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Diabetes. 2017 Oct;66(10):2583-2595. doi: 10.2337/db17-0046. Epub 2017 Aug 2.

Opposite Regulation of Insulin Sensitivity by Dietary Lipid Versus Carbohydrate Excess.

Author information

1
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
2
Department of Biology, University of Copenhagen, Copenhagen, Denmark.
3
National Institute of Nutrition and Seafood Research, Bergen, Norway.
4
Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
5
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark bkiens@nexs.ku.dk.

Abstract

To understand the mechanisms in lipid-induced insulin resistance, a more physiological approach is to enhance fatty acid (FA) availability through the diet. Nine healthy men ingested two hypercaloric diets (in 75% excess of habitual caloric intake) for 3 days, enriched in unsaturated FA (78 energy % [E%] fat) (UNSAT) or carbohydrates (80 E% carbohydrate) (CHO) as well as a eucaloric control diet (CON). Compared with CON, the UNSAT diet reduced whole-body and leg glucose disposal during a hyperinsulinemic-euglycemic clamp, while decreasing hepatic glucose production. In muscle, diacylglycerol (DAG) and intramyocellular triacylglycerol were increased. The accumulated DAG was sn-1,3 DAG, which is known not to activate PKC, and insulin signaling was intact. UNSAT decreased PDH-E1α protein content and increased inhibitory PDH-E1α Ser300 phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser300 phosphorylation was decreased, and glucose oxidation increased. After UNSAT, but not CHO, muscle glucose-6-phosphate content was 103% higher compared with CON during the clamp. Thus, PDH-E1α expression and covalent regulation, and hence the tricarboxylic acid cycle influx of pyruvate-derived acetyl-CoA relative to β-oxidation-derived acetyl-CoA, are suggested to impact on insulin-stimulated glucose uptake. Taken together, the oxidative metabolic fluxes of glucose and FA are powerful and opposite regulators of insulin action in muscle.

PMID:
28768703
DOI:
10.2337/db17-0046
[Indexed for MEDLINE]
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