The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Varman T. Samuel, Gerald I. Shulman
Varman T. Samuel, Gerald I. Shulman
Published January 4, 2016
Citation Information: J Clin Invest. 2016;126(1):12-22. https://doi.org/10.1172/JCI77812.
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The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Abstract

Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.

Authors

Varman T. Samuel, Gerald I. Shulman

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Figure 2

Mechanisms of insulin resistance.

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Mechanisms of insulin resistance. In the liver, DAG-mediated activation ...
In the liver, DAG-mediated activation of PKCε impairs hepatic insulin signaling, constraining insulin-stimulated hepatic glycogen synthesis. Hepatic lipid synthesis continues unabated. In the skelatal muscle, DAG-mediated activation of PKCθ impairs muscle insulin signaling, impeding insulin-stimulated muscle glucose uptake and leading to increased glucose delivery to the liver. Exercise can still function to promote glucose uptake. In adipose tissue, cytokine release from ATMs promotes adipose lipolysis and leads to increased release of fatty acids (FAs). This will further drive hepatic lipid synthesis and activate hepatic gluconeogenesis via acetyl-CoA–mediated (Ac-CoA–mediated) activation of PC and glycerol, increasing glucose production via substrate push. IR, insulin receptor; GP; glycogen phosphorylase; GS, glycogen synthase; LPA, lysophosphatidic acid; HL, hepatic lipase; CM-R, chylomicron remnants; VLDL, very low–density lipoprotein; CAM-KII, calmodulin kinase II; IRS1/2,insulin receptor substrate 1/2; βAR, β-adrenergic receptor; CM-TG, chylomicron- triglycergides.