Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Abstract

Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P < 0.01) i.v. infused with insulin (1.5 milliunits͞kg of fat-free mass per min) while clamping glucose, amino acids, glucagon, and growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164 -180%) encoding mitochondrial proteins (P < 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P < 0.05). Further studies demonstrated no effect of low to high insulin levels on muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16 -26% (P < 0.02) when four different substrate combinations were used. In conclusion, insulin stimulates mitochondrial oxidative phosphorylation in skeletal muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels.cytochrome c oxidase ͉ NADH dehydrogenase subunit IV ͉ amino acids ͉ citrate synthase

Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes

“…Thus, in addition to the blunted response in type 2 diabetic subjects, we found that the insulin-mediated suppression of plasma adiponectin was in fact associated with improved insulin action on R d , glucose oxidation, RQ and lipid oxidation. Also, the decrease in plasma adiponectin during physiological hyperinsulinaemia actually parallels the finding of sustained activation of glucose metabolism and insulin signalling molecules in response to insulin infusion for 3-4 h in humans [30,36,49], and insulin infusion for even longer periods (8 h) improves mitochondrial ATP production [50]. As with the ability of insulin to decrease plasma adiponectin, these actions of insulin are impaired in patients with type 2 diabetes, and are thought to contribute to insulin resistance [30,50].…”

“…Also, the decrease in plasma adiponectin during physiological hyperinsulinaemia actually parallels the finding of sustained activation of glucose metabolism and insulin signalling molecules in response to insulin infusion for 3-4 h in humans [30,36,49], and insulin infusion for even longer periods (8 h) improves mitochondrial ATP production [50]. As with the ability of insulin to decrease plasma adiponectin, these actions of insulin are impaired in patients with type 2 diabetes, and are thought to contribute to insulin resistance [30,50]. Therefore, our data suggest that insulin-mediated suppression of adiponectin may have a physiological role, which may be beneficial rather than simply reflecting the effect of chronic hyperinsulinaemia.…”

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

“…First, 2 h of physiological hyperinsulinaemia increases muscle ATP production in healthy individuals, as evaluated by nuclear magnetic resonance spectroscopy [39,40]. The same effect is seen in isolated muscle mitochondria obtained from healthy individuals after 4 h of insulin infusion, suggesting that this response it not solely due to increased substrate fluxes [41]. Analogous to the diminished effect of insulin on Tyr361 phosphorylation in insulin-resistant individuals in our study, there is an impaired effect of insulin on ATP production in patients with type 2 diabetes and high-risk individuals in these studies [39][40][41].…”

Dexamethasone impairs muscle energetics, studied by 31P NMR, in rats

“…Insulin stimulates oxidative phosphorylation capacity [3] while insulin resistance appears to inhibit respiration and decrease the efficiency of ATP production. Indeed, nonalcoholic steatohepatitis elicits mitochondrial dysfunction leading to a reduction of 30-60% in the activities of the five respiratory chain complexes in the liver.…”