title: In vivo cardiac glucose metabolism in the high-fat fed mouse: Comparison of euglycemic-hyperinsulinemic clamp derived measures of glucose uptake with a dynamic metabolomic flux profiling approach.
abstract: BACKGROUND
  Cardiac metabolism is thought to be altered in insulin resistance and type 2 diabetes (T2D). Our understanding of the regulation of cardiac substrate metabolism and insulin sensitivity has largely been derived from ex vivo preparations which are not subject to the same metabolic regulation as in the intact heart in vivo. Studies are therefore required to examine in vivo cardiac glucose metabolism under physiologically relevant conditions.
  
  
  OBJECTIVE
  To determine the temporal pattern of the development of cardiac insulin resistance and to compare with dynamic approaches to interrogate cardiac glucose and intermediary metabolism in vivo.
  
  
  RESULTS
  Studies were conducted to determine the evolution of cardiac insulin resistance in C57Bl/6 mice fed a high-fat diet (HFD) for between 1 and 16 weeks. Dynamic in vivo cardiac glucose metabolism was determined following oral administration of [U-(13)C] glucose. Hearts were collected after 15 and 60 min and flux profiling was determined by measuring (13)C mass isotopomers in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Cardiac insulin resistance, determined by euglycemic-hyperinsulinemic clamp, was evident after 3 weeks of HFD. Despite the presence of insulin resistance, in vivo cardiac glucose metabolism following oral glucose administration was not compromised in HFD mice. This contrasts our recent findings in skeletal muscle, where TCA cycle activity was reduced in mice fed a HFD. Similar to our report in muscle, glucose derived pyruvate entry into the TCA cycle in the heart was almost exclusively via pyruvate dehydrogenase, with pyruvate carboxylase mediated anaplerosis being negligible after oral glucose administration.
  
  
  CONCLUSIONS
  Under experimental conditions which closely mimic the postprandial state, the insulin resistant mouse heart retains the ability to stimulate glucose metabolism.
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia. Electronic address: greg.kowalski@deakin.edu.au.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Kowalski
authors.affiliation: Metabolomics Australia, Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: De Souza
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Risis
authors.affiliation: Brigham and Women's Hospital, Department of Medicine, Boston, MA, USA.
authors.forename: Micah L
authors.initials: ML
authors.lastname: Burch
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Hamley
authors.affiliation: Metabolomics Australia, Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kloehn
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Ahrathy
authors.initials: A
authors.lastname: Selathurai
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lee-Young
authors.affiliation: Metabolomics Australia, Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Dedreia
authors.initials: D
authors.lastname: Tull
authors.affiliation: Metabolomics Australia, Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: O'Callaghan
authors.affiliation: Metabolomics Australia, Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*
chemical_list: D005947:Glucose
keywords: Cardiac insulin resistance; Gas-chromatography mass spectrometry; Metabolomics; Stable isotopes