Lipid-induced insulin resistance: unravelling the mechanism

By V. Samuel, K. Petersen, Gerald I. Shulman. The Lancet, 2010

1,162 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/89c2041ac90d7e5a29fdc97e4a9dadd828997373

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Citations in the corpus

Adipocytokines in Obesity and Metabolic Disease (2014, positive): “This overflow of lipids from obese adipose depots has been considered a key reason for obesity-associated insulin resistance and hepa- tosteatosis for several decades (Randle et al. 1963, Samuel et al. 2010).”
Sugar, Uric Acid, and the Etiology of Diabetes and Obesity (2013, background): “In turn, the development of fatty liver is also linked with insulin resistance (43).”
Morbidity and mortality associated with obesity. (2017, background): “Obesity is associated with an increased risk of developing insulin resistance which considered a major metabolic abnormality in most patients with type 2 diabetes characterized by elevated levels of circulating insulin (75).”
Insulin receptor signaling in normal and insulin-resistant states. (2014, background): “Conversely, reducing DAG levels in skeletal muscle and liver protects mice against high-fat-diet-induced insulin resistance (Liu et al. 2007; Ahmadian et al. 2009; Samuel et al. 2010).”
Cancer cachexia: mediators, signaling, and metabolic pathways. (2012, background): “One hypothesis is that intracellular accumulation of diacylglycerol triggers activation of novel protein kinases C with subsequent impairments in insulin signaling (Samuel et al., 2010).”
Non Alcoholic Fatty Liver Disease, Hepatic Insulin Resistance and Type 2 Diabetes (2014, background): “, FATP2 and FATP5, FAT/ CD36, and caveolins).(3,8) Part of the intracellular”
A ceramide-centric view of insulin resistance. (2012, background): “The most prominent of these is diacylglycerol (DAG), which accumulates in the obese and has been suggested to activate protein kinase C (PKC) isoforms that inhibit insulin receptor substrate-1, thus blocking insulin action (Samuel et al., 2010).”
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 (2012, background): “intramyocellular TAG , hepatosteatosis) (reviewed in [74]).”
INFLAMMATION AND LIPID SIGNALING IN THE ETIOLOGY OF INSULIN RESISTANCE (2012, neutral): “These lipotoxic effects include the production of intracellular lipid mediators, such as diacylglycerols (Samuel et al., 2010), as well as more direct effects of circulating saturated fatty acids.”
The interaction of hepatic lipid and glucose metabolism in liver diseases. (2012, background): “Hepatocellular accumulation of lipotoxic intermediates such as diacylglycerol (DAG) and ceramids causes hepatic IR [5].”
Molecular mechanisms of cancer development in obesity (2011, background): “Most obese people have some degree of insulin resistanc”