[Investigation of insulin resistance in fourteen children starting a diabetes mellitus (author's transl)].
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Biomedical subjects
Publications and source records attributed to H Lestradet.
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In order to clarify the relationship between the transport of D-xylose, D-glucose, and Na in human gut, several characteristics of D-xylose uptake were examined in jejunal biopsies from 47 children (45 with normal intestinal function and 2 with glucose-galactose malabsorption). Standard in vitro techniques were used, with the following results: In tissue accumulation experiments with Ringer solution, the intracellular D-xylose concentration (C) was not significantly different from the medium D-xylose concentration (M) (C/M = 1.10 +/- 0.08). D-Xylose uptake was not affected by the disappearance of the Na electrochemical gradient in the presence of ouabain or DNP (C/M = 1.02 +/- 0.16 and 0.96 +/- 0.04, respectively). However, in Na-free solution, D-xylose uptake decreased (C/M = 0.47 +/- 0.08). The influx of 10 mM D-xylose across the luminal membrane (Jmcxyl = 1.34 mumol/h . cm2) was not significantly influenced by 2 mM phlorizin (Jmcxyl - 1.25 mumol/h . cm2), which is a competitive inhibitor of D-glucose transport. Removal of Na from the incubation medium, reduced Jmcxyl by 55%. Galactose (40 mM) and fructose (40 mM) did not inhibit Jmcxyl (2.18 and 2.27 mumol/h . cm2, respectively). In Ussing chambers, D-xylose did not stimulate the short-circuit current (Isc), neither did it interfere with the increase in Isc induced by glucose. In the congenital absence of glucose and galactose active transport, D-xylose entry into the cell was unaltered. These results support the concept that in jejunal mucosa of children, D-xylose is at least in part, transported by a system that is different from those for fructose and Na-dependent D-glucose (hexose) transport.
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Height and weight of 745 children (358 females and 387 males) under 18 years of age, presenting with insulin-dependent diabetes were compared with those of a French reference population. A similar comparison was done with a sample of 329 adults (155 females and 174 males) whose insulin-dependent diabetes had occurred before the age of 15. Results indicate that these children generally have a normal growth and reach a mean height (females : 158 cm; males : 170 cm) very similar to that of the reference population (160 and 172 cm, respectively). The same is observed for weight. However, growth retardation is observed at puberty, more frequently in males (10.8%) than in females (7.8%). Mean age at menarche is 14 years 5 months (13 years 10 months in the reference population). In males, it may be associated with insufficient treatment. This is not the case in females. There is no correlation between growth and glycosylated hemoglobin. No correlation with familial socio-economic level was found.
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To assess the role of intestinal absorption in bile secretion, the effects of milk perfusion into the duodenum on bile salt secretion were studied in children with active coeliac disease. Bile secretion was evaluated by measuring the bile salt concentration and output in the duodenum in response to a perfusion with a milk containing a casein hydrolysate as the protein source (4 ml/min/m2) followed by i.v. injection of 2 U/kg cholecystokinine (CCK). Bile salt output was estimated taking into account the dilution of the BSP perfused into the first part of the duodenum and collected 15 cm further on. Results found in nine children with active coeliac disease (A) were compared both to results for seven control children (C) and to those for three children with coeliac disease in remission (CDR). The values obtained show: 1. a significant drop in bile salt concentration and output in response to Nutramigen perfusion in groups A and CDR compared to group C; 2. a diminution in bile salt output perfusion is groups A and CDR; 3. smaller variations in bile salt output (expressed in mumol/min m2) after i.v. stimulation by CCK in group A (from 25 +/- 3.5 to 36 +/- 8.5) than in group C (from 46 +/- 6 to 52 +/- 9) or group CDR (from 19.5 +/- 1.4 to 52 +/- 20.6). However, there was no significant difference between the groups, because responses were heterogeneous; 4. there was no correlation between bile salt output or intestinal concentration of bile salt and fat absorption. These results indicate a reduction in bile salt secretion during the active phase of coeliac disease. The mechanism controlling this anomaly is not clear, since reduced bile salt output persisted after histological restoration of the duodenum.
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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.
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.
Far from exploring pancreatic endocrine function only, the oral glucose tolerance test curve depends upon a group of digestive, hepatic, tissular, hormonal and nervous processes which are worth analyzing. Tests conducted under perfectly standardized conditions, and with results lying within the limits of figures obtained in a normal population of the same age, are usually good indicators of satisfactory cellular, hepatic, and endocrine function. When figures are much outside normal limits, however, a diagnosis of diabetes or pre-diabetes should not be made immediately, but should lead to discussion, point by point, of the different variation factors possible. The simultaneous measurement of blood insulin levels had added a complement to this test essential for differentiation of the different types of hyperglycemia.
Three groups of ten similar obese children were infused with one of three protocols. Protocol I glucose only (1.15 mM/min/m2). protocol II, glucose, insulin (42 mM/min/m2). Protocol III, glucose insulin, propanolol (0.04 mg/min/m2) adrenalin (3 micrograms/min/m2). Eighteen newly diagnosed diabetic children without acidosis received glucose according to protocol II. Thirteen normal adults (controls) received glucose infusion according to protocol I. Protocols I and II were well tolerated and gave consistent results but Protocol III was not well tolerated and did not give interpretable results. In obese children steady state blood glucose levels are significantly higher than in controls but this difference was only moderate (8.8 + 0.7 mM, against 6.6 +/- 0.4 mM for protocol I). There was no difference in insulin levels. In diabetic children the steady state was more rarely obtained after a 120 min infusion and blood glucose levels were higher than in the controls or in obese children.
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Some experimental data in human jejunum suggest a Na dependence for glucose absorption and a glucose dependence for Na absorption. However, the relationship between these two transport processes is not yet known. Na+ and D-glucose absorptions were, therefore, measured simultaneously, in vitro, in isolated jejunal mucosa of children. The results are as follows: 1) the steady-state accumulation of D-glucose (C/M glucose) is a function of the Na concentration gradient between cell and medium (C/M Na). In Ringer solution, C/M glucose = 3.97 and C/M Na = 0.29; in the presence of 10(-4) M ouabain, C/M glucose = 1.63 and C/M Na = 0.60, and in Na free solution, C/M glucose = 0.99. In the presence of phloridzin, C/M Na is not statistically different from that in Ringer, but C/M glucose is significantly decreased. 2) The influx of D-glucose at the luminal membrane is a function of Na concentration in the bathing solution; it has the value of 4.41 mumole/hr cm2 in the presence of Na and of 1.65 mumole/hr cm2 in absence of Na. 3) The short-circuit current is a saturable function of D-glucose and of 3-O-D-methylglucose. The Kt for glucose is 8.01 mM. These results support the concept of a coupling between Na and D-glucose absorptions at the luminal membrane of jejunal mucosa of children.
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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.
The study of a hundred and fifteen unrelated insulin-dependent diabetes and eight families with at least two insulin-dependent diabetes members made it possible to confirm the higher frequency of HLA-B8 and B18 (p less than 0.001) among patients, producing a RR of 2.24 and 2.47 respectively. The increased B15 frequency did not achieve statistical significance. B18 whose gametic association (delta = 0.0438) was significant only in diabetic patients was often related to Aw19-2 (Aw30 + Aw31). The B8/B18 genotype gave a relative risk (RR = 4.98) which was significantly higher than that of B8, B18 and B15 heterozygotes (1.50, 1.24 and 1.39 respectively). Pairs of diabetic siblings were more frequently HLA identical than would be expected by chance, and distribution of the pairs of affected sibs into the three categories, identical, semi-identical and different, was closer to the recessive model than to the dominant one. The fact that the B8/B18 individuals had a RR slightly higher than the B8 and B18 homozygotes and distinctly higher than the heterozygotes for only one of these genes, favours the hypothesis of two dominant genes, giving the appearance of recessivity. The gene associated with B18 in Southern Europe seems to play the same part as that of the gene associated with B15 in Northern Europe.
Two groups of diabetics who were diagnosed before the age of 15 years and followed by the same doctors of 20-25 years were compared. The frequency of complications was significantly different in France compared to that in the United States. The differences may be dietary in origin because in France the diet is high in carbohydrate and low in fat but in the United States the diet is high in fat and low in carbohydrate.