GLUCOSE-INDUCED INSULIN-SECRETION IS IMPAIRED AND INSULIN-INDUCED PHOSPHORYLATION OF THE INSULIN-RECEPTOR AND INSULIN-RECEPTOR SUBSTRATE-1 ARE INCREASED IN PROTEIN-DEFICIENT RATS

Malnutrition is related to diabetes in tropical countries. In experime ntal animals, protein deficiency may affect insulin secretion. However , the effect of malnutrition on insulin receptor phosphorylation and f urther intracellular signaling events is not known. Therefore, we deci ded to evaluate the rate of insulin secretion and the early molecular steps of insulin action in insulin-sensitive tissues of an animal mode l of protein deficiency. Pancreatic islets isolated from rats fed a st andard (17%) or a low (6%) protein diet were studied for their secreto ry response to increasing concentrations of glucose in the culture med ium. Basal as well as maximal rates of insulin secretion were signific antly lower in the islets isolated from rats fed a low protein diet. M oreover, the dose-response curve to glucose was significantly shifted to the right in the islets from malnourished rats compared with islets from control rats. During an oral glucose tolerance test, there were significantly lower circulating concentrations of insulin in the serum of rats fed a low protein diet in spite of no difference in serum glu cose concentration between the groups, suggesting an increased periphe ral insulin sensitivity. Immunoblotting and immunoprecipitation were u sed to study the phosphorylation of the insulin receptor and the insul in receptor substrate-1 as well as the insulin receptor substrate-1-p8 5 subunit of phosphatidylinositol 3-kinase association in response to insulin. Values were greater in hind-limb muscle from rats fed a low p rotein diet compared with controls. No differences were detected in th e total amount of protein corresponding to the insulin receptor or ins ulin receptor substrate-1 between muscle from rats fed the two diets. Therefore, we conclude that a decreased glucose-induced insulin secret ion in pancreatic islets from protein-malnourished rats is responsible , at least in part, for an increased phosphorylation of the insulin re ceptor, insulin receptor substrate-1 and its association with phosphat idylinositol 3-kinase. These might represent some of the factors influ encing the equilibrium in glucose concentrations observed in animal mo dels of malnutrition and undernourished subjects.