HLA genotypes were ascertained in 53 French Caucasian families, comprising 68 juvenile onset insulin-dependent diabetic siblings. Among the 49 alleles detected at different loci in the HLA complex (A, C, B, Bf, DR) 4 appeared to occur at a significantly higher frequency among the 53 index cases than in a control series of 116 healthy individuals: HLA-B18 (p < 10(-3)), DRw3, DRw4 and BfF1 (p < 10(-6)). The excess of HLA identical affected siblings confirms genotype disequilibrium and supports the hypothesis of an HLA-linked gene(s) conferring susceptibility. There was no increase of homozygosity for HLA DRw3 and DRw4 whereas there was a marked excess heterozygosity for HLA DRw3/DRw4 in diabetic patients (32% versus 0% in the control series, p < 0.001). These data provide evidence for the existence of two cooperating genes, linked to each of the HLA DR alleles.

Dynamic aspects of whole body alanine and glycine metabolism have been explored in insulin-dependent (type I) diabetic subjects. Using a primed, continuous intravenous (i.v.) infusion of [2H3]alanine and [15N]glycine given simultaneously with [1-13C]leucine, whole body alanine and glycine fluxes and their rates of de novo synthesis were measured in 6 diabetic young men. Subjects were studied in the postabsorptive state, after blood glucose was clamped overnight at 15.2 +/- 0.3 mM, and then, on the following night, at 5.9 +/- 0.2 mM (insulin infusion rates of 0.24 +/- 0.09 and 1.65 +/- 0.20 U/h, respectively). In the normoglycemic state, leucine, alanine, and glycine fluxes averaged 88 +/- 4, 378 +/- 39, and 155 +/- 8 mumol X kg-1 X h-1, respectively. Based on the leucine flux, alanine and glycine de novo synthesis rates were 264 +/- 36 and 67 +/- 8 mumol X kg-1 X h-1. In the hyperglycemic state, leucine flux increased 23% (P less than 0.01), alanine flux rose slightly (+5%) but significantly (P less than 0.05), while alanine de novo synthesis and glycine flux remained unchanged and glycine de novo synthesis decreased by 33% (P less than 0.001). These results show that small alterations in peripheral alanine inflow in the hyperglycemic state reflect increased proteolysis and suggest that increased circulating plasma glucose does not contribute to de novo alanine synthesis in the absence of adequate insulin effect and/or augmented glucose tissue uptake. These observations also reveal the importance of insulin in the maintenance of whole body leucine economy, since a lower rate of insulin administration was associated with an increased rate of leucine oxidation.

Summary. The susceptibility determinants of Type 1 (insulindependent) diabetes mellitus are known to be associated with both HLA-DR3 and DR4. In our study we wished to determine if the parental origin of these antigens could influence susceptibility to the disease. We analysed the inheritance of DR3 and DR4 haplotypes from the father or mother (DR3p, DR4p, DR3m and DR4m, respectively), in the index cases and in the affected and non-affected siblings of 246 diabetic simplex and 41 multiplex families without affected parents. An independent series of 80 multiplex families (GAW 5) was also studied. Among the DR3,4 positive index cases and affected siblings, the paternal and maternal DR3 and DR4 antigens were not distributed randomly: 62% and 72%, respectively, had received DR4 from their father and DR3 from their mother (DR4p/DR3m), while only 38% and 28%, respectively, had received a paternal DR3 together with a maternal DR4 (DR3p/DR4m). This differed significantly from the 50% expected ratio (p < 0.01) and was not observed in unaffected siblings. No excess of maternal DR3 in the absence of DR4 and no excess of paternal DR4 in the absence of DR3 were observed. The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.Key words: Type 1 (insulin-dependent) diabetes mellitus, HLA DR3, 4, shared haplotypes, segregation, multiple affected siblings, risk for siblings, maternal effect.Susceptibility to Type 1 (insulin-dependent) diabetes mellitus is associated with the HLA antigens, DR3 and DR4 [1][2][3][4] in Caucasian populations. The risk for disease is greater in both unrelated subjects and in siblings of diabetic children [1-8] with a heterozygous DR3, DR4 phenotype. These observations have led to the hypothesis that two susceptibility genes associated with the DR3 and DR4 haplotype are involved in the inheritance of the disease [2, 9-13]. Though, the exact nature of the molecule(s) responsible, and their role in the pathogenesis of the disease has not been elucidated, strong evidence suggests an autoimmune mechanism, probably triggered by environmental factors [14].It has long been supposed that DR3 and DR4 associated susceptibility genes play different roles in the pathology of Type 1 diabetes, determining the clinical and genetic heterogeneity of the disease [15]. Recent data do indeed suggest that they probably do not have equivalent effects on susceptibility [16][17][18].In this study we present evidence for the different effects of the paternal or maternal origin of DR3 and DR4 antigens on the risk for siblings of diabetic children. Subjects and methodsAmong 325 unrelated, Causasian French families of Type I diabetic patients who had been consecutively ascertained for HLA typing since 1978 (Herold series), 287 families were selected according to the following criteria: (1) unaffected pa...

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In 158 obese children, aged from three months to 15 years, blood glucose, immunoreactive insulin, and free fatty acid levels were measured during a standard oral glucose tolerance test carried out prior to treatment. The results were analyzed for the total sample as well as for three age groups: 0-5 years, 6-10 years, and 11-15 years and compared with those of 70 normal-weight children matched for age and sex. Glucose tolerance is normal in the obese children. It is different from the controls only two hours after glucose loading, when a slight but significant elevation is found. The glucose levels at one and two hours are significantly higher in the obese children of group III than in the younger ones. Fasting F.F.A. levels are similar in normal and obese children, but the F.F.A. decrease following glucose absorption is significantly diminished in the obese. The F.F.A. levels of the youngest obese are significantly higher than those of the older ones. A constant and important hyperinsulinism, fasting and postabsorptive, is demonstrated in obese children of all ages, even before five years and at the beginning of obesity. Age- and sex-related differences in insulin secretion are much more marked in the obese than in normal children. The degree of hyperinsulinemia is related to the degree of obesity, but not to its duration. The results suggest that hyperinsulinism is associated with obesity from its onset rather than being a long-term consequence of overweight. However, the origin of hyperinsulinism in obesity and the mechanism of insulin resistance still remain obscure.