Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria

Abstract

Rindler PM, Crewe CL, Fernandes J, Kinter M, Szweda LI. Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria. Am J Physiol Heart Circ Physiol 305: H634 -H643, 2013. First published June 21, 2013; doi:10.1152/ajpheart.00799.2012.-Obesity enhances the risk for the development of type 2 diabetes and cardiovascular disease. Loss in insulin sensitivity and diminished ability of muscle to take up and use glucose are characteristics of type 2 diabetes. Paradoxically, regulatory mechanisms that promote utilization of fatty acids appear to initiate diet-induced insulin insensitivity. In this review, we discuss recent findings implicating increased mitochondrial production of the prooxidant H 2O2 due to enhanced utilization of fatty acids, as a signal to diminish reliance on glucose and its metabolites for energy. In the short term, the ability to preferentially use fatty acids may be beneficial, promoting a metabolic shift that ensures use of available fat by skeletal muscle and heart while preventing intracellular glucose accumulation and toxicity. However, with prolonged consumption of high dietary fat and ensuing obesity, the near exclusive dependence on fatty acid oxidation for production of energy by the mitochondria drives insulin resistance, diabetes, and cardiovascular disease. mitochondria; metabolic flexibility; redox signaling; insulin signaling; obesity THIS ARTICLE is part of a collection on Mitochondria in Cardiovascular Physiology and Disease. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…2013). The following mechanisms are likely responsible for the oxidative stress observed in hearts of fructose‐fed rats.…”

“…Second, excess in reducing equivalents (i.e., NADH and FADH 2 ) provided by enhanced fatty acid oxidation increase the QH 2 /Q ratio, which consequently increases ROS production by (1) limiting the availability of oxidized Q as an electron acceptor for complex I, (2) generating reverse electron transport back into complex I, and/or (3) increasing the electron pressure at complex III (Fisher‐Wellman and Neufer 2012; Rindler et al. 2013). This fatty acid oxidation‐dependent ROS generation may be a hallmark of T2DM and has been reported to occur in the heart (Boudina et al.…”

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

“…This includes an increase in flux through the pentose phosphate pathway and the production of glycogen. Indeed, nicotinamide‐adenine dinucleotide phosphate, reduced form, produced by the pentose phosphate pathway, can increase antioxidant capacity, and this may be a necessary adaptation that counters the increase in reactive oxygen species production that occurs with fatty acid oxidation 38, 39. However, prolonged rerouting of glucose to alternative pathways, especially when circulating glucose levels are elevated, may be detrimental for cardiac health.…”

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

“…In fact, although the observation that the cellular models of IR are characterized by persistently elevated ROS levels (Houstis et al 2006) suggests that ROS contribute to IR, there are other data that suggest a completely opposite view. At present, it is well established that H 2 O 2 is able to exert stimulatory or inhibitory effects on insulin signaling, depending on the concentration of H 2 O 2 and/or the site of production relative to various components of insulin signaling pathway(s) (Rindler et al 2013). However, it is unclear as to why in certain cellular and animal models, increased ROS levels are associated with IR and scavenging the oxidants improves metabolic homeostasis, whereas in other models, increased ROS levels are associated with improved insulin sensitivity and antioxidants make things worse.…”

“…It has been proposed that a decrease in mitochondrial fatty acid oxidation caused by mitochondrial dysfunction and/or reduced mitochondrial content leads to the accumulation of increased levels of intracellular fatty acyl-CoA and diacylglycerol, which interfere with the insulin signaling (Lowell & Shulman 2005). It has also been proposed that the development of IR in skeletal muscle is due to an enhancement in mitochondrial oxidant production in response to excess fuel relative to demand, which results, through different pathways, in decreased insulin signaling and glucose transport (Rindler et al 2013).…”