Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat
Hema Viswambharan, Nadira Yuldasheva, Helen Imrie, Katherine Bridge, Natalie J Haywood, Anna Skromna, Karen E. Hemmings, Emily R. Clark, V Kate Gatenby, Paul A. Cordell, Katie J. Simmons, Natallia Makava, Yilizila Abudushalamu, Naima Endesh, Jane Brown, Andrew MN Walker, Simon Futers, Karen E. Porter, Richard M. Cubbon, Khalid M. Naseem, Ajay M. Shah, David J. Beech, Stephen B. Wheatcroft, Mark T. Kearney, Piruthivi Sukumar
Abstract
Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell (EC) production of superoxide and a simultaneous reduction in the availability of the vasoprotective signaling radical NO. We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to IGF-1 (insulin-like growth factor-1)–mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in ECs in vivo. Methods and Results: We generated mice expressing mIGF-1Rs (mouse IGF-1 receptors), which form nonfunctioning hybrid receptors with native IRs (insulin receptors) and IGF-1R, directed to ECs under control of the Tie2 promoter-enhancer. Despite EC insulin and IGF-1 resistance, mIGFREO (mutant IGF-1R EC overexpressing) mice had enhanced insulin and IGF-1–mediated systemic glucose disposal, lower fasting free fatty acids, and triglycerides. In hyperinsulinemic-euglycemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased Nox (NADPH oxidase)-4 expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO ECs generated increased hydrogen peroxide (H 2 O 2 ), with no increase in superoxide. Treatment with catalase—a H 2 O 2 dismutase—restored insulin tolerance to WT (wild type) levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favorable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H 2 O 2 generation mediating enhanced whole-body insulin sensitivity.