Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action

Sheree D Martin; Shona Morrison; Nicky Konstantopoulos; Sean L McGee

doi:10.1016/j.molmet.2014.02.001

Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action

Mol Metab. 2014 Mar 12;3(4):408-18. doi: 10.1016/j.molmet.2014.02.001. eCollection 2014 Jul.

Authors

Sheree D Martin¹, Shona Morrison¹, Nicky Konstantopoulos¹, Sean L McGee²

Affiliations

¹ Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
² Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia ; Cell Signalling and Metabolism Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

Abstract

The contribution of mitochondrial dysfunction to insulin resistance is a contentious issue in metabolic research. Recent evidence implicates mitochondrial dysfunction as contributing to multiple forms of insulin resistance. However, some models of mitochondrial dysfunction fail to induce insulin resistance, suggesting greater complexity describes mitochondrial regulation of insulin action. We report that mitochondrial dysfunction is not necessary for cellular models of insulin resistance. However, impairment of mitochondrial function is sufficient for insulin resistance in a cell type-dependent manner, with impaired mitochondrial function inducing insulin resistance in adipocytes, but having no effect, or insulin sensitising effects in hepatocytes. The mechanism of mitochondrial impairment was important in determining the impact on insulin action, but was independent of mitochondrial ROS production. These data can account for opposing findings on this issue and highlight the complexity of mitochondrial regulation of cell type-specific insulin action, which is not described by current reductionist paradigms.

Keywords: AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; Adipocyte; BSA, bovine serum albumin; ECAR, extracellular acidification rate; FoxO1, forkhead box protein O1; G.O., glucose oxidase; GLUT4, facilitative glucose transporter isoform 4; GP, glucose production; HI-FBS, heat-inactivated foetal bovine serum; Hepatocyte; IRS1, insulin receptor substrate 1; Insulin action; LDH, lactate dehydrogenase; MMP, mitochondrial membrane potential; Mitochondria; MnTBAP, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; Reactive oxygen species; SOD, superoxide dismutase; T2D, type 2 diabetes; TNFα, tumour necrosis factor alpha.