Association between insulin resistance and the development of cardiovascular disease

Valeska Ormazabal, Soumyalekshmi Nair, Omar Elfeky, Claudio Aguayo, Carlos Salomon, Felipe A Zuñiga, Valeska Ormazabal, Soumyalekshmi Nair, Omar Elfeky, Claudio Aguayo, Carlos Salomon, Felipe A Zuñiga

Abstract

For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.

Keywords: Cardiovascular disease; Dyslipidemia; Hyperinsulinemia; Insulin resistance; Metabolism.

Figures

Fig. 1
Fig. 1
A simplified model of insulin resistance. The loss of suppressive effects of insulin on lipolysis in adipocytes increases free fatty acids. Increased free fatty acids flux to the liver stimulates the assembly and secretion of VLDL resulting in hypertriglyceridemia. Triglycerides (TG) in VLDL are transferred to both HDL and LDL through the action of cholesteryl ester transfer protein (CETP). This process results in a triglyceride-enriched HDL and LDL particle. Triglyceride-enriched HDL is more rapidly cleared from the circulation by the kidney, leaving fewer HDL particles to accept cholesterol from the vasculature. In the glucose metabolism, the insulin resistance results in decreased hepatic glycogen synthesis, owing to decreased activation of glycogen synthase, increased hepatic gluconeogenesis, and glucose delivery by the liver
Fig. 2
Fig. 2
Mechanisms implicated in the development of diabetic cardiomyopathy. Normally, the insulin signaling regulates the glucose and lipids metabolism in heart. Insulin resistance produces a metabolic derangement that results in high lipid oxidation and low of glucose oxidation. The activation of the renin–angiotensin–aldosterone system (RAAS) can cause mitochondrial dysfunction, endoplasmic reticulum stress and oxidative stress. This can results in abnormal Ca2+ handling and low ATP production leading to cardiomyocyte death. ER endoplasmic reticulum, FFA free fatty acids

References

    1. Steinberger J, Daniels SR, American Heart Association Atherosclerosis H. Obesity in the Young C. American Heart Association Diabetes C Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism) Circulation. 2003;107(10):1448–1453. doi: 10.1161/01.CIR.0000060923.07573.F2.
    1. Steinberger J, Moorehead C, Katch V, Rocchini AP. Relationship between insulin resistance and abnormal lipid profile in obese adolescents. J Pediatr. 1995;126(5 Pt 1):690–695. doi: 10.1016/S0022-3476(95)70394-2.
    1. Ferreira AP, Oliveira CE, Franca NM. Metabolic syndrome and risk factors for cardiovascular disease in obese children: the relationship with insulin resistance (HOMA-IR) Jornal de pediatria. 2007;83(1):21–26. doi: 10.2223/JPED.1562.
    1. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32(8):1754–1759. doi: 10.1161/ATVBAHA.111.241885.
    1. Wilcox G. Insulin and insulin resistance. Clin Biochem Rev. 2005;26(2):19–39.
    1. Gast KB, Tjeerdema N, Stijnen T, Smit JW, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS ONE. 2012;7(12):e52036. doi: 10.1371/journal.pone.0052036.
    1. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575–585. doi: 10.1016/j.cmet.2011.07.015.
    1. Davidson JA, Parkin CG. Is hyperglycemia a causal factor in cardiovascular disease? Does proving this relationship really matter? Yes. Diabetes Care. 2009;32(Suppl 2):S331–S333. doi: 10.2337/dc09-S333.
    1. Laakso M, Kuusisto J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol. 2014;10(5):293–302. doi: 10.1038/nrendo.2014.29.
    1. Janus A, Szahidewicz-Krupska E, Mazur G, Doroszko A. Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders. Mediators Inflamm. 2016;2016:3634948. doi: 10.1155/2016/3634948.
    1. Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC., Jr Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA. 1998;95(13):7772–7777. doi: 10.1073/pnas.95.13.7772.
    1. Bogan JS. Regulation of glucose transporter translocation in health and diabetes. Annu Rev Biochem. 2012;81:507–532. doi: 10.1146/annurev-biochem-060109-094246.
    1. Zimmer HG. Regulation of and intervention into the oxidative pentose phosphate pathway and adenine nucleotide metabolism in the heart. Mol Cell Biochem. 1996;160–161:101–109. doi: 10.1007/BF00240038.
    1. Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, Monks BR, Birnbaum MJ. Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol. 2010;30(21):5009–5020. doi: 10.1128/MCB.00797-10.
    1. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr. 2007;27:79–101. doi: 10.1146/annurev.nutr.27.061406.093734.
    1. Czech MP, Tencerova M, Pedersen DJ, Aouadi M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia. 2013;56(5):949–964. doi: 10.1007/s00125-013-2869-1.
    1. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Investig. 2000;106(2):171–176. doi: 10.1172/JCI10583.
    1. Hojlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J. 2014;61(7):B4890.
    1. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Investig. 2000;106(4):473–481. doi: 10.1172/JCI10842.
    1. Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA. Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract. 2011;93:S52–S59. doi: 10.1016/S0168-8227(11)70014-6.
    1. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995;75(3):473–486. doi: 10.1152/physrev.1995.75.3.473.
    1. Wu G, Meininger CJ. Nitric oxide and vascular insulin resistance. BioFactors (Oxford, England) 2009;35(1):21–27. doi: 10.1002/biof.3.
    1. Wang CC, Gurevich I, Draznin B. Insulin affects vascular smooth muscle cell phenotype and migration via distinct signaling pathways. Diabetes. 2003;52(10):2562–2569. doi: 10.2337/diabetes.52.10.2562.
    1. Berg J, Tymoczko J, Stryer L: Food intake and starvation induce metabolic changes. In: Biochemistry. 2002.
    1. Catalano PM. Obesity, insulin resistance and pregnancy outcome. Reproduction (Cambridge, England) 2010;140(3):365–371. doi: 10.1530/REP-10-0088.
    1. Bonora E. Insulin resistance as an independent risk factor for cardiovascular disease: clinical assessment and therapy approaches. Av Diabetol. 2005;21:255–261.
    1. Goodwin PJ, Ennis M, Bahl M, Fantus IG, Pritchard KI, Trudeau ME, Koo J, Hood N. High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome. Breast Cancer Res Treat. 2009;114(3):517–525. doi: 10.1007/s10549-008-0019-0.
    1. Seriolo B, Ferrone C, Cutolo M. Longterm anti-tumor necrosis factor-alpha treatment in patients with refractory rheumatoid arthritis: relationship between insulin resistance and disease activity. J Rheumatol. 2008;35(2):355–357.
    1. Williams T, Mortada R, Porter S. Diagnosis and treatment of polycystic ovary syndrome. Am Fam Physician. 2016;94(2):106–113.
    1. Lallukka S, Yki-Jarvinen H. Non-alcoholic fatty liver disease and risk of type 2 diabetes. Best Pract Res Clin Endocrinol Metab. 2016;30(3):385–395. doi: 10.1016/j.beem.2016.06.006.
    1. Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med. 2007;120(3 Suppl 1):S12–S18. doi: 10.1016/j.amjmed.2007.01.003.
    1. Wende AR, Abel ED. Lipotoxicity in the heart. Biochem Biophys Acta. 2010;1801(3):311–319.
    1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468):1415–1428. doi: 10.1016/S0140-6736(05)66378-7.
    1. Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004;53(11):2735–2740. doi: 10.2337/diabetes.53.11.2735.
    1. Moller DE, Kaufman KD. Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med. 2005;56:45–62. doi: 10.1146/annurev.med.56.082103.104751.
    1. Matthaei S, Stumvoll M, Kellerer M, Haring HU. Pathophysiology and pharmacological treatment of insulin resistance. Endocr Rev. 2000;21(6):585–618.
    1. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–871. doi: 10.1016/j.cell.2012.02.017.
    1. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Investig. 2016;126(1):12–22. doi: 10.1172/JCI77812.
    1. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372(6502):182–186. doi: 10.1038/372182a0.
    1. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391(6670):900–904. doi: 10.1038/36116.
    1. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta) Science. 2001;292(5522):1728–1731. doi: 10.1126/science.292.5522.1728.
    1. Saini V. Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World J Diabetes. 2010;1(3):68–75. doi: 10.4239/wjd.v1.i3.68.
    1. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Investig. 1999;103(2):253–259. doi: 10.1172/JCI5001.
    1. Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma YZ, Savoye M, Rothman DL, Shulman GI, Caprio S. Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes. 2002;51(4):1022–1027. doi: 10.2337/diabetes.51.4.1022.
    1. Unger RH, Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Related Metab Dis. 2000;24(Suppl 4):S28–S32. doi: 10.1038/sj.ijo.0801498.
    1. Dong B, Qi D, Yang L, Huang Y, Xiao X, Tai N, Wen L, Wong FS. TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes. Am J Physiol Heart Circ Physiol. 2012;303(6):H732–H742. doi: 10.1152/ajpheart.00948.2011.
    1. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig. 2003;112(12):1796–1808. doi: 10.1172/JCI200319246.
    1. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig. 2003;112(12):1821–1830. doi: 10.1172/JCI200319451.
    1. Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85 alpha—the two sides of a coin. Diabetes. 2006;55(8):2392–2397. doi: 10.2337/db06-0391.
    1. Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, Nowotny P, Waldhausl W, Marette A, Roden M. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes. 2005;54(9):2674–2684. doi: 10.2337/diabetes.54.9.2674.
    1. Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at ser-2448 is mediated by p70S6 kinase. J Biol Chem. 2005;280(27):25485–25490. doi: 10.1074/jbc.M501707200.
    1. Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol. 2004;18(8):2024–2034. doi: 10.1210/me.2003-0383.
    1. Aroor AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin. 2012;8(4):609. doi: 10.1016/j.hfc.2012.06.005.
    1. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA. 2005;293(15):1861–1867. doi: 10.1001/jama.293.15.1861.
    1. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307–312. doi: 10.1038/35053000.
    1. Liu L, Feng J, Zhang G, Yuan X, Li F, Yang T, Hao S, Huang D, Hsue C, Lou Q. Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes. Curr Med Res Opin. 2018;34(1):123–129. doi: 10.1080/03007995.2017.1364226.
    1. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. 2015;402:113–119. doi: 10.1016/j.mce.2014.11.029.
    1. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(12):1131–1141. doi: 10.1056/NEJMra1011035.
    1. Lalia AZ, Dasari S, Johnson ML, Robinson MM, Konopka AR, Distelmaier K, Port JD, Glavin MT, Esponda RR, Nair KS, et al. Predictors of whole-body insulin sensitivity across ages and adiposity in adult humans. J Clin Endocrinol Metab. 2016;101(2):626–634. doi: 10.1210/jc.2015-2892.
    1. Gonzalez N, Moreno-Villegas Z, Gonzalez-Bris A, Egido J, Lorenzo O. Regulation of visceral and epicardial adipose tissue for preventing cardiovascular injuries associated to obesity and diabetes. Cardiovasc Diabetol. 2017;16(1):44. doi: 10.1186/s12933-017-0528-4.
    1. Kim JI, Huh JY, Sohn JH, Choe SS, Lee YS, Lim CY, Jo A, Park SB, Han W, Kim JB. Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation. Mol Cell Biol. 2015;35(10):1686–1699. doi: 10.1128/MCB.01321-14.
    1. Alman AC, Smith SR, Eckel RH, Hokanson JE, Burkhardt BR, Sudini PR, Wu Y, Schauer IE, Pereira RI, Snell-Bergeon JK. The ratio of pericardial to subcutaneous adipose tissues is associated with insulin resistance. Obesity (Silver Spring, Md) 2017;25(7):1284–1291. doi: 10.1002/oby.21875.
    1. Fitzgibbons TP, Czech MP. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc. 2014;3(2):e000582. doi: 10.1161/JAHA.113.000582.
    1. Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9(5):367–377. doi: 10.1038/nrm2391.
    1. Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F. Relation between epicardial adipose tissue and left ventricular mass. Am J Cardiol. 2004;94(8):1084–1087. doi: 10.1016/j.amjcard.2004.06.075.
    1. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52(22):1793–1799. doi: 10.1016/j.jacc.2008.07.062.
    1. Nyman K, Granér M, Pentikäinen MO, Lundbom J, Hakkarainen A, Sirén R, Nieminen MS, Taskinen M-R, Lundbom N, Lauerma K. Cardiac steatosis and left ventricular function in men with metabolic syndrome. J Cardiovasc Magn Reson. 2013;15(1):103. doi: 10.1186/1532-429X-15-103.
    1. Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Physiol Rev. 2008;88(2):389–419. doi: 10.1152/physrev.00017.2007.
    1. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna RC, Muggeo M. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes. 1998;47(10):1643–1649. doi: 10.2337/diabetes.47.10.1643.
    1. Howard G, O’Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation. 1996;93(10):1809–1817. doi: 10.1161/01.CIR.93.10.1809.
    1. Tenenbaum A, Adler Y, Boyko V, Tenenbaum H, Fisman EZ, Tanne D, Lapidot M, Schwammenthal E, Feinberg MS, Matas Z, et al. Insulin resistance is associated with increased risk of major cardiovascular events in patients with preexisting coronary artery disease. Am Heart J. 2007;153(4):559–565. doi: 10.1016/j.ahj.2007.01.008.
    1. Eddy D, Schlessinger L, Kahn R, Peskin B, Schiebinger R. Relationship of insulin resistance and related metabolic variables to coronary artery disease: a mathematical analysis. Diabetes Care. 2009;32(2):361–366. doi: 10.2337/dc08-0854.
    1. Savaiano DA, Story JA. Cardiovascular disease and fiber: is insulin resistance the missing link? Nutr Rev. 2000;58(11):356–358. doi: 10.1111/j.1753-4887.2000.tb01834.x.
    1. Kong C, Elatrozy T, Anyaoku V, Robinson S, Richmond W, Elkeles RS. Insulin resistance, cardiovascular risk factors and ultrasonically measured early arterial disease in normotensive Type 2 diabetic subjects. Diabetes Metab Res Rev. 2000;16(6):448–453. doi: 10.1002/1520-7560(2000)9999:9999<::AID-DMRR154>;2-N.
    1. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Investig. 2000;106(4):453–458. doi: 10.1172/JCI10762.
    1. Bloomgarden ZT. Insulin resistance, dyslipidemia, and cardiovascular disease. Diabetes Care. 2007;30(8):2164–2170. doi: 10.2337/dc07-zb08.
    1. Kozakova M, Natali A, Dekker J, Beck-Nielsen H, Laakso M, Nilsson P, Balkau B, Ferrannini E. Insulin sensitivity and carotid intima-media thickness: relationship between insulin sensitivity and cardiovascular risk study. Arterioscler Thromb Vasc Biol. 2013;33(6):1409–1417. doi: 10.1161/ATVBAHA.112.300948.
    1. Min J, Weitian Z, Peng C, Yan P, Bo Z, Yan W, Yun B, Xukai W. Correlation between insulin-induced estrogen receptor methylation and atherosclerosis. Cardiovasc Diabetol. 2016;15(1):156. doi: 10.1186/s12933-016-0471-9.
    1. Chanda D, Luiken JJ, Glatz JF. Signaling pathways involved in cardiac energy metabolism. FEBS Lett. 2016;590(15):2364–2374. doi: 10.1002/1873-3468.12297.
    1. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA. 2000;97(4):1784–1789. doi: 10.1073/pnas.97.4.1784.
    1. Ramírez E, Picatoste B, González-Bris A, Oteo M, Cruz F, Caro-Vadillo A, Egido J, Tuñón J, Morcillo MA, Lorenzo Ó. Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: role of GLP-1 isoforms in Glut4 receptor trafficking. Cardiovasc Diabetol. 2018;17:12. doi: 10.1186/s12933-017-0643-2.
    1. Goldberg IJ. Clinical review 124: diabetic dyslipidemia: causes and consequences. J Clin Endocrinol Metab. 2001;86(3):965–971. doi: 10.1210/jcem.86.3.7304.
    1. Sparks JD, Sparks CE, Adeli K. Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2012;32(9):2104–2112. doi: 10.1161/ATVBAHA.111.241463.
    1. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414(6865):782–787. doi: 10.1038/414782a.
    1. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81(4A):7B–12B. doi: 10.1016/S0002-9149(98)00031-9.
    1. Hokanson JE. Hypertriglyceridemia and risk of coronary heart disease. Curr Cardiol Rep. 2002;4(6):488–493. doi: 10.1007/s11886-002-0112-7.
    1. Sung KC, Park HY, Kim MJ, Reaven G. Metabolic markers associated with insulin resistance predict type 2 diabetes in Koreans with normal blood pressure or prehypertension. Cardiovasc Diabetol. 2016;15:47. doi: 10.1186/s12933-016-0368-7.
    1. Ginsberg HN, Zhang YL, Hernandez-Ono A. Metabolic syndrome: focus on dyslipidemia. Obesity. 2006;14(Suppl 1):41S–49S. doi: 10.1038/oby.2006.281.
    1. Yadav R, Hama S, Liu Y, Siahmansur T, Schofield J, Syed AA, France M, Pemberton P, Adam S, Ho JH, et al. Effect of Roux-en-Y bariatric surgery on lipoproteins, insulin resistance, and systemic and vascular inflammation in obesity and diabetes. Front Immunol. 2017;8:1512. doi: 10.3389/fimmu.2017.01512.
    1. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97–105. doi: 10.1016/j.febslet.2007.11.057.
    1. den Boer MA, Voshol PJ, Kuipers F, Romijn JA, Havekes LM. Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production. Am J Physiol Endocrinol Metab. 2006;291(6):E1360–E1364. doi: 10.1152/ajpendo.00188.2006.
    1. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Investig. 2006;116(7):1813–1822. doi: 10.1172/JCI29024.
    1. Lewis GF, Steiner G. Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state. Diabetes Care. 1996;19(4):390–393. doi: 10.2337/diacare.19.4.390.
    1. Haas ME, Attie AD, Biddinger SB. The regulation of ApoB metabolism by insulin. Trends Endocrinol Metab. 2013;24(8):391–397. doi: 10.1016/j.tem.2013.04.001.
    1. Verges B. Pathophysiology of diabetic dyslipidaemia: where are we? Diabetologia. 2015;58(5):886–899. doi: 10.1007/s00125-015-3525-8.
    1. Pont F, Duvillard L, Florentin E, Gambert P, Verges B. Early kinetic abnormalities of apoB-containing lipoproteins in insulin-resistant women with abdominal obesity. Arterioscler Thromb Vasc Biol. 2002;22(10):1726–1732. doi: 10.1161/01.ATV.0000032134.92180.41.
    1. Hoogeveen RC, Gaubatz JW, Sun W, Dodge RC, Crosby JR, Jiang J, Couper D, Virani SS, Kathiresan S, Boerwinkle E, et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Arterioscler Thromb Vasc Biol. 2014;34(5):1069–1077. doi: 10.1161/ATVBAHA.114.303284.
    1. Packard CJ. Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. Biochem Soc Trans. 2003;31(Pt 5):1066–1069. doi: 10.1042/bst0311066.
    1. Sandhofer A, Kaser S, Ritsch A, Laimer M, Engl J, Paulweber B, Patsch JR, Ebenbichler CF. Cholesteryl ester transfer protein in metabolic syndrome. Obesity. 2006;14(5):812–818. doi: 10.1038/oby.2006.94.
    1. Rashid S, Watanabe T, Sakaue T, Lewis GF. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem. 2003;36(6):421–429. doi: 10.1016/S0009-9120(03)00078-X.
    1. von Bibra H, Saha S, Hapfelmeier A, Muller G, Schwarz PEH. Impact of the triglyceride/high-density lipoprotein cholesterol ratio and the hypertriglyceremic-waist phenotype to predict the metabolic syndrome and insulin resistance. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2017;49(7):542–549.
    1. Kim MK, Ahn CW, Kang S, Nam JS, Kim KR, Park JS. Relationship between the triglyceride glucose index and coronary artery calcification in Korean adults. Cardiovasc Diabetol. 2017;16(1):108. doi: 10.1186/s12933-017-0589-4.
    1. Mazidi M, Kengne AP, Katsiki N, Mikhailidis DP, Banach M. Lipid accumulation product and triglycerides/glucose index are useful predictors of insulin resistance. J Diabetes Complications. 2018;32(3):266–270. doi: 10.1016/j.jdiacomp.2017.10.007.
    1. Jorge-Galarza E, Posadas-Romero C, Torres-Tamayo M, Medina-Urrutia AX, Rodas-Diaz MA, Posadas-Sanchez R, Vargas-Alarcon G, Gonzalez-Salazar MD, Cardoso-Saldana GC, Juarez-Rojas JG. Insulin resistance in adipose tissue but not in liver is associated with aortic valve calcification. Dis Markers. 2016;2016:9085474. doi: 10.1155/2016/9085474.
    1. Zhou MS, Schulman IH, Zeng Q. Link between the renin–angiotensin system and insulin resistance: implications for cardiovascular disease. Vasc Med. 2012;17(5):330–341. doi: 10.1177/1358863X12450094.
    1. Zhou MS, Schulman IH, Raij L. Nitric oxide, angiotensin II, and hypertension. Semin Nephrol. 2004;24(4):366–378. doi: 10.1016/j.semnephrol.2004.04.008.
    1. Landsberg L. Insulin resistance and hypertension. Clin Exp Hypertens. 1999;21(5–6):885–894. doi: 10.3109/10641969909061017.
    1. Briet M, Schiffrin EL. Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol. 2010;6(5):261–273. doi: 10.1038/nrneph.2010.30.
    1. Oana F, Takeda H, Hayakawa K, Matsuzawa A, Akahane S, Isaji M, Akahane M. Physiological difference between obese (fa/fa) Zucker rats and lean Zucker rats concerning adiponectin. Metabolism. 2005;54(8):995–1001. doi: 10.1016/j.metabol.2005.02.016.
    1. Goossens GH. The renin–angiotensin system in the pathophysiology of type 2 diabetes. Obesity Facts. 2012;5(4):611–624. doi: 10.1159/000342776.
    1. Schulman IH, Zhou MS. Vascular insulin resistance: a potential link between cardiovascular and metabolic diseases. Curr Hypertens Rep. 2009;11(1):48–55. doi: 10.1007/s11906-009-0010-0.
    1. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016;12(3):144–153. doi: 10.1038/nrendo.2015.216.
    1. Zhou MS, Schulman IH, Raij L. Vascular inflammation, insulin resistance, and endothelial dysfunction in salt-sensitive hypertension: role of nuclear factor kappa B activation. J Hypertens. 2010;28(3):527–535. doi: 10.1097/HJH.0b013e3283340da8.
    1. Andreozzi F, Laratta E, Sciacqua A, Perticone F, Sesti G. Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells. Circ Res. 2004;94(9):1211–1218. doi: 10.1161/01.RES.0000126501.34994.96.
    1. Wei Y, Whaley-Connell AT, Chen K, Habibi J, Uptergrove GM, Clark SE, Stump CS, Ferrario CM, Sowers JR. NADPH oxidase contributes to vascular inflammation, insulin resistance, and remodeling in the transgenic (mRen2) rat. Hypertension. 2007;50(2):384–391. doi: 10.1161/HYPERTENSIONAHA.107.089284.
    1. Matsuura K, Hagiwara N. The pleiotropic effects of ARB in vascular endothelial progenitor cells. Curr Vasc Pharmacol. 2011;9(2):153–157. doi: 10.2174/157016111794519345.
    1. Group NS, McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362(16):1477–1490. doi: 10.1056/NEJMoa1001121.
    1. Perlstein TS, Henry RR, Mather KJ, Rickels MR, Abate NI, Grundy SM, Mai Y, Albu JB, Marks JB, Pool JL, et al. Effect of angiotensin receptor blockade on insulin sensitivity and endothelial function in abdominally obese hypertensive patients with impaired fasting glucose. Clin Sci (Lond) 2012;122(4):193–202. doi: 10.1042/CS20110284.
    1. Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113(15):1888–1904. doi: 10.1161/CIRCULATIONAHA.105.563213.
    1. Tousoulis D, Simopoulou C, Papageorgiou N, Oikonomou E, Hatzis G, Siasos G, Tsiamis E, Stefanadis C. Endothelial dysfunction in conduit arteries and in microcirculation. Novel therapeutic approaches. Pharmacol Ther. 2014;144(3):253–267. doi: 10.1016/j.pharmthera.2014.06.003.
    1. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–1143. doi: 10.1161/hc0902.104353.
    1. Westergren HU, Svedlund S, Momo RA, Blomster JI, Wahlander K, Rehnstrom E, Greasley PJ, Fritsche-Danielson R, Oscarsson J, Gan LM. Insulin resistance, endothelial function, angiogenic factors and clinical outcome in non-diabetic patients with chest pain without myocardial perfusion defects. Cardiovasc Diabetol. 2016;15:36. doi: 10.1186/s12933-016-0353-1.
    1. Dinesh Shah A, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP, Deanfield J, Smeeth L, Timmis A, Hemingway H. Type 2 diabetes and incidence of a wide range of cardiovascular diseases: a cohort study in 1.9 million people. Lancet. 2015;385(Suppl 1):S86. doi: 10.1016/S0140-6736(15)60401-9.
    1. Martin-Timon I, Sevillano-Collantes C, Segura-Galindo A, Del Canizo-Gomez FJ. Type 2 diabetes and cardiovascular disease: have all risk factors the same strength? World J Diabetes. 2014;5(4):444–470. doi: 10.4239/wjd.v5.i4.444.
    1. Ciccone MM, Cortese F, Gesualdo M, Donvito I, Carbonara S, De Pergola G. A glycemic threshold of 90 mg/dl promotes early signs of atherosclerosis in apparetly healthy overweight/obese subjects. Endocr Metab Immune Disord Drug Targets. 2016;16(4):288–295. doi: 10.2174/1871530317666161205124955.
    1. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141(6):421–431. doi: 10.7326/0003-4819-141-6-200409210-00007.
    1. Meyer ML, Gotman NM, Soliman EZ, Whitsel EA, Arens R, Cai J, Daviglus ML, Denes P, Gonzalez HM, Moreiras J, et al. Association of glucose homeostasis measures with heart rate variability among Hispanic/Latino adults without diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Cardiovasc Diabetol. 2016;15:45. doi: 10.1186/s12933-016-0364-y.
    1. Paneni F, Volpe M, Luscher TF, Cosentino F. SIRT1, p66(Shc), and Set7/9 in vascular hyperglycemic memory: bringing all the strands together. Diabetes. 2013;62(6):1800–1807. doi: 10.2337/db12-1648.
    1. Ceriello A. The emerging challenge in diabetes: the “metabolic memory”. Vasc Pharmacol. 2012;57(5–6):133–138. doi: 10.1016/j.vph.2012.05.005.
    1. Fiorentino TV, Prioletta A, Zuo P, Folli F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 2013;19(32):5695–5703. doi: 10.2174/1381612811319320005.
    1. Pistrosch F, Natali A, Hanefeld M. Is hyperglycemia a cardiovascular risk factor? Diabetes Care. 2011;34(Suppl 2):S128–S131. doi: 10.2337/dc11-s207.
    1. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–1070. doi: 10.1161/CIRCRESAHA.110.223545.
    1. Nowotny K, Jung T, Hohn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015;5(1):194–222. doi: 10.3390/biom5010194.
    1. Yan SF, Ramasamy R, Schmidt AM. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res. 2010;106(5):842–853. doi: 10.1161/CIRCRESAHA.109.212217.
    1. Sonnenblick EH, Stam AC., Jr Cardiac muscle: activation and contraction. Annu Rev Physiol. 1969;31:647–674. doi: 10.1146/annurev.ph.31.030169.003243.
    1. Johansen L, Quistorff B. 31P-MRS characterization of sprint and endurance trained athletes. Int J Sports Med. 2003;24(3):183–189. doi: 10.1055/s-2003-39085.
    1. Duffield R, Dawson B, Goodman C. Energy system contribution to 100-m and 200-m track running events. J Sci Med Sport. 2004;7(3):302–313. doi: 10.1016/S1440-2440(04)80025-2.
    1. Kassiotis C, Rajabi M, Taegtmeyer H. Metabolic reserve of the heart: the forgotten link between contraction and coronary flow. Prog Cardiovasc Dis. 2008;51(1):74–88. doi: 10.1016/j.pcad.2007.11.005.
    1. Kota SK, Kota SK, Jammula S, Panda S, Modi KD. Effect of diabetes on alteration of metabolism in cardiac myocytes: therapeutic implications. Diabetes Technol Ther. 2011;13(11):1155–1160. doi: 10.1089/dia.2011.0120.
    1. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85(3):1093–1129. doi: 10.1152/physrev.00006.2004.
    1. Carley AN, Severson DL. Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochem Biophys Acta. 2005;1734(2):112–126.
    1. Brandt JM, Djouadi F, Kelly DP. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem. 1998;273(37):23786–23792. doi: 10.1074/jbc.273.37.23786.
    1. Goodwin GW, Taegtmeyer H. Improved energy homeostasis of the heart in the metabolic state of exercise. Am J Physiol Heart Circ Physiol. 2000;279(4):H1490–H1501. doi: 10.1152/ajpheart.2000.279.4.H1490.
    1. Opie LH. Cardiac metabolism–emergence, decline, and resurgence. Part II. Cardiovasc Res. 1992;26(9):817–830. doi: 10.1093/cvr/26.9.817.
    1. Henning SL, Wambolt RB, Schonekess BO, Lopaschuk GD, Allard MF. Contribution of glycogen to aerobic myocardial glucose utilization. Circulation. 1996;93(8):1549–1555. doi: 10.1161/01.CIR.93.8.1549.
    1. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. The Journal of nutrition. 2004;134(3):489–492. doi: 10.1093/jn/134.3.489.
    1. Shao D, Tian R. Glucose transporters in cardiac metabolism and hypertrophy. Comp Physiol. 2015;6(1):331–351. doi: 10.1002/cphy.c150016.
    1. Malfitano C, de Souza Junior AL, Carbonaro M, Bolsoni-Lopes A, Figueroa D, de Souza LE, Silva KA, Consolim-Colombo F, Curi R, Irigoyen MC. Glucose and fatty acid metabolism in infarcted heart from streptozotocin-induced diabetic rats after 2 weeks of tissue remodeling. Cardiovasc Diabetol. 2015;14:149. doi: 10.1186/s12933-015-0308-y.
    1. Kolwicz SC, Jr, Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res. 2013;113(5):603–616. doi: 10.1161/CIRCRESAHA.113.302095.
    1. Wright JJ, Kim J, Buchanan J, Boudina S, Sena S, Bakirtzi K, Ilkun O, Theobald HA, Cooksey RC, Kandror KV, et al. Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc Res. 2009;82(2):351–360. doi: 10.1093/cvr/cvp017.
    1. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009;20(2):72–77. doi: 10.1016/j.tem.2008.11.001.
    1. Ajith TA, Jayakumar TG. Peroxisome proliferator-activated receptors in cardiac energy metabolism and cardiovascular disease. Clin Exp Pharmacol Physiol. 2016;43(7):649–658. doi: 10.1111/1440-1681.12579.
    1. Oakes ND, Thalen P, Aasum E, Edgley A, Larsen T, Furler SM, Ljung B, Severson D. Cardiac metabolism in mice: tracer method developments and in vivo application revealing profound metabolic inflexibility in diabetes. Am J Physiol Endocrinol Metab. 2006;290(5):E870–E881. doi: 10.1152/ajpendo.00233.2005.
    1. D’Souza K, Nzirorera C, Kienesberger PC. Lipid metabolism and signaling in cardiac lipotoxicity. Biochem Biophys Acta. 2016;1860(10):1513–1524.
    1. Goldberg IJ, Trent CM, Schulze PC. Lipid metabolism and toxicity in the heart. Cell Metab. 2012;15(6):805–812. doi: 10.1016/j.cmet.2012.04.006.
    1. Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. Biochem Biophys Acta. 2002;1585(2–3):202–212.
    1. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res. 2008;49(10):2101–2112. doi: 10.1194/jlr.M800147-JLR200.
    1. Liu Y, Neumann D, Glatz JF, Luiken JJ. Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction. Prostaglandins Leukot Essent Fatty Acids. 2016 doi: 10.1016/j.plefa.2016.06.002.
    1. Feuvray D, Idell-Wenger JA, Neely JR. Effects of ischemia on rat myocardial function and metabolism in diabetes. Circ Res. 1979;44(3):322–329. doi: 10.1161/01.RES.44.3.322.
    1. Fricovsky ES, Suarez J, Ihm SH, Scott BT, Suarez-Ramirez JA, Banerjee I, Torres-Gonzalez M, Wang H, Ellrott I, Maya-Ramos L, et al. Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol. 2012;303(7):R689–R699. doi: 10.1152/ajpregu.00548.2011.
    1. Hwang YC, Kaneko M, Bakr S, Liao H, Lu Y, Lewis ER, Yan S, Ii S, Itakura M, Rui L, et al. Central role for aldose reductase pathway in myocardial ischemic injury. FASEB J. 2004;18(11):1192–1199. doi: 10.1096/fj.03-1400com.
    1. Zuurbier CJ, Eerbeek O, Goedhart PT, Struys EA, Verhoeven NM, Jakobs C, Ince C. Inhibition of the pentose phosphate pathway decreases ischemia–reperfusion-induced creatine kinase release in the heart. Cardiovasc Res. 2004;62(1):145–153. doi: 10.1016/j.cardiores.2004.01.010.
    1. Salabei JK, Lorkiewicz PK, Mehra P, Gibb AA, Haberzettl P, Hong KU, Wei X, Zhang X, Li Q, Wysoczynski M, et al. Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem. 2016;291(26):13634–13648. doi: 10.1074/jbc.M116.722496.
    1. Keller U, Lustenberger M, Stauffacher W. Effect of insulin on ketone body clearance studied by a ketone body “clamp” technique in normal man. Diabetologia. 1988;31(1):24–29.
    1. van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res. 2000;45(2):279–293. doi: 10.1016/S0008-6363(99)00263-1.
    1. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Kruger M, Hoppel CL, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133(8):698–705.
    1. Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, Huang Y, Haldar S, Verdin E. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell metabolism. 2017;26(3):547–557. doi: 10.1016/j.cmet.2017.08.004.
    1. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell metabolism. 2017;26(3):539–546. doi: 10.1016/j.cmet.2017.08.005.
    1. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 2010;468(7327):1100–1104. doi: 10.1038/nature09584.
    1. Kosinski C, Jornayvaz FR: Effects of Ketogenic Diets on Cardiovascular Risk Factors: Evidence from Animal and Human Studies. Nutrients 2017, 9(5).
    1. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the atkins, ornish, weight watchers, and zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005;293(1):43–53. doi: 10.1001/jama.293.1.43.
    1. Kim JA, Wei Y, Sowers JR. Role of mitochondrial dysfunction in insulin resistance. Circ Res. 2008;102(4):401–414. doi: 10.1161/CIRCRESAHA.107.165472.
    1. Jeong EM, Chung J, Liu H, Go Y, Gladstein S, Farzaneh-Far A, Lewandowski ED, Dudley SC., Jr Role of mitochondrial oxidative stress in glucose tolerance, insulin resistance, and cardiac diastolic dysfunction. J Am Heart Assoc. 2016;5(5):e003046. doi: 10.1161/JAHA.115.003046.
    1. Mei Y, Thompson MD, Cohen RA, Tong X. Endoplasmic reticulum stress and related pathological processes. J Pharm Biomed Anal. 2013;1(2):1000107.
    1. Taddeo EP, Laker RC, Breen DS, Akhtar YN, Kenwood BM, Liao JA, Zhang M, Fazakerley DJ, Tomsig JL, Harris TE, et al. Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Mol Metab. 2014;3(2):124–134. doi: 10.1016/j.molmet.2013.11.003.
    1. Mandavia CH, Aroor AR, Demarco VG, Sowers JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. 2013;92(11):601–608. doi: 10.1016/j.lfs.2012.10.028.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner