Insulin Action and Distribution of Tissue Blood Flow

Abstract

Insulin resistance has emerged as a critical risk factor for a plethora of chronic disorders, and it is a hallmark of the metabolic syndrome. Resistance is a risk factor not only for diabetes but also for dyslipidemia (1, 2), hypertension (3), cardiovascular disease (2, 4), colon cancer (5, 6), and possibly breast cancer (7). Individuals with functioning β-cells respond to insulin resistance with elevated insulin secretion; whether resistance per se or compensatory hyperinsulinemia accounts for the pathogenesis of various chronic conditions remains under study (8). Because of the central importance of insulin resistance in chronic disease, a monumental effort has been put forth over the last three decades to understand its mechanisms, resulting in the well-described insulin signaling pathways as well as glucose transporter mobilization (9). It has been assumed that defects in insulin action in vivo can be understood by identifying the specific step or steps in the signaling/mobilization cascade that are blocked in normally insulin-sensitive tissues, including skeletal muscle, adipose tissue, and liver. Particular progress has been made recently regarding the insulin resistance due to elevated free fatty acid concentration. Yu et al. (10) have suggested that free fatty acids increased intracellular fatty acyl-coenzyme A. The latter is proposed to activate protein kinase C-θ and phosphorylation of insulin receptor substrate 1. The resultant decrease in insulin receptor substrat…