Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity inskeletal muscle and myocardium of streptozocin-induced diabetic rats

Insulin-dependent diabetes in rats is characterized by abnormalities of pos t-binding insulin signaling reactions that are not fully corrected by exoge nous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocar dium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated d iabetic rats, and diabetic rats transplanted with syngeneic islets under th e kidney capsule were studied. Compared with controls, diabetic rats were c haracterized by multiple insulin signaling abnormalities in skeletal muscle , which included 1) increased insulin-stimulated tyrosine phosphorylation o f the insulin receptor beta-subunit and insulin receptor substrates IRS-1 a nd IRS-2, 2) increased substrate tyrosine phosphorylation in the basal stat e, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and i nsulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-l immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinas e activity in low-density microsomes, A similar augmentation of insulin rec eptor and substrate tyrosine phosphorylation in response to STZ-diabetes wa s also found in myocardium, although with lower magnitude than that found i n skeletal muscle, In addition, STZ-diabetes resulted in decreased IRS-1 an d increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium, Thus, insulin delivered into the syst emic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopen ic diabetes.