Lipid-induced insulin resistance: unravelling the mechanism - PubMed (original) (raw)
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Lipid-induced insulin resistance: unravelling the mechanism
Varman T Samuel et al. Lancet. 2010.
Abstract
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.
Copyright 2010 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Conflicts of interest
We declare that we have no conflicts of interest.
Figures
Figure 1. Glucose-fatty-acid cycle proposed by Randle and colleagues
CoA=coenzyme A. PDH=pyruvate dehydrogenase. PFK=phosphofructokinase. G6P=glucose-6-phosphate. HK=hexokinase. Red circle with minus sign represents inhibition. Black line with arrowhead represents increase or accumulation of substrate. Blue dotted line with arrowhead indicates a pathway that is inhibited.
Figure 2. Mechanisms of insulin sensitivity and resistance in muscle and liver
(A) Insulin-sensitive muscle. (B) Insulin-resistant muscle. (C) Insulin-sensitive liver. (D) Insulin-resistant liver. IRS=insulin-receptor substrate. IR=insulin receptor. PI3K=1-phosphatidylinositol 3-kinase. GLUT4=glucose transporter 4. DAG=diacylglycerol. PKC=protein kinase C. Ser=serine. Thr=threonine. FOX01=forkhead box O1. FOXA2=forkhead box A2. G6P=glucose-6-phosphate. GS=glycogen synthase. GSK=glycogen synthase kinase. Green circle with plus sign represents activation. Red circle with minus sign represents inactivation. Solid line with arrowhead represents increase or accumulation of substrate. Dotted line indicates inhibition of pathway.
References
- Prentice AM, Hennig BJ, Fulford AJ. Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? Int J Obes (Lond) 2008;32:1607–1610. - PubMed
- Harris JL, Pomeranz JL, Lobstein T, Brownell KD. A crisis in the marketplace: how food marketing contributes to childhood obesity and what can be done. Annu Rev Public Health. 2009;30:211–225. - PubMed
- Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser. 2003;916:1–149. - PubMed
- Mendez MA, Monteiro CA, Popkin BM. Overweight exceeds underweight among women in most developing countries. Am J Clin Nutr. 2005;81:714–721. - PubMed
- Sherry B, Mei Z, Scanlon KS, Mokdad AH, Grummer-Strawn LM. Trends in state-specific prevalence of overweight and underweight in 2- through 4-year-old children from low-income families from 1989 through 2000. Arch Pediatr Adolesc Med. 2004;158:1116–1124. - PubMed
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