title: Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria.
abstract: 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 H2O2 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.
authors.affiliation: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;
authors.forename: Paul M
authors.initials: PM
authors.lastname: Rindler
authors.forename: Clair L
authors.initials: CL
authors.lastname: Crewe
authors.forename: Jolyn
authors.initials: J
authors.lastname: Fernandes
authors.forename: Michael
authors.initials: M
authors.lastname: Kinter
authors.forename: Luke I
authors.initials: LI
authors.lastname: Szweda
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000453:epidemiology; D003920:Diabetes Mellitus / Q000453:epidemiology; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000378:metabolism; D010084:Oxidation-Reduction; D012307:Risk Factors
chemical_list: D005227:Fatty Acids; D005947:Glucose
keywords: insulin signaling; metabolic flexibility; mitochondria; obesity; redox signaling