Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans

Abstract

Muscle insulin resistance is a key feature of obesity and type 2 diabetes and is strongly associated with increased intramyocellular lipid content and inflammation. However, the cellular and molecular mechanisms responsible for causing muscle insulin resistance in humans are still unclear. To address this question, we performed serial muscle biopsies in healthy, lean subjects before and during a lipid infusion to induce acute muscle insulin resistance and assessed lipid and inflammatory parameters that have been previously implicated in causing muscle insulin resistance. We found that acute induction of muscle insulin resistance was associated with a transient increase in total and cytosolic diacylglycerol (DAG) content that was temporally associated with protein kinase (PKC)θ activation, increased insulin receptor substrate (IRS)-1 serine 1101 phosphorylation, and inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation and AKT2 phosphorylation. In contrast, there were no associations between insulin resistance and alterations in muscle ceramide, acylcarnitine content, or adipocytokines (interleukin-6, adiponectin, retinol-binding protein 4) or soluble intercellular adhesion molecule-1. Similar associations between muscle DAG content, PKCθ activation, and muscle insulin resistance were observed in healthy insulin-resistant obese subjects and obese type 2 diabetic subjects. Taken together, these data support a key role for DAG activation of PKCθ in the pathogenesis of lipid-induced muscle insulin resistance in obese and type 2 diabetic individuals.lipotoxicity | insulin signaling

Dysregulation of muscle glycogen synthase in recovery from exercise in type 2 diabetes

“…Indeed, the observed exerciseinduced increase in plasma NEFA, which was sustained at least 3 h into recovery in both groups as shown previously [38], is a physiological response that might explain the lack of increase in whole-body insulin-stimulated glucose metabolism by both changes in substrate preferences and perhaps signalling mechanisms [39][40][41]. Moreover, NEFA levels remained elevated during the post-exercise clamp in the diabetic individuals.…”

Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes

“…It should be noted that adjusting for circulating NEFA abolished the association of V : O 2max and ΔRQ with insulin sensitivity, underlining the superior importance of lipidaemia in insulin resistance. Although the only-marginal associations of V : O 2max and ΔRQ with M value in women may suggest a sex-specific difference, NEFA elevation has comparable effects on insulin resistance and muscle energy metabolism in both men and women [1]. Thus, the observed differences in the associations could also be due to the lower statistical power of the analyses of the female study population (n = 43).…”

“…Furthermore ΔRQ related positively, whereas fasting RQ related negatively, to serum NEFA, reflecting higher fasting lipid oxidation. Lipid elevation can give rise to diacylglycerols, which contribute to insulin resistance [1]. However, NEFA concentrations vary substantially in obese and T2D patients and may be higher during short-term fasting even in insulin-sensitive humans [7].…”

“…Blood glucose concentration was measured by the hexokinase method (EPOS 5060 analyser; Eppendorf, Hamburg, Germany), serum concentrations of insulin and C-peptide chemoluminimetrically, NEFA microfluorimetrically [1] (n = 78), triacylglycerols on a Cobas C311 analyser (Roche Diagnostics, Mannheim, Germany), and high-sensitivity C-reactive protein (hsCRP) on a Roche Hitachi 912 analyser (Roche Diagnostics, Mannheim, Germany). Explorative genotyping for single-nucleotide polymorphisms (SNPs) of genes known to affect mitochondrial function and/or insulin sensitivity (PPARG, NDUFB6, PGC1α [also known as PPARGC1A], PPARA, ADRB2 and FTO) was performed in 134 participants (see electronic supplementary material [ESM]).…”

“…The latter comprise excess lipid availability with activation of the diacylglycerol-protein kinase C pathway [1] abnormalities in mitochondrial function [2] and glucose toxicity, at least in individuals with overt type 2 diabetes mellitus.…”