Biomedical subjects
Publications and source records attributed to I Deschamps.
A model with a susceptibility gene unlinked to HLA but in interaction with this system is shown to fit the data on familial distribution in 30 multiplex families of juvenile insulin-dependent diabetes.
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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.
The lod score method has been applied to 28 informative families with at least one child suffering from juvenile insulin-dependent diabetes (JIDD), assuming autosomal recessive inheritance, for detection of linkage between HLA and a susceptibility locus for this disease. These 28 families were pooled with 21 other families from the literature. The maximum lod scores were obtained for recombination fractions from 4 to 16%, according to the level of penetrance (10 to 90%). These high estimates of the recombination fraction are not in agreement with the hypothesis that the association between JIDD and specific HLA haplotypes is due to a simple linkage disequilibrium between the HLA region and a susceptibility locus for JIDD.
To improve understanding of the relationships between gastric inhibitory polypeptide (GIP) and insulin secretion and food intake in obesity, immunoreactive insulin and immunoreactive GIP were measured in 5 obese children during PO glucose tolerance test carried out before and after diet. Before diet, mean insulin levels were normal at fasting and rose after glucose ingestion. The mean fasting immunoreactive GIP level was very high (1235 +- 209 pg/ml) compared to that of 8 healthy adult controls (411 +/- 44 pg/ml) and remained at this level throughout the test. There was only a short postabsorptive rise to 1515 +/- 158 pg/ml at 30 min, which was not significantly different either from the patients' basal values or from the 30-min control values (1356 +/- 67 pg/ml). After dieting for 3 to 7 months, immunoreactive insulin responses returned to normal ranges. Concomitantly, both basal and total GIP release diminished significantly (basal GIP, 343 +/- 92 pg/ml; area under the GIP curve, 3820 and 1694 pg/ml/hr before and after diet, respectively). The postabsorptive GIP increment, however, rose significantly from 180 pg/ml/hr, before diet, to 665 pg/ml/hr afterwards. These results might be compatible with the hypothesis that in obesity, hyperinsulinemia, and overactivity of the GIP cells are associated phenomena caused by overeating and reversed by reduced food intake. However, several contradictory findings remain unexplained. The discrepancy between insignificant postabsorptive GIP increments and elevated insulin responses before diet casts doubts on the causal relationship between GIP and insulin secretion. The small GIP rise might be due to a limited secretory capacity of the GIP cells or to a diminished stimulatory capacity of glucose. The constantly high level of GIP might reflect chronic hypersecretion and/or some defect in basal regulation and feedback control of GIP release. The change caused by dietary measures in the GIP secretion pattern provides evidence that in obese children, basal GIP secretion in influenced by nutritional factors.
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Insulin secretion is partially regulated by hormonal and nervous signals arising from the duodenum. To ascertain the role of absorption through the villi on insulin secretion, the blood levels of immunoreactive insulin (IRI) in 13 normal children (T) were compared with those in 13 with flat jejunal mucosae (MJP). The bowel was stimulated by the infusion of Nutramigen direct into the duodenum at 4 ml/mn m2. In the control group (T) IRI increased from the 10th minute of the perfusion to reach a plateau after the first hour (256 +/- 107 pmol/l). In the MJP group the rise of IRI was delayed and the plateau lower (169 +/- 25 pmol/1) but the difference in the two groups was not statistically significant. During the first 10 minutes when there is no significant change in blood glucose levels IRI levels increased in the T group (p less than 0.01) but there was no significant change in the MJP group. These results suggest that when villi are intact stimulation of the duodenum causes insulin secretion; but when there are no villi, there is a delay in the secretion.
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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.
In 70 healthy children aged from three months to 15 years, blood glucose, immunoreactive insulin, and free fatty acids were measured during a three-hour glucose tolerance test. The results are presented for the whole group as well as for three age groups: three months-five years, six-10 years, and 11-15 years. It is demonstrated that (1) glucose levels are significantly lower in young children (younger than five years); (2) there are no significant age-related changes in free fatty acid concentration; (3) insulin levels are increasing constantly and significantly with age, the most strikingly at the age of onset of puberty; the absence of notable changes in glucose tolerance results in a rise of the I/G ratio as well. The causes for the increase of insulin secretion with age, whether of peripheral or pancreatic order, are still speculative.
A significant increase in basic and post-stimulation insulin secretion was observed in 173 obese children undergoing oral glucose tolerance tests. The hyperinsulinism, which was not related to hyperclycemia, was more important in older and heavier children. It was also observed however in younger children since the onset of obesity. It may therefore play a role in the maintenance of the obesity but also in its development. Various hypothesis to explain the origin of this hyperinsulinism and the adaptation of the system to it are discussed.
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