Mechanisms of Insulin Resistance in Obesity

  • David E. Kelley
  • Jean-Aime Simoneau
Part of the Contemporary Biomedicine book series (CB, volume 15)


Insulin resistance of skeletal muscle is a metabolic complication of obesity (1,2) that contributes substantially to the risk for diabetes, hypertension, dyslipidemia, and atherosclerosis in obese individuals. The precise etiology of insulin resistance remains uncertain. One area of potential importance in the pathogenesis of insulin resistance in obesity is glucose and fatty acid substrate competition. Glucose and fatty acid substrate competition is commonly referred to as the “Randle cycle,” so named to recognize the contribution that Randle and his colleagues made in postulating a mechanism by which FFA could induce insulin resistance (3,5). The hypothesis is that oxidation of fatty acids by skeletal muscle, driven by a concentration-dependent uptake of plasma FFA, inhibits glucose oxidation and glycolysis, with consequent inhibition of the uptake of plasma glucose. Because the mass of adipose tissue is increased in obesity and, more specifically, because suppression of lipolysis by insulin is impaired in obese individuals (6,7), the metabolic milieu in obesity seems appropriate for glucose/FFA substrate competition to contribute to insulin resistance. There is, however, skepticism regarding the relevance of substrate competition as a mechanism of insulin resistance in obesity (8–10). The metabolic profile of insulin-resistant glucose metabolism in skeletal muscle of obese individuals is characterized by a substantial impairment in glycogen synthesis with lesser defects of glucose oxidation or glycolysis. This pattern of insulin resistance also applies to noninsulin-dependent diabetes mellitus (NIDDM). Because of the apparent difference between the metabolic pattern of insulin resistance observed and that predicted by the postulates of the Randle cycle, it has been argued that substrate competition is unlikely to have a key role in the pathogenesis of insulin resistance in obesity. A number of clinical investigations have, however, begun to renew interest in the role that substrate competition may play in the insulin resistance of obesity (11–14), and one of the goals of this chapter is to examine these developments. First, the classic tenets of the Randle hypothesis have been challenged by studies indicating that FFA can induce insulin resis­tance in the pathway of glycogen synthesis. In an even more fundamental revi­sion of the role that substrate competition may have in obesity, recent studies suggest that part of the expression of insulin resistance of skeletal muscle in obe­sity is an impaired capacity for utilization of plasma FFA.


Skeletal Muscle Insulin Resistance Glucose Oxidation Oxidative Capacity Visceral Obesity 
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© Springer Science+Business Media New York 1997

Authors and Affiliations

  • David E. Kelley
  • Jean-Aime Simoneau

There are no affiliations available

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