Novel Link Between Inflammation, Endothelial Dysfunction, and Muscle Insulin Resistance

  1. Franck Mauvais-Jarvis
  1. Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Comprehensive Center on Obesity, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  1. Corresponding author: Franck Mauvais-Jarvis, f-mauvais-jarvis{at}northwestern.edu.

In response to development of the euglycemic-hyperinsulinemic clamp technique in the 1980s, much emphasis was placed on skeletal muscle as the major site of insulin resistance in patients with type 2 diabetes (1). Following the discovery of the insulin receptor (IR) tyrosine kinase activity by Ron Kahn and colleagues (2) and the importance of IR substrate molecules in the 1990s (3,4), attention was directed on intrinsic alterations in the insulin signaling cascade in skeletal muscle and liver as fundamental causes of insulin resistance. In 1996, I joined Ron Kahn's laboratory as a participant in the gold rush to discover novel mechanisms responsible for insulin resistance. It was a time of intellectual and scientific awakening. With the advent of the Cre/loxP system, came the first surprise: muscle-specific IR knockout (MIRKO) mice showed no alterations in glucose homeostasis. Rather, they developed visceral adiposity (5). MIRKO mice exhibited impaired insulin activation of muscle glycogen synthase resulting in decreased muscle glycogen content (6,7). MIRKO mice also displayed reduced insulin-stimulated muscle glucose uptake during the euglycemic-hyperinsulinemic clamp (6). However, under physiological conditions of a glucose tolerance test, MIRKO mice had near normal skeletal muscle glucose uptake and did not display insulin resistance (7). Conversely, disruption of insulin action in the hepatocyte-specific IR knockout mouse produced severe resistance to the blood glucose–lowering effect of insulin (8). Together with the MIRKO, the hepatocyte-specific IR knockout mouse demonstrated …

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