America Becoming Diabetes Nation

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

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:

1. 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.
2. 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

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

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

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

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.

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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.
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Bill would let schools give emergency diabetes injection

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

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

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

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

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?

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

>>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

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

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

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

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

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).


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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.