https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=32125087&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 321250872021051420210514
1753-04071272020JulJournal of diabetesJ DiabetesImpaired substrate-mediated cardiac mitochondrial complex I respiration with unaltered regulation of fatty acid metabolism and oxidative stress status in type 2 diabetic Asian Indians.542555542-55510.1111/1753-0407.13031The cardiovascular complications associated with type 2 diabetes mellitus could be attributed to changes in myocardial mitochondrial metabolism. Though it is a known fact that permeabilized cardiac muscle fibers and isolated mitochondria are metabolically compromised in the Caucasian population, studies of Asian Indian myocardial mitochondrial function are lacking. Thus, the objective of the present study is to analyze if there is altered cardiac mitochondrial substrate utilization in diabetic Asian Indians.Mitochondrial substrate utilization was measured using high-resolution respirometry in isolated mitochondria prepared from right atrial appendage tissues of diabetic and nondiabetic subjects undergoing coronary artery bypass graft surgery. Western blotting and densitometric analysis were also done to compare the levels of proteins involved in fatty acid metabolism and regulation.The mitochondrial oxygen consumption rate for fatty acid substrate was shown to be decreased in diabetic subjects compared to nondiabetic subjects along with an unvaried mitochondrial DNA copy number and uniform levels of electron transport chain complex proteins and proteins involved in fatty acid metabolism and regulation. Decreased glutamate but unchanged pyruvate-mediated state 3 respiration were also observed in diabetic subjects.The current study reports deranged cardiac mitochondrial fatty acid-mediated complex I respiration in type 2 diabetic Asian Indians with comparable levels of regulators of fatty acid oxidation to that of nondiabetic myocardium. Altered glutamate-mediated mitochondrial respiration also points toward possible alterations in mitochondrial complex I activity. When compared with previous reports on other ethnic populations, the current study suggests that Asian Indian population too have altered cardiac mitochondrial substrate utilization.© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.JayakumariNandini RNRDepartment of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.RajendranRaji SRSDepartment of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.SivasailamAshokADepartment of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.VimalaSurabhi SSSDepartment of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.NandaSaurabhSDepartment of Cardiovascular and Thoracic Surgery, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.ManjunathaShankarappaSDivision of Endocrinology, Diabetes, Metabolism, Nutrition, Mayo Clinic, Rochester, Minnesota, USA.Department of Physiology, All India Institute of Medical Sciences, Bibi Nagar, Telangana, India.PillaiVivek VVVDepartment of Cardiovascular and Thoracic Surgery, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.KarunakaranJayakumarJDepartment of Cardiovascular and Thoracic Surgery, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.GopalaSrinivasS0000-0001-5885-6256Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, India.engJournal Article20200406
AustraliaJ Diabetes1015043261753-04070Fatty Acids0Reactive Oxygen SpeciesEC 7.1.1.2Electron Transport Complex IIMDiabetes Mellitus, Type 2metabolismElectron Transport Complex ImetabolismFatty AcidsmetabolismFemaleHumansIndiaLipid MetabolismphysiologyMaleMiddle AgedMitochondria, HeartmetabolismMyocardiummetabolismMyocytes, CardiacmetabolismOxidative StressphysiologyOxygen ConsumptionphysiologyReactive Oxygen Speciesmetabolism背景: 2型糖尿病心血管并发症可能与心肌线粒体代谢改变有关。虽然在白种人群中通透性心肌纤维和分离的线粒体在代谢上受到损害是众所周知的事实, 但对亚裔印度人心肌线粒体功能的研究还很缺乏。因此, 本研究旨在分析在糖尿病亚裔印度人中是否存在心肌线粒体底物利用率的改变。 方法: 采用高分辨率呼吸计量仪, 测定糖尿病和非糖尿病冠脉搭桥术患者的右心耳分离的线粒体底物利用率。蛋白免疫印迹和密度分析也被用来比较脂肪酸代谢和调节相关的蛋白质水平。 结果: 糖尿病患者与非糖尿病患者相比, 线粒体脂肪酸底物耗氧率降低, 线粒体DNA拷贝数相同, 电子传递链复合物蛋白和脂肪酸代谢调节蛋白水平一致。在糖尿病患者中也观察到谷氨酸减少, 但丙酮酸介导的状态三呼吸速率不变。 结论: 本研究报告了在2型糖尿病亚裔印度人中, 脂肪酸介导的心肌线粒体复合体I呼吸紊乱, 而脂肪酸氧化调节水平则与非糖尿病人群的心肌相当。改变谷氨酸介导的线粒体呼吸也可能导致线粒体复合物I活性的改变。与以前其他种族群体的报告相比, 目前的研究表明亚洲印度群体心肌线粒体底物的利用也发生了改变。.© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.2型糖尿病Asian Indianscardiac mitochondriafatty acid metabolismsirtuinstype 2 diabetes mellitus亚洲印度人去乙酰化酶心肌线粒体脂肪酸代谢20191224202012220202102020346020215156020203460ppublish3212508710.1111/1753-0407.13031REFERENCESWHO | Global report on diabetes. http://www.who.int/diabetes/global-report/en/. Accessed July 20, 2018.Marciniak C, Marechal X, Montaigne D, Neviere R, Lancel S. Cardiac contractile function and mitochondrial respiration in diabetes-related mouse models. Cardiovasc Diabetol. 2014;13:118. https://doi.org/10.1186/s12933-014-0118-7.Ramachandran A, Ma RCW, Snehalatha C. Diabetes in Asia. Lancet. 2010;375(9712):408-418. https://doi.org/10.1016/S0140-6736(09)60937-5.Anjana RM, Unnikrishnan R, Mugilan P, et al. Causes and predictors of mortality in Asian Indians with and without diabetes-10 year follow-up of the Chennai Urban Rural Epidemiology Study (CURES - 150). PLoS One. 2018;13(7):e0197376. https://doi.org/10.1371/journal.pone.0197376.Ramachandran A, Snehalatha C, Kapur A, et al. High prevalence of diabetes and impaired glucose tolerance in India: National Urban Diabetes Survey. Diabetologia. 2001;44(9):1094-1101. https://doi.org/10.1007/s001250100627.Ramachandran A, Snehalatha C, Latha E, Manoharan M, Vijay V. Impacts of urbanisation on the lifestyle and on the prevalence of diabetes in native Asian Indian population. Diabetes Res Clin Pract. 1999;44(3):207-213.The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impa… - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/16391903. Accessed September 25, 2019.Low risk threshold for acquired diabetogenic factors in Asian Indians. - PubMed - NCBI. https://www.ncbi.nlm.nih.gov/pubmed/15331198. Accessed September 25, 2019.Chandalia M, Lin P, Seenivasan T, et al. Insulin resistance and body fat distribution in South Asian men compared to caucasian men. PLoS One. 2007;2(8):e812. https://doi.org/10.1371/journal.pone.0000812.Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96(7):2190-2196.Scheuermann-Freestone M, Madsen PL, Manners D, et al. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation. 2003;107(24):3040-3046. https://doi.org/10.1161/01.CIR.0000072789.89096.10.Diamant M, Lamb HJ, Groeneveld Y, et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol. 2003;42(2):328-335.Peterson LR, Herrero P, Schechtman KB, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation. 2004;109(18):2191-2196. https://doi.org/10.1161/01.CIR.0000127959.28627.F8.Rijzewijk LJ, van der Meer RW, Lamb HJ, et al. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol. 2009;54(16):1524-1532. https://doi.org/10.1016/j.jacc.2009.04.074.Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol. 2009;54(20):1891-1898. https://doi.org/10.1016/j.jacc.2009.07.031.Montaigne D, Marechal X, Coisne A, et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation. 2014;130(7):554-564. https://doi.org/10.1161/CIRCULATIONAHA.113.008476.Croston TL, Thapa D, Holden AA, et al. Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. Am J Physiol Heart Circ Physiol. 2014;307(1):H54-H65. https://doi.org/10.1152/ajpheart.00845.2013.Duicu OM, Lighezan R, Sturza A, et al. Assessment of mitochondrial dysfunction and monoamine oxidase contribution to oxidative stress in human diabetic hearts. Oxid Med Cell Longev. 2016;2016:8470394-12. https://doi.org/10.1155/2016/8470394.Bertrand L, Horman S, Beauloye C, Vanoverschelde J-L. Insulin signalling in the heart. Cardiovasc Res. 2008;79(2):238-248. https://doi.org/10.1093/cvr/cvn093.Jenkins Y, Sun T-Q, Markovtsov V, et al. AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. PLoS One. 2013;8(12):e81870. https://doi.org/10.1371/journal.pone.0081870.Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med. 2000;10(6):238-245.Bharathi SS, Zhang Y, Mohsen A-W, et al. Sirtuin 3 (SIRT3) Protein Regulates Long-chain Acyl-CoA Dehydrogenase by Deacetylating Conserved Lysines Near the Active Site. J Biol Chem. 2013;288(47):33837-33847. https://doi.org/10.1074/jbc.M113.510354.Ichihara S, Suzuki Y, Chang J, et al. Involvement of oxidative modification of proteins related to ATP synthesis in the left ventricles of hamsters with cardiomyopathy. Sci Rep. 2017;7(1):9243. https://doi.org/10.1038/s41598-017-08546-1.Gnaiger E, Boushel R, Søndergaard H, et al. Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and Caucasians in the arctic winter. Scand J Med Sci Sports. 2015;25(suppl 4):126-134. https://doi.org/10.1111/sms.12612.MiPNet20.06 IsolationMouseHeart-mt - Bioblast. https://wiki.oroboros.at/index.php/MiPNet20.06_IsolationMouseHeart-mt. Accessed September 25, 2019.Bai R-K, Wong L-JC. Simultaneous detection and quantification of mitochondrial DNA deletion(s), depletion, and over-replication in patients with mitochondrial disease. J Mol Diagn. 2005;7(5):613-622. https://doi.org/10.1016/S1525-1578(10)60595-8.Dimmock D, Tang L-Y, Schmitt ES, Wong L-JC. Quantitative evaluation of the mitochondrial DNA depletion syndrome. Clin Chem. 2010;56(7):1119-1127. https://doi.org/10.1373/clinchem.2009.141549.Real-Time Quantitative PCR Analysis of Mitochondrial DNA Content - Venegas - 2011 - Current Protocols in Human Genetics - Wiley Online Library. https://currentprotocols.onlinelibrary.wiley.com/doi/abs/10.1002/0471142905.hg1907s68. Accessed January 21, 2020.Cooper LB, Yap J, Tay WT, et al. Multi-ethnic comparisons of diabetes in heart failure with reduced ejection fraction: insights from the HF-ACTION trial and the ASIAN-HF registry. Eur J Heart Fail. June 2018;20:1281-1289. https://doi.org/10.1002/ejhf.1223.Abate N, Chandalia M, Snell PG, Grundy SM. Adipose tissue metabolites and insulin resistance in nondiabetic Asian Indian men. J Clin Endocrinol Metab. 2004;89(6):2750-2755. https://doi.org/10.1210/jc.2003-031843.Nair KS, Bigelow ML, Asmann YW, et al. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes. 2008;57(5):1166-1175. https://doi.org/10.2337/db07-1556.Asmann YW, Stump CS, Short KR, et al. Skeletal muscle mitochondrial functions, mitochondrial DNA copy numbers, and gene transcript profiles in type 2 diabetic and nondiabetic subjects at equal levels of low or high insulin and euglycemia. Diabetes. 2006;55(12):3309-3319. https://doi.org/10.2337/db05-1230.Chattopadhyay M, Guhathakurta I, Behera P, et al. Mitochondrial bioenergetics is not impaired in nonobese subjects with type 2 diabetes mellitus. Metabolism. 2011;60(12):1702-1710. https://doi.org/10.1016/j.metabol.2011.04.015.Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsøe R, Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia. 2007;50(4):790-796. https://doi.org/10.1007/s00125-007-0594-3.Buchanan J, Mazumder PK, Hu P, et al. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology. 2005;146(12):5341-5349. https://doi.org/10.1210/en.2005-0938.Song J, Yang B, Jia X, et al. Distinctive roles of sirtuins on diabetes, protective or detrimental? Front Endocrinol (Lausanne). 2018;9:724. https://doi.org/10.3389/fendo.2018.00724.Lou P-H, Lucchinetti E, Scott KY, et al. Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats. Physiological Reports. 2017;5(16):e13388. https://doi.org/10.14814/phy2.13388.Sun Y, Tian Z, Liu N, et al. Exogenous H2S switches cardiac energy substrate metabolism by regulating SIRT3 expression in db/db mice. J Mol Med. 2018;96(3-4):281-299. https://doi.org/10.1007/s00109-017-1616-3.Marfella R, Esposito K, Nappo F, et al. Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes. 2004;53(9):2383-2391.Jayakumari NR, Reghuvaran AC, Rajendran RS, et al. Are nitric oxide-mediated protein modifications of functional significance in diabetic heart? ye'S, -NO', wh'Y-NO't? Nitric Oxide. 2014;43:35-44. https://doi.org/10.1016/j.niox.2014.08.002.Ruegsegger GN, Manjunatha S, Summer P, et al. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J. 2019;33(3):4458-4472. https://doi.org/10.1096/fj.201802043R.Oikawa M, Kagaya Y, Otani H, et al. Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol. 2005;45(11):1849-1855. https://doi.org/10.1016/j.jacc.2005.02.065.