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
AU - Kiens, Bente
N1 - CURIS 2017 NEXS 265
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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 hyper-insulinemic-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-E1a protein content and increased inhibitory PDH-E1a Ser300 phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1a 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-E1a expression and covalent regulation, and hence the tricarboxylic acid cycle influx of pyruvate-derived acetyl-CoA relative to b-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 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 hyper-insulinemic-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-E1a protein content and increased inhibitory PDH-E1a Ser300 phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1a 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-E1a expression and covalent regulation, and hence the tricarboxylic acid cycle influx of pyruvate-derived acetyl-CoA relative to b-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
SN - 0012-1797
VL - 66
SP - 2583
EP - 2595
JO - Diabetes
JF - Diabetes
IS - 10
ER -