title: Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle.
abstract: The role of mitochondrial dysfunction in the development of insulin resistance and type 2 diabetes remains controversial. In order to specifically define the relationship between insulin receptor (InsR) signaling, insulin resistance, hyperglycemia, hyperlipidemia and mitochondrial function, we analyzed mitochondrial performance of insulin-sensitive, slow-oxidative muscle in four different mouse models. In obese but normoglycemic ob/ob mice as well as in obese but diabetic mice under high-fat diet, mitochondrial performance remained unchanged even though intramyocellular diacylglycerols (DAGs), triacylglycerols (TAGs), and ceramides accumulated. In contrast, in muscle-specific InsR knockout (MIRKO) and streptozotocin (STZ)-treated hypoinsulinemic, hyperglycemic mice, levels of mitochondrial respiratory chain complexes and mitochondrial function were markedly reduced. In STZ, but not in MIRKO mice, this was caused by reduced transcription of mitochondrial genes mediated via decreased PGC-1α expression. We conclude that mitochondrial dysfunction is not causally involved in the pathogenesis of obesity-associated insulin resistance under normoglycemic conditions. However, obesity-associated type 2 diabetes and accumulation of DAGs or TAGs is not associated with impaired mitochondrial function. In contrast, chronic hypoinsulinemia and hyperglycemia as seen in STZ-treated mice as well as InsR deficiency in muscle of MIRKO mice lead to mitochondrial dysfunction. We postulate that decreased mitochondrial mass and/or performance in skeletal muscle of non-diabetic, obese or type 2 diabetic, obese patients observed in clinical studies must be explained by genetic predisposition, physical inactivity, or other still unknown factors.
authors.affiliation: Institute for Vegetative Physiology, University of Cologne, 50931, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Franko
authors.forename: J C
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: M
authors.initials: M
authors.lastname: Böse
authors.forename: C
authors.initials: C
authors.lastname: Sanchez-Lasheras
authors.forename: S
authors.initials: S
authors.lastname: Brodesser
authors.forename: O
authors.initials: O
authors.lastname: Krut
authors.forename: W S
authors.initials: WS
authors.lastname: Kunz
authors.forename: D
authors.initials: D
authors.lastname: Wiedermann
authors.forename: M
authors.initials: M
authors.lastname: Hoehn
authors.forename: O
authors.initials: O
authors.lastname: Stöhr
authors.forename: L
authors.initials: L
authors.lastname: Moll
authors.forename: S
authors.initials: S
authors.lastname: Freude
authors.forename: W
authors.initials: W
authors.lastname: Krone
authors.forename: M
authors.initials: M
authors.lastname: Schubert
authors.forename: R J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D000818:Animals; D001343:Autophagy; D001786:Blood Glucose; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D015870:Gene Expression; D005963:Glucosylceramides / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D013311:Streptozocin; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D001786:Blood Glucose; D045222:Electron Transport Chain Complex Proteins; D005963:Glucosylceramides; D007328:Insulin; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D008315:Malondialdehyde; D013311:Streptozocin; D002334:Carnitine O-Palmitoyltransferase