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Review
, 55 Suppl 2 (Suppl 2), S9-S15

Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction

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Review

Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction

Katsutaro Morino et al. Diabetes.

Abstract

Recent studies using magnetic resonance spectroscopy have shown that decreased insulin-stimulated muscle glycogen synthesis due to a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of type 2 diabetes. The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-epsilon, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. More recently, magnetic resonance spectroscopy studies in healthy lean elderly subjects and healthy lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial function may predispose these individuals to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can be mostly attributed to reductions in mitochondrial density. By elucidating the cellular and molecular mechanisms responsible for insulin resistance, these studies provide potential new targets for the treatment and prevention of type 2 diabetes.

Figures

FIG. 1
FIG. 1
The molecular mechanism of fat-induced insulin resistance in skeletal muscle (A) and liver (B). A: Increases in intramyocellular fatty acyl CoAs and diacylglycerol due to increased delivery from plasma and/or reduced β-oxidation due to mitochondrial dysfunction activate serine/threonine kinases such as protein kinase C (PKC-θ rodents, PKC-β and -δ humans) in skeletal muscle. The activated kinases phosphorylate serine residues on IRS-1 and inhibit insulin-induced PI 3-kinase activity, resulting in reduced insulin-stimulated AKT2 activity. Lowered AKT2 activity fails to activate GLUT4 translocation, and other downstream AKT2-dependent events, and consequently insulin-induced glucose uptake is reduced. B: Increases in hepatic diacylglycerol content due to increased delivery of fatty acids from the plasma and/or increased de novo lipid synthesis and/or reduced β-oxidation activate protein kinase C-ε (and potentially other serine kinases), leading to reduced insulin receptor kinase activity and reduced IRS-2 tyrosine phosphorylation, resulting in reduced insulin stimulation of glycogen synthase activation and decreased phosphorylation of forkhead box protein O (FOXO), leading to increased hepatic gluconeogenesis. DAG, diacylglycerol; PTB, phosphotyrosine binding domain; PH, pleckstrin homology domain; SH2, src homology domain; GSK3, glycogen synthase kinase-3.
FIG. 2
FIG. 2
Serine/threonine phosphorylation on IRS-1. IRS-1 contains ~70 potential serine/threonine sites. Shown here are the individual residues on mouse IRS-1 and human IRS-1. In addition, the serine/threonine kinases, hormone, and circulating factors that lead to the phosphorylation on IRS-1 at specific sites are shown. The top row illustrates reported animal or human models in which these phosphorylation sites have been confirmed in vivo. Each residue is drawn corresponding to the position based on homology between the humans and mice. PCOS, polycystic ovarian syndrome; T2DM, type 2 diabetes.
FIG. 3
FIG. 3
The molecular mechanism of mitochondrial (Mt) biogenesis. Mitochondria have their own genome, which encodes 13 proteins, 2 rRNAs, and 22 tRNAs. It is also known that most of the mitochondrial proteins are encoded by the nuclear genome and translated proteins are transported into mitochondria. Extracellular stimuli induce mitochondrial biogenesis through PGC-1 in brown fat and skeletal muscle. Increased PGC-1 protein expression leads to increases in the expression of its target genes, including NRF-1. NRF-1 is a transcription factor stimulating many nuclear-encoded mitochondrial genes such as OXPHOS genes and mtTFA, a key transcriptional factor for the mitochondrial genome. mtTFA can bind to the D-loop of the mitochondrial genome and increase transcription of mitochondrial genes and replication of mitochondrial DNA. ATPsyn, ATP synthase; CytC, cytochrome C; MTCOI, mitochondrial cytochrome c oxidase subunit 1.

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