TY - JOUR

T1 - Opposite regulation of insulin sensitivity by dietary lipid versus carbohydrate excess

AU - Lundsgaard, Annemarie

AU - Sjøberg, Kim Anker

AU - Høeg, Louise Dalgas

AU - Jeppesen, Jacob

AU - Jordy, Andreas Børsting

AU - Serup, Annette Karen Lundbeck

AU - Fritzen, Andreas Mæchel

AU - Pilegaard, Henriette

AU - Myrmel, Lene Secher

AU - Madsen, Lise

AU - Wojtaszewski, Jørgen

AU - Richter, Erik A.

AU - Kiens, Bente

N1 - CURIS 2017 NEXS 265

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.2337/db17-0046

DO - 10.2337/db17-0046

M3 - Journal article

C2 - 28768703

VL - 66

SP - 2583

EP - 2595

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 10

ER -