The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome

Abstract

The metabolic syndrome is a clustering of cardiovascular risk factors, including insulin resistance, abdominal obesity, dyslipidemia, and hypertension, and is associated with other comorbidities such as a proinflammatory state and nonalcoholic fatty liver disease (NAFLD). Its prevalence is high, especially among developed countries, and mainly reflects overnutrition and sedentary lifestyle. Moreover, the developing countries are not spared, as obesity and its related problems such as the metabolic syndrome are increasing quickly. We review the potential primary role of skeletal muscle insulin resistance in the pathophysiology of the metabolic syndrome, showing that in lean, young, insulin-resistant individuals, impaired muscle glucose transport and glycogen synthesis redirect energy derived from carbohydrate into hepatic de novo lipogenesis, promoting the development of atherogenic dyslipidemia and NAFLD. The demonstration of a link between skeletal muscle insulin resistance and the metabolic syndrome offers opportunities in targeting early defects in muscle insulin action in order to counteract the development of the disease and its related complications.

Figure 1

Molecular mechanisms of skeletal muscle insulin resistance. Increases in intramyocellular fatty acyl CoAs and diacylglycerol due to increased delivery from plasma and/or reduced oxidation due to mitochondrial dysfunction trigger a serine/threonine kinases cascade initiated by novel protein kinase C. This ultimately leads to activation of serine residues on IRS-1 and inhibits insulin-induced PI3-kinase activity, resulting in reduced insulin-stimulated muscle glucose transport and reduced muscle glycogen synthesis. DAG, diacylglycerol; GSK3, glycogen synthase kinase-3; PH, pleckstrin homology domain; PI3, phosphatidyl inositol 3-kinase; PTB, phosphotyrosine binding domain. Copyright 2006 American Diabetes Association. From Reference , with permission from The American Diabetes Association.

Figure 2

Cholesterol metabolism induced by hepatic de novo lipogenesis. Skeletal muscle insulin resistance increases hepatic de novo lipogenesis, which leads to increased hepatic triglycerides (TGs). TGs can be exchanged for high-density lipoprotein (HDL) cholesterol in the presence of increased plasma very-low-density lipoprotein (VLDL) concentrations and normal activity of cholesteryl ester transfer protein (CETP), where a VLDL particle donates a molecule of TG to an HDL particle in return for one of the cholesteryl ester (CE) molecules from HDL. The TG-rich HDL particle can be hydrolyzed of its TG, leading to dissociation of the apolipoprotein A-1 (apoA-1) protein. The free apoA-1 is cleared more rapidly in plasma than the apoA-1 bound to HDL particles, resulting in reduced circulating apoA-1, HDL cholesterol, and the number of HDL particles. FFA, free fatty acid.

Figure 3

Fate of ingested carbohydrates in insulin-resistant and insulin-sensitive subjects. Copyright 2007 from Reference , National Academy of Sciences, USA.