Effectiveness of Telmisartan as an Adjunct to Metformin in Treating Type II Diabetes Mellitus in Rats


The monitoring reports of most patients with type II diabetes mellitus (T2DM) revealed that monotherapy with metformin could not achieve long-term glycemic control. Thus, we designed this study aiming to investigate the effect of telmisartan, a unique AT1 receptor antagonist and a partial agonist of peroxisome-proliferator activated receptor gamma (PPARγ), individually and as an adjunct to metformin, on a rat model that simulates the metabolic characteristics of human T2DM. Adult male Wistar rats were fed high-fat, high-fructose diet (HFFD) for 8 weeks followed by a single low dose of streptozotocin (STZ) (35 mg/kg/day, i.p.) rendering them diabetic and insulin resistant. The effectiveness of both drugs and their combination was tested by assessing the changes in the levels of serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, lipid profile and adiponectin. In addition, the level of reduced glutathione (GSH) in the liver, was investigated. Results showed that the addition of telmisartan to metformin successfully restored serum glucose back to normal levels and corrected the altered serum total cholesterol (TC), triglycerides (TG) and adiponectin, emphasizing the potential role of telmisartan as an adjunct to metformin.

Share and Cite:

R. Salama, M. Schaalan, M. Ibrahim, A. Khalifa and A. Elkoussi, "Effectiveness of Telmisartan as an Adjunct to Metformin in Treating Type II Diabetes Mellitus in Rats," Open Journal of Endocrine and Metabolic Diseases, Vol. 3 No. 3, 2013, pp. 186-196. doi: 10.4236/ojemd.2013.33026.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Astrup and N. Finer, “Redefining Type 2 Diabetes: ‘Diabesity’ or ‘Obesity Dependent Diabetes Mellitus’?” Obesity Reviews, Vol. 1, No. 2, 2000, pp. 57-59. doi:10.1046/j.1467-789x.2000.00013.x
[2] H. Basciano, L. Federico and K. Adeli, “Fructose, Insulin Resistance and Metabolic Dyslipidemia,” Nutrition & Metabolism (London), Vol. 2, No. 1, 2005, p. 5. doi:10.1186/1743-7075-2-5
[3] S. E. Inzucchi, D. G. Maggs, G. R. Spollett, S. L. Page, F. S. Rife, V. Walton and G. I. Shulman, “Efficacy and Metabolic Effects of Metformin and Troglitazone in Type II Diabetes Mellitus,” The New England Journal of Medicine, Vol. 338, No. 13, 1998, pp. 867-872. doi:10.1056/NEJM199803263381303
[4] K. Cusi, A. Consoli and R. A. DeFronzo, “Metabolic Effects of Metformin on Glucose and Lactate Metabolism in Noninsulin-Dependent Diabetes Mellitus,” The Journal of Clinical Endocrinology & Metabolism, Vol. 81, No. 11, 1996, pp. 4059-4067. doi:10.1210/jc.81.11.4059
[5] C. R. Sirtori and C. Pasik, “Re-Evaluation of a Biguanide, Metformin: Mechanism of Action and Tolerability,” Pharmacological Research, Vol. 30, No. 3, 1994, pp. 187-228. doi:10.1016/1043-6618(94)80104-5
[6] S. Z. Duan, M. G. Usher and R. M. Mortensen, “Peroxisome Proliferator-Activated Receptor-Gamma-Mediated Effects in the Vasculature,” Circulation Research, Vol. 102, No. 3, 2008, pp. 283-294. doi:10.1161/CIRCRESAHA.107.164384
[7] M. Watanbe, K. Inukai, T. Sumita, K. Ikebukuro, D. Ito, S. Kurihara, H. Ono, T. Awata and S. Katayama, “Effects of Telmisartan on Insulin Resistance in Japanese Type 2 Diabetic Patients,” Internal Medicine, Vol. 49, No. 17, 2010, pp. 1843-1847. doi:10.2169/internalmedicine.49.3189
[8] K. Srinivasan, B. Viswanad, L. Asrat, C. L. Kaul and P. Ramarao, “Combination of High-Fat Diet-Fed and Low-Dose Streptozotocin-Treated Rat: A Model for Type 2 Diabetes and Pharmacological Screening,” Pharmacological Research, Vol. 52, No. 4, 2005, pp. 313-320. doi:10.1016/j.phrs.2005.05.004
[9] S. Matthaei, J. P. Reibold, A. Hamann, H. Benecke, H. U. Haring, H. Greten and H. H. Klein, “In Vivo Metformin Treatment Ameliorates Insulin Resistance: Evidence for Potentiation of Insulin-Induced Translocation and Increased Functional Activity of Glucose Transporters in Obese (Fa/Fa) Zucker Rat Adipocytes,” Endocrinology, Vol. 133, No. 1, 1993, pp. 304-311. doi:10.1210/en.133.1.304
[10] G. Hasegawa, M. Fukui, H. Hosoda, M. Asano, I. Harusato, M. Tanaka, E. Shiraishi, T. Senmaru, K. Sakabe, M. Yamasaki, J. Kitawaki, A. Fujinami, M. Ohta, H. Obayashi and N. Nakamura, “Telmisartan, an Angiotensin II Type 1 Receptor Blocker, Prevents the Development of Diabetes in Male Spontaneously Diabetic Torii Rats,” European Journal of Pharmacology, Vol. 605, No. 1-3, 2009, pp. 164-169. doi:10.1016/j.ejphar.2009.01.001
[11] A. Psyrogiannis, V. Kyriazopoulou, A. Symeonidis, M. Leotsinidis and V. A. G. Vagenakis, “Relative Iron Overload: in Offspring of Patients with Type 2 Diabetes Mellitus: A New Component in the Conundrum of Insulin Resistance Syndrome?” Hormones (Athens), Vol. 2, No. 3, 2003, pp. 161-168.
[12] P. Trinder, “Determination of Blood Glucose Using 4-Amino Phenazone as Oxygen Acceptor,” Journal of Clinical Pathology, Vol. 22, No. 2, 1969, p. 246. doi:10.1136/jcp.22.2.246-b
[13] C. R. Morgan and A. Lazarow, “Immunoassay of Insulin Using a Two-Antibody System,” Proceedings of the Society for Experimental Biology and Medicine, Vol. 110, 1962, pp. 29-32. doi:10.3181/00379727-110-27411
[14] D. R. Matthews, J. P. Hosker, A. S. Rudenski, B. A. Naylor, D. F. Treacher and R. C. Turner, “Homeostasis Model Assessment: Insulin Resistance and Beta-Cell Function from Fasting Plasma Glucose and Insulin Concentrations in Man,” Diabetologia, Vol. 28, No. 7, 1985, pp. 412-419. doi:10.1007/BF00280883
[15] C. C. Allain, L. S. Poon, C. S. Chan, W. Richmond and P. C. Fu, “Enzymatic Determination of Total Serum Cholesterol,” Clinical Chemistry, Vol. 20, No. 4, 1974, pp. 470-475.
[16] A. W. Wahlefeld, “Triglycerides Determination after Enzymatic Hydrolysis,” In: H. U. Bergmeyer, Ed., Methods of Enzymatic Analysis, Academic Press, New York, 1974, pp. 1831-1835.
[17] C. Matsubara, Y. Nishikawa, Y. Yoshida and K. Takamura, “A Spectrophotometric Method for the Determination of Free Fatty Acid in Serum Using Acyl-Coenzyme A Synthetase and Acyl-Coenzyme A Oxidase,” Analytical Biochemistry, Vol. 130, No. 1, 1983, pp. 128-133. doi:10.1016/0003-2697(83)90659-0
[18] Y. Nakano, S. Tajima, A. Yoshimi, H. Akiyama, M. Tsushima, T. Tanioka, T. Negoro, M. Tomita and T. Tobe, “A Novel Enzyme-Linked Immunosorbent Assay Specific for High-Molecular-Weight Adiponectin,” The Journal of Lipid Research, Vol. 47, No. 7, 2006, pp. 1572-1582. doi:10.1194/jlr.D600010-JLR200
[19] E. Beutler, O. Duron and B. M. Kelly, “Improved Method for the Determination of Blood Glutathione,” Journal of Laboratory and Clinical Medicine, Vol. 61, No. 3, 1963, pp. 882-888.
[20] M. Schaalan, H. S. El-Abhar, M. Barakat and E. S. El-Denshary, “Westernized-Like-Diet-Fed Rats: Effect on Glucose Homeostasis, Lipid Profile, and Adipocyte Hormones and Their Modulation by Rosiglitazone and Glimepiride,” Journal of Diabetes and Its Complications, Vol. 23, No. 3, 2009, pp. 199-208. doi:10.1016/j.jdiacomp.2008.02.003
[21] M. F. Schaalan, “Effects of Pioglitazone and/or Simvastatin on Circulating TNFα and Adiponectin Levels in Insulin Resistance,” Journal of Immunotoxicology, Vol. 9, No. 2, 2012, pp. 201-209. doi:10.3109/1547691X.2012.660998
[22] E. Esteve, W. Ricart and J. M. Fernández-Real, “Adipocytokines and Insulin Resistance: The Possible Role of Lipocalin-2, Retinol Binding Protein-4, and Adiponectin,” Diabetes Care, Vol. 32, Supplement 2, 2009, pp. S362-S367.
[23] H. S. El-Abhar and M. Schaalan, “Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect,” PloS One, Vol. 7, No. 5, 2012, p. e37757. doi:10.1371/journal.pone.0037757
[24] E. Y. Sozmen, B. Sozmen, Y. Delen and T. Onat, “Catalase/Superoxide Dismutase (SOD) and Catalase/Paraoxonase (PON) Ratios May Implicate Poor Glycemic Control,” Archives of Medical Research, Vol. 32, No. 4, 2001, pp. 283-287. doi:10.1016/S0188-4409(01)00285-5
[25] O. O. Erejuwa, S. A. Sulaiman, M. S. Wahab, K. N. Sirajudeen, M. S. Salleh and S. Gurtu, “Glibenclamide or Metformin Combined with Honey Improves Glycemic Control in Streptozotocin-Induced Diabetic Rats,” International Journal of Biological Sciences, Vol. 7, No. 2, 2011, pp. 244-252. doi:10.7150/ijbs.7.244
[26] P. Bansal, P. Paul, J. Mudgal, P. G Nayak, S. Thomas Pannakal, K. I. Priyadarsini and M. K. Unnikrishnan, “Antidiabetic, Antihyperlipidemic and Antioxidant Effects of the Flavonoid Rich Fraction of Pilea microphylla (L.) in High Fat Diet/Streptozotocin-Induced Diabetes in Mice,” Experimental and Toxicologic Pathology, Vol. 64, No. 6, 2012, pp. 651-658.
[27] P. Matafome, T. Louro, L. Rodrigues, J. Crisóstomo, E. Nunes, C. Amaral, P. Monteiro, A. Cipriano and R. Seica, “Metformin and Atorvastatin Combination Further Protect the Liver in Type 2 Diabetes with Hyperlipidaemia,” Diabetes/Metabolism Research and Reviews, Vol. 27, No. 1, 2011, pp. 54-62. doi:10.1002/dmrr.1157
[28] F. Hu, X. Li, L. Zhao, S. Feng and C. Wang, “Antidiabetic Properties of Purified Polysaccharide from Hedysarum Polybotrys,” Canadian Journal of Physiology and Pharmacology, Vol. 88, No. 1, 2010, pp. 64-72. doi:10.1139/Y09-098
[29] G. da Silva Xavier, I. Leclerc, A. Varadi, T. Tsuboi, S. K. Moule and G. A. Rutter, “Expression. Role for AMP-Activated Protein Kinase in Glucose-Stimulated Insulin Secretion and Preproinsulin Gene Expression,” Biochemical Journal, Vol. 371, No. Pt 3, 2003, pp. 761-774.
[30] S. Zhang and K. H. Kim, “Glucose Activation of Acetyl-Coa Carboxylase in Association with Insulin Secretion in a Pancreatic Beta-Cell,” Journal of Endocrinology, Vol. 147, No. 1, 1995, pp. 33-41. doi:10.1677/joe.0.1470033
[31] V. Souza-Mello, B. M. Gregório, F. S. Cardoso-de-Lemos, L. de Carvalho, M. B. Aguila and C. A. Mandarim-de-Lacerda, “Comparative Effects of Telmisartan, Sitagliptin and Metformin Alone or in Combination on Obesity, Insulin Resistance, and Liver and Pancreas Remodelling in C57BL/6 Mice Fed on a Very High-Fat Diet,” Clinical Science (London), Vol. 119, No. 6, 2010, pp. 239-250. doi:10.1042/CS20100061
[32] A. Benhaddou-Andaloussi, L. Martineau, T. Vuong, B. Meddah, P. Madiraju, A. Settaf and P. S. Haddad, “The in Vivo Antidiabetic Activity of Nigella sativa Is Mediated through Activation of the AMPK Pathway and Increased Muscle Glut4 Content,” Evidence-Based Complementary and Alternative Medicine, Vol. 2011, 2011, Article ID: 538671. doi:10.1155/2011/538671
[33] K. W. Ong, A. Hsu, L. Song, D. Huang and B. K. Tan, “Polyphenols-Rich Vernonia Amygdalina Shows Anti-Diabetic Effects in Streptozotocin-Induced Diabetic Rats,” Journal of Ethnopharmacology, Vol. 133, No. 2, 2011, pp. 598-607. doi:10.1016/j.jep.2010.10.046
[34] G. B. Behera, A. N. Kurnool, M. Baidya, B. S. Kumar and S. Bilal, “Anti-Hyperglyceamic, Anti-Hyperlipidemic and Antioxidant Activity of the Stem of Glinus oppositifolius (L.) AUG. DC,” International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 3, No. 1, 2011, pp. 1080-1090.
[35] O. O. Erejuwa, S. A. Sulaiman, M. S. Wahab, S. K. Salam, M. S. Salleh and S. Gurtu, “Comparison of Antioxidant Effects of Honey, Glibenclamide, Metformin, and Their Combinations in the Kidneys of Streptozotocin-Induced Diabetic Rats,” International Journal of Molecular Sciences, Vol. 12, No. 1, 2011, pp. 829-843. doi:10.3390/ijms12010829
[36] B. R. Goyal, K. Parmar, R. K. Goyal and A. A. Mehta, “Beneficial Role of Telmisartan on Cardiovascular Complications Associated with Stz-Induced Type 2 Diabetes In Rats,” Pharmacological Reports, Vol. 63, No. 4, 2011, pp. 956-966.
[37] S. Fujisaka, I. Usui, Y. Kanatani, M. Ikutani, I. Takasaki, K. Tsuneyama, Y. Tabuchi, A. Bukhari, Y. Yamazaki, H. Suzuki, S. Senda, A. Aminuddin, Y. Nagai, K. Takatsu, M. Kobayashi and K. Tobe, “Telmisartan Improves Insulin Resistance and Modulates Adipose Tissue Macrophage Polarization in High-Fat-Fed Mice,” Endocrinology, Vol. 152, No. 5, 2011, pp. 1789-1799. doi:10.1210/en.2010-1312
[38] A. Zanchi, A. G. Dulloo, C. Perregaux, J. P. Montani and M. Burnier, “Telmisartan Prevents the Glitazone-Induced Weight Gain without Interfering with Its Insulin-Sensitizing Properties,” Endocrinology and Metabolism: American Journal of Physiology, Vol. 293, No. 1, 2007, pp. E91-E95. doi:10.1152/ajpendo.00024.2007
[39] A. A. Fouad, A. I. Al-Sultan, M. T. Yacoubi and W. Gomaa, “Ameliorative Effects of Telmisartan in Diabetic Rats with Indomethacin-Induced Gastric Ulceration,” European Journal of Pharmacology, Vol. 637, No. 1-3, 2010, pp. 162-170. doi:10.1016/j.ejphar.2010.04.007
[40] Z. Guo, C. Zheng, Z. Qin and P. Wei, “Effect of Telmisartan on the Expression of Cardiac Adiponectin and Its Receptor 1 in Type 2 Diabetic Rats,” Journal of Pharmacy and Pharmacology, Vol. 63, No. 1, 2011, pp. 87-94. doi:10.1111/j.2042-7158.2010.01157.x
[41] X. Rong, Y. Li, K. Ebihara, M. Zhao, J. Naowaboot, T. Kusakabe, K. Kuwahara, M. Murray and K. Nakao, “Angiotensin II Type 1 Receptor-Independent Beneficial Effects of Telmisartan on Dietary-Induced Obesity, Insulin Resistance and Fatty Liver in Mice,” Diabetologia, Vol. 53, No. 8, 2010, pp. 1727-1731. doi:10.1007/s00125-010-1744-6
[42] S. C. Benson, H. A. Pershadsingh, C. I. Ho, A. Chittiboyina, P. Desai, M. Pravenec, N. Qi, J. Wang, M. A. Avery and T. W. Kurtz, “Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist with Selective PPARgamma-Modulating Activity,” Hypertension, Vol. 43, No. 5, 2004, pp. 993-1002. doi:10.1007/s00125-010-1744-6
[43] B. Gross and B. Staels, “PPAR Agonists: Multimodal Drugs for the Treatment of Type-2 Diabetes,” Best Practice & Research: Clinical Endocrinology & Metabolism, Vol. 21, No. 4, 2007, pp. 687-710. doi:10.1016/j.beem.2007.09.004
[44] G. Svegliati-Baroni, C. Candelaresi, S. Saccomanno, G. Ferretti, T. Bachetti, M. Marzioni, S. De Minicis, L. Nobili, R. Salzano, A. Omenetti, D. Pacetti, S. Sigmund, A. Benedetti and A. Casini, “A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats: Role of Peroxisome Proliferator-Activated Receptor-Alpha and n-3 Polyunsaturated Fatty Acid Treatment on Liver Injury,” American Journal of Pathology, Vol. 169, No. 3, 2006, pp. 846-860. doi:10.1016/j.beem.2007.09.004
[45] T. Kakuma, K. Gotoh, T. Masaki, E. Itateyama, N. Abe and H. Yoshimatsu, “Telmisartan Reduced Abdominal Circumference and Body Weight with Decreasing Triglyceride Level in Patients with Type 2 Diabetes and Metabolic Syndrome,” Obesity Research & Clinical Practice, Vol. 4, No. 2, 2009, pp. e145-e152. doi:10.1016/j.orcp.2009.12.003
[46] P. Pacher, I. G. Obrosova, J. G. Mabley and C. Szabó, “Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies,” Current Medicinal Chemistry, Vol. 12, No. 3, 2005, pp. 267-275. doi:10.2174/0929867053363207
[47] A. A. Hamed and H. A. Malek, “Effect of Telmisartan in Experimentally Induced Diabetetes Mellitus in Rats,” International Journal of Health Sciences, Vol. 1, No. 2, 2007, pp. 249-256.
[48] K. Wellington, “Rosiglitazone/Metformin,” Drugs, Vol. 65, No. 11, 2005, pp. 1581-1592. doi:10.2165/00003495-200565110-00013
[49] J. Rosenstock, J. Rood, A. Cobitz, N. Biswas, H. Chou and A. Garber, “Initial Treatment with Rosiglitazone/ Metformin Fixed-Dose Combination Therapy Compared with Monotherapy with Either Rosiglitazone or Metformin in Patients with Uncontrolled Type 2 Diabetes,” Diabetes, Obesity and Metabolism, Vol. 8, No. 6, 2006, pp. 650-660. doi:10.1111/j.1463-1326.2006.00659.x

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.