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

• Published in: Biochemical and biophysical research communications 2015-08, Vol.463 (4), p.818-824
• Main Authors: Kowalski, Greg M., De Souza, David P., Risis, Steve, Burch, Micah L., Hamley, Steven, Kloehn, Joachim, Selathurai, Ahrathy, Lee-Young, Robert S., Tull, Dedreia, O'Callaghan, Sean, McConville, Malcolm J., Bruce, Clinton R.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; CARBON 13; CARBOXYLASE; Cardiac insulin resistance; COMPARATIVE EVALUATIONS; Diet, High-Fat; EVOLUTION; FATS; GAS CHROMATOGRAPHY; Gas Chromatography-Mass Spectrometry; GLUCOSE; Glucose - metabolism; Glucose Clamp Technique; HEART; Hyperinsulinism - metabolism; IN VIVO; INSULIN; Insulin Resistance; Male; MASS; MASS SPECTROSCOPY; METABOLISM; Metabolomics; MICE; Mice, Inbred C57BL; MUSCLES; Myocardium - metabolism; ORAL ADMINISTRATION; SENSITIVITY; Stable isotopes; UPTAKE
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.06.019

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. 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. 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-13C] glucose. Hearts were collected after 15 and 60 min and flux profiling was determined by measuring 13C 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. Under experimental conditions which closely mimic the postprandial state, the insulin resistant mouse heart retains the ability to stimulate glucose metabolism. •Insulin clamp was used to determine the evolution of cardiac insulin resistance.•Clamp measures were compared to a dynamic metabolomics approach.•The clamp revealed the presence of cardiac insulin resistance after 3 weeks of HFD.•Cardiac glucose metabolism was not affected by HFD during an oral glucose challenge.