Greg M Kowalski1, David P De Souza2, Steve Risis3, Micah L Burch4, Steven Hamley5, Joachim Kloehn2, Ahrathy Selathurai5, Robert S Lee-Young3, Dedreia Tull2, Sean O'Callaghan2, Malcolm J McConville2, Clinton R Bruce5. 1. 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. 2. Metabolomics Australia, Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia. 3. Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia. 4. Brigham and Women's Hospital, Department of Medicine, Boston, MA, USA. 5. Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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: Greg M Kowalski; Steven Hamley; Ahrathy Selathurai; Joachim Kloehn; David P De Souza; Sean O'Callaghan; Brunda Nijagal; Dedreia L Tull; Malcolm J McConville; Clinton R Bruce Journal: Sci Rep Date: 2016-06-07 Impact factor: 4.379
Authors: Victoria C Foletta; Michelle Palmieri; Joachim Kloehn; Shaun Mason; Stephen F Previs; Malcolm J McConville; Oliver M Sieber; Clinton R Bruce; Greg M Kowalski Journal: Metabolites Date: 2016-10-13
Authors: Kirstie A De Jong; Liam G Hall; Mark C Renton; Timothy Connor; Sheree D Martin; Greg M Kowalski; Christopher S Shaw; Clinton R Bruce; Kirsten F Howlett; Sean L McGee Journal: Mol Metab Date: 2020-10-21 Impact factor: 7.422