Immunologic issues in type 1 diabetes.

Jay Skyler, Miami, FL, presented the results of the parenteral substudy arm of the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1), in which relatives of patients with type 1 diabetes, whose risk of type 1 diabetes is 10to 20-fold greater than that of the general population, were screened for islet cell antibodies (ICAs) and enrolled in a study of insulin administration if they showed high risk of developing diabetes. Animal studies in female nonobese diabetic (NOD) mice have shown this to be an effective treatment, and in the early 1990s, Keller et al. (1) reported a pilot study of 12 individuals with a predicted risk of diabetes; 5 subjects were treated with insulin and 7 subjects declined treatment. By 2.5 years, all of those who declined treatment had developed diabetes; at 5 years, only half of the intervention group had the disease. The DPT-1 was initiated in 1993. Screening began in February 1994 and randomization began in January 1995; 339 subjects were enrolled, with follow-up ending 13 April 2001. Screening of 89,827 relatives, with 84,228 samples analyzed, showed that 3,152 (3.7%) were ICA positive. A total of 2,103 subjects were staged, 535 having low first-phase insulin response. Of 372 subjects who were eligible for randomization, 339 were randomized. Skyler pointed out that 354 of the 3,152 ICA-positive individuals had actually already developed diabetes, with 156 identified before further testing. The projected annual event rate was 21%, and the actual finding was of 15.1% developing diabetes (in addition to those developing diabetes before randomization). Of the patients who developed diabetes, 60% were sibs, 25% were parents, 4% were offspring, and 8% were other relatives. All were ICA and insulin autoantibody (IAA) positive. At baseline, 48.1% were female, 45.4% were below age 10 years, 38.9% were 11–20 years of age, and 15.6% were over 21 years of age; 93.5% were Caucasian, reflecting the ethnic distribution of type 1 diabetes in the U.S., although ICA positivity was seen in 3% of relatives, regardless of ethnic background. A total of 169 were in the intervention group, and 170 were observed. Individuals were followed for an average of 3.7 years. Of the subjects followed, 60% developed diabetes by 5 years. Those with impaired glucose tolerance (IGT) and those with normal glucose tolerance had a 22 and 10% rate of diabetes development per year, respectively. Those 6 years of age progressed at a rate similar to those aged 6–12 years. Those 15 years of age progressed at a much slower rate, which implies that studies confined to older individuals will need even larger numbers. Those with ICA alone progressed at a slower rate than those with the presence of more than one antibody. Coming as a great disappointment to the audience, Skyler reported, “There was no impact of [parenteral] insulin therapy on delaying or preventing the onset of diabetes.” Also, and again disappointingly, C-peptide showed no difference with or without treatment. The insulin intervention did cause some hypoglycemia. There were 93.6 presumed events (not documented but responding to carbohydrate ingestion) per 100 patient years in the treated patients, as opposed to 57 events in the control subjects. Documented hypoglycemia occurred in 59 vs. 11 patients/100 patient-years, and severe hypoglycemia did not occur. There was no difference between the groups in any measure of cognitive function, and those with definite hypoglycemia also had no change in cognitive function. Skyler suggested that, perhaps, this group was studied “too late.” An ongoing oral antigen trial in subjects with a 5-year risk of 26– 50% (less than that in the parenteral arm) is in progress and may be successful, despite the current study being negative. Stoever et al. (1092-P) reported that the dose of subcutaneous insulin administered in the DPT-1 did not suppress endogenous insulin secretion, suggesting that failure of the study to prevent diabetes may be related to lack of -cell rest (abstract numbers refer to the Abstracts of the 61st Annual Meeting of the American Diabetes Association, Diabetes 50 [Suppl. 2]:1–A649). Insulin treatment in the study may, however, have suppressed the T-cell response to human islet proteins. Brooks-Worrell et al. (313-PP) studied a group of 16 patients in the DPT-1, showing that there was some immune effect of the intervention. T-cell responses to human islet proteins, measured using cellular immunoblotting, showed that five of six untreated patients showed response to a mean of eight islet antigens, while three of the insulin-treated patients showed no response and, on average, there was response to only one antigen, similar to that seen in individuals from a normal population. At follow-up, the untreated patients showed increasing response, while none of the 10 treated patients did so. Thus, insulin treatment may produce an immunosuppressive effect on T-cell proliferative responsiveness to islet proteins in subjects at high risk for developing clinical type 1 diabetes, although no clinical benefit was demonstrated. Several studies at the ADA meeting did show hints of promising treatment strategies. Vitamin E given with nicotinic acid in a setting of tight glycemic control ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●