title: Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action.
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.
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
authors.forename: Sheree D
authors.initials: SD
authors.lastname: Martin
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
authors.forename: Shona
authors.initials: S
authors.lastname: Morrison
authors.affiliation: Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
authors.forename: Nicky
authors.initials: N
authors.lastname: Konstantopoulos
authors.affiliation: 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.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
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