI. This technique allows researchers to observe this early inflammatory process over time. “Thus, we have the means to non-invasively monitor the initiation and progression of insulitis in mouse models of type 1 diabetes in vivo and in real time,” said Diane Mathis, Ph.D., of Joslin Diabetes Center.

The researchers say that this new imaging process may prove an invaluable aid in helping researchers and clinicians to spot early insulitis and to monitor how it changes, during the development of disease and after experimental or therapeutic interventions aimed at stopping its progression. Further, they point out that the technique already has been used safely and effectively by the MGH group in human clinical trials to detect the spread of prostate cancer to the lymph nodes. “Given the known safety of magnetic nanoparticles in humans, the technology might someday be used in individuals who are genetically at risk for diabetes to detect this autoimmune process in its earliest stages,” suggests Joslin's Dr. Christophe Benoist.

This research was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Regenerating insulin cells found in pancreas

2004-09-03T05:51:00.000-07:00

From the University of Toronto

Researchers ID cells in mouse pancreas capable of generating beta cells

University of Toronto researchers have identified individual cells in the adult mouse pancreas capable of generating insulin-producing beta cells.

Their research, published Aug. 22 in the online edition of Nature Biotechnology, offers hope for the millions of diabetics worldwide who take insulin injections to compensate for defective pancreatic islets. Healthy islets, made up largely of beta cells, release insulin to help regulate the body's blood sugar levels.

"People have been intensely searching for pancreatic stem cells for a while now, and so our discovery of precursor cells within the adult pancreas that are capable of making new pancreatic cells is very exciting," says Simon Smukler, a PhD candidate in U of T's Department of Medical Genetics and Microbiology, who was one of the lead researchers. He conducted the study along with U of T MD/PhD candidate Raewyn Seaberg and their supervisor, Professor Derek van der Kooy.

The scientists are now hoping to extend their research to prove that these precursor cells are truly stem cells. True stem cells must exhibit two properties: the ability to renew themselves over the entire life of the organism and some ability for the parent cell to generate varied cell types – for example islet cells and exocrine cells. Pancreatic stem cells could provide a plentiful supply of beta cells for transplant treatments.

A finding Smukler considers equally exciting is their discovery that these pancreatic cells generated both beta cells and neurons, cells associated with the workings of the brain and the nervous system.

"The existing dogma regarding how development occurs states that fairly early in development, there is a distinction made between a group of cells destined to make the brain and another group destined to make the pancreas," he says. "The idea that a single cell within the pancreas could make both beta cells and neurons is intriguing."

U of T has a proud history of both diabetes and stem-cell research. Frederick Banting and Charles Best discovered insulin here in the 1920s, while years later, Drs. Ernest McCulloch and James Till first described the stem-cell concept.

This study was supported by the Stem Cell Network and the Canadian Institutes for Health Research. Zeenat Ashgar and Michael Wheeler from the U of T's Department of Physiology, Grigori Enikolopov of New York's Cold Spring Harbor Laboratory and Stem Cell Network members Timothy Kieffer of the University of British Columbia and Gregory Korbutt of the University of Alberta also contributed to the research.

"This remarkable discovery is a case study in cross-Canada cooperation," says Dr. Ron Worton, Scientific Director of the Stem Cell Network. "The research offers considerable new hope for people living with diabetes."

Blocking Interaction of Proteins Prevents Diabetes in Mice

2004-08-13T06:00:00.000-07:00

From the JDRF and UC San Francisco:

JDRF-funded researchers have identified a protein on immune T cells that triggers type 1 diabetes in mice when it interacts with another protein found in cells of the pancreas. The scientists report that blocking the interaction prevents the disease without compromising normal immune defenses or causing measurable side effects.

The finding points to a possible strategy for preventing type 1 diabetes in humans, since the mouse T cell protein has a counterpart in the human immune system. The study, led by Jeffrey Bluestone, Ph.D., and Lewis Lanier, Ph.D., of the University of California, San Francisco (UCSF), was published in the June issue of the journal Immunity. The research was funded as part of the JDRF Center for Islet Transplantation at University of California, San Francisco/University of Minnesota

The T cell protein, called NKG2D, is a receptor on the surface of certain T cells called CD8 lymphocytes. Scientists became interested in NKG2D after observing the development of diabetes in nonobese diabetic (NOD) mice, the animal model for type 1 diabetes. In NOD mice, some CD8 T cells invade the pancreas when the animals are only three weeks old. These invading T cells, unlike most others, express the NKG2D receptor. Ten to 20 weeks later, the animals develop the disease.

The other protein of interest, called RAE-1, has been found on cells infected by bacteria or viruses. Normally, the RAE-1 protein binds to NKG2D, alerting CD8 T cells and other immune system molecules to attack and eliminate the pathogen. By this mechanism, the body ensures that foreign, or “non-self” material is flagged and destroyed.

The UCSF researchers were surprised to find that RAE-1 also is present in the pancreas of nonobese diabetic (NOD) mice. This presence of RAE-1 in the pancreatic cells, and the expression of NKG2D by the invading T cells, suggested than an interaction between the two proteins may play a role in type 1 diabetes.

When the scientists used antibodies to prevent RAE-1 from binding its receptor (NKG2D) on the CD8 lymphocytes, the mice were completely protected from the disease. (The effect is like plugging a keyhole so that even the correct key won’t turn the ignition). “You don’t need a calculator to tell the treatment group from the placebo group. It’s 100 percent effective,” Dr. Lanier, said in a press statement.

The researchers expect that a “humanized” antibody to human NKG2D, working in a similar manner, could provide an effective type 1 diabetes treatment in people. The finding is important, because unlike other treatments reported in NOD mice, this therapy was effective even when given relatively late in disease progression.

Insulin Pump Beats Shots for Young Diabetics

2004-08-08T00:33:00.000-07:00

From Reuters Health:

NEW YORK - Continuous insulin infusion delivered by a portable pump is more effective than multiple daily injections of insulin in controlling blood sugar levels in young people with type 1 diabetes, according to a new study.

Moreover, most patients chose to continue with or switch to insulin pumps after the study was over, Elizabeth A. Doyle and colleagues from the Yale University School of Medicine in New Haven report in the medical journal Diabetes Care.

The researchers randomly assigned 32 patients aged 8 to 21 to treatment with pump-delivered continuous subcutaneous insulin infusion (CSII) or to once-daily long-acting insulin (glargine) plus fast-acting insulin injections before meals and snacks, for 16 weeks.

Blood levels of hemoglobin A1c - an indicator of long-term blood glucose control - did not change in the multi-injection group, but dropped to target levels in the insulin pump patients.

The researchers point out that glargine cannot be mixed with rapid-acting insulin, so therapy with this insulin analog requires patients to give themselves injections with fast-acting insulin before meals and large snacks. The need for multiple daily injections can make compliance difficult, they add.

In fact, at the close of the study, 14 of the 16 patients on CSII chose to continue using the infusion pumps, while 12 of the 16 patients on multiple daily injections switched to CSII.

The team calls for further studies but concludes that "in the context of a short-term randomized clinical trial, we observed a considerably greater improvement in hemoglobin A1c levels with CSII than with glargine. It should be noted, however, that no single approach to treatment is ideal for every patient."

SOURCE: Diabetes Care, July 2004.

Eating Disturbances More Common in Diabetic Girls

2004-08-08T00:24:00.000-07:00

From Reuters:

NEW YORK - Preteen and early teenage girls with type 1 diabetes experience eating disturbances more often than girls without the condition, according to Canadian researchers.

As reported in the journal Diabetes Care, Dr. Patricia Colton and colleagues, from the University of Toronto, compared the rate of eating disturbances in 101 diabetic and 303 non-diabetic girls.

The subjects completed the Children's Eating Disorder Examination interview, and the investigators assessed socioeconomic status, body weight, and various diabetes-related factors.

The same proportion of diabetic and nondiabetic girls - 16 percent - reported at least one disturbed eating episode in the previous month. However, 8 percent of diabetic girls reported currently engaging in at least two disturbed eating behaviors compared with just 1 percent of non-diabetic girls.

Eleven percent of girls with diabetes reported dieting in the previous month, not that much different from the rate in the non-diabetic group - 15 percent. On the other hand, 10 percent of diabetic girls took part in excessive exercise for weight control compared with only 1 percent of girls without diabetes.

Binge eating was also more common among diabetic girls (3 percent) than among non-diabetic girls (0.3 percent).

Given these findings, the researchers conclude that eating disorder "screening and prevention programs for (diabetic girls) should begin in the preteen years."

SOURCE: Diabetes Care, July 2004.

Heart Enlargement Appears Early in Type 1 Diabetes Patients

2004-08-07T23:55:00.000-07:00

From Reuters Health

NEW YORK - Children and adolescents with insulin-dependent (type 1) diabetes, particularly girls, show early signs of changes in the heart, a research team in Belgium has found.

Dr. Bert E. Suys at University Hospital of Antwerp and colleagues used ultrasound to examine the hearts of 80 young people with diabetes and 52 age-matched control subjects.

As reported in the medical journal Diabetes Care, the wall of the left ventricle, the main pumping chamber of the heart, was thicker in girls with diabetes than in the non-diabetic group. The hearts of diabetic girls also showed delayed relaxation between heartbeats.

For boys, the only difference between those with and without diabetes was in the relaxation time.

Suys and his associates theorize that, in children, "perhaps already a small increase in blood glucose is sufficient to initiate changes in the cardiovascular system," thus underscoring the importance of long-term blood sugar control.

Patients with diabetes may benefit from drugs like ACE inhibitors and beta-blockers that are used to treat heart failure, the researchers add, but only further research will clarify this issue.

Scads of research

2004-08-07T21:54:00.000-07:00

The JDRF is all about research. It's right there in the organization's name.

The leadership has a profound belief that cures for Type I diabetes can and will be found through research. It is the driving principle behind everything the organization does.

In the coming weeks, you will discover in this space some of the latest results of that research from around the globe. This offering is not meant to be comprehensive, but rather an updated sampler of the tremendous stides being made with the money groups like Team Shelby raise.