Skip to main content

Advertisement

SpringerLink
Log in

Diabetic cardiomyopathy: molecular mechanisms, detrimental effects of conventional treatment, and beneficial effects of natural therapy

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstarct

Diabetic complications are among the largely exigent health problems currently. Cardiovascular complications, including diabetic cardiomyopathy (DCM), account for more than 80% of diabetic deaths. Investigators are exploring new therapeutic targets to slow or abate diabetes because of the growing occurrence and augmented risk of deaths due to its complications. Research on rodent models of type 1 and type 2 diabetes mellitus, and the use of genetic engineering techniques in mice and rats have significantly sophisticated for our understanding of the molecular mechanisms in human DCM. DCM is featured by pathophysiological mechanisms that are hyperglycemia, insulin resistance, oxidative stress, left ventricular hypertrophy, damaged left ventricular systolic and diastolic functions, myocardial fibrosis, endothelial dysfunction, myocyte cell death, autophagy, and endoplasmic reticulum stress. A number of molecular and cellular pathways, such as cardiac ubiquitin proteasome system, FoxO transcription factors, hexosamine biosynthetic pathway, polyol pathway, protein kinase C signaling, NF-κB signaling, peroxisome proliferator-activated receptor signaling, Nrf2 pathway, mitogen-activated protein kinase pathway, and micro RNAs, play a major role in DCM. Currently, there are a few drugs for the management of DCM and some of them have considerable adverse effects. So, researchers are focusing on the natural products to ameliorate it. Hence, in this review, we discuss the pathogical, molecular, and cellular mechanisms of DCM; the current diagnostic methods and treatments; adverse effects of conventional treatment; and beneficial effects of natural product-based therapeutics, which may pave the way to new treatment strategies.

Graphical Abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Aneja A, Tang W, Bansilal S et al (2008) Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 121:748–757. https://doi.org/10.1016/j.amjmed.2008.03.046

    Article  PubMed  Google Scholar 

  2. Rubler S, Dlugash J, Yuceoglu YZ (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30:595–602. https://doi.org/10.1016/0002-9149(72)90595-4

    Article  PubMed  CAS  Google Scholar 

  3. Bugger H, Abel ED (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57:660–671. https://doi.org/10.1007/s00125-014-3171-6

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Kohli S, Chhabra A, Jaiswal A, Rustagi Y, Sharma M, Rani V (2013) Curcumin suppresses gelatinase B mediated norepinephrine induced stress in H9C2 cardiomyocytes. PLoS One 8:76519. https://doi.org/10.1371/journal.pone.0076519

    Article  CAS  Google Scholar 

  5. Alonso N, Moliner P, Mauricio D (2018) Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv Exp Med Biol 1067:197–217. https://doi.org/10.1007/5584_2017_105

    Article  PubMed  Google Scholar 

  6. WHO (2016) Global report on diabetes, ISBN 978 92 4 156525 7

  7. Goyal BR, Mehta AA (2012) Diabetic cardiomyopathy: pathophysiological mechanisms and cardiac dysfunction. Hum Exp Toxicol 32:1–20. https://doi.org/10.1177/0960327112450885

    Article  CAS  Google Scholar 

  8. Li B, Zheng Z, Wei Y, Wang M, Peng J, Kang T, Huang X, Xiao J, Li Y, Li Z (2011) Therapeutic effects of neuregulin-1 in diabetic cardiomyopathy rats. Cardiovasc Diabetol 10:69. https://doi.org/10.1186/1475-2840-10-69

    Article  PubMed  PubMed Central  Google Scholar 

  9. Saravanan G, Ponmurugan P, Sathiyavathi M, Vadivukkarasi S, Sengottuvelu S (2013) Cardioprotective activity of Amaranthus viridis Linn: effect on serum marker enzymes, cardiac troponin and antioxidant system in experimental myocardial infarcted rats. Int J Cardiol 165:494–498. https://doi.org/10.1016/j.ijcard.2011.09.005

    Article  PubMed  CAS  Google Scholar 

  10. Bodiga VL, Eda SR, Bodiga S (2014) Advanced glycation end products: role in pathology of diabetic cardiomyopathy. Heart Fail Rev 19:49–63. https://doi.org/10.1007/s10741-013-9374-y

    Article  PubMed  CAS  Google Scholar 

  11. Sathibabu Uddandrao VV, Brahmanaidu P, Nivedha PR, Vadivukkarasi S, Saravanan G (2018) Beneficial role of some natural products to attenuate the diabetic cardiomyopathy through Nrf2 pathway in cell culture and animal models. Cardiovasc Toxicol 18:199–205. https://doi.org/10.1007/s12012-017-9430-2

    Article  PubMed  CAS  Google Scholar 

  12. Khan JN, Wilmot EG, Leggate M (2014) Subclinical diastolic dysfunction in young adults with type 2 diabetes mellitus: a multiparametric contrast-enhanced cardiovascular magnetic resonance pilot study assessing potential mechanisms. Eur Heart J Cardiovasc Imaging 15:1263–1269. https://doi.org/10.1093/ehjci/jeu121

    Article  PubMed  Google Scholar 

  13. Fuentes-Antras J, Ioan AM, Tunon J, Egido J, Lorenzo O (2014) Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol 2014:847827. https://doi.org/10.1155/2014/847827

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Heiko Bugger DAE (2009) Rodent models of diabetic cardiomyopathy. Dis Model Mech 2:454–466. https://doi.org/10.1242/dmm.001941

    Article  PubMed  CAS  Google Scholar 

  15. Coort SL, Hasselbaink DM, Koonen DP et al (2004) Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes 53:1655–1663. https://doi.org/10.2337/diabetes.53.7.1655

    Article  PubMed  CAS  Google Scholar 

  16. Wang P, Lloyd SG, Zeng H, Bonen A, Chatham JC (2005) Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol 288:2102–2110. https://doi.org/10.1152/ajpheart.00935.2004

    Article  CAS  Google Scholar 

  17. Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M et al (2009) Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ Res 104:1085–1094. https://doi.org/10.1161/CIRCRESAHA.108.189316

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Wright JJ, Kim J, Buchanan J, Boudina S, Sena S, Bakirtzi K, Ilkun O, Theobald HA, Cooksey RC, Kandror KV, Abel ED (2009) Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc Res 82:351–360. https://doi.org/10.1093/cvr/cvp017

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Rennison JH, McElfresh TA et al (2009) Prolonged exposure to high dietary lipids is not associated with lipotoxicity in heart failure. J Mol Cell Cardiol 46:883–890. https://doi.org/10.1016/j.yjmcc.2009.02.019

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Ahmed SS, Jafer GA, Narang RM et al (1975) Preclinical abnormality of left ventricular function in diabetes mellitus. Am Heart J 89:153–158. https://doi.org/10.1016/0002-8703(75)90039-3

    Article  PubMed  CAS  Google Scholar 

  21. Fang ZY, Najos-Valencia O, Leano R, Marwick TH (2003) Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine. J Am Coll Cardiol 42:46–53. https://doi.org/10.1016/S0735-1097(03)00654-5

    Article  CAS  Google Scholar 

  22. Thompson GR, Partridge J (2004) Coronary calcification score: the coronary-risk impact factor. Lancet 363:557–559. https://doi.org/10.1016/S0140-6736(04)15544-X

    Article  PubMed  CAS  Google Scholar 

  23. Ficaro EP, Corbett JR (2004) Advances in quantitative perfusion SPECT imaging. J Nucl Cardiol 11:62–70. https://doi.org/10.1016/j.nuclcard.2003.10.007

    Article  PubMed  Google Scholar 

  24. Schinkel AF, Bax JJ, Valkema R, Elhendy A, van Domburg R, Vourvouri EC, Bountioukos MA, Krenning EP, Roelandt JR, Poldermans D (2003) Effect of diabetes mellitus on myocardial 18F-FDG SPECT using acipimox for the assessment of myocardial viability. J Nucl Med 44:877–883

    PubMed  Google Scholar 

  25. Soriano FG, Pacher P, Mabley J, Liaudet L, Szabo C (2001) Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res 89:684–691. https://doi.org/10.1161/hh2001.097797

    Article  PubMed  CAS  Google Scholar 

  26. Coats AJ, Anker SD (2000) Insulin resistance in chronic heart failure. J Cardiovasc Pharmacol 35:9–14. https://doi.org/10.1016/j.jacc.2008.03.044

    Article  Google Scholar 

  27. Stanley WC, Marzilli M (2003) Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine. Fundam Clin Pharmacol 17:133–145. https://doi.org/10.1046/j.1472-8206.2003.00154.x

    Article  PubMed  CAS  Google Scholar 

  28. Turan B (2010) Role of antioxidants in redox regulation of diabetic cardiovascular complications. Curr Pharm Biotechnol 11:819–836. https://doi.org/10.2174/138920110793262123

    Article  PubMed  CAS  Google Scholar 

  29. Brunner F, Bras-Silva C, Cerdeira AS, Leite-Moreira AF (2006) Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. Pharmacol Ther 111:508–531. https://doi.org/10.1016/j.pharmthera.2005.11.001

    Article  PubMed  CAS  Google Scholar 

  30. Brahmanaidu P, Sathibabu Uddandrao VV, Saravanan G (2017) Reversal of endothelial dysfunction in aorta of streptozotocinnicotinamide-induced type-2 diabetic rats by S-Allylcysteine. Mol Cell Biochem 432:25–32. https://doi.org/10.1007/s11010-017-2994-0

    Article  PubMed  CAS  Google Scholar 

  31. Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J (2001) Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes 50:2363–2375. https://doi.org/10.2337/diabetes.50.10.2363

    Article  PubMed  CAS  Google Scholar 

  32. Vinereanu D, Nicolaides E, Boden L, Payne N, Jones CJ, Fraser AG (2003) Conduit arterial stiffness is associated with impaired left ventricular subendocardial function. Heart 89:449–451. https://doi.org/10.1136/heart.89.4.449

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Argirova MD, Ortwerth BJ (2003) Activation of protein-bound copper ions during early glycation: study on two proteins. Arch Biochem Biophys 420:176–184. https://doi.org/10.1016/j.abb.2003.09.005

    Article  PubMed  CAS  Google Scholar 

  34. Riehle C, Wende AR, Sena S, Pires KM, Pereira RO, Zhu Y, Bugger H, Frank D, Bevins J, Chen D, Perry CN, Dong XC, Valdez S, Rech M, Sheng X, Weimer BC, Gottlieb RA, White MF, Abel ED (2013) Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. J Clin Invest 123:5319–5333. https://doi.org/10.1172/JCI71171

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Lakshmanan AP, Harima M, Suzuki K, Soetikno V, Nagata M, Nakamura T, Takahashi T, Sone H, Kawachi H, Watanabe K (2013) The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic nonobese type 2 diabetic rats: a differential role of unfolded protein response (UPR) signaling proteins. Int J Biochem Cell Biol 45:438–447. https://doi.org/10.1016/j.biocel.2012.09.017

    Article  PubMed  CAS  Google Scholar 

  36. Frieler RA, Mortensen RM (2015) Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation 131:1019–1030. https://doi.org/10.1161/CIRCULATIONAHA.114.008788

    Article  PubMed  PubMed Central  Google Scholar 

  37. Li J, Ma W, Yue G, Tang Y, Kim IM, Weintraub NL, Wang X, Su H (2017) Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy. J Mol Cell Cardiol 102:53–60. https://doi.org/10.1016/j.yjmcc.2016.11.013

    Article  PubMed  CAS  Google Scholar 

  38. Asghar O, Al-Sunni A, Khavandi K, Withers S et al (2009) Diabetic cardiomyopathy. Clin Sci 116:741–760. https://doi.org/10.1042/CS20080500

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Tang M, Huang Li J et al (2010) Proteasome functional insufficiency activates the calcineurin-NFAT pathway in cardiomyocytes and promotesmaladaptive remodelling of stressed mouse hearts. Cardiovasc Res 88:424–433. https://doi.org/10.1093/cvr/cvq217

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Ferdous A, Battiprolu PK, Ni YG, Rothermel BA, Hill JA (2010) FoxO, autophagy, and cardiac remodeling. J Cardiovasc Transl Res 3:355–364. https://doi.org/10.1007/s12265-010-9200-z

    Article  PubMed  PubMed Central  Google Scholar 

  41. Marsh SA, DellItalia LJ, Chatham JC (2011) Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice. Amino Acids 40:819–828. https://doi.org/10.1007/s00726-010-0699-8

    Article  PubMed  CAS  Google Scholar 

  42. Wollaston-Hayden EE, Harris RB, Liu B, Bridger R, Xu Y et al (2015) Global O-GlcNAc levels modulate transcription of the adipocyte secretome during chronic insulin resistance. Front Endocrinol (Lausanne) 5:223. https://doi.org/10.3389/fendo.2014.00223

    Article  Google Scholar 

  43. Rajamani U, Essop MF (2010) Hyperglycemia-mediated activation of the hexosamine biosynthetic pathway results in myocardial apoptosis. Am J Physiol Cell Physiol 299:139–147. https://doi.org/10.1152/ajpcell.00020.2010

    Article  CAS  Google Scholar 

  44. Gabbay KH (1973) The sorbitol pathway and the complications of diabetes. N Engl J Med 288:831–836. https://doi.org/10.1056/NEJM197304192881609

    Article  PubMed  CAS  Google Scholar 

  45. Brahmanaidu P, Sathibabu Uddandrao VV, Pothani S, Saravanan G et al (2016) Effects of S-allylcysteine on biomarkers of polyol pathway in experimental type II diabetes in rats. Can J Dia 40:442–448. https://doi.org/10.1016/j.jcjd.2016.03.006

    Article  Google Scholar 

  46. Huynh K, Bianca C et al (2014) Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 142:375–415. https://doi.org/10.1016/j.pharmthera.2014.01.003

    Article  PubMed  CAS  Google Scholar 

  47. Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128:191–227. https://doi.org/10.1016/j.pharmthera.2010.04.005

    Article  PubMed  CAS  Google Scholar 

  48. Palomer XL, Salvado E, Barroso Vazquez-Carrera M (2013) An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. Int J Cardiol 168:3160–3172. https://doi.org/10.1016/j.ijcard.2013.07.150

    Article  PubMed  Google Scholar 

  49. Turner NA, Mughal RS, Warburton P et al (2007) Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Cardiovasc Res 76:81–90. https://doi.org/10.1016/j.cardiores.2007.06.003

    Article  PubMed  CAS  Google Scholar 

  50. Duncan JG (2011) Peroxisome proliferator activated receptor-alpha (PPAR alpha) and PPAR gamma coactivator-1alpha (PGC-1 alpha) regulation of cardiac metabolism in diabetes. Pediatr Cardiol 32:323–328. https://doi.org/10.1007/s00246-011-9889-8

    Article  PubMed  PubMed Central  Google Scholar 

  51. Burkart EM, Sambandam N, Han X, Gross RW, Courtois M, Gierasch CM, Shoghi K, Welch MJ, Kelly DP (2007) Nuclear receptors PPAR beta/delta and PPAR alpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest 117:3930–3939. https://doi.org/10.1172/JCI32578

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Luo J, Wu S, Liu J, Li Y, Yang H, Kim T, Zhelyabovska O, Ding G, Zhou Y, Yang Y, Yang Q (2010) Conditional PPARgamma knockout from cardiomyocytes of adult mice impairs myocardial fatty acid utilization and cardiac function. Am J Transl Res 3:61–72

    PubMed  PubMed Central  Google Scholar 

  53. Calvert JW, Jha S, Gundewar S, Elrod JW, Ramachandran A, Pattillo CB, Kevil CG, Lefer DJ (2009) Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res 105:365–374. https://doi.org/10.1161/CIRCRESAHA.109.199919

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Zhang Z, Wang S, Zhou S, Yan X, Wang Y, Chen J, Mellen N, Kong M, Gu J, Tan Y, Zheng Y, Cai L (2014) Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. J Mol Cell Cardiol 77:42–52. https://doi.org/10.1016/j.yjmcc.2014.09.022

    Article  PubMed  CAS  Google Scholar 

  55. Marber MS, Rose B, Wang Y (2011) The p38 mitogen-activated protein kinase pathway-a potential target for intervention in infarction, hypertrophy, and heart failure. J Mol Cell Cardiol 51:485–490. https://doi.org/10.1016/j.yjmcc.2010.10.021

    Article  PubMed  CAS  Google Scholar 

  56. Min W, Bin ZW, Quan ZB, Hui ZJ, Sheng FG (2009) The signal transduction pathway of PKC/NF-κB/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats. Cardiovasc Diabetol 8(1):8. https://doi.org/10.1186/1475-2840-8-8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Bernardo BC, Charchar FJ, Lin RC, McMullen JR (2012) A microRNA guide for clinicians and basic scientists: background and experimental techniques. Heart Lung Circ 21:131–142. https://doi.org/10.1016/j.hlc.2011.11.002

    Article  PubMed  CAS  Google Scholar 

  58. Kartha RV, Subramanian S (2010) MicroRNAs in cardiovascular diseases: biology and potential clinical applications. J Cardiovasc Transl Res 3:256–270. https://doi.org/10.1007/s12265-010-9172-z

    Article  PubMed  Google Scholar 

  59. Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105. https://doi.org/10.1101/gr.082701.108

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Jeyabal P, Thandavarayan RA, Joladarashi D, Suresh Babu S, Krishnamurthy S, Bhimaraj A, Youker KA, Kishore R, Krishnamurthy P (2016) Micro- RNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1. Biochem Biophys Res Commun 471:423–429. https://doi.org/10.1016/j.bbrc.2016.02.065

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Raut SK, Kumar A, Singh GB, Nahar U, Sharma V, Mittal A, Sharma R, Khullar M (2015) miR-30c mediates upregulation of Cdc42 and Pak1 in diabetic cardiomyopathy. Cardiovasc Ther 33:89–97. https://doi.org/10.1111/1755-5922.12113

    Article  PubMed  CAS  Google Scholar 

  62. Li X, Du N, Zhang Q et al (2014) MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy. Cell Death Dis 5:1479. https://doi.org/10.1038/cddis.2014.430

    Article  CAS  Google Scholar 

  63. Von Bibra H, Siegmund T, Hansen A et al (2007) Augmentation of myocardial function by improved glycemic control in patients with type 2 diabetes mellitus. Dtsch Med Wochenschr 132:729–734. https://doi.org/10.1055/s-2007-973608

    Article  Google Scholar 

  64. Konduracka E, Gackowski A, Rostoff P, Galicka-Latala D, Frasik W, Piwowarska W (2007) Diabetes-specific cardiomyopathy in type 1 diabetes mellitus: no evidence for its occurrence in the era of intensive insulin therapy. Eur Heart J 28:2465–2471. https://doi.org/10.1093/eurheartj/ehm361

    Article  PubMed  Google Scholar 

  65. Nguyen NDT, Le LT (2012) Targeted proteins for diabetes drug design. Adv Nat Sci Nanosci Nanotechnol 3:1–9. https://doi.org/10.1088/2043-6262/3/1/013001

    Article  Google Scholar 

  66. Tiwari N, Thakur AK, Kumar V, Dey A, Kumar V (2014) Therapeutic targets for diabetes mellitus: an update. Pharmacol Biopharm 3:117. https://doi.org/10.4172/2167-065X.1000117

    Article  CAS  Google Scholar 

  67. Lebovitz HE (1997) Alpha-Glucosidase inhibitors. Endocrinol Metab Clin N Am 26:539–551. https://doi.org/10.1016/S0889-8529(05)70266-8

    Article  CAS  Google Scholar 

  68. Andreadis EA, Katsanou PM, Georgiopoulos DX, Tsourous G, Yfanti G, Gouveri E, Diamantopoulos E (2009) The effect of metformin on the incidence of type 2 diabetes mellitus and cardiovascular disease risk factors in overweight and obese subjects the Carmos study. Exp Clin Endocrinol Diabetes 117:175–180. https://doi.org/10.1055/s-0028-1087177

    Article  PubMed  CAS  Google Scholar 

  69. Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, Li H, Rathi S, Dong Y, Tian R, Kem D, Zou MH (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60:1770–1778. https://doi.org/10.2337/db10-0351

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Young LH (2003) Insulin resistance and the effects of thiazolidinediones on cardiac metabolism. Am J Med 115:75–80. https://doi.org/10.1016/j.amjmed.2003.09.013

    Article  Google Scholar 

  71. Zaman AK, Fujii S, Goto D, Furumoto T, Mishima T, Nakai Y, Dong J, Imagawa S, Sobel BE, Kitabatake A (2004) Salutary effects of attenuation of angiotensin ii on coronary perivascular fibrosis associated with insulin resistance and obesity. J Mol Cell Cardiol 37:525–535. https://doi.org/10.1016/j.yjmcc.2004.05.006

    Article  PubMed  CAS  Google Scholar 

  72. Adeghate E, Kalasz H, Veress G, Teke K (2010) Medicinal chemistry of drugs used in diabetic cardiomyopathy. Curr Med Chem 17:517–551. https://doi.org/10.2174/092986710790416281

    Article  PubMed  CAS  Google Scholar 

  73. Kawasaki D, Kosugi K, Waki H, Yamamoto K, Tsujino T, Masuyama T (2007) Role of activated renin-angiotensin system in myocardial fibrosis and left ventricular diastolic dysfunction in diabetic patients–reversal by chronic angiotensin ii type 1a receptor blockade. Circ J 71:524–529. https://doi.org/10.1253/circj.71.524

    Article  PubMed  CAS  Google Scholar 

  74. Westermann D, Rutschow S, Jager S, Linderer A, Anker S, Riad A, Unger T, Schultheiss HP, Pauschinger M, Tschope C (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56:641–646. https://doi.org/10.2337/db06-1163

    Article  PubMed  CAS  Google Scholar 

  75. Solomon SD, Skali H, Anavekar NS, Bourgoun M, Barvik S, Ghali JK, Warnica JW, Khrakovskaya M, Arnold JMO, Schwartz Y, Velazquez EJ, Califf RM, McMurray JV, Pfeffer MA (2005) Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 111:3411–3419. https://doi.org/10.1161/CIRCULATIONAHA.104.508093

    Article  PubMed  CAS  Google Scholar 

  76. Fang ZY, Prins JB, Marwick TH (2004) Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25:543–567. https://doi.org/10.1210/er.2003-0012

    Article  PubMed  CAS  Google Scholar 

  77. Veeraveedu PT, Watanabe K, Ma M, Gurusamy N, Palaniyandi SS, Wen J, Prakash P, Wahed MII, Kamal FA, Mito S, Kunisaki M, Kodama M, Aizawa Y (2006) Comparative effects of pranidipine with amlodipine in rats with heart failure. Pharmacology 77:1–10. https://doi.org/10.1159/000091746

    Article  PubMed  CAS  Google Scholar 

  78. Rajanikant GK, Zemke D, Kassab M, Majid A (2007) The therapeutic potential of statins in neurological disorders. Curr Med Chem 14:103–112. https://doi.org/10.2174/092986707779313462

    Article  PubMed  CAS  Google Scholar 

  79. Nisbet JC, Sturtevant JM, Prins JB (2004) Metformin and serious adverse effects. Med J Aust 180:53–54

    PubMed  Google Scholar 

  80. Lund A, Knop FK (2012) Worry vs. knowledge about treatment-associated hypoglycaemia and weight gain in type 2 diabetic patients on metformin and/or sulphonylurea. Curr Med Res Opin 28:731–736. https://doi.org/10.1185/03007995.2012.681639

    Article  PubMed  CAS  Google Scholar 

  81. Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM (2008) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57:1723–1729. https://doi.org/10.2337/db07-1472

    Article  PubMed  CAS  Google Scholar 

  82. Nicolle LE, Capuano G, Ways K, Usiskin K (2012) Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study. Curr Med Res Opin 28:1167–1171. https://doi.org/10.1185/03007995.2012.689956

    Article  PubMed  CAS  Google Scholar 

  83. fa V d l, Lucassen PL, Akkermans RP et al (2005) Alpha-glucosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care 28:154–163. https://doi.org/10.2337/diacare.28.1.154

    Article  Google Scholar 

  84. Cobble M (2012) Differentiating among incretin-based therapies in the management of patients with type 2 diabetes mellitus. Diabetol Metab Syndr 4:8. https://doi.org/10.1186/1758-5996-4-8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Ferwana M, Firwana B, Hasan R, al-Mallah MH, Kim S, Montori VM, Murad MH (2013) Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med 30:1026–1032. https://doi.org/10.1111/dme.12144

    Article  PubMed  CAS  Google Scholar 

  86. Campbell RK, Cobble ME, Reid TS, Shomali ME (2010) Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies. J Fam Pract 59:20–27

    Google Scholar 

  87. Kokil GR, Veedu RN, Ramm GA, Prins JB, Parekh HS (2015) Type 2 diabetes mellitus: limitations of conventional therapies and intervention with nucleic acid-based therapeutics. Chem Rev 115:4719–4743. https://doi.org/10.1021/cr5002832

    Article  PubMed  CAS  Google Scholar 

  88. Saravanan G, Ponmurugan P (2012) Antidiabetic effect of S-allylcysteine: effect on thyroid hormone and circulatory antioxidant system in experimental diabetic rats. J Diab Comp 26:280–285. https://doi.org/10.1016/j.jdiacomp.2012.03.024

    Article  Google Scholar 

  89. Sathibabu Uddandrao VV, Brahmanaidu P, Saravanan G (2017) Therapeutical perspectives of S-allylcysteine: effect on diabetes and other disorders in animal models. Cardiovasc Hematol Agents Med Chem 15:71–77. https://doi.org/10.2174/1871525714666160418114120

    Article  CAS  Google Scholar 

  90. Saravanan G, Ponmurugan P, Senthil kumar GP, Rajarajan T (2009) Modulatory effect of S-allylcysteine on glucose metabolism in streptozotocin induced diabetic rats. J Funct Foods 1:336–340. https://doi.org/10.1016/j.jff.2009.09.001

    Article  CAS  Google Scholar 

  91. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L (2009) Antioxidant properties of an endogenous thiol: alpha-lipoic acid, useful in the prevention of cardiovascular diseases. J Cardiovasc Pharmacol 54:391–398. https://doi.org/10.1097/FJC.0b013e3181be7554

    Article  PubMed  CAS  Google Scholar 

  92. Li C-j, Lv L, Li H, Yu D-m (2012) Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid. Cardiovasc Diabetol 11:73. https://doi.org/10.1186/1475-2840-11-73

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. Li H, Xia N, Forstermann U (2012) Cardiovascular effects and molecular targets of resveratrol. Nitric Oxide 26:102–110. https://doi.org/10.1016/j.niox.2011.12.006

    Article  PubMed  CAS  Google Scholar 

  94. Dolinsky VW, Dyck JR (2011) Calorie restriction and resveratrol in cardiovascular health and disease. Biochem Biophys Acta 1812:1477–1489. https://doi.org/10.1016/j.bbadis.2011.06.010

    Article  PubMed  CAS  Google Scholar 

  95. Guo S, Yao Q, Ke Z, Chen H, Wu J, Liu C (2015) Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK. Mol Cell Endocrinol 412:85–94. https://doi.org/10.1016/j.mce.2015.05.034

    Article  PubMed  CAS  Google Scholar 

  96. Shehzad A, Ha T, Subhan F, Lee YS (2011) New mechanisms and the anti-inflammatory role of curcumin in obesity and obesity-related metabolic diseases. Eur J Nutr 50:151–161. https://doi.org/10.1007/s00394-011-0188-1

    Article  PubMed  CAS  Google Scholar 

  97. Wei Y, Jiliang W, Fei C et al (2012) Curcumin alleviates diabetic cardiomyopathy in experimental diabetic rats. PLoS One 7(52013):e52013. https://doi.org/10.1371/journal.pone.0052013

    Article  CAS  Google Scholar 

  98. Xu K, Chu F, Li G, Xu X, Wang P, Song J, Zhou S, Lei H (2014) Oleanolic acid synthetic oligoglycosides: a review on recent progress in biological activities. Pharmazie 69:483–495. https://doi.org/10.1691/ph.2014.3933

    Article  PubMed  CAS  Google Scholar 

  99. Li WF, Wang P, Li H, Li TY, Feng M, Chen SF (2017) Oleanolic acid protects against diabetic cardiomyopathy via modulation of the nuclear factor erythroid 2 and insulin signaling pathways. Exp Ther Med 14:848–854. https://doi.org/10.3892/etm.2017.4527

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  100. Agyemang K, Han L, Liu E, Zhang Y, Wang T, Gao X (2013) Recent advances in Astragalus membranaceus anti-diabetic research: pharmacological effects of its phytochemical constituents. Evid Based Complement Alternat Med 2013:654643. https://doi.org/10.1155/2013/654643

    Article  PubMed  PubMed Central  Google Scholar 

  101. Chen W, Xia P et al (2012) Improvement of myocardial glycolipid metabolic disorder in diabetic hamster with Astragalus polysaccharides treatment. Mol Biol Rep 39:7609–7615. https://doi.org/10.1007/s11033-012-1595-y

    Article  PubMed  CAS  Google Scholar 

  102. Sun S, Yang S, Dai M, Jia X, Wang Q, Zheng Z, Mao Y (2017) The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose -stimulated H9C2 cells. BMC Complement Altern Med 17:310. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x

    Article  PubMed  PubMed Central  Google Scholar 

  103. Yu Y, Zheng G (2017) Troxerutin protects against diabetic cardiomyopathy through NF κB/AKT/IRS1 in a rat model of type 2 diabetes. Mol Med Rep 15:3473–3478. https://doi.org/10.3892/mmr.2017.6456

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  104. Hamblin M, Friedman DB, Hill S, Caprioli RM, Smith HM, Hill MF (2007) Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy. J Mol Cell Cardiol 42:884–895. https://doi.org/10.1016/j.yjmcc.2006.12.018

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  105. Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD (2011) Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60:3055–3066. https://doi.org/10.2337/db11-0807

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  106. Tsuda H, Ohshima Y, Nomoto H, Fujita KI, Matsuda E, Iigo M, Takasuka N, Moore MA (2004) Cancer prevention by natural compounds. Drug Metab Pharmacokinet 19:245–263. https://doi.org/10.2133/dmpk.19.245

    Article  PubMed  CAS  Google Scholar 

  107. Yeh CT, Ching LC, Yen GC (2009) Inducing gene expression of cardiac antioxidant enzymes by dietary phenolic acids in rats. J Nut Biochem 20:163–171. https://doi.org/10.1016/j.jnutbio.2008.01.005

    Article  CAS  Google Scholar 

  108. Leung L, Kwong M, Hou S, Lee C, Chan JY (2003) Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem 278:48021–48029. https://doi.org/10.1074/jbc.M308439200

    Article  PubMed  CAS  Google Scholar 

  109. Niu L, He XH, Wang QW, Fu MY, Xu F, Xue Y, Wang ZZ, An XJ (2015) Polyphenols in regulation of redox signaling and inflammation during cardiovascular diseases. Cell Biochem Biophys 72:485–494. https://doi.org/10.1007/s12013-014-0492-5

    Article  PubMed  CAS  Google Scholar 

  110. Li M, Jiang Y, Jing W, Sun B, Miao C, Ren L (2013) Quercetin provides greater cardioprotective effect than its glycoside derivative rutin on isoproterenol-induced cardiac fibrosis in the rat. Can J Physiol Pharmacol 91:951–959. https://doi.org/10.1139/cjpp-2012-0432

    Article  PubMed  CAS  Google Scholar 

  111. Panchal SK, Poudyal H, Brown L (2012) Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. J Nutr 142:1026–1032. https://doi.org/10.3945/jn.111.157263

    Article  PubMed  CAS  Google Scholar 

  112. Guo H, Zhang X, Cui Y, Zhou H, Xu D, Shan T, Zhang F, Guo Y, Chen Y, Wu D (2015) Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. Toxicol Appl Pharmacol 287:168–177. https://doi.org/10.1016/j.taap.2015.06.002

    Article  PubMed  CAS  Google Scholar 

  113. Gao L, Yao R, Liu Y, Wang Z, Huang Z, du B, Zhang D, Wu L, Xiao L, Zhang Y (2017) Isorhamnetin protects against cardiac hypertrophy through blocking PI3K-AKT pathway. Mol Cell Biochem 429:167–177. https://doi.org/10.1007/s11010-017-2944-x

    Article  PubMed  CAS  Google Scholar 

  114. Nakayama A, Morita H, Nakao T, Yamaguchi T, Sumida T, Ikeda Y, Kumagai H, Motozawa Y, Takahashi T, Imaizumi A, Hashimoto T, Nagai R, Komuro I (2015) A food-derived flavonoid luteolin protects against angiotensin II-induced cardiac remodeling. PLoS One 10(0137106):e0137106. https://doi.org/10.1371/journal.pone.0137106

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  115. Naidu PB, Uddandrao S, Naik RR et al (2016) Ameliorative potential of gingerol: promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in rats. Mol Cell Endocrinol 419:139–147. https://doi.org/10.1016/j.mce.2015.10.007

    Article  CAS  Google Scholar 

  116. Kalaivani A, Uddandrao VVS, Parim B et al (2018) Reversal of high fat diet-induced obesity through modulating lipid metabolic enzymes and inflammatory markers expressions in rats. Arch Physiol Biochem. https://doi.org/10.1080/13813455.2018.1452036

  117. Kalaivani A, Sathibabu Uddandrao VV, Brahmanaidu P, Saravanan G, Nivedha PR, Tamilmani P, Swapna K, Vadivukkarasi S (2017) Anti obese potential of Cucurbita maxima seeds oil: effect on lipid profile and histoarchitecture in high fat diet induced obese rats. Nat Prod Res. https://doi.org/10.1080/14786419.2017.1389939

  118. Meriga B, Parim B, Chunduri VR, Naik RR, Nemani H, Suresh P, Ganapathy S, Uddandrao S (2017) Antiobesity potential of Piperonal: promising modulation of body composition, lipid profiles and obesogenic marker expression in HFD-induced obese rats. Nut Met 14:76. https://doi.org/10.1186/s12986-017-0228-9

    Article  CAS  Google Scholar 

  119. Sathibabu Uddandrao VV, Brahmanaidu P, Meriga B, Saravanan G (2016) The potential role of S-allylcysteine as antioxidant against various disorders in animal models. Oxid Antioxid Med Sci 5:79–86. https://doi.org/10.5455/oams.240716.rv.025

    Article  Google Scholar 

  120. Ghanshyam P, Chhayakanta P, Shankar MU et al (2012) Investigation of possible hypoglycemic and hypolipidemic effect of methanolic extract of Sesbania grandiflora. Int Res J Pharm 3:275–280

    Google Scholar 

  121. Nandi MK, Garabadu D, Krishnamurthy S, Singh TD, Singh VP (2014) Methanolic fruit extract of Sesbania grandiflora exhibits anti-hyperglycemic activity in experimental type-2 diabetes mellitus model. Ann Biol Res 5:50–58

    Google Scholar 

  122. Sangeetha A, Sriram Prasath G, Subramanian S (2014) Antihyperglycemic and antioxidant potentials of Sesbania grandiflora leaves studies in STZ induced experimental diabetic rats. Int J Pharm Sci Res 5:2266–2275. https://doi.org/10.13040/IJPSR.0975-8232.5(6).2266-75

    Article  Google Scholar 

  123. Islam T, Rahman A, Islam AU (2013) In vitro effect of aqueous extract of fresh leaves of Abroma augusta L on the diffusion of glucose. Bangladesh Pharm J 16:21–26. https://doi.org/10.3329/bpj.v16i1.14486

    Article  Google Scholar 

  124. Khanra R, Dewanjee S, Dua T, Sahu R, Gangopadhyay M, De Feo V, Zia-Ul-Haq M (2015) Abroma augusta L. (Malvaceae) leaf extract attenuates diabetes induced nephropathy and cardiomyopathy via inhibition of oxidative stress and inflammatory response. J Transl Med 13:6. https://doi.org/10.1186/s12967-014-0364-1

    Article  PubMed  PubMed Central  Google Scholar 

  125. Wang C, Aungi HH, Zhang B et al (2008) Chemopreventive effects of heat-processed Panax quinquefolius root on human breast cancer cells. Anticancer Res 28:2545–2552

    PubMed  CAS  PubMed Central  Google Scholar 

  126. Sen S, Chen S, Wu Y, Feng B, Lui E, Chakrabarti S (2012) Preventive effects of north American ginseng (Panax quinquefolius) on diabetic retinopathy and cardiomyopathy. Phytother Res 27:290–298. https://doi.org/10.1002/ptr.4719

    Article  PubMed  Google Scholar 

  127. Padiya R, Banerjee SK (2013) Garlic as an anti-diabetic agent: recent progress and patent reviews. Recent Pat Food Nutr Agric 5:105–127. https://doi.org/10.2174/18761429113059990002

    Article  PubMed  CAS  Google Scholar 

  128. Erejuwa OO, Sulaiman SA, Ab Wahab MS, Sirajudeen KN, Salleh S, Gurtu S (2012) Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress. Oxidative Med Cell Longev 2012:374037. https://doi.org/10.1155/2012/374037

    Article  Google Scholar 

  129. Amagase H, Petesch BL, Matsuura H, Kasuga S, Itakura Y (2001) Intake of garlic and its bioactive components. J Nut 131:955–962. https://doi.org/10.1093/jn/131.3.955S

    Article  Google Scholar 

  130. Hiramatsu K, Tsuneyoshi T, Ogawa T, Morihara N (2016) Aged garlic extract enhances heme oxygenase-1 and glutamate–cysteine ligase modifier subunit expression via the nuclear factor erythroid 2-related factor 2-antioxidant response element signaling pathway in human endothelial cells. Nut Res 36:143–149. https://doi.org/10.1016/j.nutres.2015.09.018

    Article  CAS  Google Scholar 

  131. Sun Z, Chin YE, Zhang DD (2009) Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol 29:2658–2672. https://doi.org/10.1128/MCB.01639-08

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  132. Khatua TN, Adela R, Banerjee SK (2013) Garlic and cardioprotection: insights into the molecular mechanisms. Can J Physiol Pharma 91:448–458. https://doi.org/10.1139/cjpp-2012-0315

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are thankful to Innovation in Science Pursuit for Inspired Research (INSPIRE), Department of Science & Technology (DST). Govt. of India for providing the financial assistance and faculty fellowship (Grant No: DST/INSPIRE/04/2016/000893). The authors are also thankful to Indian Council of Medical Research, Government of India for providing laboratory and library facilities. The authors are also thankful to Dr. Mir Irfan and Dr. Syed S.Y.H. Qadri, Dr. Harishankar Nemani for helpful comments, and Mr. Srinivas for technical help.

Author information

Authors and Affiliations

  1. Animal Physiology and Biochemistry Laboratory, ICMR-National Animal Resource Facility for Biomedical Research (NARFBR), Hyderabad, Telangana, 500007, India

    Brahmanaidu Parim

  2. Center for Biological Sciences, Department of Biochemistry, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, Tamil Nadu, 637215, India

    V. V. Sathibabu Uddandrao & Ganapathy Saravanan

Authors
  1. Brahmanaidu Parim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. V. Sathibabu Uddandrao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ganapathy Saravanan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brahmanaidu Parim.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parim, B., Sathibabu Uddandrao, V.V. & Saravanan, G. Diabetic cardiomyopathy: molecular mechanisms, detrimental effects of conventional treatment, and beneficial effects of natural therapy. Heart Fail Rev 24, 279–299 (2019). https://doi.org/10.1007/s10741-018-9749-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-018-9749-1

Keywords

Search

Navigation