Effect of docosahexaenoic acid supplementation on inflammatory cytokine levels in infants at high genetic risk for type 1 diabetes.

OBJECTIVE: Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic ß-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D. RESEARCH DESIGN AND METHODS: This was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell (RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide (LPS), 1 µg/mL. RESULTS: The levels of RBC DHA were increased by 61-100% in treated compared to control infants at ages 6-36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1ß, TNFα, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein (hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing ≥two persistently positive biochemical islet autoantibodies. CONCLUSIONS: This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced.

Participant and parent experiences in the oral insulin study of the Diabetes Prevention Trial for Type 1 Diabetes.

OBJECTIVE: To assess the experiences of participants and parents of children in the oral insulin study of the Diabetes Prevention Trial - Type 1. METHOD: Before trial results were publicized, surveys were completed by 124 participants and 219 parents of children in the oral trial. RESULTS: Although most of those surveyed were positive about the trial, survey results suggest that participant perspective (adult, child, parent, and gender), study procedures, and beliefs about placebo vs. active drug assignment have important implications for planning future clinical trials. Parents and children reported greater distress, worry, and difficulty making the decision to join the trial compared with adult participants. Mothers and female participants were particularly interested in additional psychosocial support during the study. Random assignment was viewed negatively by both parents and children, and close observation for diabetes onset was viewed as the most favorable aspect of the study. Adherence to study procedures declined over time and behaviors outside the study protocol to prevent/delay diabetes onset were common, particularly among those who believed the participant was taking a placebo. Children and respondents who believed that the participant was taking the active drug expressed confidence in oral insulin's ability to delay or prevent type 1 diabetes. CONCLUSIONS: Although most participants were positive about the trial and many expressed optimism about the intervention's potential for success, future trials need to address negative reactions to random assignment, the unique concerns of children and their parents, declining adherence, and behaviors - external to the trial - designed to delay or prevent diabetes.

The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results.

OBJECTIVES: TrialNet's goal to test preventions for type 1 diabetes has created an opportunity to gain new insights into the natural history of pre-type 1 diabetes. The TrialNet Natural History Study (NHS) will assess the predictive value of existing and novel risk markers for type 1 diabetes and will find subjects for prevention trials. RESEARCH DESIGN AND METHODS: The NHS is a three-phase, prospective cohort study. In phase 1 (screening), pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512, and islet cell antibodies) are measured. Phase 2 (baseline risk assessment) includes oral glucose tolerance tests (OGTTs) in antibody-positive subjects and estimation of 5-yr diabetes risks according to the OGTT and number of confirmed positive antibody tests. Phase 3 (follow-up risk assessments) requires OGTTs every 6 months. In phases 2 and 3, samples are collected for future tests of T-lymphocyte function, autoantibody isotypes, RNA gene expression, and proteomics. The primary outcome is diabetes onset. RESULTS: Of 12 636 relatives screened between March 2004 and December 2006, 605 (4.8%) were positive for at least one biochemical antibody. Of these, 322 were confirmed antibody positive and completed phase 2, of whom 296 subjects were given preliminary 5-yr diabetes risks of <25% (n = 132), > or =25% (n = 36), and > or =50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, > or =25%; 3 or more, > or =50%) and/or an abnormal OGTT (> or =50%). CONCLUSIONS: The NHS is identifying potential prevention trial subjects and is assembling a large cohort that will provide new natural history information about pre-type 1 diabetes. Follow-up to diabetes will help establish the biological significance and clinical value of novel type 1 diabetes risk markers.

Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1.

OBJECTIVE: This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes. RESEARCH DESIGN AND METHODS: We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26-50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes. RESULTS: Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) > or =80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015). CONCLUSIONS: It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.

Incident dysglycemia and progression to type 1 diabetes among participants in the Diabetes Prevention Trial-Type 1.

OBJECTIVE: We studied the incidence of dysglycemia and its prediction of the development of type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, we assessed whether dysglycemia was sustained. RESEARCH DESIGN AND METHODS: Participants (n = 515) in the Diabetes Prevention Trial-Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for type 1 diabetes prediction. RESULTS: Of 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month visit was highly predictive of the development of type 1 diabetes, both in those aged <13 years (P < 0.001) and those aged > or =13 years (P < 0.01). Those aged <13 years with dysglycemia at the 6-month visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis. CONCLUSIONS: ICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is strongly predictive of type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of type 1 diabetes.

Type 1 Diabetes TrialNet--an international collaborative clinical trials network.

Type 1 Diabetes TrialNet is an international consortium of clinical research centers aimed at the prevention or delay of type 1 diabetes (T1D). The fundamental goal of TrialNet is to counter the T1D disease process by immune modulation and/or enhancement of beta cell proliferation and regeneration. To achieve this goal, TrialNet researchers are working to better understand the natural history of the disease, to identify persons at risk, and to clinically evaluate novel therapies that balance potential risks and benefits. The particular focus is on studies of preventive measures. In addition, TrialNet evaluates therapies in individuals with newly diagnosed T1D with preserved beta cell function to help determine the risk/benefit profile and gain an initial assessment of potential efficacy in preservation of beta cell function, so that promising agents can be studied in prevention trials. In addition, TrialNet evaluates methodologies that enhance the conduct of its clinical trials, which includes tests of outcome assessment methodology, the evaluation of surrogate markers, and mechanistic studies laying the foundation for future clinical trials.

Glucose and C-peptide changes in the perionset period of type 1 diabetes in the Diabetes Prevention Trial-Type 1.

OBJECTIVE: We examined metabolic changes in the period immediately after the diagnosis of type 1 diabetes and in the period leading up to its diagnosis in Diabetes Prevention Trial-Type 1 (DPT-1) participants. RESEARCH DESIGN AND METHODS: The study included oral insulin trial participants and parenteral insulin trial control subjects (n = 63) in whom diabetes was diagnosed by a 2-h diabetic oral glucose tolerance test (OGTT) that was confirmed by another diabetic OGTT within 3 months. Differences in glucose and C-peptide levels between the OGTTs were assessed. RESULTS: Glucose levels increased at 90 (P = 0.006) and 120 min (P < 0.001) from the initial diabetic OGTT to the confirmatory diabetic OGTT (mean +/- SD interval 5.5 +/- 2.8 weeks). Peak C-peptide levels fell substantially between the OGTTs (median change -14.3%, P < 0.001). Among the 55 individuals whose last nondiabetic OGTT was approximately 6 months before the initial diabetic OGTT, peak C-peptide levels decreased between these two OGTTs (median change -14.0%, P = 0.052). Among those same individuals the median change in peak C-peptide levels from the last normal OGTT to the confirmatory OGTT (interval 7.5 +/- 1.3 months) was -23.8% (P < 0.001). Median rates of change in peak C-peptide levels were 0.00 ng x ml(-1) x month(-1) (P = 0.468, n = 36) from approximately 12 to 6 months before diagnosis, -0.10 ng x ml(-1) x month(-1) (P = 0.059, n = 55) from 6 months before diagnosis to diagnosis, and -0.43 ng x ml(-1) x month(-1) (P = 0.002, n = 63) from the initial diabetic OGTT to the confirmatory diabetic OGTT. CONCLUSIONS: It seems that postchallenge C-peptide levels begin to decrease appreciably in the 6 months before diagnosis and decrease even more rapidly within 3 months after diagnosis.

Participant and parent experiences in the parenteral insulin arm of the diabetes prevention trial for type 1 diabetes.

OBJECTIVE: To assess participant and parent experiences in the parenteral insulin arm of the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1). RESEARCH DESIGN AND METHODS: Before trial results were publicized, surveys were completed by 82 intervention participants (the intervention group) (who received annual 4-day insulin infusions and daily insulin injections), 81 closely monitored control subjects (the closely monitored group), and 135 parents of children in the trial. RESULTS: Survey results suggest that participant perspective (adult, child, parent, and sex), study procedures, and group assignment have important implications when planning clinical trials. Parents rated the trial more favorably but worried about hypoglycemia and diabetes onset. Children had the least favorable reaction to the study. Parents preferred assignment to the intervention group; child/adult participants preferred assignment to the closely monitored group. The intervention group rated the annual 4-day insulin infusions more negatively than all other study procedures. Intervention group participants/parents reported poorer insulin injection adherence over the course of the study. Intervention group participants, parents, and female subjects expressed an interest in additional psychosocial support during the trial. Random assignment was viewed negatively by both study groups. Close observation for diabetes onset was viewed as the most favorable aspect of the study. Behaviors outside of the study protocol to prevent or delay diabetes onset were common and should be monitored in future prevention studies. CONCLUSIONS: Overall, most participants were positive about the trial, and many expressed optimism about the intervention's potential for success. These results have implications for study design, recruitment, and retention procedures in future prevention trials.