11th World Congress on Endocrinology and Metabolic Disorders
Associate Professor, University of Saskatchewan College of Medicine, Canada
Title: Heme oxygenase is an important switch-box that ameliorates cardio-renal complications in diabetes
Biography: Joseph Fomusi Ndisang
Impaired insulin signaling and deregulated glucose metabolism are associated with the progressive alterations in structure and function of vital organs like the heart and kidneys in diabetic patients. Our recent studies indicate that upregulating the heme oxygenase (HO) system with HO-inducers like hemin and heme-arginate potentiates insulin signaling and improve glucose metabolism in different animal models of type-1 and type-2 diabetes including (i) streptozotocininduced diabetic rats, (ii) Zucker diabetic fatty rats (ZDF), (iii) obese Zucker rats, (iv) GotoKakizaki rats (lean type-2 diabetic model) as well as other models that display glucose intolerance like spontaneously hypertensive rats and uninephrectomized DOCA-salt hypertensive rats, suggesting a universal role of the HO-system in regulating insulin signaling and glucose metabolism. The administration of HO-inducers (i) attenuated inflammatory mediators including cytokines like TNF-α, IL-6, IL-1β that in turn stimulate chemokines such as MCP-1 and MIP-1α to promote macrophage-M1 infiltration, (ii) suppressed oxidative stress including NF-κB, activating-protein (AP)-1, AP-2, and c-Jun-N-terminal-kinaseand 8-isoprostane, (iii) enhanced fundamental proteins implicated in the insulin signal transduction pathway like IRS-1, PI3K and PKB, (iv) reduced insulin/glucose intolerance (IPITT), (v) increased insulin sensitivity and the inability of insulin to enhance GLUT4 was overturned. These were associated with improved cardiac hemodynamics and the attenuation of cardiac hypertrophy, collagen deposition in cardiomyocytes and the reduction of left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte hypertrophy. Similarly, HO reduced renal histological lesions such as glomerulosclerosis, tubular necrosis, tubular vacuolization, interstitial macrophage infiltration and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Thus, diabetic complications such as cardiomyopathy and nephropathy were markedly improved. Taken together, these studies suggest that the HO-system could be considered and important switch box that when potentiated adequately can rescue organ damage in diabetes.