Distinct Mechanisms for Globular Adiponectin That Integrate Vascular and Metabolic Actions of Insulin to Help Maintain Coordinated Cardiovascular and Glucose Homeostasis

Abstract

In the current issue of Circulation Research , Zhao et al1 present interesting and important studies describing mechanisms by which insulin and adiponectin interact to integrate cardiovascular and metabolic physiology. The mechanism revealed by these studies uses both parallel and distinct pathways that may have important implications for the pathophysiology of diabetes mellitus, obesity, and their cardiovascular complications, as well as for the development of novel effective therapies in the future. Article, see p 1263 The molecular signaling pathways in skeletal muscle and adipose tissue responsible for direct actions of insulin to enhance glucose uptake and disposal involve activation of the insulin receptor, which then initiates a signaling cascade, involving IRS-1/PI3K/PDK-1/Akt and PKC-ζ, that culminates further downstream in the translocation of insulin response glucose transporters (GLUT4) from intracellular compartments to the cell surface, where GLUT4 acts as a facilitative transporter to drive glucose down its concentration gradient.2,3 Strikingly similar insulin signaling pathways in vascular endothelium involving insulin receptor/IRS-1/PI3K/PDK-1/Akt/eNOS promote increased production of the potent vasodilator nitric oxide that increases blood flow and capillary recruitment leading to increased delivery of the substrate (glucose) and the hormone (insulin) to metabolic targets, including skeletal muscle.4,5 These vascular actions of insulin represent a secondary mechanism for insulin to promote glucose uptake and disposal. Indeed, ≈40% of insulin-stimulated glucose uptake in skeletal muscle may be attributed to vascular actions of insulin in conduit arteries and recruitment of nutritive capillaries.6,7 In addition, the transendothelial transport of insulin has recently been identified as a potential rate-limiting step in metabolic actions of insulin.8–10 Taken together, it is apparent that reciprocal relationships between insulin resistance and endothelial dysfunction help tie together metabolic diseases with their …