Opposite Regulation of Insulin Sensitivity by Dietary Lipid Versus Carbohydrate Excess

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 -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 phosphorylation and FA oxidation. CHO increased whole-body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser 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.

Fatty acid type–specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle

“…Muscle sn ‐1,3 DAG and IMTG content for the Unsat group has been previously published by Lundsgaard et al . (17).…”

“…This is congruent with an accumulating body of evidence (46–50) suggesting that acutely augmented availability of circulating lipids does not inhibit insulin‐stimulated muscle glucose uptake by regulation at the proximal part of the canonical insulin signaling. We recently demonstrated that consumption of a hypercaloric HFD enriched in Unsats for 3 d increased FA oxidation and inhibited muscle pyruvate dehydrogenase phosphoregulation, resulting in accumulation of glucose‐6‐phosphate content compared to the Con diet (17). This diet‐induced inhibition of pyruvate dehydrogenase correlated to the reduced insulin‐stimulated glucose uptake in muscle (17).…”

“…We recently demonstrated that consumption of a hypercaloric HFD enriched in Unsats for 3 d increased FA oxidation and inhibited muscle pyruvate dehydrogenase phosphoregulation, resulting in accumulation of glucose‐6‐phosphate content compared to the Con diet (17). This diet‐induced inhibition of pyruvate dehydrogenase correlated to the reduced insulin‐stimulated glucose uptake in muscle (17). Whether the consumption of Sats induces a similar regulation on insulin‐stimulated glucose uptake in humans remains to be elucidated.…”

“…Subject characteristics are given in Table 1 . Subject characteristics for the Unsat group (17) and for all the 17 subjects as a whole (18) have been previously published.…”

A 7‐day high‐fat, high‐calorie diet induces fibre‐specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle

“…Importantly, it was recently reported that 3 days of excessive dietary fat intake reduced insulin‐stimulated leg glucose uptake without changes in skeletal muscle signalling (Lundsgaard et al . ). This is very similar to our own observations, where 7 days on a HFHC diet resulted in reduced postprandial glycaemic control that was attributable to reduced glucose clearance (determined using dual‐glucose tracers during an oral glucose challenge) despite maintained skeletal muscle insulin signalling (Parry et al .…”