The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

Abstract

In most natural habitats, calorie availability is scarce and unpredictable, necessitating the evolution of systems for the efficient storage and utilization of energy. But in our modern, mechanized society, caloric demands are minimized, while highly palatable, calorie-dense foods and beverages are readily available. These changes have fostered the current pandemic of obesity and comorbid conditions of nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and type 2 diabetes (T2D). Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. We will first review the role of insulin and nutrients (specifically glucose and fatty acids) in nutrient storage ( Figure 1) and then use this framework to explore the various defects that give rise to insulin resistance and T2D (Figure 2). Postprandial hepatic glucose and lipid metabolismThe simple act of eating rapidly shifts hepatic glucose metabolism from glucose production to glucose storage, a complex transition regulated by multiple factors including nutrients, alterations in pancreatic and enteric hormones, and neural regulation. Insulin is a crucial regulator of this transition, primarily by activating glycogen synthase (1). The importance of insulin is seen in patients with type 1 diabetes (T1D), who only synthesize one-third the amount of hepatic glycogen as control subjects after a mixed meal (2). Yet, hyperinsulinemia, in the absence of hyperglycemia, promotes hepatic glycogen cycling with minimal net hepatic glycogen synthesis (1). And hyperglycemia, without hyperinsulinemia, inhibits hepatic glycogenolysis via glucose-mediated inhibition of glycogen phosphorylase (3), with minimal net hepatic glycogen synthesis (1). The combination of hyperinsulinemia and hyperglycemia maximizes net hepatic glycogen synthesis (1). Other nutrients further optimize net hepatic glycogen synthesis, such as activation of glucokinase by catalytic quantities of fructose (4).Hepatic insulin action requires a coordinated relay of intracellular signals (Figure 1 and ref. 5). Insulin activates the insulin receptor tyrosine kinase (IRTK), with subsequent activation of kinases including 3-phosphoinositide-dependent kinase-1 (PDK1) and mTORC2 (6), which converge on Akt phosphorylation (6-8). The pattern of insulin delivery may also impact Akt phosphorylation, with pulsatile portal delivery (which better mimics physiology) leading to greater activation than continuous, fixed insulin delivery (9). Activation of Akt is the integral result of multiple inputs to regulate hepatic glucose and lipid metabolism. This model has been used to explain how insulin suppresses hepatic glucose production via (i) lowering expression of gluconeogenic enzymes via phosphorylation and nuclear exclusion of FOXO1 and (ii) inactivation of glycogen synthase kinase 3β (GSK3β), which permits the activation of glycogen synthase.Recent studies challenge the primacy of the Akt/GSK3β/ glycogen synthase branch in the regulation ...

Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes

“…It seems that lipolysis induced by kin-2 RNAi may not be accompanied by an increase in whole-body energy expenditure so that mobilized lipid metabolites may be redistributed to other tissues, unlike fasting. In mammals, ectopic lipid accumulation in liver or muscle is closely associated with insulin resistance and metabolic diseases (53). Thus, it is feasible that lipolysis induced by kin-2 RNAi may mediate ectopic lipid accumulation.…”

“…On the contrary, lipodystrophy and cachexia are frequently associated with insulin resistance (83)(84)(85). In addition, there is a close correlation between insulin resistance and hyperlipidemia in metabolic diseases (53). Intriguingly, it has been reported that a human patient lacking FSP27 showed partial lipodystrophy and insulin resistance (86).…”

Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon?

“…NAFLD is an example of ectopic fat accumulation in liver and this lipid accumulation is usually associated with insulin resistance, abnormal substrate fluxes [28], increased secretion of hepatokines [29], increased gluconeogenesis, decreased glycogen synthesis and inhibition of insulin signalling pathways [30,31]. When excess hepatic lipid accumulates (NAFLD), it not only has the potential for causing insulin resistance but there is also the potential for chronic liver inflammation, increasing risk of progressive fibrotic liver disease, cirrhosis and hepatocellular carcinoma.…”

“…Such an effect occurs in sedentary obese individuals, who do not benefit from the ameliorating effect of increased muscle activity and increased mitochondrial fatty acid oxidation, which would normally buffer the liver from the burden of high FFA levels [33]. With the increased fluxes of long chain fatty acyl CoAs through the liver, evidence is accumulating that hepatic lipid accumulation is capable of promoting hepatic insulin resistance and hepatic inflammation through accumulation of di-acyl glycerols (DAGs) and protein kinase Cε (PKC-ε) activity, inhibiting the insulin signalling pathway and promoting insulin resistance (reviewed in detail in [28]). The conversion from TAG to DAG is mediated by adipose triglyceride lipase (ATGL) and comparative Gene Identification-58 (CGI-58) is an activator of ATGL.…”

“…Once liberated from triacylglycerol, glycerol is not re-esterified back into triacylglycerol by the adipocyte, because the adipocyte does not possess the required glycerol kinase activity. Consequently, increased triacylglycerol hydrolysis results in increased glycerol fluxes to the liver, increasing the production of dihydroacetone phosphate, hepatic gluconeogenesis and the production of hepatic glucose [28].…”