Insulin-induced vasodilatation: physiology or pharmacology?

Abstract

Ever since the pioneering studies performed by Andres, Rabinowitz and Zierler 40 years ago [1‐4], investigators interested in insulin action considered insulin resistance in obesity [3], hypertension [5], insulin-dependent (IDDM) [6] and non-insulin-dependent diabetes mellitus (NIDDM) [7] to be primarily a problem of glucose utilization in peripheral tissues, which was independent of glucose delivery. However, a series of studies published since 1990, notably by Alain Baron and his associates, demonstrated that under certain conditions insulin increased leg blood flow [8], and that defects in this action of insulin were likely to contribute significantly to insulin resistance of glucose uptake caused by obesity [8], hypertension [9], IDDM [10] and NIDDM [11]. These latter findings contradicted the vast majority of earlier data and created a controversy regarding the role, or lack thereof, of defects in insulin stimulated blood flow in the pathogenesis of insulin resistance of glucose uptake. It is the purpose of the ensuing review to try to discuss the reasons for the discrepant findings. We will first review a series of studies performed in our own laboratory, which were designed to resolve the “flow controversy”. These studies examined whether the blood flow response to insulin is influenced by: i) the method used to quantitate blood flow; ii) the anatomical location of the flow measurement; iii) dose and duration of the insulin exposure; iv) individual factors such as limb muscularity, physical fitness and endothelial function, defined as the ability to vasodilate in response to nitric oxide (NO) synthesis-dependent vasodilatators. We will try to establish whether this physiological knowledge helps to explain the discrepancies observed in the studies performed in various insulin resistant conditions. We will then review the studies directly testing the hypothesis that an increase in blood flow enhances glucose uptake, and discuss the possibility that various vasoactive agents may change total flow similarly but have distinct effects on flow distribution. Finally, we will review studies relating insulin’s vascular effects to endothelial function, which have opened up an entirely new perspective for understanding how insulin resistance might predispose to vascular disease.