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Lilly Lecture 2003

The Struggle for Mastery in Insulin Action: From Triumvirate to Republic

From the Department of Medicine, Naomi Berrie Diabetes Center, College of Physicians & Surgeons of Columbia University, Columbia University, New York, New York

Type 2 diabetes arises from a combination of impaired insulin action and defective pancreatic ß-cell function. Classically, the two abnormalities have been viewed as distinct yet mutually detrimental processes. The combination of impaired insulin-dependent glucose metabolism in skeletal muscle and impaired ß-cell function causes an increase of hepatic glucose production, leading to a constellation of tissue abnormalities that has been referred to as the diabetes "ruling triumvirate." Targeted mutagenesis in mice has led to a critical reappraisal of the integrated physiology of insulin action. These studies indicate that insulin resistance in skeletal muscle and adipose tissue does not necessarily lead to hyperglycemia, so long as insulin sensitivity in other tissues is preserved. Additional data suggest a direct role of insulin signaling in ß-cell function and regulation of ß-cell mass, thus raising the possibility that insulin resistance may be the overarching feature of diabetes in all target tissues. I propose that we replace the original picture of a ruling triumvirate with that of a squabbling republic in which every tissue contributes to the onset of the disease.

Abbreviations: Fox, forkhead box-containing protein; Irs, insulin receptor substrate; Insr, insulin receptor; Neurog3, Neurogenin3; PGC, peroxisome proliferator–activated receptor- coactivator; PI3K, phosphatidylinositol 3-kinase

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