Bioenergetic functions in subpopulations of heart mitochondria are preserved in a non-obese type 2 diabetes rat model (Goto-Kakizaki)

Abstract

A distinct bioenergetic impairment of heart mitochondrial subpopulations in diabetic cardiomyopathy is associated with obesity; however, many type 2 diabetic (T2DM) patients with high-risk for cardiovascular disease are not obese. In the absence of obesity, it is unclear whether bioenergetic function in the subpopulations of mitochondria is affected in heart with T2DM. To address this issue, a rat model of non-obese T2DM was used to study heart mitochondrial energy metabolism, measuring bioenergetics and enzyme activities of the electron transport chain (etc). oxidative phosphorylation in the presence of substrates for ETC and ETC activities in both populations of heart mitochondria in T2DM rats were unchanged. Despite the preservation of mitochondrial function, aconitase activity in T2DM heart was reduced, suggesting oxidative stress in mitochondria. Our study indicate that metabolic function of heart mitochondria is unchanged in the face of oxidative stress and point to a critical role of obesity in T2DM cardiomyopathy.www.nature.com/scientificreports www.nature.com/scientificreports/ between diastolic dysfunction and cardiac triglyceride levels which are higher in healthy obese subjects and lean and obese diabetic patients than lean healthy subjects 11,12 .Cardiac abnormalities in obese and type 2 diabetic patients have been investigated with animal models of obesity and type 1 diabetes (T1DM) and T2DM 6 in which cardiac contractile efficiency and mitochondrial metabolism showed progressive declines 13,14 with an increased reactive oxygen species (ROS) production and lipid peroxidation. Although both model of type 1 and 2 are used to study diabetic cardiomyopathy, differences in bioenergetic function exist between them. In T1DM mice fed a regular chow diet, cardiac dysfunction was reported without any mitochondrial respiration defects, but in T2DM mice fed with high-fat diet, insulin resistance was accompanied by impairment of oxidative phosphorylation 5 . Nevertheless, these studies did not investigate the subpopulations of heart mitochondria (subsarcolemmal and interfibrillar), which have been reported to be differently affected by cardiomyopathy in hamster 15 and mice with T1DM 16 and T2DM 17 .Among the animal models 18 of diabetic cardiomyopathy, Goto-Kakizaki (GK) rats 6,19 have the unique feature of being insulin-resistant without obesity 20,21 . The GK model was reported to have a mild cardiomyopathy characterized by diastolic dysfunction 20 . Increased susceptibility to oxidative stress was observed in GK heart mitochondria 22 , but bioenergetic functions were not reported.A previous study in skeletal muscle of GK rats showed preserved bioenergetic function in both mitochondrial subpopulations 23 . In the current study, we evaluated bioenergetic function in heart mitochondrial subpopulations of the same non-obese diabetic GK rats at 18 and 28 weeks and found that metabolic function is preserved in both subpopulations of mitochondria despite induced mitochondrial stress. Scientific RepoRtS |(2020) 10:54...

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