Generic placeholder image

Current Drug Therapy

Editor-in-Chief

ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

Review Article

Therapeutic Repurposing of Antidiabetic Drugs in Diabetes-associated Comorbidities

Author(s): Kalyani Pathak*, Manash Pratim Pathak, Riya Saikia, Urvashee Gogoi, Ratna Jyoti Das, Pompy Patowary, Partha Pratim Kaishap, Smita Bordoloi, Jyotirmoy Das, Himangshu Sarma, Mohammad Zaki Ahmad and Aparoop Das

Volume 19, Issue 2, 2024

Published on: 30 May, 2023

Page: [178 - 194] Pages: 17

DOI: 10.2174/1574885518666230516150404

Price: $65

Abstract

Background: Diabetic patients suffer from various comorbidities like cardiovascular diseases (CVDs), cancer, obesity, cognitive impairment, gout, leishmaniasis, etc.

Objective: We aimed to review the pathological links between diabetes and its comorbidities and discuss the justification for using antidiabetic drugs in diabetes and associated comorbidities.

Methods: Diabetic patients accompanied by comorbidities had to undergo a multidrug regimen apart from their common antidiabetic drugs, which affects their quality of life. There have been reports that some antidiabetic drugs ameliorate the comorbidities associated with diabetes. For instance, metformin is implicated in CVDs, cancer, as well as in cognitive impairment like Alzheimer's disease (AD); glyburide, a sulfonylurea, is found to be effective against leishmaniasis; and voglibose, an α- glucosidase inhibitor, is found to have suitable binding property against SARS-CoV-2 infection in diabetic patients. Targeting the comorbidities of diabetes with antidiabetic drugs may reduce the load of multidrug therapy in diabetic patients.

Results: The effectiveness of antidiabetic drugs against some diabetic comorbidities between the two pathophysiological conditions, i.e., diabetes and its comorbidities, may be due to certain bidirectional links like inflammation, oxidative stress, disruption in the metabolic milieu and obesity. There are published reports of the repurposing of antidiabetic drugs for specific diseases, however, compiled repurposed reports of antidiabetic drugs for a wide range of diseases are scarce.

Conclusion: In this review, we attempt to justify the use of antidiabetic drugs in diabetes and associated comorbidities.

Graphical Abstract

[1]
Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 diabetes – global burden of disease and forecasted trends. J Epidemiol Glob Health 2019; 10(1): 107-11.
[http://dx.doi.org/10.2991/jegh.k.191028.001] [PMID: 32175717]
[2]
International Diabetes Federation. Diabetes facts & figures 2021. Available from: https://idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html
[3]
Bruce CR, Hamley S, Ang T, Howlett KF, Shaw CS, Kowalski GM. Translating glucose tolerance data from mice to humans: Insights from stable isotope labelled glucose tolerance tests. Mol Metab 2021; 53: 101281.
[http://dx.doi.org/10.1016/j.molmet.2021.101281] [PMID: 34175474]
[4]
Martín-Timón I, Sevillano-Collantes C, Segura-Galindo A, Del Cañizo-Gómez FJ. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J Diabetes 2014; 5(4): 444-70.
[http://dx.doi.org/10.4239/wjd.v5.i4.444] [PMID: 25126392]
[5]
Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41(2): 255-323.
[http://dx.doi.org/10.1093/eurheartj/ehz486] [PMID: 31497854]
[6]
Schubert M, Hansen S, Leefmann J, Guan K. Repurposing antidiabetic drugs for cardiovascular disease. Front Physiol 2020; 11: 568632.
[http://dx.doi.org/10.3389/fphys.2020.568632] [PMID: 33041865]
[7]
Duncan BB, Schmidt MI, Pankow JS, et al. Low-grade systemic inflammation and the development of type 2 diabetes mellitus [ndash]: The ARIC Study. Diabetes 2003; 52(7): 1799-805.
[http://dx.doi.org/10.2337/diabetes.52.7.1799]
[8]
Matheus AS de M. Tannus LRM, Cobas RA, Palma CCS, Negrato CA, Gomes M de B. Impact of diabetes on cardiovascular disease: An update. Int J Hypertens 2013; 2013: 653789.
[9]
Vicenová B, Vopálenský V, Burýšek L, Pospíšek M. Emerging role of interleukin-1 in cardiovascular diseases. Physiol Res 2009; 58(4): 481-98.
[http://dx.doi.org/10.33549/physiolres.931673] [PMID: 19093736]
[10]
Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 2005; 16(S1): S30-3.
[http://dx.doi.org/10.1681/ASN.2004110970] [PMID: 15938030]
[11]
Kannel WB. Lipids, diabetes, and coronary heart disease: Insights from the Framingham Study. Am Heart J 1985; 110(5): 1100-7.
[http://dx.doi.org/10.1016/0002-8703(85)90224-8] [PMID: 4061265]
[12]
Mooradian AD, Albert SG, Haas MJ. Low serum high-density lipoprotein cholesterol in obese subjects with normal serum triglycerides: The role of insulin resistance and inflammatory cytokines. Diabetes Obes Metab 2007; 9(3): 441-3.
[http://dx.doi.org/10.1111/j.1463-1326.2006.00636.x] [PMID: 17391174]
[13]
Barouch LA, Berkowitz DE, Harrison RW, O’Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation 2003; 108(6): 754-9.
[http://dx.doi.org/10.1161/01.CIR.0000083716.82622.FD] [PMID: 12885755]
[14]
Kim M, Oh J, Sakata S, et al. Role of resistin in cardiac contractility and hypertrophy. J Mol Cell Cardiol 2008; 45(2): 270-80.
[http://dx.doi.org/10.1016/j.yjmcc.2008.05.006] [PMID: 18597775]
[15]
Williams IL, Noronha B, Zaman AG. Review: The management of acute myocardial infarction in patients with diabetes mellitus. Br J Diabetes Vasc Dis 2003; 3(5): 319-24.
[http://dx.doi.org/10.1177/14746514030030050201]
[16]
Qu S, Zhu B. The relationship between diabetes mellitus and cancers and its underlying mechanisms. Front Endocrinol 2022; 13: 800995.
[17]
Hua F, Yu JJ, Hu ZW. Diabetes and cancer, common threads and missing links. Cancer Lett 2016; 374(1): 54-61.
[http://dx.doi.org/10.1016/j.canlet.2016.02.006] [PMID: 26879686]
[18]
Wang X, Ding S. The biological and pharmacological connections between diabetes and various types of cancer. Pathol Res Pract 2021; 227: 153641.
[http://dx.doi.org/10.1016/j.prp.2021.153641] [PMID: 34619575]
[19]
Arcaro A. Targeting the insulin-like growth factor-1 receptor in human cancer. Front Pharmacol 2013; 4: 30.
[http://dx.doi.org/10.3389/fphar.2013.00030] [PMID: 23525758]
[20]
Belfiore A, Frasca F. IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 2008; 13(4): 381-406.
[http://dx.doi.org/10.1007/s10911-008-9099-z] [PMID: 19016312]
[21]
Cao J, Yee D. Disrupting insulin and IGF receptor function in cancer. Int J Mol Sci 2021; 22(2): 555.
[http://dx.doi.org/10.3390/ijms22020555] [PMID: 33429867]
[22]
Scully T, Ettela A, LeRoith D, Gallagher EJ. Obesity, type 2 diabetes, and cancer risk. Front Oncol 2021; 10: 615375.
[http://dx.doi.org/10.3389/fonc.2020.615375] [PMID: 33604295]
[23]
Garg SK, Maurer H, Reed K, Selagamsetty R. Diabetes and cancer: Two diseases with obesity as a common risk factor. Diabetes Obes Metab 2014; 16(2): 97-110.
[http://dx.doi.org/10.1111/dom.12124] [PMID: 23668396]
[24]
Chang SC, Yang WCV. Hyperglycemia, tumorigenesis, and chronic inflammation. Crit Rev Oncol Hematol 2016; 108: 146-53.
[http://dx.doi.org/10.1016/j.critrevonc.2016.11.003] [PMID: 27931833]
[25]
Du X, Stockklauser-Färber K, Rösen P. Generation of reactive oxygen intermediates, activation of NF-κB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radic Biol Med 1999; 27(7-8): 752-63.
[http://dx.doi.org/10.1016/S0891-5849(99)00079-9] [PMID: 10515579]
[26]
Gupta S, Chough E, Daley J, et al. Hyperglycemia increases endothelial superoxide that impairs smooth muscle cell Na+ -K+ -ATPase activity. Am J Physiol Cell Physiol 2002; 282(3): C560-6.
[http://dx.doi.org/10.1152/ajpcell.00343.2001] [PMID: 11832341]
[27]
Pitocco D, Tesauro M, Alessandro R, Ghirlanda G, Cardillo C. Oxidative stress in diabetes: Implications for vascular and other complications. Int J Mol Sci 2013; 14(11): 21525-50.
[http://dx.doi.org/10.3390/ijms141121525] [PMID: 24177571]
[28]
Heidari F, Rabizadeh S, Mansournia MA, et al. Inflammatory, oxidative stress and anti-oxidative markers in patients with endometrial carcinoma and diabetes. Cytokine 2019; 120: 186-90.
[http://dx.doi.org/10.1016/j.cyto.2019.05.007] [PMID: 31100682]
[29]
Vaupel P, Multhoff G. Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol 2021; 599(6): 1745-57.
[http://dx.doi.org/10.1113/JP278810] [PMID: 33347611]
[30]
Ma L, Zong X. Metabolic symbiosis in chemoresistance: Refocusing the role of aerobic glycolysis. Front Oncol 2020; 10: 5.
[http://dx.doi.org/10.3389/fonc.2020.00005] [PMID: 32038983]
[31]
Lee W, Yoo W, Chae H. ER stress and autophagy. Curr Mol Med 2015; 15(8): 735-45.
[http://dx.doi.org/10.2174/1566524015666150921105453] [PMID: 26391548]
[32]
Lin Y, Jiang M, Chen W, Zhao T, Wei Y. Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response. Biomed Pharmacother 2019; 118: 109249.
[http://dx.doi.org/10.1016/j.biopha.2019.109249] [PMID: 31351428]
[33]
Heni M, Kullmann S, Preissl H, Fritsche A, Häring HU. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol 2015; 11(12): 701-11.
[http://dx.doi.org/10.1038/nrendo.2015.173] [PMID: 26460339]
[34]
Naser KA, Gruber A, Thomson GA. The emerging pandemic of obesity and diabetes: Are we doing enough to prevent a disaster? Int J Clin Pract 2006; 60(9): 1093-7.
[http://dx.doi.org/10.1111/j.1742-1241.2006.01003.x] [PMID: 16939551]
[35]
Algoblan A, Alalfi M, Khan M. Mechanism linking diabetes mellitus and obesity. Diabetes Metab Syndr Obes 2014; 7: 587-91.
[http://dx.doi.org/10.2147/DMSO.S67400] [PMID: 25506234]
[36]
Ye J. Mechanisms of insulin resistance in obesity. Front Med 2013; 7(1): 14-24.
[http://dx.doi.org/10.1007/s11684-013-0262-6] [PMID: 23471659]
[37]
Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med 2017; 23(7): 804-14.
[http://dx.doi.org/10.1038/nm.4350] [PMID: 28697184]
[38]
Pathak MP, Patowary P, Goyary D, Das A, Chattopadhyay P. β-caryophyllene ameliorated obesity-associated airway hyperresponsiveness through some non-conventional targets. Phytomedicine 2021; 89: 153610.
[http://dx.doi.org/10.1016/j.phymed.2021.153610] [PMID: 34175589]
[39]
Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116(7): 1793-801.
[http://dx.doi.org/10.1172/JCI29069] [PMID: 16823477]
[40]
Belosludtsev KN, Belosludtseva NV, Dubinin MV. Diabetes mellitus, mitochondrial dysfunction and Ca2+-dependent permeability transition pore. Int J Mol Sci 2020; 21(18): 6559.
[http://dx.doi.org/10.3390/ijms21186559] [PMID: 32911736]
[41]
Zhang AMY, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in obesity, inflammation, and cancer. Diabetes Metab J 2021; 45(3): 285-311.
[http://dx.doi.org/10.4093/dmj.2020.0250] [PMID: 33775061]
[42]
Aouichat S, Navarro-Alarcon M, Alarcón-Guijo P, et al. Melatonin improves endoplasmic reticulum stress-mediated IRE1α pathway in Zücker diabetic fatty rat. Pharmaceuticals 2021; 14(3): 232.
[http://dx.doi.org/10.3390/ph14030232] [PMID: 33800157]
[43]
Ben-Shlomo A, Melmed S. Acromegaly. Endocrinol Metab Clin North Am 2008; 37(1): 101-22. viii.
[http://dx.doi.org/10.1016/j.ecl.2007.10.002] [PMID: 18226732]
[44]
Nabarro JDN. Acromegaly. Clin Endocrinol 1987; 26(4): 481-512.
[http://dx.doi.org/10.1111/j.1365-2265.1987.tb00805.x] [PMID: 3308190]
[45]
Biering H, Knappe G, Gerl H, Lochs H. Prevalence of diabetes in acromegaly and Cushing syndrome. Acta Med Austriaca 2000; 27(1): 27-31.
[http://dx.doi.org/10.1046/j.1563-2571.2000.00106.x] [PMID: 10812460]
[46]
Resmini E, Minuto F, Colao A, Ferone D. Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. Acta Diabetol 2009; 46(2): 85-95.
[http://dx.doi.org/10.1007/s00592-009-0112-9] [PMID: 19322513]
[47]
Kreze A, Kreze-Spirova E, Mikulecky M. Risk factors for glucose intolerance in active acromegaly. Braz J Med Biol Res 2001; 34(11): 1429-33.
[http://dx.doi.org/10.1590/S0100-879X2001001100009] [PMID: 11668352]
[48]
Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing’s syndrome. Endocrinol Metab Clin North Am 2008; 37(1): 135-49. ix.
[http://dx.doi.org/10.1016/j.ecl.2007.10.010] [PMID: 18226734]
[49]
Faggiano A, Pivonello R, Spiezia S, et al. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 2003; 88(6): 2527-33.
[http://dx.doi.org/10.1210/jc.2002-021558] [PMID: 12788849]
[50]
Terzolo M, Allasino B, Bosio S, et al. Hyperhomocysteinemia in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2004; 89(8): 3745-51.
[http://dx.doi.org/10.1210/jc.2004-0079] [PMID: 15292300]
[51]
Tauchmanovà L, Rossi R, Biondi B, et al. Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk. J Clin Endocrinol Metab 2002; 87(11): 4872-8.
[http://dx.doi.org/10.1210/jc.2001-011766] [PMID: 12414841]
[52]
Connell JMC, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens 1987; 5(4): 425-34.
[http://dx.doi.org/10.1097/00004872-198708000-00007] [PMID: 2822795]
[53]
Roubsanthisuk W, Watanakejorn P, Tunlakit M, Sriussadaporn S. Hyperthyroidism induces glucose intolerance by lowering both insulin secretion and peripheral insulin sensitivity. J Med Assoc Thai 2006; 89(S5): S133-40.
[PMID: 17718254]
[54]
Mouradian M, Abourizk N. Diabetes mellitus and thyroid disease. Diabetes Care 1983; 6(5): 512-20.
[http://dx.doi.org/10.2337/diacare.6.5.512] [PMID: 6400713]
[55]
Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndr 2020; 14(4): 303-10.
[http://dx.doi.org/10.1016/j.dsx.2020.04.004] [PMID: 32298981]
[56]
Abdi A, Jalilian M, Sarbarzeh PA, Vlaisavljevic Z. Diabetes and COVID-19: A systematic review on the current evidences. Diabetes Res Clin Pract 2020; 166: 108347.
[http://dx.doi.org/10.1016/j.diabres.2020.108347] [PMID: 32711003]
[57]
Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: From pathophysiology to clinical management. Nat Rev Endocrinol 2021; 17(1): 11-30.
[http://dx.doi.org/10.1038/s41574-020-00435-4] [PMID: 33188364]
[58]
Fleming N, Sacks LJ, Pham CT, Neoh SL, Ekinci EI. An overview of COVID‐19 in people with diabetes: Pathophysiology and considerations in the inpatient setting. Diabet Med 2021; 38(3): e14509.
[http://dx.doi.org/10.1111/dme.14509] [PMID: 33377213]
[59]
Yin Y, Rohli KE, Shen P, Lu H, Liu Y, Dou Q. The epidemiology, pathophysiological mechanisms, and management toward COVID-19 patients with Type 2 diabetes: A systematic review. Prim Care Diabetes 2021; 15(6): 899-909.
[60]
Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus. Am J Physiol Endocrinol Metab 2020; 318(5): E736-41.
[http://dx.doi.org/10.1152/ajpendo.00124.2020] [PMID: 32228322]
[61]
Calvert JW, Gundewar S, Jha S, et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008; 57(3): 696-705.
[http://dx.doi.org/10.2337/db07-1098] [PMID: 18083782]
[62]
He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes 2013; 62(4): 1270-81.
[http://dx.doi.org/10.2337/db12-0533] [PMID: 23223177]
[63]
Johnson R, Dludla P, Joubert E, et al. Aspalathin, a dihydrochalcone C -glucoside, protects H9c2 cardiomyocytes against high glucose induced shifts in substrate preference and apoptosis. Mol Nutr Food Res 2016; 60(4): 922-34.
[http://dx.doi.org/10.1002/mnfr.201500656] [PMID: 26773306]
[64]
Noyan-Ashraf MH, Momen MA, Ban K, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 2009; 58(4): 975-83.
[http://dx.doi.org/10.2337/db08-1193] [PMID: 19151200]
[65]
Birnbaum Y, Tran D, Bajaj M, Ye Y. DPP-4 inhibition by linagliptin prevents cardiac dysfunction and inflammation by targeting the Nlrp3/ASC inflammasome. Basic Res Cardiol 2019; 114(5): 35.
[http://dx.doi.org/10.1007/s00395-019-0743-0] [PMID: 31388770]
[66]
Zhou Y, Wang H, Man F, et al. Sitagliptin protects cardiac function by reducing nitroxidative stress and promoting autophagy in zucker diabetic fatty (ZDF) rats. Cardiovasc Drugs Ther 2018; 32(6): 541-52.
[http://dx.doi.org/10.1007/s10557-018-6831-9] [PMID: 30328028]
[67]
Tanajak P, Sa-nguanmoo P, Sivasinprasasn S, et al. Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J Endocrinol 2018; 236(2): 69-84.
[http://dx.doi.org/10.1530/JOE-17-0457] [PMID: 29142025]
[68]
Andreadou I, Efentakis P, Balafas E, et al. Empagliflozin limits myocardial infarction in vivo and cell death in vitro: Role of STAT3, mitochondria, and redox aspects. Front Physiol 2017; 8: 1077.
[http://dx.doi.org/10.3389/fphys.2017.01077] [PMID: 29311992]
[69]
Chandreyee D, Payel D, Bhattacharjee A. Repurposing of anti-diabetic drug in cancer prevention. Nov Approaches Cancer Study 2020; 4(5)
[http://dx.doi.org/10.31031/NACS.2020.04.000598]
[70]
Shafiei-Irannejad V, Samadi N, Salehi R, Yousefi B, Zarghami N. New insights into antidiabetic drugs: Possible applications in cancer treatment. Chem Biol Drug Des 2017; 90(6): 1056-66.
[http://dx.doi.org/10.1111/cbdd.13013] [PMID: 28456998]
[71]
Núñez M, Medina V, Cricco G, et al. Glibenclamide inhibits cell growth by inducing G0/G1 arrest in the human breast cancer cell line MDA-MB-231. BMC Pharmacol Toxicol 2013; 14(1): 6.
[http://dx.doi.org/10.1186/2050-6511-14-6] [PMID: 23311706]
[72]
Xu K, Sun G, Li M, Chen H, Zhang Z, Qian X. Glibenclamide targets sulfonylurea receptor 1 to inhibit p70S6K activity and upregulate KLF4 expression to suppress non-small cell lung carcinoma. Mol Cancer Ther 18(11): 2085-96.
[73]
Pasello G, Urso L, Conte P, Favaretto A. Effects of sulfonylureas on tumor growth: A review of the literature. Oncologist 2013; 18(10): 1118-25.
[http://dx.doi.org/10.1634/theoncologist.2013-0177] [PMID: 24043597]
[74]
Fröhlich E, Wahl R. Chemotherapy and chemoprevention by thiazolidinediones. BioMed Res Int 2015; 2015: 845340.
[http://dx.doi.org/10.1155/2015/845340]
[75]
Olatunde A, Nigam M, Singh RK, et al. Cancer and diabetes: the interlinking metabolic pathways and repurposing actions of antidiabetic drugs. Cancer Cell Int 2021; 21(1): 499.
[http://dx.doi.org/10.1186/s12935-021-02202-5] [PMID: 34535145]
[76]
van de Haar HJ. Microvascular and blood-brain barrier dysfunction in Alzheimer’s disease. Maastricht University 2016. Available from: https://cris.maastrichtuniversity.nl/en/publications/8d33e17e-ade6-459b-b6a3-87758859abf9
[77]
Renner S, Bessonov A, Simmel FC. Voltage-controlled insertion of single α-hemolysin and Mycobacterium smegmatis nanopores into lipid bilayer membranes. Appl Phys Lett 2011; 98(8): 083701.
[http://dx.doi.org/10.1063/1.3558902]
[78]
Drejer K, Vaag A, Bech K, Hansen P, Sørensen AR, Mygind N. Intranasal administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects. Diabet Med 1992; 9(4): 335-40.
[http://dx.doi.org/10.1111/j.1464-5491.1992.tb01792.x] [PMID: 1600703]
[79]
Freiherr J, Hallschmid M, Frey WH II, et al. Intranasal insulin as a treatment for Alzheimer’s disease: A review of basic research and clinical evidence. CNS Drugs 2013; 27(7): 505-14.
[http://dx.doi.org/10.1007/s40263-013-0076-8] [PMID: 23719722]
[80]
Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: An overview. Clin Sci 2012; 122(6): 253-70.
[http://dx.doi.org/10.1042/CS20110386] [PMID: 22117616]
[81]
Zhao M, Li XW, Chen DZ, et al. Neuro-protective role of metformin in patients with acute stroke and type 2 diabetes mellitus via AMPK/Mammalian target of rapamycin (mTOR) signaling pathway and oxidative stress. Med Sci Monit 2019; 25: 2186-94.
[http://dx.doi.org/10.12659/MSM.911250] [PMID: 30905926]
[82]
Fang W, Zhang J, Hong L, et al. Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J Affect Disord 2020; 260: 302-13.
[http://dx.doi.org/10.1016/j.jad.2019.09.013] [PMID: 31521867]
[83]
Paudel YN, Angelopoulou E, Piperi C, Gnatkovsky V, Othman I, Shaikh MF. From the molecular mechanism to preclinical results: Anti-epileptic effects of fingolimod. Curr Neuropharmacol 2020; 18(11): 1126-37.
[http://dx.doi.org/10.2174/1570159X18666200420125017] [PMID: 32310049]
[84]
Wang X, Luo C, Mao XY, et al. Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats. Brain Res 2019; 1719: 30-9.
[http://dx.doi.org/10.1016/j.brainres.2019.05.023] [PMID: 31121159]
[85]
Sharma D, Verma S, Vaidya S, Kalia K, Tiwari V. Recent updates on GLP-1 agonists: Current advancements & challenges. Biomed Pharmacother 2018; 108: 952-62.
[http://dx.doi.org/10.1016/j.biopha.2018.08.088] [PMID: 30372907]
[86]
Hayes MR. Neuronal and intracellular signaling pathways mediating GLP-1 energy balance and glycemic effects. Physiol Behav 2012; 106(3): 413-6.
[http://dx.doi.org/10.1016/j.physbeh.2012.02.017] [PMID: 22366059]
[87]
Mansur RB, Lee Y, Subramaniapillai M, Brietzke E, McIntyre RS. Cognitive dysfunction and metabolic comorbidities in mood disorders: A repurposing opportunity for glucagon-like peptide 1 receptor agonists? Neuropharmacology 2018; 136(Pt B): 335-42.
[88]
Pipatpiboon N, Pintana H, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption. Eur J Neurosci 2013; 37(5): 839-49.
[http://dx.doi.org/10.1111/ejn.12088] [PMID: 23240760]
[89]
Gault VA, Lennox R, Flatt PR. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline. Diabetes Obes Metab 2015; 17(4): 403-13.
[http://dx.doi.org/10.1111/dom.12432] [PMID: 25580570]
[90]
Lehrke M, Lazar MA. The many faces of PPARgamma. Cell 2005; 123(6): 993-9.
[http://dx.doi.org/10.1016/j.cell.2005.11.026] [PMID: 16360030]
[91]
Chao EC, Henry RR. SGLT2 inhibition-A novel strategy for diabetes treatment. Nat Rev Drug Discov 2010; 9(7): 551-9.
[http://dx.doi.org/10.1038/nrd3180] [PMID: 20508640]
[92]
Nauck M. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther 2014; 8: 1335-80.
[http://dx.doi.org/10.2147/DDDT.S50773] [PMID: 25246775]
[93]
Sa-nguanmoo P, Tanajak P, Kerdphoo S, et al. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Toxicol Appl Pharmacol 2017; 333: 43-50.
[http://dx.doi.org/10.1016/j.taap.2017.08.005] [PMID: 28807765]
[94]
El-SaberBatiha G. Beshbishy AM, Ikram M, Mulla ZS, Abd El-Hack ME, Taha ME. The pharmacological activity, biochemical properties, and pharmacokinetics of the major natural polyphenolic flavonoid: Quercetin. Foods 2020; 9: 374.
[95]
Haddad P, Eid H. The antidiabetic potential of quercetin: underlying mechanisms. Curr Med Chem 2017; 24(4): 355-64.
[http://dx.doi.org/10.2174/0929867323666160909153707] [PMID: 27633685]
[96]
Bule M, Abdurahman A, Nikfar S, Abdollahi M, Amini M. Antidiabetic effect of quercetin: A systematic review and meta-analysis of animal studies. Food Chem Toxicol 2019; 125: 494-502.
[http://dx.doi.org/10.1016/j.fct.2019.01.037] [PMID: 30735748]
[97]
Chen J, Deng X, Liu N, et al. Quercetin attenuates tau hyperphosphorylation and improves cognitive disorder via suppression of ER stress in a manner dependent on AMPK pathway. J Funct Foods 2016; 22: 463-76.
[http://dx.doi.org/10.1016/j.jff.2016.01.036]
[98]
Yao S, Sang H, Song G, et al. Quercetin protects macrophages from oxidized low-density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress-C/EBP homologous protein pathway. Exp Biol Med 2012; 237(7): 822-31.
[http://dx.doi.org/10.1258/ebm.2012.012027] [PMID: 22829699]
[99]
Pei B, Yang M, Qi X, Shen X, Chen X, Zhang F. Quercetin ameliorates ischemia/reperfusion-induced cognitive deficits by inhibiting ASK1/JNK3/caspase-3 by enhancing the Akt signaling pathway. Biochem Biophys Res Commun 2016; 478(1): 199-205.
[http://dx.doi.org/10.1016/j.bbrc.2016.07.068] [PMID: 27450812]
[100]
Wang LW, Chang YC, Chen SJ, et al. TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain. J Neuroinflammation 2014; 11(1): 215.
[http://dx.doi.org/10.1186/s12974-014-0215-2] [PMID: 25540015]
[101]
Sabogal-Guáqueta AM, Muñoz-Manco JI, Ramírez-Pineda JR, Lamprea-Rodriguez M, Osorio E, Cardona-Gómez GP. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 2015; 93: 134-45.
[http://dx.doi.org/10.1016/j.neuropharm.2015.01.027]
[102]
Souza CG, Riboldi BP, Hansen F, et al. Chronic sulforaphane oral treatment accentuates blood glucose impairment and may affect GLUT3 expression in the cerebral cortex and hypothalamus of rats fed with a highly palatable diet. Food Funct 2013; 4(8): 1271-6.
[http://dx.doi.org/10.1039/c3fo60039d] [PMID: 23797263]
[103]
Pu D, Zhao Y, Chen J, et al. Protective effects of sulforaphane on cognitive impairments and AD-like lesions in diabetic mice are associated with the upregulation of nrf2 transcription activity. Neuroscience 2018; 381: 35-45.
[http://dx.doi.org/10.1016/j.neuroscience.2018.04.017] [PMID: 29684505]
[104]
Lazzaroni E, Ben Nasr M, Loretelli C, et al. Anti-diabetic drugs and weight loss in patients with type 2 diabetes. Pharmacol Res 2021; 171: 105782.
[http://dx.doi.org/10.1016/j.phrs.2021.105782] [PMID: 34302978]
[105]
Franz MJ, VanWormer JJ, Crain AL, et al. Weight-loss outcomes: A systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc 2007; 107(10): 1755-67.
[http://dx.doi.org/10.1016/j.jada.2007.07.017] [PMID: 17904936]
[106]
Rucker D, Padwal R, Li SK, Curioni C, Lau DCW. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335(7631): 1194-9.
[http://dx.doi.org/10.1136/bmj.39385.413113.25] [PMID: 18006966]
[107]
Padwal R, Klarenbach S, Wiebe N, et al. Bariatric surgery: A systematic review and network meta-analysis of randomized trials. Obes Rev 2011; 12(8): 602-21.
[http://dx.doi.org/10.1111/j.1467-789X.2011.00866.x] [PMID: 21438991]
[108]
Scarpello JHB, Howlett HCS. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008; 5(3): 157-67.
[http://dx.doi.org/10.3132/dvdr.2008.027] [PMID: 18777488]
[109]
Yasuda N, Inoue T, Nagakura T, et al. Metformin causes reduction of food intake and body weight gain and improvement of glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in Zucker fa/fa rats. J Pharmacol Exp Ther 2004; 310(2): 614-9.
[http://dx.doi.org/10.1124/jpet.103.064964] [PMID: 15039452]
[110]
shan LW, Wen JP, Li L, Sun RX, Wang J, Xian YX. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res 2012; 1444: 11-9.
[111]
Beck B. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos Trans R Soc Lond B Biol Sci 2006; 361(1471): 1159-85.
[http://dx.doi.org/10.1098/rstb.2006.1855] [PMID: 16874931]
[112]
Lundkvist P, Sjöström CD, Amini S, Pereira MJ, Johnsson E, Eriksson JW. Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab 2017; 19(1): 49-60.
[http://dx.doi.org/10.1111/dom.12779] [PMID: 27550386]
[113]
Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 2012; 97(3): 1020-31.
[http://dx.doi.org/10.1210/jc.2011-2260] [PMID: 22238392]
[114]
Oyama K, Raz I, Cahn A, Kuder J, Murphy SA, Bhatt DL. Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE–TIMI 58 trial. Eur Heart J 2021; ehab530.
[http://dx.doi.org/10.1093/eurheartj/ehab530] [PMID: 34427295]
[115]
Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2008; 30(8): 1448-60.
[116]
Folli F, Guardado Mendoza R. Potential use of exenatide for the treatment of obesity. Expert Opin Investig Drugs 2011; 20(12): 1717-22.
[http://dx.doi.org/10.1517/13543784.2011.630660] [PMID: 22017240]
[117]
Basolo A, Burkholder J, Osgood K, Graham A, Bundrick S, Frankl J. Exenatide has a pronounced effect on energy intake but not energy expenditure in non-diabetic subjects with obesity: A randomized, double-blind, placebo-controlled trial. Metabolism 2018; 85: 116-25.
[118]
Shpakov AO. Improvement effect of metformin on female and male reproduction in endocrine pathologies and its mechanisms. Pharmaceuticals 2021; 14(1): 42.
[http://dx.doi.org/10.3390/ph14010042] [PMID: 33429918]
[119]
Batandier C, Guigas B, Detaille D, et al. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr 2006; 38(1): 33-42.
[http://dx.doi.org/10.1007/s10863-006-9003-8] [PMID: 16732470]
[120]
Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From mechanisms of action to therapies. Cell Metab 2014; 20(6): 953-66.
[http://dx.doi.org/10.1016/j.cmet.2014.09.018] [PMID: 25456737]
[121]
Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin: Clinical relevance. Clin Pharmacokinet 2003; 42(9): 819-50.
[http://dx.doi.org/10.2165/00003088-200342090-00003] [PMID: 12882588]
[122]
Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: Progress, challenges and recommendations. Nat Rev Drug Discov 2019; 18(1): 41-58.
[http://dx.doi.org/10.1038/nrd.2018.168] [PMID: 30310233]
[123]
Khayyat AN, Abbas HA, Mohamed MFA, Asfour HZ, Khayat MT, Ibrahim TS. Not only antimicrobial: Metronidazole mitigates the virulence of proteus mirabilis isolated from macerated diabetic foot ulcer. Appl Sci 2021; 11(15): 6847.
[124]
Pollack RM, Donath MY, LeRoith D, Leibowitz G. Anti-inflammatory agents in the treatment of diabetes and its vascular complications. Diabetes Care 2016; 39(S2): S244-52.
[http://dx.doi.org/10.2337/dcS15-3015] [PMID: 27440839]
[125]
Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab 2020; 32(1): 15-30.
[http://dx.doi.org/10.1016/j.cmet.2020.04.001] [PMID: 32333835]
[126]
Ursini F, Russo E, Pellino G, et al. Metformin and autoimmunity: A “new deal” of an old drug. Front Immunol 2018; 9: 1236.
[http://dx.doi.org/10.3389/fimmu.2018.01236] [PMID: 29915588]
[127]
Allam AN, Mehanna MM. Formulation, physicochemical characterization and in-vivo evaluation of ion-sensitive metformin loaded-biopolymeric beads. Drug Dev Ind Pharm 2016; 42(3): 497-505.
[http://dx.doi.org/10.3109/03639045.2015.1058815] [PMID: 26114554]
[128]
Liu Y, Jia Y, Yang K, et al. Metformin restores tetracyclines susceptibility against multidrug resistant bacteria. Adv Sci 2020; 7(12): 1902227.
[http://dx.doi.org/10.1002/advs.201902227] [PMID: 32596101]
[129]
Kuryłowicz A, Koźniewski K. Anti-inflammatory strategies targeting metaflammation in type 2 diabetes. Molecules 2020; 25(9): 2224.
[http://dx.doi.org/10.3390/molecules25092224] [PMID: 32397353]
[130]
Solis-Herrera C, Triplitt C, Garduno-Garcia JJ, Adams J, DeFronzo RA, Cersosimo E. Mechanisms of glucose lowering of dipeptidyl peptidase-4 inhibitor sitagliptin when used alone or with metformin in type 2 diabetes: A double-tracer study. Diabetes Care 2013; 36(9): 2756-62.
[http://dx.doi.org/10.2337/dc12-2072] [PMID: 23579178]
[131]
Liao X, Song L, Zeng B, et al. Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis. EBioMedicine 2019; 44: 665-74.
[http://dx.doi.org/10.1016/j.ebiom.2019.03.057] [PMID: 30922964]
[132]
Abbas HA, Hegazy WAH. Repurposing anti-diabetic drug “Sitagliptin” as a novel virulence attenuating agent in Serratia marcescens. PLoS One 2020; 15(4): e0231625.
[http://dx.doi.org/10.1371/journal.pone.0231625] [PMID: 32298346]
[133]
Hegazy WAH, Khayat MT, Ibrahim TS, Youns M, Mosbah R, Soliman WE. Repurposing of antidiabetics as Serratia marcescens virulence inhibitors. Braz J Microbiol 2021; 52(2): 627-38.
[http://dx.doi.org/10.1007/s42770-021-00465-8] [PMID: 33686563]
[134]
Abbas HA, Elsherbini AM, Shaldam MA. Repurposing metformin as a quorum sensing inhibitor in Pseudomonas aeruginosa. Afr Health Sci 2017; 17(3): 808-19.
[http://dx.doi.org/10.4314/ahs.v17i3.24] [PMID: 29085409]
[135]
Krajačić MB, Kujundžić N, Dumić M, et al. Synthesis, characterization and in vitro antimicrobial activity of novel sulfonylureas of 15-membered azalides. J Antibiot 2005; 58(6): 380-9.
[http://dx.doi.org/10.1038/ja.2005.48] [PMID: 16156514]
[136]
Kreisberg JF, Ong NT, Krishna A, et al. Growth inhibition of pathogenic bacteria by sulfonylurea herbicides. Antimicrob Agents Chemother 2013; 57(3): 1513-7.
[http://dx.doi.org/10.1128/AAC.02327-12] [PMID: 23263008]
[137]
Lee W, Park EJ, Kwak S, Lee KC, Na DH, Bae JS. Trimeric PEG-conjugated exendin-4 for the treatment of sepsis. Biomacromolecules 2016; 17(3): 1160-9.
[http://dx.doi.org/10.1021/acs.biomac.5b01756] [PMID: 26905040]
[138]
Ramudu DB, Babu PH, Venkateswarlu N, Vijaya T, Rasheed S, Raju CN. Sulfonylurea derivatives of tolbutamide analogues: Synthesis and evaluation of antimicrobial and antioxidant activities. Indian J Chem Sec B Org Med Chem 2018; 57: 127-35.
[139]
Lowes DJ, Hevener KE, Peters BM. Second-generation antidiabetic sulfonylureas inhibit candida albicans and candidalysin-mediated activation of the NLRP3 inflammasome. Antimicrob Agents Chemother 2020; 64(2): e01777-19.
[http://dx.doi.org/10.1128/AAC.01777-19] [PMID: 31712208]
[140]
Koh GCKW, Weehuizen TA, Breitbach K, Krause K, de Jong HK, Kager LM. Glyburide reduces bacterial dissemination in a mouse model of melioidosis. PLoS Negl Trop Dis 2013; 7(10): e2500.
[http://dx.doi.org/10.1371/journal.pntd.0002500]
[141]
Anwar A, Siddiqui R, Shah MR, Khan NA. Antidiabetic drugs and their nanoconjugates repurposed as novel antimicrobial agents against Acanthamoeba castellanii. J Microbiol Biotechnol 2019; 29(5): 713-20.
[http://dx.doi.org/10.4014/jmb/1903.03009]
[142]
Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab 2018; 27(4): 740-56.
[http://dx.doi.org/10.1016/j.cmet.2018.03.001] [PMID: 29617641]
[143]
Moreira GV, Azevedo FF, Ribeiro LM, et al. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem 2018; 62: 143-54.
[http://dx.doi.org/10.1016/j.jnutbio.2018.07.009] [PMID: 30292107]
[144]
Culha MG, Inkaya AC, Yildirim E, Unal S, Serefoglu EC. Glucagon like peptide-1 receptor agonists may ameliorate the metabolic adverse effect associated with antiretroviral therapy. Med Hypotheses 2016; 94: 151-3.
[http://dx.doi.org/10.1016/j.mehy.2016.07.016] [PMID: 27515222]
[145]
Masadeh M, Mhaidat NM, Alazzam SI, Alzoubi KH. Investigation of the antibacterial activity of pioglitazone. Drug Des Devel Ther 2011; 5: 421-5.
[http://dx.doi.org/10.2147/DDDT.S24126] [PMID: 22087061]
[146]
Ribeiro NQ, Santos APN, Emídio ECP, et al. Pioglitazone as an adjuvant of amphotericin B for the treatment of cryptococcosis. Int J Antimicrob Agents 2019; 54(3): 301-8.
[http://dx.doi.org/10.1016/j.ijantimicag.2019.06.020] [PMID: 31279153]
[147]
Sucheta Tahlan S, Verma PK. Biological potential of thiazolidinedione derivatives of synthetic origin. Chem Cent J 2017; 11(1): 130.
[http://dx.doi.org/10.1186/s13065-017-0357-2] [PMID: 29222671]
[148]
Marques LPJ, Mendonça NA, Müller L, André ACPD, Madeira EPQ, Vieira LMSF. Impact of sodium-glucose cotransporter-2 inhibitors-induced glucosuria in the incidence of urogenital infection on postmenopausal women with diabetes. Postgrad Med 2020; 132(8): 697-701.
[http://dx.doi.org/10.1080/00325481.2020.1816360] [PMID: 33016178]
[149]
Dandona P, Ghanim H. Diabetes, obesity, COVID-19, insulin, and other antidiabetes drugs. Diabetes Care 2021; 44(9): 1929-33.
[http://dx.doi.org/10.2337/dci21-0003] [PMID: 34244331]
[150]
Yang Y, Cai Z, Zhang J. Insulin treatment may increase adverse outcomes in patients with COVID-19 and diabetes: A systematic review and meta-analysis. Front Endocrinol 2021; 12: 696087.
[http://dx.doi.org/10.3389/fendo.2021.696087] [PMID: 34367067]
[151]
Yunusa I, Love BL, Cai C, et al. Trends in insulin prescribing for patients with diabetes during the COVID-19 pandemic in the US. JAMA Netw Open 2021; 4(11): e2132607.
[http://dx.doi.org/10.1001/jamanetworkopen.2021.32607] [PMID: 34730822]
[152]
Scheen AJ. Metformin and COVID-19: From cellular mechanisms to reduced mortality. Diabetes Metab 2020; 46(6): 423-6.
[http://dx.doi.org/10.1016/j.diabet.2020.07.006] [PMID: 32750451]
[153]
Bailey CJ, Gwilt M. Diabetes, metformin and the clinical course of Covid-19: outcomes, mechanisms and suggestions on the therapeutic use of metformin. Front Pharmacol 2022; 13: 784459.
[http://dx.doi.org/10.3389/fphar.2022.784459] [PMID: 35370738]
[154]
Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract 2006; 60(11): 1454-70.
[http://dx.doi.org/10.1111/j.1742-1241.2006.01178.x] [PMID: 17073841]
[155]
Scheen AJ. DPP-4 inhibition and COVID-19: From initial concerns to recent expectations. Diabetes Metab 2021; 47(2): 101213.
[http://dx.doi.org/10.1016/j.diabet.2020.11.005] [PMID: 33249199]
[156]
Fadini GP, Morieri ML, Longato E, et al. Exposure to dipeptidyl‐peptidase‐4 inhibitors and COVID ‐19 among people with type 2 diabetes: A case‐control study. Diabetes Obes Metab 2020; 22(10): 1946-50.
[http://dx.doi.org/10.1111/dom.14097] [PMID: 32463179]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy