The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Varman T. Samuel, Gerald I. Shulman
Varman T. Samuel, Gerald I. Shulman
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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 3

Insulin regulates hepatic glucose metabolism directly via hepatic insulin action and indirectly via adipose insulin action.

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Insulin regulates hepatic glucose metabolism directly via hepatic insuli...
(A) Insulin regulates hepatic glucose metabolism through both a direct mechanism and an indirect mechanism. The direct mechanism is mediated through activation of hepatocyte insulin receptors, which decreases hepatic glucose production acutely by activating hepatic glycogen synthesis and chronically through transcriptional downregulation of gluconeogenic enzymes, predominately by FOXO1 phosphorylation. Insulin also suppresses hepatic glucose metabolism by an indirect mechanism mediated by insulin action on WAT. Insulin inhibition of lipolysis suppresses fatty acid and glycerol turnover. This decreases fatty acid (FA) delivery to the liver, leading to reductions in hepatic acetyl-CoA (Ac-CoA) content, which in turn leads to allosteric reductions in hepatic PC activity and flux. Additionally, insulin suppression of lipolysis decreases glycerol delivery to liver and decreases conversion of glycerol to glucose. PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose 6-phosphatase. (B) In T2D, dysregulation of hepatic and adipose insulin action both contribute to hyperglycemia. Impaired hepatic insulin signaling, mediated by DAG/PKCĪµ inhibition of insulin receptor kinase activity, results in reduced insulin activation of hepatic glycogen synthesis and postprandial hyperglycemia. Adipose tissue inflammation and adipose insulin resistance results in increased rates of lipolysis and increased rates of FA and glycerol delivery to the liver. Increased FA delivery to the liver increases hepatic Ac-CoA content, leading to allosteric activation of PC activity and PC flux that increases hepatic gluconeogenesis. Additionally, increased glycerol delivery to the liver further increases hepatic gluconeogenesis through a substrate push mechanism. Dotted lines represent decreased action or flux. DHAP, dihydroxyacetone phosphate.