Diacylglycerol-mediated insulin resistance

Abstract

Understanding the molecular mechanisms of insulin resistance remains a major medical challenge of the twenty-first century. Over the last half-century, many hypotheses have been proposed to explain insulin resistance, and, most recently, inflammation associated with alterations in adipocytokines has become the prevailing hypothesis. Here we discuss diacylglycerol-mediated insulin resistance as an alternative and unifying hypothesis to explain the most common forms of insulin resistance associated with obesity and type 2 diabetes mellitus, as well as lipodystrophy and aging.

Figure 1

Molecular mechanisms of cellular insulin resistance in muscle and liver. Increased intracellular diacyglycerols lead to activation of PKC-θ and PKC-ε in skeletal muscle and liver, respectively, which, in turn, decreases insulin-stimulated IRS-1/IRS-2 tyrosine phosphorylation, PI3K activation and downstream insulin signaling. (a) In the muscle, this results in decreased muscle glycogen synthesis, owing to reduced insulin-stimulated GLUT4 translocation to the plasma membrane. (b) In the liver, this results in decreased hepatic glycogen synthesis, owing to decreased activation of glycogen synthase, and increased hepatic gluconeogenesis. The use of transgenic and knockout mice, as well as antisense oligonucleotides to knock down specific proteins, has allowed the validation of the diacylglycerol-mediated insulin hypothesis of insulin resistance through the manipulation of key proteins in the pathway. KO, knockout; GLUT4, glucose transporter type 4; TAG, triacylglycerol; LPL, lipoproteinlipase; Tg, transgenic; FATP-1, fatty acid transport protein-1; DGAT, diacylglycerol O-acyltransferase; UCP3, uncoupling protein-3; GS, glycogen synthase; LCAD, long-chain acyl-CoA dehydrogenase; mtGPAT, mitochondrial glycerol-3-phosphate acyltransferase; ASO, antisense oligonucleotide.

Figure 2

Mechanisms for intracellular diacylglycerol (DAG) accumulation in muscle and liver. DAGs accumulate in skeletal muscle and liver when the rate of fatty acid delivery to these tissues exceeds the rates of intracellular fat oxidation and/or conversion to neutral lipid. The four main causes of net DAG accumulation are excess caloric intake, defects in adipocyte metabolism (which would include lipid storage and lipolysis), defects in mitochondrial fatty acid oxidation and gene variation in apolipoprotein C3, leading to inhibition of lipoprotein lipase activity. TCA, tricarboxylic acid.