title: Genetic loss of insulin receptors worsens cardiac efficiency in diabetes.
abstract: OBJECTIVE
  To determine the contribution of insulin signaling versus systemic metabolism to metabolic and mitochondrial alterations in type 1 diabetic hearts and test the hypothesis that antecedent mitochondrial dysfunction contributes to impaired cardiac efficiency (CE) in diabetes.
  
  
  RESULTS
  Control mice (WT) and mice with cardiomyocyte-restricted deletion of insulin receptors (CIRKO) were rendered diabetic with streptozotocin (WT-STZ and CIRKO-STZ, respectively), non-diabetic controls received vehicle (citrate buffer). Cardiac function was determined by echocardiography; myocardial metabolism, oxygen consumption (MVO(2)) and CE were determined in isolated perfused hearts; mitochondrial function was determined in permeabilized cardiac fibers and mitochondrial proteomics by liquid chromatography mass spectrometry. Pyruvate supported respiration and ATP synthesis were equivalently reduced by diabetes and genotype, with synergistic impairment in ATP synthesis in CIRKO-STZ. In contrast, fatty acid delivery and utilization was increased by diabetes irrespective of genotype, but not in non-diabetic CIRKO. Diabetes and genotype synergistically increased MVO(2) in CIRKO-STZ, leading to reduced CE. Irrespective of diabetes, genotype impaired ATP/O ratios in mitochondria exposed to palmitoyl carnitine, consistent with mitochondrial uncoupling. Proteomics revealed reduced content of fatty acid oxidation proteins in CIRKO mitochondria, which were induced by diabetes, whereas tricarboxylic acid cycle and oxidative phosphorylation proteins were reduced both in CIRKO mitochondria and by diabetes.
  
  
  CONCLUSIONS
  Deficient insulin signaling and diabetes mediate distinct effects on cardiac mitochondria. Antecedent loss of insulin signaling markedly impairs CE when diabetes is induced, via mechanisms that may be secondary to mitochondrial uncoupling and increased FA utilization.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.forename: Christian
authors.initials: C
authors.lastname: Riehle
authors.forename: Bharat
authors.initials: B
authors.lastname: Jaishy
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wende
authors.forename: Joseph
authors.initials: J
authors.lastname: Tuinei
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Jamie
authors.initials: J
authors.lastname: Soto
authors.forename: Karla M
authors.initials: KM
authors.lastname: Pires
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Heather A
authors.initials: HA
authors.lastname: Theobald
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wayment
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.forename: Bart C
authors.initials: BC
authors.lastname: Weimer
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology; D055786:Gene Knockout Techniques; D006321:Heart / Q000503:physiopathology*; D066298:In Vitro Techniques; D007328:Insulin / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D053141:Organelle Size; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010101:Oxygen Consumption; D020543:Proteome / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics*; D000071247:Uncoupling Protein 3
chemical_list: D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D020543:Proteome; D017382:Reactive Oxygen Species; D000071247:Uncoupling Protein 3; D011972:Receptor, Insulin