Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart

Abstract

The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor ␤-subunit, insulin receptor substrate (IRS)-2, and p52Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52Shc are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin. Diabetes 50:2709 -2720, 2001

Functional defects in adenylyl cyclase signaling mechanisms of insulin and relaxin in skeletal muscles of rat with streptozotocin type 1 diabetes

“…As shown in our study, the insulin binding capacity of the receptors in the skeletal muscles of STZ diabetic rats significantly increases due to the increase in receptor number with high and low affinity to the hormone (Table 1). Our data concerning the characteristics of insulin receptor are in agreement with that obtained by the same method in rat skeletal muscles [23,24]. It allows us to conclude that functional disturbance in insulin-competent ACSM should not be ascribed to the decreasing of insulin receptor activity.…”

“…The functional changes in the insulin signaling system we found in the skeletal muscles of STZ diabetic rats are similar to that in the myocardium of these animals [24,28,32]. In particular, in the myocardium of diabetic rats, the following events were observed: an increase in insulin receptor number, increase in insulin-induced phosphorylation of insulin receptor and its substrates (IRS1-and IRS2-proteins), and stimulation of PI-3K activity.…”

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

“…However, GSK3 activity was elevated approximately twofold in skeletal muscle samples from human patients with type 2 diabetes [128]. There was also decreased insulin-induced serine-phosphorylation of GSK3 in the myocardium of diabetic rats [129]. Thus, while still few, these studies indicate that the effects of insulin-resistance on GSK3 vary considerably among different tissues with some evidence of dephosphorylated, hyperactive GSK3 associated with insulin deficiency.…”

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

“…In the myocardium of STZ-diabetic rats, systenic insulin administration results in an enhanced activity of most of the components of the PI3-K/ Akt signaling cascade, including an increase in Akt phosphorylation (Laviola et al, 2001). However, baseline Akt phosphorylation of serine-473, although not of threonine-308, and Akt activity (as determined by in vitro assay) showed reductions in STZ-diabetic rats (Laviola et al, 2001). Gerhardinger and coworkers (Gerhardinger et al, 2001) found that STZ-diabetic rats given low-dose insulin treatment tended to exhibit enhanced retinal Akt phosphorylation.…”

“…Indeed, STZ-induced diabetic rats demonstrate baseline reductions in cardiac Akt activity (Dobrzynski et al, 2002). In the myocardium of STZ-diabetic rats, systenic insulin administration results in an enhanced activity of most of the components of the PI3-K/ Akt signaling cascade, including an increase in Akt phosphorylation (Laviola et al, 2001). However, baseline Akt phosphorylation of serine-473, although not of threonine-308, and Akt activity (as determined by in vitro assay) showed reductions in STZ-diabetic rats (Laviola et al, 2001).…”