Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 315, Issue 2, Pages E258-E266Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00386.2017
Keywords
glucose oxidation; hyperinsulinemic-euglycemic clamp; insulin resistance; muscle insulin action; Randle cycle
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Funding
- Australian Government Department of Health National Health and Medical Research Council [1003313, 535921]
- University of New South Wales
- Australian Postgraduate Awards
- NIFA [811096, 1003313] Funding Source: Federal RePORTER
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Pyruvate dehydrogenase (PDH) activity is a key component of the glucose/fatty acid cycle hypothesis for the regulation of glucose uptake and metabolism. We have investigated whether acute activation of PDH in muscle can alleviate the insulin resistance caused by feeding animals a high-fat diet (HFD). The importance of PDH activity in muscle glucose disposal under insulin-stimulated conditions was determined by infusing the PDH kinase inhibitor dichloroacctate (DCA) into HFD-fcd Wistar rats during a hyperinsulincmiceuglycemic clamp. Acute DCA infusion did not alter glucose infusion rate, glucose disappearance, or hepatic glucose production but did decrease plasma lactate levels. DCA substantially increased muscle PDH activity; however, this did not improve insulin-stimulated glucose uptake in insulin-resistant muscle of IIFD rats. DCA infusion increased the flux of pyruvate to acetyl-CoA and reduced glucose incorporation into glycogen and alanine in muscle. Similarly, in isolated muscle, DCA treatment increased glucose oxidation and decreased glycogen synthesis without changing glucose uptake. These results suggest that, although PDH activity controls the conversion of pyruvate to acetyl-CoA for oxidation, this has little effect on glucose uptake into muscle under insulin-stimulated conditions.
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