Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes

By Ralph DeFronzo, D. Tripathy. Diabetes Care, 2009

1,906 citations recorded by the source corpus.

Insulin resistance is a characteristic feature of type 2 diabetes and plays a major role in the pathogenesis of the disease (1,2). Although β-cell failure is the sine qua non for development of type 2 diabetes, skeletal muscle insulin resistance is considered to be the initiating or primary defect that is evident decades before β-cell failure and overt hyperglycemia develops (3,4). Insulin resistance is defined as a reduced response of target tissues (compared with subjects with normal glucose tolerance [NGT] without a family history of diabetes), such as the skeletal muscle, liver, and adipocytes, to insulin. Because skeletal muscle is the predominant site of insulin-mediated glucose uptake in the postprandial state, here we will focus on recent advances about the time of onset, as well as the mechanism, of the skeletal muscle insulin resistance. The euglycemic insulin clamp technique (5) is considered to be the gold standard for measuring insulin action in vivo. With this technique, whole-body insulin action is quantified as the rate of exogenous glucose infusion (plus any residual hepatic glucose production) required to maintain the plasma glucose concentration at euglycemic levels in response to a fixed increment in the plasma insulin concentration. Because 80–90% of the infused glucose is taken up by skeletal muscle under conditions of euglycemic hyperinsulinemia, insulin sensitivity measured with the insulin clamp technique primarily reflects skeletal muscle (6). Another advantage of this technique is that it can be combined with indirect calorimetry to measure different substrate oxidation rates and with muscle biopsy to examine the biochemical/molecular etiology of the insulin resistance. Measurement of insulin sensitivity by the frequently sampled intravenous glucose tolerance test reflects both hepatic and peripheral insulin resistance and correlates well with the insulin clamp technique (7). Because insulin clamp studies are not feasible in large …

Subfields: Cell Biology, Molecular Biology, Physiology

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Citations in the corpus

• Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 (2012, background): “Prospective studies first identify insulin resistance in human skeletal muscle, which is thought to contribute, via a dys-metabolic process, to the emergence of phenotypic disease [3, 74].”
• Insulin Resistance: From Mechanisms to Therapeutic Strategies (2021, background): “Insulin resistance in skeletal muscle Insulin-stimulated glucose consumption is largely conducted in skeletal muscle, and thus, muscular insulin resistance could affect whole-body metabolism [28].”
• Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes (2020, background): “Skeletal muscle is the principal organ for insulin-stimulated glucose uptake (i.e., capable for 80% of glucose disposal in human), and muscle IR plays a key part in T2D etiology (DeFronzo and Tripathy, 2009; Honka et al., 2018).”
• Metabolic flexibility in health and disease (2017, neutral): “, 2012), and an enormous body of work supports a causal role for skeletal muscle insulin resistance in type 2 diabetes (DeFronzo and Tripathy, 2009; Petersen et al., 2007).”