Delay of Type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial

Abstract

Type 1 diabetes is an autoimmune disorder in which the destruction of insulin-producing beta-cells can be detected years before the clinical manifestation of the disease [1]. Selective autoantibody assays and metabolic testing can now identify first degree relatives of Type I diabetic patients, in whom the risk of diabetes is over 80 % at 5 years [2,3]. The ability to identify subjects at risk makes the exploration of immune intervention strategies to halt or even prevent betacell destruction a major goal. Growing evidence in animal models of Type I diabetes mellitus suggests Diabetologia (1998) Summary The Schwabing Insulin Prophylaxis Trial is a randomised, controlled pilot study designed to examine whether insulin therapy can delay or prevent the clinical onset of Type I diabetes in high risk first degree relatives of people with the disease. First degree relatives of patients with Type I diabetes, who were aged 4 years or more, had an islet cell antibody (ICA) value more than 20 Junevile Diabetes Foundation Units (JDF-U), a reduced first phase insulin response (FPI) to an i. v. glucose tolerance test less than the 5th centile, and a normal oral glucose tolerance test were eligible for the trial. Between January 1989 and October 1995, 1736 relatives of patients with Type I diabetes were screened for ICA. We identified 64 cases (3.7 %) with ICA values more than 20 JDF-U. Of ICA positive relatives, 17 (27 %) had a low FPI and were eligible for enrolment. Of these 14 agreed to participate, of whom 7 were randomised to the treatment group and 7 to the control group. In the treatment group, human insulin was administered i. v. by continuous infusion for 7 days, followed by daily s. c. injections for 6 months. Intravenous insulin infusions were repeated every 12 months. In the treatment group 3 of the 7 individuals (follow-up from time of eligibility: 2.3 to 7.1 years) and in the control group 6 of the 7 untreated individuals (1.7 to 7.1 years) developed clinical diabetes. Life table analysis showed that clinical onset of Type I diabetes was delayed in insulin-treated subjects compared with control subjects (means ± SEM diabetes-free survival: 5.0 ± 0.9 years vs 2.3 ± 0.7 years, p < 0.03). Insulin levels after i. v. glucose increased in the first year of intervention therapy. Titres of ICA, and antibodies to glutamic acid decarboxylase, and tyrosine phosphatase-like protein IA2 remained unchanged. These data suggest that insulin prophylaxis can delay the onset of overt diabetes in high risk relatives. This is encouraging in view of 1) the continuing American Diabetes Prevention Trial, which is currently testing the effect of parenteral insulin in a large nation-wide study and 2) the initiation of pilot trials to determine whether new antigen-specific intervention is more effective in delaying the clinical onset of Type I diabetes. [Diabetologia (1998)

Extrapancreatic insulin-producing cells in multiple organs in diabetes

“…7). Pilot studies suggest that low-dose insulin therapy may also delay the onset of diabetes in individuals with insulin and other autoantibodies (31)(32)(33), although a recent clinical trial failed to delay the onset of diabetes in patients with a high risk for type 1 diabetes (34). The most likely mechanism for the prevention of diabetes in mice and people by low-dose insulin therapy is the induction of tolerance to insulin.…”

Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.

“…All of the 7 nontreated islet antibody-positive control fir s tdegree relatives developed type 1 diabetes, 0.4, 0.4, 0.7, 2.6, 3.7, 4.2, and 6.5 years after randomization. Of these subjects, 4 had IAAs at entry into the study, 2 developed weak IAAs at diabetes onset, and 1 remained IAA - (9). IAA subclasses were heterogeneous in these subjects.…”

“…In humans, attempts to modulate -cell autoimmunity by administering the -c e l l -s p e c i fic antigen insulin to subjects either during the prediabetic stage (8,9) or at the manifestation of the disease (10,11) have also been suggested to be effective, as the onset of diabetes could be delayed or clinical remission could be improved. The issue of whether protection in humans is also through induction of protective Th2 immunity has not been examined.…”

“…In this study, we measured IgG subclass responses to insulin to test the hypothesis that immunization with antigens will induce Th2 immunity to specific antigens and induce spreading to Th2 immunity to other islet autoantigens. We investigated the course of the humoral immune response to insulin by determining total and specific IgG antibody subclass titers in the following groups: 1) patients treated with intravenous and subcutaneous insulin or with subcutaneous insulin alone from diabetes onset; 2) a group of newly diagnosed patients who were treated with cyclosporin A (CsA) or placebo and subcutaneous insulin for 12 months in the European-Canadian Cyclosporin Trial (16,17); and 3) prediabetic first-degree rel-atives treated with intravenous and subcutaneous insulin in the Schwabing Insulin Prophylaxis (SIP) pilot intervention trial (9). Changes in the subclass of antibodies to GAD and I A-2 after insulin therapy were also investigated.…”

“…First-degree relatives treated with insulin prophylaxis. A total of 14 islet cell antibody (ICA)-positive first-degree relatives were randomized to either the insulin prophylaxis (n = 7) or control arm (n = 7) in the SIP trial (9). All had ICA values >20 Juvenile Diabetes Foundation units, a first-phase insulin response to an intravenous glucose tolerance test (IVGTT) less than the 5th percentile of control subjects (<65 µU/ml), and a normal oral glucose tolerance test before entry into the study.…”