Aldosterone Suppresses Insulin Signaling Via the Downregulation of Insulin Receptor Substrate-1 in Vascular Smooth Muscle Cells

Abstract

Abstract-Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using 3 H-labeled 2-deoxy-D-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (nϭ4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 mol/L; nϭ4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 mol/L; nϭ4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 mol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (nϭ4). In addition, proteasome inhibitor MG132 (1 mol/L) prevented insulin receptor substrate-1 degradation (nϭ4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; nϭ4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; nϭ4) glucose uptake by 50%, which was reversed by eplerenone (10 mol/L; nϭ4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress. Key Words: aldosterone Ⅲ oxidative stress Ⅲ insulin receptor substrate-1 Ⅲ insulin resistance Ⅲ type 2 diabetes mellitus Ⅲ metabolic syndrome Ⅲ eplerenone I nsulin resistance is a key attribute of type 2 diabetes and the metabolic syndrome. 1,2 Systemic glucose metabolism is maintained in the liver and skeletal muscle, and in the insulin resistant state, insulin-stimulated glucose uptake is attenuated and accompanied with subsequent increases in blood glucose concentration. High blood glucose concentration induces secretion of insulin from the pancreas and results in hyperinsulinemia. Both hyperglycemia and hyperinsulinemia affect the vasculature and are associated with microangiopathy, including retinopathy and nephropathy, and macroangiopathy, including cardiovascular disease and atherosclerosis. 3 Insulin resistance in the vasculature might also affect systemic glucose metabolism. However, the involvement of normal insulin signaling contributes to arteriosclerosis. 4,5 On the other hand, serine phosphorylation and degradation of insulin receptor substrate-1 (IRS-1) is a possible...

Aldosterone and Metabolic Syndrome

“…[67][68][69] Only recent evidence suggests that aldosterone may impair insulin signaling by downregulating insulin receptor substrate-1 in vascular smooth muscle cells. 70 In summary, no conclusions can be drawn from these studies as to whether aldosterone, per se, on the one hand or elevated blood pressure on the other hand, as a concomitant component of the MSyn and a possible consequence of elevated aldosterone levels, is the causative factor for impaired glucose homeostasis. The causal relationship between aldosterone and insulin resistance/hyperinsulinemia remains unclear.…”

Role of aldosterone and angiotensin II in insulin resistance: an update

“…In addition, RAAS activation results in increased signalling through the Rho and Rho Kinase pathways, which also participate in the development of hypertrophy, VSMCs migration, proliferation, inflammation, and hyperplasia in cardiovascular tissue. 28 On the other hand, it has been demonstrated that insulin resistance related to aldosterone results in c-Src and ROS-mediated increase in proteasomal degradation of Insulin Substrate 1 (IRS-1) in VSMCs, 29 demonstrating a novel mechanism of aldosteroneinduced insulin resistance and further implicating mineralocorticoids in the pathogenesis of insulin resistance in the vasculature. Similar experiments 30 have also confirmed that Ang II reduces IRS-1 levels in VSMCs through Src activation, and also through tyrosine phosphorylation of PDK1 and increased production of ROS that also result in abnormal serine phosphorylation and increased proteasomal degradation of IRS-1.…”

Aldosterone and the mineralocorticoid receptor in insulin resistance and diabetes

“…These actions initially cause endothelial dysfunction and ultimately impair insulin action at the target tissue [26][27][28] . In addition, MCR activation in vascular smooth muscle cells reduces the expression of insulin receptor substrate-1 (IRS-1) and downstream Akt signaling, directly inducing insulin resistance 29,30 . In the same cell type, MCR activation induces anomalous formation of insulin receptor/ insulin-like growth factor-1 receptor dimers in the plasma membrane 31,32 , further impeding insulin signaling.…”