Family and population studies indicate that predisposition to insulin-dependent (
To improve criteria for entry into future trials of immunosuppression, we enrolled 40 children with recent-onset Type I insulin-dependent diabetes in a pilot trial of cyclosporine. Twenty-seven patients were able to discontinue insulin therapy 48 +/- 5 days after the start of immunosuppression. At four months, their fasting and postprandial blood glucose concentrations averaged 110 and 160 mg per deciliter (6.1 and 8.9 mmol per liter) with a mean hemoglobin A1c level of 6.15 percent. Seventy-five percent of these patients with early remission still did not need insulin at 12 months, and their glycemic control was similar to that at 4 months. The major differences between the 27 patients with remission and the 13 without remission were the duration of symptoms before diagnosis (26.8 vs. 48.0 days, P less than 0.01), the degree of weight loss (3.2 vs. 10 percent of body weight, P less than 0.001), the initial hemoglobin A1c level (10.7 vs. 13.2 percent, P less than 0.001), and the frequency of ketoacidosis (11 vs. 61.5 percent, P less than 0.001). The lesser degree of weight loss was the strongest independent predictor of remission. The response of C-peptide to intravenous glucagon (0.50 vs. 0.17 pmol per milliliter, P less than 0.05) was also an independent predictor. No differences were observed between the two groups of patients in age, sex, HLA phenotype, autoantibodies to insulin or islet-cell antigens, or doses or trough levels of cyclosporine. Only minimal manifestations of toxicity were detected over the period of observation. We conclude that early treatment with cyclosporine in children with recent-onset Type I diabetes can induce remission from insulin dependence, with half the patients not requiring insulin after a full year.
A sample of 100 individuals from 50 French families of known pedigrees were typed for 14 loci of the HLA region (DPB1, DQB1, DQA1, DRB1, DRB3, 4, 5, C4B, C4A, Bf, C2, TNFa, TNFb, B, Cw, A). Linkage disequilibrium in each pair of loci was investigated by an exact test using a Markov chain algorithm. The results indicate no disequilibrium between DPB1 and the other loci, whereas the other class II genes are all significantly linked to each other. Linkage disequilibrium is also detected between some pairs of class I and class II-class I loci despite the long physical distance separating the loci (eg A-B, Cw-DRB1). On the other hand, some contiguous loci of the class III region are found to be in equilibrium with each other. Several hypotheses including selection, but also unequal allelic diversity at different MHC loci are discussed to explain this complex pattern of linkage disequilibrium.
DNA restriction fragments of the genes encoding HLA class II-,( antigens were compared in 34 patients with insulin-dependent diabetes mellitus and 34 HLA-DRmatched healthy individuals. Ninety-three fragments, determined by six restriction enzymes (EcoRI, EcoRV, HindIll, BamHI, Pvu II, and Taq I), were analyzed: (i) A DR Taq I 12.7-kilobase-pair fragment might be a marker for the extended haplotype HLA-B8,DR3. (ii) In controls, DR4 haplotypes are associated with two distinct clusters of DQ restriction fragments (DQR4 and DQR5). Almost all (94%) DR4 patients belong to the DQR4 and not to the DQR5 cluster. This suggests that, among HLA-DR4 haplotypes, only DQR4 haplotypes are involved in susceptibility to insulin-dependent diabetes mellitus. (iiW) A DR Taq I 14.5-kilobase-pair fragment was found to be strongly associated with DQR4, mainly in DR3/DR4 heterozygous patients (P = 5 x 10-4). However, these results must be interpreted with caution, taking into account the high number of statistical tests performed.Insulin-dependent diabetes mellitus (IDDM) is a familial disorder of glucose metabolism in which a strong association with HLA antigens suggests that genetic components play a role in its etiology. About 90% of Caucasian patients suffering from juvenile-onset IDDM carry the DR3 antigen, the DR4 antigen, or both (1). Heterozygous DR3/4 individuals are particularly susceptible. Various modes of inheritance have been proposed to account for these observations, but no consensus has emerged.The class II products of the major histocompatibility complex, involved in the immune response, can be divided into at least three subgroups according to their primary structure and the mapping of their genes: HLA-DR, -DQ, and -DP. The genes of these membrane glycoproteins encode heterodimers of an a chain (34,000 daltons) and a 83 chain (29,000 daltons). Polymorphisms have been reported for most of these genes, and particularly for the /3 genes. These polymorphisms, initially detected through serological or cellular methods, have recently been analyzed with restriction endonucleases and probes specific for a and P3 genes (2-5). Of all the immunologically defined polymorphisms, the strongest associations with IDDM have been found with HLA-DR. DR products could be involved in the etiology of IDDM; however, since this association is partial, it may affect the participation of other genetic determinants in the class II region.The present study attempts to define at the genomic level, using HLA class II probes, polymorphisms that could differentiate between patients and controls matched for HLA-DR phenotypes. Recent studies following this approach appear promising (6,7). This study was performed on a sample consisting of IDDM patients and HLA-DR phenotypically identical control subjects. The DNAs of these individuals were digested by six restriction enzymes. MATERIALS AND METHODSPatients. Thirty Caucasian IDDM patients were selected at random, and four DR2 IDDM patients with onset before age 25 were selected. Controls were ...
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