Exercise and Stevia Rebaudiana (R) Extracts Attenuate Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

Author(s): Abdelaziz M. Hussein*, Elsayed A. Eid, Ismaeel Bin-Jaliah, Medhat Taha, Lashin S. Lashin

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 20 , Issue 7 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background and Aims: In the current work, we studied the effects of exercise and stevia rebaudiana (R) extracts on diabetic cardiomyopathy (DCM) in type 2 diabetic rats and their possible underlying mechanisms.

Methods: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group, b) DM group, type 2 diabetic rats received 2 ml oral saline daily for 4 weeks, c) DM+ Exercise, type 2 diabetic rats were treated with exercise for 4 weeks and d) DM+ stevia R extracts: type 2 diabetic rats received methanolic stevia R extracts. By the end of the experiment, serum blood glucose, HOMA-IR, insulin and cardiac enzymes (LDH, CK-MB), cardiac histopathology, oxidative stress markers (MDA, GSH and CAT), myocardial fibrosis by Masson trichrome, the expression of p53, caspase-3, α-SMA and tyrosine hydroxylase (TH) by immunostaining in myocardial tissues were measured.

Results: T2DM caused a significant increase in blood glucose, HOMA-IR index, serum CK-MB and LDH, myocardial damage and fibrosis, myocardial MDA, myocardial α-SMA, p53, caspase-3, Nrf2 and TH density with a significant decrease in serum insulin and myocardial GSH and CAT (p< 0.05). On the other hand, treatment with either exercise or stevia R extracts significantly improved all studied parameters (p< 0.05). Moreover, the effects of stevia R was more significant than exercise (p< 0.05).

Conclusion: Both exercise and methanolic stevia R extracts showed cardioprotective effects against DCM and Stevia R offered more cardioprotective than exercise. This cardioprotective effect of these lines of treatment might be due to attenuation of oxidative stress, apoptosis, sympathetic nerve density and fibrosis and upregulation of the antioxidant transcription factor, Nrf2.

Keywords: Type 2 DM, cardiomyopathy, oxidative stress, nrf2, α-SMA, p53, caspase-3, tyrosine hydroxylase, exercise, stevia.

[1]
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care, 2014, 37(Suppl. 1), S81-S90.
[http://dx.doi.org/10.2337/dc14-S081] [PMID: 24357215]
[2]
Global report on diabetes; World Health Organization: Geneva, 2016.
[3]
IDF , Diabetes Atlas International Diabetes Federation Brussels; Belgium, 2017.
[4]
Mathers, C.D.; Loncar, D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med., 2006, 3(11) e442
[http://dx.doi.org/10.1371/journal.pmed.0030442] [PMID: 17132052]
[5]
Kumar, P.J.; Clark, M. Diabetes mellitus and other disorders of metabolismTextbook of Medicine; Kumar, P.J.; Clark, M., Eds.; , 2007, pp. 1069-1122.
[6]
Karnik, A.A.; Fields, A.V.; Shannon, R.P. Diabetic cardiomyopathy. Curr. Hypertens. Rep., 2007, 9(6), 467-473.
[http://dx.doi.org/10.1007/s11906-007-0086-3] [PMID: 18367010]
[7]
Murarka, S.; Movahed, M.R. Diabetic cardiomyopathy. J. Card. Fail., 2010, 16(12), 971-979.
[http://dx.doi.org/10.1016/j.cardfail.2010.07.249] [PMID: 21111987]
[8]
Jia, G.; Hill, M.A.; Sowers, J.R. Diabetic Cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ. Res., 2018, 122(4), 624-638.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311586] [PMID: 29449364]
[9]
Marwick, T.H.; Ritchie, R.; Shaw, J.E.; Kaye, D. Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J. Am. Coll. Cardiol., 2018, 71(3), 339-351.
[http://dx.doi.org/10.1016/j.jacc.2017.11.019] [PMID: 29348027]
[10]
Poirier, P.; Bogaty, P.; Garneau, C.; Marois, L.; Dumesnil, J.G. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care, 2001, 24(1), 5-10.
[http://dx.doi.org/10.2337/diacare.24.1.5] [PMID: 11194240]
[11]
Mishra, P.K.; Ying, W.; Nandi, S.S.; Bandyopadhyay, G.K.; Patel, K.K.; Mahata, S.K. Diabetic cardiomyopathy: an im-munometabolic perspective. Front. Endocrinol. (Lausanne), 2017, 8, 72.
[http://dx.doi.org/10.3389/fendo.2017.00072] [PMID: 28439258]
[12]
Alonso, N.; Moliner, P.; Mauricio, D. Pathogenesis, clinical fea-tures and treatment of diabetic cardiomyopathy. Adv. Exp. Med. Biol., 2018, 1067, 197-217.
[http://dx.doi.org/10.1007/5584_2017_105] [PMID: 28980272]
[13]
Anderson, E.J.; Kypson, A.P.; Rodriguez, E.; Anderson, C.A.; Lehr, E.J.; Neufer, P.D. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J. Am. Coll. Cardiol., 2009, 54(20), 1891-1898.
[http://dx.doi.org/10.1016/j.jacc.2009.07.031] [PMID: 19892241]
[14]
Yue, Y.; Meng, K.; Pu, Y.; Zhang, X. Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res. Clin. Pract., 2017, 133, 124-130.
[http://dx.doi.org/10.1016/j.diabres.2017.08.018] [PMID: 28934669]
[15]
Frustaci, A.; Kajstura, J.; Chimenti, C.; Jakoniuk, I.; Leri, A.; Maseri, A.; Nadal-Ginard, B.; Anversa, P. Myocardial cell death in human diabetes. Circ. Res., 2000, 87(12), 1123-1132.
[http://dx.doi.org/10.1161/01.RES.87.12.1123] [PMID: 11110769]
[16]
Defronzo, R.A. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes, 2009, 58(4), 773-795.
[http://dx.doi.org/10.2337/db09-9028] [PMID: 19336687]
[17]
Miccoli, R.; Penno, G.; Del Prato, S. Multidrug treatment of type 2 diabetes: a challenge for compliance. Diabetes Care, 2011, 34(Suppl. 2), S231-S235.
[http://dx.doi.org/10.2337/dc11-s235] [PMID: 21525461]
[18]
Seuring, T.; Archangelidi, O.; Suhrcke, M. The Economic Costs of Type 2 Diabetes: A Global Systematic Review. Pharmacoeconomics, 2015, 33(8), 811-831.
[http://dx.doi.org/10.1007/s40273-015-0268-9] [PMID: 25787932]
[19]
Triplitt, C. Drug Interactions of Medications Commonly Used in Diabetes. Diabetes Spectr., 2006, 19(4), 202-211.
[http://dx.doi.org/10.2337/diaspect.19.4.202]
[20]
Hansen, D.; Dendale, P.; van Loon, L.J.; Meeusen, R. The impact of training modalities on the clinical benefits of exercise intervention in patients with cardiovascular disease risk or type 2 diabetes mellitus. Sports Med., 2010, 40(11), 921-940.
[http://dx.doi.org/10.2165/11535930-000000000-00000] [PMID: 20942509]
[21]
Lavie, C.J.; Johannsen, N.; Swift, D.; Sénéchal, M.; Earnest, C.; Church, T.; Hutber, A.; Sallis, R.; Blair, S.N. Exercise is Medi-cine - the importance of physical activity, exercise training, car-diorespiratory fitness and obesity in the prevention and treat-ment of type 2 Diabetes. Eur Endocrinol, 2014, 10(1), 18-22.
[http://dx.doi.org/10.17925/EE.2014.10.01.18] [PMID: 29872459]
[22]
Jakicic, J.M.; Jaramillo, S.A.; Balasubramanyam, A.; Bancroft, B.; Curtis, J.M.; Mathews, A.; Pereira, M.; Regensteiner, J.G.; Ribisl, P.M. Look AHEAD Study Group. Effect of a lifestyle intervention on change in cardiorespiratory fitness in adults with type 2 diabetes: results from the Look AHEAD Study. Int. J. Obes., 2009, 33(3), 305-316.
[http://dx.doi.org/10.1038/ijo.2008.280] [PMID: 19153582]
[23]
Kumar, H.; Singh, K.; Kumar, S. 2C-Methyl- D- erythritol 2,4-cyclodiphosphate synthase from Stevia rebaudiana Bertoni is a functional gene. Mol. Biol. Rep., 2012, 39(12), 10971-10978.
[http://dx.doi.org/10.1007/s11033-012-1998-9] [PMID: 23065206]
[24]
Ferrazzano, G.F.; Cantile, T.; Alcidi, B.; Coda, M.; Ingenito, A.; Zarrelli, A.; Di Fabio, G.; Pollio, A. Is Stevia rebaudiana Bertoni a non cariogenic sweetener? A review. Molecules, 2015, 21(1) E38
[http://dx.doi.org/10.3390/molecules21010038] [PMID: 26712732]
[25]
Jeppesen, P.B.; Gregersen, S.; Rolfsen, S.E.; Jepsen, M.; Colombo, M.; Agger, A.; Xiao, J.; Kruhøffer, M.; Orntoft, T.; Hermansen, K. Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat. Metabolism, 2003, 52(3), 372-378.
[http://dx.doi.org/10.1053/meta.2003.50058] [PMID: 12647278]
[26]
Thomas, J.E.; Stevia, G.M.J. It’s not just about calories. Open Obes. J., 2010, 2, 101-109.
[http://dx.doi.org/10.2174/1876823701002010101]
[27]
Bayat, E.; Dastgheib, S.; Egdar, S.; Mokarram, P. Effect of the Aquatic Extract of Stevia on the Serum Level of Interleukin-6 in Streptozotocin-Nicotinamide Induced Diabetic Rats. Shiraz E Med. J., 2017, 18(2)
[http://dx.doi.org/10.17795/semj45015]
[28]
Hussein, Ael-A.; Omar, N.M.; Sakr, H.; Elsamanoudy, A.Z.; Shaheen, D. Modulation of metabolic and cardiac dysfunctions by insulin sensitizers and angiotensin receptor blocker in rat model of type 2 diabetes mellitus. Can. J. Physiol. Pharmacol., 2011, 89(3), 216-226.
[http://dx.doi.org/10.1139/Y11-012] [PMID: 21423295]
[29]
Elsaid, F.H.; Khalil, A.A.; Ibrahim, E.M.; Mansour, A.; Hussein, A.M. Effects of exercise and stevia on renal ischemia/reperfusion injury in rats. Acta Sci. Pol. Technol. Aliment., 2019, 18(3), 317-332.
[http://dx.doi.org/10.17306/J.AFS.2019.0652] [PMID: 31569913]
[30]
El-Mousalamy, A.M.D.; Hussein, S.A.M.; Hussein, A.M.; Mahmoud, S.A.; El Azab, K.M. Reno Protective Effect of Meth-anolic Stevia Rebaudiana Bertoni Leaves Extract and Its Phenolic Compounds in Type-1- Diabetes. Egypt. J. Chem., 2018, 61(4), 609-615.
[31]
Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 1985, 28(7), 412-419.
[http://dx.doi.org/10.1007/BF00280883] [PMID: 3899825]
[32]
Shokeir, A.A.; Hussein, A.M.; Barakat, N.; Abdelaziz, A.; Elgarba, M.; Awadalla, A. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf-2-dependent genes by ischaemic pre-conditioning and post-conditioning: new adaptive endogenous protective responses against renal ischaemia/reperfusion injury. Acta Physiol. (Oxf.), 2014, 210(2), 342-353.
[http://dx.doi.org/10.1111/apha.12164] [PMID: 24010821]
[33]
Yu, H.; Zhen, J.; Yang, Y.; Gu, J.; Wu, S.; Liu, Q. Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model. J. Cell. Mol. Med., 2016, 20(4), 623-631.
[http://dx.doi.org/10.1111/jcmm.12739] [PMID: 26869403]
[34]
Hussein, A.A.; Abdel-Aziz, A.; Gabr, M.; Hemmaid, K.Z. Myocardial and metabolic dysfunction in type 2 diabetic rats: impact of ghrelin. Can. J. Physiol. Pharmacol., 2012, 90(1), 99-111.
[http://dx.doi.org/10.1139/y11-103] [PMID: 22188509]
[35]
Naidu, P.B.; Ponmurugan, P.; Begum, M.S.; Mohan, K.; Meriga, B. RavindarNaik, R.; Saravanan, G. Diosgenin reorganises hy-perglycaemia and distorted tissue lipid profile in high-fat diet-streptozotocin-induced diabetic rats. J. Sci. Food Agric., 2015, 95(15), 3177-3182.
[http://dx.doi.org/10.1002/jsfa.7057] [PMID: 25530163]
[36]
Taheri Rouhi, S.Z.; Sarker, M.M.R.; Rahmat, A.; Alkahtani, S.A.; Othman, F. The effect of pomegranate fresh juice versus pomegranate seed powder on metabolic indices, lipid profile, inflammatory biomarkers, and the histopathology of pancreatic islets of Langerhans in streptozotocin-nicotinamide induced type 2 diabetic Sprague-Dawley rats. BMC Complement. Altern. Med., 2017, 17(1), 156.
[http://dx.doi.org/10.1186/s12906-017-1667-6] [PMID: 28288617]
[37]
Ahmad, U.; Ahmad, R.S. Anti diabetic property of aqueous extract of Stevia rebaudiana Bertoni leaves in Streptozotocin-induced diabetes in albino rats. BMC Complement. Altern. Med., 2018, 18(1), 179.
[http://dx.doi.org/10.1186/s12906-018-2245-2] [PMID: 29890969]
[38]
Novoa, U.; Arauna, D.; Moran, M.; Nuñez, M.; Zagmutt, S.; Saldivia, S.; Valdes, C.; Villaseñor, J.; Zambrano, C.G.; Gonzalez, D.R. High-intensity exercise reduces cardiac fibrosis and hypertrophy but does not restore the nitroso-redox imbalance in diabetic cardiomyopathy. Oxid. Med. Cell. Longev., 2017. 20177921363
[http://dx.doi.org/10.1155/2017/7921363] [PMID: 28698769]
[39]
Attia, H.M.; Taha, M. Protective effect of captopril on cardiac fibrosis in diabetic albino rats: a histological and immunohisto-chemical study. Benha Med. J., 2018, 35(3), 378.
[http://dx.doi.org/10.4103/bmfj.bmfj_122_18]
[40]
Yang, R.; Jia, Q.; Liu, X.F.; Ma, S.F. Effect of genistein on myocardial fibrosis in diabetic rats and its mechanism. Mol. Med. Rep., 2018, 17(2), 2929-2936.
[PMID: 29257312]
[41]
Chengji, W.; Xianjin, F. Exercise protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway in rats. J. Cell. Physiol., 2019, 234(2), 1682-1688.
[http://dx.doi.org/10.1002/jcp.27038] [PMID: 30076729]
[42]
Yang, R.; Jia, Q.; Liu, X.; Gao, Q.; Wang, L.; Ma, S. Effect of hydrogen sulfide on oxidative stress and endoplasmic reticulum stress in diabetic cardiomyopathy Zhongguo ying yong sheng li xue za zhi= Zhongguo yingyong shenglixue zazhi= Chinese journal of applied physiology,, 2016, 32(1), 8-12.
[43]
Wilson, A.J.; Gill, E.K.; Abudalo, R.A.; Edgar, K.S.; Watson, C.J.; Grieve, D.J. Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting. Heart, 2018, 104(4), 293-299.
[http://dx.doi.org/10.1136/heartjnl-2017-311448] [PMID: 28954833]
[44]
Muthusamy, V.R.; Kannan, S.; Sadhaasivam, K.; Gounder, S.S.; Davidson, C.J.; Boeheme, C.; Hoidal, J.R.; Wang, L.; Rajasekaran, N.S. Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free Radic. Biol. Med., 2012, 52(2), 366-376.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.440] [PMID: 22051043]
[45]
Narasimhan, M.; Rajasekaran, N.S. Exercise, Nrf2 and antioxi-dant signaling in cardiac aging. Front. Physiol., 2016, 7, 241.
[http://dx.doi.org/10.3389/fphys.2016.00241] [PMID: 27378947]
[46]
Kanter, M.; Aksu, F.; Takir, M.; Kostek, O.; Kanter, B.; Oymagil, A. Effects of low intensity exercise against apoptosis and oxida-tive stress in streptozotocin-induced diabetic rat heart. Exp. Clin. Endocrinol. Diabetes, 2017, 125(9), 583-591.
[http://dx.doi.org/10.1055/s-0035-1569332] [PMID: 26824288]
[47]
Grijalva, J.; Hicks, S.; Zhao, X.; Medikayala, S.; Kaminski, P.M.; Wolin, M.S.; Edwards, J.G. Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats. Cardiovasc. Diabetol., 2008, 7, 34.
[http://dx.doi.org/10.1186/1475-2840-7-34] [PMID: 19019231]
[48]
Gimenes, C.; Gimenes, R.; Rosa, C.M.; Xavier, N.P.; Campos, D.H.; Fernandes, A.A.; Cezar, M.D.; Guirado, G.N.; Cicogna, A.C.; Takamoto, A.H.; Okoshi, M.P.; Okoshi, K. Low intensity physical exercise attenuates cardiac remodeling and myocardial oxidative stress and dysfunction in diabetic rats. J. Diabetes Res., 2015. 2015457848
[http://dx.doi.org/10.1155/2015/457848] [PMID: 26509175]
[49]
Veeranki, S.; Givvimani, S.; Kundu, S.; Metreveli, N.; Pushpakumar, S.; Tyagi, S.C. Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice. J. Mol. Cell. Cardiol., 2016, 92, 163-173.
[http://dx.doi.org/10.1016/j.yjmcc.2016.01.023] [PMID: 26827898]
[50]
Gu, J.; Wang, S.; Guo, H.; Tan, Y.; Liang, Y.; Feng, A.; Liu, Q.; Damodaran, C.; Zhang, Z.; Keller, B.B.; Zhang, C.; Cai, L. Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis. Cell Death Dis., 2018, 9(2), 82.
[http://dx.doi.org/10.1038/s41419-017-0093-5] [PMID: 29362483]
[51]
Cheng, S.M.; Ho, T.J.; Yang, A.L.; Chen, I.J.; Kao, C.L.; Wu, F.N.; Lin, J.A.; Kuo, C.H.; Ou, H.C.; Huang, C.Y.; Lee, S.D. Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways in streptozotocin-induced diabetic rats. Int. J. Cardiol., 2013, 167(2), 478-485.
[http://dx.doi.org/10.1016/j.ijcard.2012.01.031] [PMID: 22341695]
[52]
Silva, E.; Natali, A.J.; Silva, M.F.; Gomes, G.J.; Cunha, D.N.; Ramos, R.M.; Toledo, M.M.; Drummond, F.R.; Belfort, F.G.; Novaes, R.D.; Maldonado, I.R. Ventricular remodeling in growing rats with experimental diabetes: The impact of swimming training. Pathol. Res. Pract., 2013, 209(10), 618-626.
[http://dx.doi.org/10.1016/j.prp.2013.06.009] [PMID: 23910625]
[53]
Asbun, J.; Villarreal, F.J. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J. Am. Coll. Cardiol., 2006, 47(4), 693-700.
[http://dx.doi.org/10.1016/j.jacc.2005.09.050] [PMID: 16487830]
[54]
Petrov, V.V.; Fagard, R.H.; Lijnen, P.J. Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension, 2002, 39(2), 258-263.
[http://dx.doi.org/10.1161/hy0202.103268] [PMID: 11847194]
[55]
Li, C.J.; Lv, L.; Li, H.; Yu, D.M. Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid. Cardiovasc. Diabetol., 2012, 11, 73.
[http://dx.doi.org/10.1186/1475-2840-11-73] [PMID: 22713251]
[56]
Hafstad, A.D.; Lund, J.; Hadler-Olsen, E.; Höper, A.C.; Larsen, T.S.; Aasum, E. High- and moderate-intensity training normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity. Diabetes, 2013, 62(7), 2287-2294.
[http://dx.doi.org/10.2337/db12-1580] [PMID: 23493573]
[57]
Lund, J.; Hafstad, A.D.; Boardman, N.T.; Rossvoll, L.; Rolim, N.P.; Ahmed, M.S.; Florholmen, G.; Attramadal, H.; Wisløff, U.; Larsen, T.S.; Aasum, E. Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice. Am. J. Physiol. Heart Circ. Physiol., 2015, 308(8), H823-H829.
[http://dx.doi.org/10.1152/ajpheart.00734.2014] [PMID: 25637547]
[58]
Otake, H.; Suzuki, H.; Honda, T.; Maruyama, Y. Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart. Int. Heart J., 2009, 50(5), 627-641.
[http://dx.doi.org/10.1536/ihj.50.627] [PMID: 19809211]
[59]
Bakovic, M.; Filipovic, N.; Ferhatovic Hamzic, L.; Kunac, N.; Zdrilic, E.; Vitlov Uljevic, M.; Kostic, S.; Puljak, L.; Vukojevic, K. Changes in neurofilament 200 and tyrosine hydroxylase expression in the cardiac innervation of diabetic rats during aging. Cardiovasc. Pathol., 2018, 32, 38-43.
[http://dx.doi.org/10.1016/j.carpath.2017.11.003] [PMID: 29175663]
[60]
Thaung, H.A.; Baldi, J.C.; Wang, H-Y.; Hughes, G.; Cook, R.F.; Bussey, C.T.; Sheard, P.W.; Bahn, A.; Jones, P.P.; Schwenke, D.O. Increased efferent cardiac sympathetic nerve activity and defective intrinsic heart rate regulation in type 2 diabetes. Diabetes 2015, db140955. Diabetes, 2015, 64(8), 2944-2956.
[http://dx.doi.org/10.2337/db14-0955]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 7
Year: 2020
Published on: 08 September, 2020
Page: [1117 - 1132]
Pages: 16
DOI: 10.2174/1871530320666200420084444
Price: $65

Article Metrics

PDF: 39
HTML: 1