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.
View: Text | PDF
Review

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

×

Figure 4

Insulin regulates hepatic lipid metabolism directly via hepatic insulin signaling and indirectly via adipose and muscle insulin action.

Options: View larger image (or click on image) Download as PowerPoint
Insulin regulates hepatic lipid metabolism directly via hepatic insulin ...
(A) Muscle insulin action promotes postprandial muscle glucose uptake, and adipose insulin action decreases hepatic fatty acid (FA) delivery and reesterification of hepatic FAs into triglycerides. Direct hepatic insulin action will activate de novo lipogenesis and conversion of excess carbohydrate substrate into triglyceride and will promote export of hepatic triglyceride to adipose tissue as very low–density lipoprotein (VLDL). DNL, de novo lipogenesis. (B) Selective muscle insulin resistance in the prediabetic state, due to selective ectopic IMCL accumulation and DAG/PKCθ-mediated inhibition of muscle insulin signaling, leads to decreased insulin-stimulated glucose transport activity. This diverts ingested glucose to the liver, where the combination of postprandial hyperinsulinemia and hyperglycemia stimulates hepatic de novo lipogenesis, resulting in increased VLDL production, hypertriglyceridemia, and reductions in plasma HDL. (C) With the progression to hepatic steatosis and impaired insulin signaling in all key insulin-responsive tissues (liver, skeletal muscle, and adipose tissue), rates of adipose tissue lipolysis are increased, resulting in increased FA delivery to liver, which results in increased hepatic esterification of fatty acids to triglyceride. This process is regulated predominately by a substrate push mechanism and is independent of insulin signaling in the hepatocyte. In contrast, hepatic de novo lipogenesis, which is dependent on hepatic insulin signaling, is reduced. Dotted lines represent decreased action or decreased flux.