Molecular Mechanisms of Insulin Resistance That Impact Cardiovascular Biology

Cecilia C. Low Wang; Marc L. Goalstone; Boris Draznin


Diabetes. 2004;53(11) 

In This Article

Abstract and Introduction

Insulin resistance is concomitant with type 2 diabetes, obesity, hypertension, and other features of the metabolic syndrome. Because insulin resistance is associated with cardiovascular disease, both scientists and physicians have taken great interest in this disorder. Insulin resistance is associated with compensatory hyperinsulinemia, but individual contributions of either of these two conditions remain incompletely understood and a subject of intense investigation. One possibility is that in an attempt to overcome the inhibition within the metabolic insulin-signaling pathway, hyperinsulinemia may continue to stimulate the mitogenic insulin-signaling pathway, thus exerting its detrimental influence. Here we discuss some of the effects of insulin resistance and mechanisms of potentially detrimental influence of hyperinsulinemia in the presence of metabolic insulin resistance.

Insulin resistance is a prevalent medical condition that accompanies type 2 diabetes, obesity, hypertension, metabolic syndrome, and polycystic ovary disease.[1] Furthermore, offspring of insulin-resistant individuals are less sensitive to insulin when compared with control subjects,[2] suggesting a hereditary nature of at least some components of insulin resistance.

Insulin resistance has elicited great interest in medical and scientific communities because of its association with cardiovascular disease.[3,4] However, the molecular mechanism(s) tying insulin resistance to the development and/or progression of atherosclerosis remains enigmatic.

The term "insulin resistance" as it is used in clinical and experimental settings underscores the inability of insulin to promote normal homeostasis of glucose. In other words, a suboptimal strength of insulin action demands the presence of higher-than-normal concentrations of insulin in order to maintain normoglycemia and normal utilization of glucose by insulin target tissues. Thus, the term "insulin resistance" implies the existence of metabolic insulin resistance, which reflects an inadequate effect of insulin on glucose metabolism, but does not address other aspects of insulin action. However, insulin, the most potent anabolic hormone in the body, exerts a multitude of effects on lipid and protein metabolism, ion and amino acid transport, cell cycle and proliferation, cell differentiation, and nitric oxide (NO) synthesis.[5]

Therefore, it is critically important to understand whether insulin resistance affects all aspects of insulin action equally. Physiologically, the fact that the half-maximal effective concentration of insulin action ranges widely, depending on the insulin action studied, has been known for a long time.[6] Inhibition of lipolysis appears to be the most sensitive to insulin, while insulin effect on glucose oxidation is among the least sensitive. Conceivably, therefore, insulin resistance could affect certain aspects of insulin action to a greater extent than others.

The second important concept is to distinguish the influence of insulin resistance from that of compensatory hyperinsulinemia that invariably accompanies insulin resistance. If the detrimental influence of insulin resistance is a consequence of reduced insulin action, then compensatory hyperinsulinemia is merely an innocent bystander and has no effect of its own. In contrast, if certain aspects of insulin action are not affected by the diminished strength of insulin, then the presence of compensatory hyperinsulinemia may have its own influence. As a result, compensatory hyperinsulinemia may stimulate or even overstimulate certain aspects of insulin action in various cells and tissues. Clinical and epidemiological studies yielded mixed information and failed to provide definitive evidence either in favor of or against the role of hyperinsulinemia per se.

Therefore, the truly critical point in understanding the role of insulin resistance is to determine whether diminished insulin action (effect of insulin resistance) may coexist with normal or even enhanced insulin action (effect of hyperinsulinemia) within the same tissue and within the same cell. This task became feasible with the unraveling of the intracellular insulin-signaling cascade. Initial studies elucidated the two major postreceptor signaling pathways that convey the insulin signal downstream.[7,8] One pathway, involving the phosphorylation of insulin receptor substrate (IRS)-1 and -2 and activation of phosphatidylinosital (PI) 3-kinase appears to be absolutely necessary for mediating metabolic effects of insulin.[9,10] This pathway also contributes to the mitogenic aspects of insulin action. The second signaling pathway appears to involve the phosphorylation of Shc and activation of Ras, Raf, MEK, and mitogen-activated protein (MAP) kinases (Erk 1 and 2). In contrast to the IRS/PI 3-kinase pathway, activation of the Shc-Ras-MAP kinase intermediates contributes solely to the nuclear and mitogenic effects of insulin and plays no role in conveying the metabolic action of insulin.[11,12]

Subsequent experiments have introduced a concept of "selective insulin resistance." This concept has received its first experimental support from the work of Jiang et al.[13] and Cusi et al.[14] Jiang et al.[13] compared insulin signaling via the PI 3-kinase and Erk MAP kinase pathways in vascular tissue of lean and obese Zucker rats in both in vivo and ex vivo studies. Both experimental approaches (i.e., in vivo and ex vivo) clearly demonstrated a significant decrease in the ability of insulin to stimulate the phosphorylation of IRS-1, the association of the p85 regulatory subunit of PI 3-kinase with IRS-1, the activity of PI 3-kinase, and the phosphorylation of Akt (a downstream serine kinase of the PI 3-kinase pathway) in the vasculature of obese insulin-resistant rats. In contrast, the stimulatory effect of insulin on Erk MAP kinase remained intact in these animals.

Cusi et al.[14] performed somewhat similar experiments in humans and assessed the two pathways of insulin signaling in muscle biopsy samples obtained from patients with type 2 diabetes, obese nondiabetic individuals, and lean control subjects before and after euglycemic-hyperinsulinemic clamp. Insulin stimulation of the PI 3-kinase pathway was dramatically reduced in obese nondiabetic individuals and virtually absent in type 2 diabetic patients. In contrast, insulin stimulation of the Erk MAP kinase pathway was normal in obese and diabetic subjects. Subsequent studies have also demonstrated a differential impact of insulin resistance on these two pathways of insulin signaling.[15,16]