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Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis
Robert K. Semple, … , Stephen O’Rahilly, David B. Savage
Robert K. Semple, … , Stephen O’Rahilly, David B. Savage
Published January 26, 2009
Citation Information: J Clin Invest. 2009;119(2):315-322. https://doi.org/10.1172/JCI37432.
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Research Article Article has an altmetric score of 4

Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

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Abstract

Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

Authors

Robert K. Semple, Alison Sleigh, Peter R. Murgatroyd, Claire A. Adams, Les Bluck, Sarah Jackson, Alessandra Vottero, Dipak Kanabar, Valentine Charlton-Menys, Paul Durrington, Maria A. Soos, T. Adrian Carpenter, David J. Lomas, Elaine K. Cochran, Phillip Gorden, Stephen O’Rahilly, David B. Savage

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Body composition and plasma lipid parameters in a subgroup of patients w...

Body composition and plasma lipid parameters in a subgroup of patients with severe insulin resistance due to loss-of-function insulin receptor (INSR) or AKT2 mutations


Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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