Journal
LANCET
Volume 375, Issue 9733, Pages 2267-2277Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0140-6736(10)60408-4
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Funding
- Veterans Administration
- US Public Health Service [R01 AG-23686, R01 DK-49230, P01 DK-068229, R01 DK-40936, P30 DK-45735, U24 DK-59635, UL1 RR-024139, K23 RR17404, UL1 RR024139]
- American Diabetes Association
- NATIONAL CENTER FOR RESEARCH RESOURCES [K23RR017404, UL1RR024139] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P01DK068229, P30DK045735, R01DK049230, R01DK040936, U24DK059635] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R56AG023686, R01AG023686] Funding Source: NIH RePORTER
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Insulin resistance has long been associated with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitising effects of thiazolidinediones.
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