Insulin action and distribution of tissue blood flow.

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 -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 Cand phosphorylation of insulin receptor substrate 1. The resultant decrease in insulin receptor substrate 1 phosphorylation reduces activity of phosphatidylinositol 3-kinase activity and insulin signaling. Focus on insulin resistance has emerged naturally from cellular studies. There are, however, important contrasts between insulin action in vitro and in the intact organism. Once secreted, insulin must traverse the convoluted pathway from the pancreatic islets to receptors on insulin-sensitive tissues. Due to a highly fenestrated endothelium, access to hepatocytes in vivo is virtually immediate. However, significant barriers exist to insulin action on skeletal muscle as well as adipose, the most abundant insulin-sensitive tissues. Those barriers relate to insulin access to receptors as well as access of glucose and other blood-borne nutrients to the consuming tissues. Glucose access to tissue metabolism can be limited by blood flow distribution pattern, if the rate of transport of glucose across the capillary endothelium is rapid. Because of its size, insulin access to receptors may be limited by transendothelial transport, which can be rate-limiting for stimulation of glucose disposal (11). Thus, in vivo, the overall effect of insulin can depend upon access of hormones and substrates to skeletal muscle cells, as well as the postreceptor events that follow insulin binding. The important but still unanswered question is the extent to which hemodynamic mechanisms may contribute to insulin resistance in pathological states. Baron and his colleagues (12–14) pioneered the concept that insulin acts as a vasodilator and can thereby control access of glucose as well as insulin to skeletal muscle and fat. They demonstrated that the insulin effect is nitric oxidedependent and the vasodilatory effect of insulin was reduced in insulin-resistant obese subjects, or those with diabetes. However, hemodynamic effects of insulin were most prominent at supraphysiological concentrations of the hormone, and skepticism remained regarding the importance of blood flow reductions per se mediating insulin resistance in vivo. An important advance was introduced by Clark and colleagues (15, 16). These authors suggested that insulin might control the bulk flow through tissues which consume glucose—nutritive vs. nonnutritive pathways. Thus, the possibility was introduced that total flow might change little, but shifts could occur, increasing access of insulin and substrates to tissues that are metabolic consumers, as opposed to flow pathways that bypass insulin-sensitive glucose-consuming tissues. The same group has exploited the endothelium-dependent reaction whereby 1-methylxanthine is converted to 1-methylurate, a reaction that is catalyzed by the enzyme xanthine oxidase, which is localized in the capillary endothelium. Also, they exploited an approach in which contrast-enhanced ultrasound is used to detect labeled albumin containing microbubbles as a noninvasive method to identify perfusion through insulin-sensitive muscle tissue, and they have confirmed that supraphysiological insulin levels increase perfusion through capillaries in human volunteers (17, 18). Thus, it is clear that insulin can regulate the distribution of flow through insulin-sensitive tissues, and changes in distribution pattern could conceivably contribute to insulin resistance. An alternative approach to examining the effect of insulin on blood flow distribution is to exploit access to interstitial fluid. Renkin (19) originally defined the relationship between flux of solute from blood to tissue. In the present issue, Gudbjörnsdóttir et al. (20) have exploited the Renkin analysis to examine the effects of hyperinsulinemia on what fraction of the glucose or insulin that enters the tissue exits radially— presumably to interstitial fluid bathing insulin-sensitive cells—and what fraction passes through to the venous blood. The calculation of this fraction required measurements of blood flow through the deep muscles of the forearm, which they measured with plethysmography, as well as measurements of interstitial fluid concentrations of glucose and insulin. What is impressive is that these measurements were made in conscious human volunteers during several protocols, including the oral glucose tolerance test and the hyperinsulinemic clamp. The authors calculate that the so called permeability fraction, a measure of the fraction of substance entering the tissue to exit radially through the endothelium, increased substantially during the oral glucose tolerance test. They reported a very low permeability fraction 0021-972X/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(10):4556–4558 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-031431