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
Monday, June 27, 2005
Monday, June 13, 2005
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.”
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.”
Friday, June 10, 2005
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).
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.
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.
Monday, June 06, 2005
Univ. of Texas researchers get $2.1 million for development of an alternative to daily injections
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
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
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