Opposite regulation of insulin sensitivity by dietary lipid versus carbohydrate excess

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To understand the mechanisms in lipid-induced insulin resistance, a more physiologic approach is to enhance FA availability through the diet. Nine healthy men ingested two hypercaloric diets (+75 E%) for three days, enriched in unsaturated FA (78 E% fat; UNSAT) or carbohydrates (80 E% carbohydrate; CHO) as well as a eucaloric control diet (CON). Compared to CON, UNSAT reduced whole body and leg glucose disposal during a hyperinsulinemic-euglycemic clamp, while decreasing hepatic glucose production. In muscle, DAG and IMTG 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 Ser(300) phosphorylation and FA oxidation. CHO increased whole body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser(300) phosphorylation was decreased, and glucose oxidation increased. After UNSAT, but not CHO, muscle G6P content was 103 % higher compared to CON during the clamp. Thus, PDH-E1α expression and covalent regulation, and hence the TCA influx of pyruvate-derived acetyl-CoA relative to beta-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.

Original languageEnglish
JournalDiabetes
Volume66
Issue number10
Pages (from-to)2583-2595
Number of pages13
ISSN0012-1797
DOIs
Publication statusPublished - 2017

    Research areas

  • Journal Article

ID: 181945697