Skip to main content
SpringerLink
Log in

Role of Sodium-Glucose Co-transporters on Cardiac Function in Metabolic Syndrome Mammalians

  • Chapter
  • First Online:
Biochemistry of Cardiovascular Dysfunction in Obesity

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 20))

Abstract

Metabolic syndrome (MetS) is increasingly common among humans all over the world and a combination of serious pathological conditions occurred together. MetS induces increasing of risks for several organ dysfunctions including heart and type 2 diabetes (T2DM) since it is closely linked to overweight or obesity and inactivity among humans, currently, also linking to insulin resistance. To prevent MetS, it is needed first to have a healthy lifestyle, however, several therapeutic approaches also are in used to lighten its risky effects. Sodium-glucose co-transporter 2 (SGLT2) and 1 (SGLT1) inhibitors are relatively new glucose-lowering agents that work by increasing urinary glucose excretion through the kidneys, exerting their action independently of insulin. However, there are a number of side effects of these agents in humans with MetS. Nevertheless, different research teams, recently, demonstrated that SGLT2 inhibitors (SGLT2is) exert important cardioprotective effects in patients with MetS and T2DM via lowering the high risks for cardiovascular morbidity and mortality. Furthermore, it has been also emphasized that SGLT2is-associated cardioprotection in insulin-resistant overweights rats includes prevention of prolongation in ventricular-repolarization via marked augmentation of mitochondrial function together with normalization of oxidative stress followed by improvement of fusion-fission proteins, without its glucose-lowering effect. Moreover, two recent clinical studies announced that SGLT2is, electrophysiologically, could provide marked protective effects on electrocardiographic parameters in T2DM patients. Therefore, in the present review article, it has been documented the recent data related to SGLT2is on both experimental and clinical studies and their outcomes in terms of either adverse, beneficial, or both effects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ilkun O, Boudina S (2013) Cardiac dysfunction and oxidative stress in the metabolic syndrome: an update on antioxidant therapies. Curr Pharm Des 19(27):4806–4817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bugger H, Abel ED (2008) Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin Sci (Lond) 114(3):195–210

    Article  CAS  Google Scholar 

  3. Palmieri VO et al (2006) Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome. J Nutr 136(12):3022–3026

    Article  CAS  PubMed  Google Scholar 

  4. Grundy SM (2007) Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab 92(2):399–404

    Article  CAS  PubMed  Google Scholar 

  5. Armutcu F et al (2008) Oxidative stress markers, C-reactive protein and heat shock protein 70 levels in subjects with metabolic syndrome. Clin Chem Lab Med 46(6):785–790

    Article  CAS  PubMed  Google Scholar 

  6. Grundy SM et al (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: executive summary. Crit Pathw Cardiol 4(4):198–203

    Article  PubMed  Google Scholar 

  7. Nicolson GL (2007) Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem 100(6):1352–1369

    Article  CAS  PubMed  Google Scholar 

  8. Voulgari C et al (2010) The impact of metabolic syndrome on left ventricular myocardial performance. Diabetes Metab Res Rev 26(2):121–127

    Article  CAS  PubMed  Google Scholar 

  9. Okatan EN, Durak AT, Turan B (2016) Electrophysiological basis of metabolic-syndrome-induced cardiac dysfunction. Can J Physiol Pharmacol 94(10):1064–1073

    Article  CAS  PubMed  Google Scholar 

  10. Durak A et al (2017) Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats. Can J Physiol Pharmacol 95(11):1335–1342

    Article  CAS  PubMed  Google Scholar 

  11. Okatan EN et al (2015) Profiling of cardiac beta-adrenoceptor subtypes in the cardiac left ventricle of rats with metabolic syndrome: comparison with streptozotocin-induced diabetic rats. Can J Physiol Pharmacol 93(7):517–525

    Article  CAS  PubMed  Google Scholar 

  12. Ford ES et al (2003) The metabolic syndrome and antioxidant concentrations: findings from the Third National Health and Nutrition Examination Survey. Diabetes 52(9):2346–2352

    Article  CAS  PubMed  Google Scholar 

  13. Chinali M et al (2008) Cardiac markers of pre-clinical disease in adolescents with the metabolic syndrome: the strong heart study. J Am Coll Cardiol 52(11):932–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Meigs JB et al (2007) Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study. Diabetes Care 30(10):2529–2535

    Article  CAS  PubMed  Google Scholar 

  15. Boudina S et al (2009) Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 119(9):1272–1283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Saraiva RM et al (2007) Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice. Nitric Oxide 16(3):331–338

    Article  CAS  PubMed  Google Scholar 

  17. Serpillon S et al (2009) Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol 297(1):H153–62

    Google Scholar 

  18. Isomaa B et al (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24(4):683–689

    Article  CAS  PubMed  Google Scholar 

  19. Ford ES, Giles WH (2003) A comparison of the prevalence of the metabolic syndrome using two proposed definitions. Diabetes Care 26(3):575–581

    Article  PubMed  Google Scholar 

  20. Tenerz A et al (2003) Diabetes, insulin resistance, and the metabolic syndrome in patients with acute myocardial infarction without previously known diabetes. Diabetes Care 26(10):2770–2776

    Article  PubMed  Google Scholar 

  21. Aijaz B et al (2008) Abnormal cardiac structure and function in the metabolic syndrome: a population-based study. Mayo Clin Proc 83(12):1350–1357

    Article  PubMed  Google Scholar 

  22. Huang PL (2009) eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab 20(6):295–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marfella R et al (2009) Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome. J Lipid Res 50(11):2314–2323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kishi S et al (2014) Association of obesity in early adulthood and middle age with incipient left ventricular dysfunction and structural remodeling: the CARDIA study (Coronary Artery Risk Development in Young Adults). JACC Heart Fail 2(5):500–508

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ayaz M et al (2002) Protective effect of selenium treatment on diabetes-induced myocardial structural alterations. Biol Trace Elem Res 89(3):215–226

    Article  CAS  PubMed  Google Scholar 

  26. Boudina S et al (2007) Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56(10):2457–2466

    Article  CAS  PubMed  Google Scholar 

  27. Boveris A (1984) Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. Methods Enzymol 105:429–435

    Article  CAS  PubMed  Google Scholar 

  28. St-Pierre J et al (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277(47):44784–44790

    Article  CAS  PubMed  Google Scholar 

  29. Duncan JG et al (2007) Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation 115(7):909–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Neubauer S et al (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96(7):2190–2196

    Article  CAS  PubMed  Google Scholar 

  31. Peterson LR et al (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109(18):2191–2196

    Article  PubMed  Google Scholar 

  32. Anderson EJ et al (2009) Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 54(20):1891–1898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nakamura H et al (2012) p53 promotes cardiac dysfunction in diabetic mellitus caused by excessive mitochondrial respiration-mediated reactive oxygen species generation and lipid accumulation. Circ Heart Fail 5(1):106–115

    Article  CAS  PubMed  Google Scholar 

  34. Durak A et al (2018) A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. Cardiovasc Diabetol 17(1):144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Oliveira PJ et al (2003) Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS Lett 554(3):511–514

    Article  CAS  PubMed  Google Scholar 

  36. Perrone-Filardi P et al (2015) The role of metabolic syndrome in heart failure. Eur Heart J 36(39):2630–2634

    Article  CAS  PubMed  Google Scholar 

  37. Gaddam KK, Ventura HO, Lavie CJ (2011) Metabolic syndrome and heart failure–the risk, paradox, and treatment. Curr Hypertens Rep 13(2):142–148

    Article  CAS  PubMed  Google Scholar 

  38. Gupta PP, Fonarow GC, Horwich TB (2015) Obesity and the obesity paradox in heart failure. Can J Cardiol 31(2):195–202

    Article  PubMed  Google Scholar 

  39. Lavie CJ et al (2013) Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. JACC Heart Fail 1(2):93–102

    Article  PubMed  Google Scholar 

  40. Oreopoulos A et al (2008) Body mass index and mortality in heart failure: a meta-analysis. Am Heart J 156(1):13–22

    Article  PubMed  Google Scholar 

  41. Kalantar-Zadeh K et al (2004) Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 43(8):1439–1444

    Article  PubMed  Google Scholar 

  42. Kenchaiah S et al (2002) Obesity and the risk of heart failure. N Engl J Med 347(5):305–313

    Article  PubMed  Google Scholar 

  43. Ather S et al (2012) Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 59(11):998–1005

    Article  PubMed  PubMed Central  Google Scholar 

  44. Mentz RJ et al (2014) Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol 64(21):2281–2293

    Article  PubMed  PubMed Central  Google Scholar 

  45. Vella S et al (2010) The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 53(5):809–820

    Article  CAS  PubMed  Google Scholar 

  46. George P, McCrimmon RJ (2013) Potential role of non-insulin adjunct therapy in Type 1 diabetes. Diabet Med 30(2):179–188

    Article  CAS  PubMed  Google Scholar 

  47. Garg SK et al (2013) Effect of sitagliptin on post-prandial glucagon and GLP-1 levels in patients with type 1 diabetes: investigator-initiated, double-blind, randomized, placebo-controlled trial. Endocr Pract 19(1):19–28

    Article  PubMed  Google Scholar 

  48. Washburn WN, Poucher SM (2013) Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs 22(4):463–486

    Article  CAS  PubMed  Google Scholar 

  49. Zinman B et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128

    Article  CAS  PubMed  Google Scholar 

  50. Verma S et al (2018) Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME(R) randomised trial. Diabetologia 61(8):1712–1723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fitchett D et al (2018) Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME(R) trial. Eur Heart J 39(5):363–370

    Article  CAS  PubMed  Google Scholar 

  52. Neal B et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657

    Article  CAS  PubMed  Google Scholar 

  53. Verma S, McMurray JJV (2019) The serendipitous story of SGLT2 inhibitors in heart failure. Circulation 139(22):2537–2541

    Article  PubMed  Google Scholar 

  54. Kosiborod M et al (2017) Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation 136(3):249–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ye Y et al (2017) SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther 31(2):119–132

    Google Scholar 

  56. Packer M et al (2017) Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2(9):1025–1029

    Article  PubMed  Google Scholar 

  57. van Baar MJB et al (2018) SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care 41(8):1543–1556

    Article  PubMed  CAS  Google Scholar 

  58. Lahnwong S, Chattipakorn SC, Chattipakorn N (2018) Potential mechanisms responsible for cardioprotective effects of sodium-glucose co-transporter 2 inhibitors. Cardiovasc Diabetol 17(1):101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vrhovac I et al (2015) Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch 467(9):1881–1898

    Article  CAS  PubMed  Google Scholar 

  60. Sattar N et al (2016) SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia 59(7):1333–1339

    Article  PubMed  PubMed Central  Google Scholar 

  61. Plosker GL (2012) Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs 72(17):2289–2312

    Article  CAS  PubMed  Google Scholar 

  62. Lamos EM, Younk LM, Davis SN (2013) Canagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol 9(6):763–775

    Article  CAS  PubMed  Google Scholar 

  63. Saeed MA, Narendran P (2014) Dapagliflozin for the treatment of type 2 diabetes: a review of the literature. Drug Des Devel Ther 8:2493–2505

    CAS  PubMed  PubMed Central  Google Scholar 

  64. De Nicola L et al (2014) Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis 64(1):16–24

    Article  PubMed  CAS  Google Scholar 

  65. Ferrannini E, Mark M, Mayoux E (2016) CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 39(7):1108–1114

    Article  PubMed  Google Scholar 

  66. Lopaschuk GD et al (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258

    Article  CAS  PubMed  Google Scholar 

  67. Baartscheer A et al (2017) Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia 60(3):568–573

    Article  CAS  PubMed  Google Scholar 

  68. Chilton R et al (2015) Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab 17(12):1180–1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lee TM, Chang NC, Lin SZ (2017) Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 104:298–310

    Article  CAS  PubMed  Google Scholar 

  70. Garvey WT et al (2018) Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes. Metabolism 85:32–37

    Article  CAS  PubMed  Google Scholar 

  71. Sato T et al (2018) The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 17(1):6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Khalaf KI, Taegtmeyer H (2012) After avandia: the use of antidiabetic drugs in patients with heart failure. Tex Heart Inst J 39(2):174–178

    PubMed  PubMed Central  Google Scholar 

  73. Han S et al (2008) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57(6):1723–1729

    Article  CAS  PubMed  Google Scholar 

  74. Hansen HH et al (2014) The sodium glucose cotransporter type 2 inhibitor empagliflozin preserves beta-cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat. J Pharmacol Exp Ther 350(3):657–664

    Article  PubMed  CAS  Google Scholar 

  75. Hinnen D (2013) The role of the kidney in hyperglycemia: a new therapeutic target in type 2 diabetes mellitus. J Cardiovasc Nurs 28(2):157–165

    Article  PubMed  Google Scholar 

  76. Novak LM, Kruger DF (2017) Bolstering your armamentarium with SGLT2 inhibitors. Nurse Pract 42(10):28–34

    Article  PubMed  Google Scholar 

  77. Lim S, Eckel RH, Koh KK (2018) Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors. Atherosclerosis 272:33–40

    Article  CAS  PubMed  Google Scholar 

  78. Vasilakou D et al (2013) Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 159(4):262–274

    Article  PubMed  Google Scholar 

  79. Han JH et al (2017) The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE (-/-) mice fed a western diet. Diabetologia 60(2):364–376

    Article  CAS  PubMed  Google Scholar 

  80. Sato T et al (2017) Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes. Diabet Med 34(10):1367–1371

    Article  CAS  PubMed  Google Scholar 

  81. Hsia DS, Heymsfield SB (2018) Reducing diabetes risk at an early age. Nat Med 24(6):708–710

    Article  CAS  PubMed  Google Scholar 

  82. Jia X et al (2018) SGLT2 inhibitors and cardiovascular outcomes: current perspectives and future potentials. Curr Diab Rep 18(9):63

    Article  CAS  PubMed  Google Scholar 

  83. Zhang XL et al (2018) Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc 7(2)

    Google Scholar 

  84. Verma S, McMurray JJV (2018) SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 61(10):2108–2117

    Article  CAS  PubMed  Google Scholar 

  85. Kashiwagi Y et al (2015) Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS ONE 10(6):e0130605

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Habibi J et al (2017) Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol 16(1):9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Kusaka H et al (2016) Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol 15(1):157

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Lin B et al (2014) Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 13:148

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Hammoudi N et al (2017) Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc Drugs Ther 31(3):233–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liang L, Jiang J, Frank SJ (2000) Insulin receptor substrate-1-mediated enhancement of growth hormone-induced mitogen-activated protein kinase activation. Endocrinology 141(9):3328–3336

    Article  CAS  PubMed  Google Scholar 

  91. Zhou Y, Wu W (2017) The sodium-glucose co-transporter 2 inhibitor, empagliflozin, protects against diabetic cardiomyopathy by inhibition of the endoplasmic reticulum stress pathway. Cell Physiol Biochem 41(6):2503–2512

    Article  CAS  PubMed  Google Scholar 

  92. Tanajak P et al (2018) Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J Endocrinol 236(2):69–84

    Article  CAS  PubMed  Google Scholar 

  93. Shi X et al (2017) Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial? Mol Cell Biochem 433(1–2):97–102

    Article  CAS  PubMed  Google Scholar 

  94. Januzzi JL Jr et al (2017) Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol 70(6):704–712

    Article  CAS  PubMed  Google Scholar 

  95. Marx N, McGuire DK (2016) Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J 37(42):3192–3200

    Article  CAS  PubMed  Google Scholar 

  96. Tanaka A, Node K (2017) Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology. J Cardiol 69(3):501–507

    Article  PubMed  Google Scholar 

  97. Aydemir-Koksoy A et al (2010) Antioxidant treatment protects diabetic rats from cardiac dysfunction by preserving contractile protein targets of oxidative stress. J Nutr Biochem 21(9):827–833

    Article  CAS  PubMed  Google Scholar 

  98. Ayaz M et al (2004) Effects of selenium on altered mechanical and electrical cardiac activities of diabetic rat. Arch Biochem Biophys 426(1):83–90

    Article  CAS  PubMed  Google Scholar 

  99. Yamamoto E et al (2006) Enhancement of cardiac oxidative stress by tachycardia and its critical role in cardiac hypertrophy and fibrosis. J Hypertens 24(10):2057–2069

    Article  CAS  PubMed  Google Scholar 

  100. Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86(5):494–501

    Article  CAS  PubMed  Google Scholar 

  101. Turan B (2010) Role of antioxidants in redox regulation of diabetic cardiovascular complications. Curr Pharm Biotechnol 11(8):819–836

    Article  CAS  PubMed  Google Scholar 

  102. Turan B, Vassort G (2011) Ryanodine receptor: a new therapeutic target to control diabetic cardiomyopathy. Antioxid Redox Signal 15(7):1847–1861

    Article  CAS  PubMed  Google Scholar 

  103. Vassort G, Turan B (2010) Protective role of antioxidants in diabetes-induced cardiac dysfunction. Cardiovasc Toxicol 10(2):73–86

    Article  CAS  PubMed  Google Scholar 

  104. Okatan EN, Tuncay E, Turan B (2013) Cardioprotective effect of selenium via modulation of cardiac ryanodine receptor calcium release channels in diabetic rat cardiomyocytes through thioredoxin system. J Nutr Biochem 24(12):2110–2118

    Article  CAS  PubMed  Google Scholar 

  105. Oelze M et al (2014) The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE 9(11):e112394

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Giorgi C et al (2012) Mitochondrial Ca(2+) and apoptosis. Cell Calcium 52(1):36–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nazarewicz RR et al (2013) Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress. Am J Physiol Heart Circ Physiol 305(8):H1131–H1140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jeong EM et al (2016) Role of mitochondrial oxidative stress in glucose tolerance, insulin resistance, and cardiac diastolic dysfunction. J Am Heart Assoc 5(5)

    Google Scholar 

  109. Carafoli E, Lehninger AL (1971) A survey of the interaction of calcium ions with mitochondria from different tissues and species. Biochem J 122(5):681–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Denton RM, McCormack JG (1980) The role of calcium in the regulation of mitochondrial metabolism. Biochem Soc Trans 8(3):266–268

    Article  CAS  PubMed  Google Scholar 

  111. Rizzuto R et al (1992) Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature 358(6384):325–327

    Article  CAS  PubMed  Google Scholar 

  112. Mansouri A et al (2006) Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging. Mech Ageing Dev 127(3):298–306

    Article  CAS  PubMed  Google Scholar 

  113. Dey S et al (2018) Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ Res 123(3):356–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Owada T et al (2017) Resolution of mitochondrial oxidant stress improves aged-cardiovascular performance. Coron Artery Dis 28(1):33–43

    Article  PubMed  Google Scholar 

  115. Galloway CA, Yoon Y (2015) Mitochondrial dynamics in diabetic cardiomyopathy. Antioxid Redox Signal 22(17):1545–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Montaigne D et al (2014) Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130(7):554–564

    Article  CAS  PubMed  Google Scholar 

  117. Sharp WW et al (2015) Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model. Crit Care Med 43(2):e38-47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Duncan JG (2011) Mitochondrial dysfunction in diabetic cardiomyopathy. Biochim Biophys Acta 1813(7):1351–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ong SB et al (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121(18):2012–2022

    Article  CAS  PubMed  Google Scholar 

  120. Lucas E et al (2016) Obesity-induced cardiac lipid accumulation in adult mice is modulated by G protein-coupled receptor kinase 2 levels. Cardiovasc Diabetol 15(1):155

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Yang XH et al (2017) The relationship between insulin sensitivity and heart rate-corrected QT interval in patients with type 2 diabetes. Diabetol Metab Syndr 9:69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Torekov SS et al (2014) KCNQ1 long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia. Diabetes 63(4):1315–1325

    Article  CAS  PubMed  Google Scholar 

  123. Alpert MA (2001) Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. Am J Med Sci 321(4):225–236

    Article  CAS  PubMed  Google Scholar 

  124. Gastaldelli A et al (2000) Insulin prolongs the QTc interval in humans. Am J Physiol Regul Integr Comp Physiol 279(6):R2022–R2025

    Article  CAS  PubMed  Google Scholar 

  125. de Simone G et al (1994) Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults. Hypertension 23(5):600–606

    Article  PubMed  Google Scholar 

  126. Yaras N et al (2005) Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart. Diabetes 54(11):3082–3088

    Article  CAS  PubMed  Google Scholar 

  127. Wehrens XH, Marks AR (2003) Altered function and regulation of cardiac ryanodine receptors in cardiac disease. Trends Biochem Sci 28(12):671–678

    Article  CAS  PubMed  Google Scholar 

  128. Choi KM et al (2002) Defective intracellular Ca(2+) signaling contributes to cardiomyopathy in Type 1 diabetic rats. Am J Physiol Heart Circ Physiol 283(4):H1398–H1408

    Article  CAS  PubMed  Google Scholar 

  129. Pierce GN, Kutryk MJ, Dhalla NS (1983) Alterations in Ca2+ binding by and composition of the cardiac sarcolemmal membrane in chronic diabetes. Proc Natl Acad Sci USA 80(17):5412–5416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fein FS, Sonnenblick EH (1994) Diabetic cardiomyopathy. Cardiovasc Drugs Ther 8(1):65–73

    Article  CAS  PubMed  Google Scholar 

  131. Rubler S et al (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30(6):595–602

    Article  CAS  PubMed  Google Scholar 

  132. Priest BT, McDermott JS (2015) Cardiac ion channels. Channels (Austin) 9(6):352–359

    Article  Google Scholar 

  133. Lambert R et al (2015) Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport. J Am Heart Assoc 4(9):e002183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Baartscheer A et al (2005) Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res 65(1):83–92

    Article  CAS  PubMed  Google Scholar 

  135. Baartscheer A et al (2003) Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res 57(4):1015–1024

    Article  CAS  PubMed  Google Scholar 

  136. Liu T, O’Rourke B (2008) Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ Res 103(3):279–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Liu T et al (2014) Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res 115(1):44–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Joubert M et al (2017) The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes 66(4):1030–1040

    Article  CAS  PubMed  Google Scholar 

  139. Olgar Y, Turan B (2019) A sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin comparison with insulin shows important effects on Zn(2+)-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress (1). Can J Physiol Pharmacol 97(6):528–535

    Article  CAS  PubMed  Google Scholar 

  140. Lim VG et al (2019) SGLT2 inhibitor, canagliflozin, attenuates myocardial infarction in the diabetic and nondiabetic heart. JACC Basic Transl Sci 4(1):15–26

    Article  PubMed  PubMed Central  Google Scholar 

  141. Vardeny O, Vaduganathan M (2019) Practical guide to prescribing sodium-glucose cotransporter 2 inhibitors for cardiologists. JACC Heart Fail 7(2):169–172

    Article  PubMed  Google Scholar 

  142. Garcia-Ropero A et al (2019) Metabolism of the failing heart and the impact of SGLT2 inhibitors. Expert Opin Drug Metab Toxicol 15(4):275–285

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All experimental studies mentioned in this text were supported by a grant from TUBITAK SBAG-214S254.

Author information

Authors and Affiliations

  1. Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey

    Belma Turan

Authors
  1. Belma Turan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Belma Turan .

Editor information

Editors and Affiliations

  1. Asper Clinical Research Institute, St. Boniface Hospital, Winnipeg, MB, Canada

    Paramjit S. Tappia

  2. Institute of Cardiovascular Sciences, St. Boniface Hospital, Winnipeg, MB, Canada

    Sukhwinder K. Bhullar

  3. Institute of Cardiovascular Sciences, St. Boniface Hospital, Winnipeg, MB, Canada

    Naranjan S. Dhalla

Ethics declarations

The author declares no competing interests.

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Turan, B. (2020). Role of Sodium-Glucose Co-transporters on Cardiac Function in Metabolic Syndrome Mammalians. In: Tappia, P.S., Bhullar, S.K., Dhalla, N.S. (eds) Biochemistry of Cardiovascular Dysfunction in Obesity. Advances in Biochemistry in Health and Disease, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-47336-5_7

Download citation

Publish with us

Policies and ethics

Search

Navigation