Disordered lipid metabolism and the pathogenesis of insulin resistance

Abstract

Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metabolism and insulin resistance. As "mouse models of insulin resistance" were comprehensively reviewed in Physiological Reviews by Nandi et al. in 2004, we will concentrate on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight.

Figures

Figure 1. Relative contribution of gluconeogenesis and glycogenolysis to glucose production during fasting

(Data derived from Rothman DL et al. Science 254: 573–576, 1991; and Petersen KF et al. Am. J. Physiol. 270: E186–E191, 1996.)

Figure 2. Mechanism of fatty acid induced insulin resistance in muscle (A) and liver (B)

Fatty acid metabolites (LCCoA, DAG), which may accumulate within myotubules and hepatocytes due to increased fatty acid delivery and/ or decreased mitochondrial oxidation, trigger a serine/threonine kinase cascade (possibly involving nPKC, IKKβ and/ or JNK-1). This ultimately induces serine/ threonine phosphorylation of critical IRS-1 sites (at least in muscle), thereby inhibiting IRS-1/2 tyrosine phosphorylation and activation of PI 3-kinase, resulting in i) reduced insulin–stimulated glucose transport in muscle; and ii) reduced glycogen synthesis and increased gluconeogenesis in liver. GLUT4, glucose transporter 4; LCCoA, long chain acylcoenzymeA; DAG, diacylglycerol; IRS, insulin receptor substrate; PI3-kinase, phosphoinositol 3-kinase; nPKCs, novel protein kinase Cs; JNK-1, Jun kinase-1; IKK β; IκB kinase-β.

Figure 2. Mechanism of fatty acid induced insulin resistance in muscle (A) and liver (B)

Fatty acid metabolites (LCCoA, DAG), which may accumulate within myotubules and hepatocytes due to increased fatty acid delivery and/ or decreased mitochondrial oxidation, trigger a serine/threonine kinase cascade (possibly involving nPKC, IKKβ and/ or JNK-1). This ultimately induces serine/ threonine phosphorylation of critical IRS-1 sites (at least in muscle), thereby inhibiting IRS-1/2 tyrosine phosphorylation and activation of PI 3-kinase, resulting in i) reduced insulin–stimulated glucose transport in muscle; and ii) reduced glycogen synthesis and increased gluconeogenesis in liver. GLUT4, glucose transporter 4; LCCoA, long chain acylcoenzymeA; DAG, diacylglycerol; IRS, insulin receptor substrate; PI3-kinase, phosphoinositol 3-kinase; nPKCs, novel protein kinase Cs; JNK-1, Jun kinase-1; IKK β; IκB kinase-β.