Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)–nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction

Abstract

Aims/hypothesis Insulin effects reportedly involve reactive oxygen species (ROS) and oxidative stress in vitro, but skeletal muscle oxidative stress is an emerging negative regulator of insulin action following high-fat feeding. NEFA may enhance oxidative stress and insulin resistance. We investigated the acute impact of insulin with or without NEFA elevation on muscle ROS generation and insulin signalling, and the potential association with altered muscle mitochondrial function. Methods We used hyperinsulinaemic-euglycaemic clamping, 150 min, without or with lipid infusion to modulate plasma NEFA concentration in lean rats. Results Insulin and glucose (Ins) infusion selectively enhanced xanthine oxidase-dependent muscle ROS generation. Ins with lipid infusion (Ins+NEFA) lowered whole-body glucose disposal and muscle insulin signalling, and these effects were associated with high muscle mitochondrial ROS generation and activation of the proinflammatory nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) pathway. Antioxidant infusion prevented NEFA-induced systemic insulin resistance and changes in muscle mitochondrial ROS generation, IκB-NFκB pathway and insulin signalling. Changes in insulin sensitivity and signalling were independent of changes in mitochondrial enzyme activity and ATP production, which, in turn, were not impaired by changes in ROS generation under any condition. Conclusions/interpretation Acute muscle insulin effects include enhanced ROS generation through xanthine oxidase. Additional NEFA elevation enhances mitochondrial ROS generation, activates IκB-NFκB and reduces insulin signalling. These alterations are not associated with acute reductions in mitochondrial enzyme activity and ATP production, and are reversed by antioxidant infusion. Thus, NEFA acutely cause systemic and muscle insulin resistance by enhancing muscle oxidative stress through mitochondrial ROS generation and IκB-NFκB activation.

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

“…A potential limitation of the present study is that only the 16 week endpoint variables were examined, making it impossible to comment on the favourable short-term effects of antioxidant treatment on insulin sensitivity that have been reported by others [47]. Nor can we exclude putative beneficial effects of SkQ treatment upon prolonged exposure.…”

Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases

“…They are also available from the tibia, femur, sternum, lumbar spine. The acquisition sites of BM-MSCs in large animals are the same as humans, however, rabbits' BM-MSCs need to be extracted in the middle of the tibia or femur bone marrow (11)(12)(13). The proportion of BM-MSCs nucleated cell population accounts for less than 0.0001% of them, however they can easily be isolated and expanded by using certain cell culture techniques (10).…”

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

“…Furthermore, an increase in plasma FFA leads to endothelial activation, inflammation and thrombosis which may initiate early vascular abnormalities that promote atherosclerosis [72][73][74][75][76][77]. Elevation of plasma FFA, in addition to producing peripheral and hepatic insulin resistance, also activates the proinflammatory NFκB pathway [73][74][75][76][77][78][79][80][81][82][83][84] resulting in increased hepatic expression of several proinflammatory cytokines including TNF-α, IL1-β, IL6, matrix metalloproteinases and an increase in circulating MCP-1 [85][86][87][88][89], supporting the notion that FFA is an important link between hypertriglyceridemia and the development of inflammatory changes [90][91][92][93][94][95][96][97][98][99]. Moreover, elevated plasma FFA levels, via producing insulin resistance and hyperinsulinemia, promote a state of increased tendency for thrombosis and decreased ability to fibrinolysis.…”