A PHYSIOLOGIC APPROACH TO INVESTIGATE LIPID-INDUCED INSULIN RESISTANCE INDEPENDENT OF OBESITY
In a new article published in Diabetes (August 2017) by Danish Diabetes Academy PhD Annemarie Lundsgaard and colleagues from Section of Molecular Physiology, University of Copenhagen, it is investigated how substrate metabolism of skeletal muscle is altered in response to excess dietary provision of fatty acids or carbohydrates in healthy subjects.
AN EXPERIMENTAL SETTING WITH A PHYSIOLOGICAL APPROACH WAS APPLIED
It is well documented that insulin´s ability to stimulate glucose disposal is reduced when healthy subjects are subjected to intravenous lipid infusion. By use of this model the causative mechanisms in muscle have been investigated, though with inconsistent findings as to whether or not insulin signaling is impaired.
An experimental setting with a more physiologic approach was thus applied, with fatty acid availability being enhanced through the diet. Healthy men ingested a high-fat diet with 78E% fat (mainly unsaturated fat) under conditions of 75% energy surplus. To separate lipid oversupply from caloric oversupply, a high-carbohydrate diet with matched energy surplus was also provided, together with a control diet in a cross-over design. The intervention period was set to three days.
METABOLIC SUBSTRATE FLUX REGULATES INSULIN ACTION
The high-fat diet reduced insulin-stimulated glucose disposal during a hyperinsulinemic-euglycemic clamp by 20%. This reduction could not be ascribed to impaired insulin signaling in skeletal muscle. Accumulation of the lipid intermediate diacylglycerol was obtained, but it was notably the sn-1,3 diacylglycerol isoform, known not to interfere with insulin signaling. Rather, it was found that the high-fat diet increased pyruvate dehydrogenase E1α phosphorylation, and thereby decreased activity of the pyruvate dehydrogenase complex. The resulting decrease in pyruvate conversion to acetyl-CoA enabled an increased TCA influx of acetyl-CoA from beta-oxidation and thereby increased fatty acid oxidation. The reciprocal aspect was observed after the high-carbohydrate diet, after which the insulin-stimulated glucose disposal was increased.
The results suggest that a high fat intake is associated with a moderate downregulation of insulin action to stimulate glucose uptake in healthy humans when coupled with marked energy excess. This was related to a switch in mitochondrial substrate selection, why oxidative fluxes of glucose and fatty acids seemed to oppositely determine insulin action. After the high-fat diet, increased muscle G6P content was observed during insulin-stimulation, likely related to slowing of glycolysis upstream of pyruvate dehydrogenase. This G6P accumulation did potentially lead to inhibition glucose uptake, proving the concept of a Randle´s cycle-related mechanism.
When putting the results in perspective, the downregulation of muscle glucose uptake under conditions of high fat availability may, at least in healthy subjects, reflect an appropriate and reversible substrate switch, rather than a pathologic insulin resistance.
AUTHORS AND AFFILIATION
Anne-Marie Lundsgaard1, Kim A. Sjøberg1, Louise D. Høeg1, Jacob Jeppesen1, Andreas B. Jordy1, Annette K. Serup1, Andreas M. Fritzen1, Henriette Pilegaard2, Lene S. Myrmel3, Lise Madsen3,4, Jørgen F. P. Wojtaszewski1, Erik A. Richter1, Bente Kiens1
1Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
2Department of Biology, University of Copenhagen, Copenhagen, Denmark
3National Institute of Nutrition and Seafood Research, Bergen, Norway
4Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark
Source: Diabetes