An Insight into the Combat Strategies for the Treatment of Type 2 Diabetes
Mellitus

Gita      Chawla; Tathagata      Pradhan; Ojasvi      Gupta
doi:10.2174/1389557523666230517113936
Abstract

Diabetes is a chronic, and metabolic disorder that has gained epidemic proportions in the past few decades creating a threat throughout the globe. It is characterized by increased glucose levels that may be due to immune-mediated disorders (T1DM), insulin resistance or inability to produce sufficient insulin by β-pancreatic cells (T2DM), gestational, or an increasingly sedentary lifestyle. The progression of the disease is marked by several pathological changes in the body like nephropathy, retinopathy, and various cardiovascular complications. Treatment options for T1DM are majorly focused on insulin replacement therapy. While T2DM is generally treated through oral hypoglycemics that include metformin, sulfonylureas, thiazolidinediones, meglitinides, incretins, SGLT-2 inhibitors, and amylin antagonists. Multidrug therapy is often recommended when patients are found incompliant with the first-line therapy. Despite the considerable therapeutic benefits of these oral hypoglycemics, there lie greater side effects (weight variation, upset stomach, skin rashes, and risk of hepatic disease), and limitations including short half-life, frequent dosing, and differential bioavailability which inspires the researchers to pursue novel drug targets and small molecules having promising clinical efficacy posing minimum side-effects. This review summarizes some of the current emerging novel approaches along with the conventional drug targets to treat type 2 diabetes.
« Previous Next »
Graphical Abstract

[1]
Sun, H.; Saeedi, P.; Karuranga, S.; Pinkepank, M.; Ogurtsova, K.; Duncan, B.B.; Stein, C.; Basit, A.; Chan, J.C.N.; Mbanya, J.C.; Pavkov, M.E.; Ramachandaran, A.; Wild, S.H.; James, S.; Herman, W.H.; Zhang, P.; Bommer, C.; Kuo, S.; Boyko, E.J.; Magliano, D.J. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract.,  2022, 183, 109119.
 [http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID:  34879977]

[2]
Lee, C.; Colagiuri, S. Diagnostic criteria and classification. Diabetes. epidemiology, genetics, pathogenesis, diagnosis,prevention, and treatment ,  2018, pp. 23-39.

[3]

WHO. Classification of diabetes mellitus; , 2019.

[4]
Roep, B.O.; Thomaidou, S.; van Tienhoven, R.; Zaldumbide, A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nat. Rev. Endocrinol.,  2021, 17(3), 150-161.
 [http://dx.doi.org/10.1038/s41574-020-00443-4] [PMID:  33293704]

[5]
Katsarou, A.; Gudbjörnsdottir, S.; Rawshani, A.; Dabelea, D.; Bonifacio, E.; Anderson, B.J.; Jacobsen, L.M.; Schatz, D.A.; Lernmark, Å. Type 1 diabetes mellitus. Nat. Rev. Dis. Primers,  2017, 3(1), 17016.
 [http://dx.doi.org/10.1038/nrdp.2017.16] [PMID:  28358037]

[6]
Janež, A.; Guja, C.; Mitrakou, A.; Lalic, N.; Tankova, T.; Czupryniak, L.; Tabák, A.G.; Prazny, M.; Martinka, E.; Smircic-Duvnjak, L. Insulin therapy in adults with type 1 diabetes mellitus: A narrative review. Diabetes Ther.,  2020, 11(2), 387-409.
 [http://dx.doi.org/10.1007/s13300-019-00743-7] [PMID:  31902063]

[7]
Padhi, S.; Nayak, A.K.; Behera, A. Type II diabetes mellitus: A review on recent drug based therapeutics. Biomed. Pharmacother.,  2020, 131, 110708.
 [http://dx.doi.org/10.1016/j.biopha.2020.110708] [PMID:  32927252]

[8]
Stumvoll, M.; Goldstein, B.J.; van Haeften, T.W. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet,  2005, 365(9467), 1333-1346.
 [http://dx.doi.org/10.1016/S0140-6736(05)61032-X] [PMID:  15823385]

[9]
Tomic, D.; Shaw, J.E.; Magliano, D.J. The burden and risks of emerging complications of diabetes mellitus. Nat. Rev. Endocrinol.,  2022, 18(9), 525-539.
 [http://dx.doi.org/10.1038/s41574-022-00690-7] [PMID:  35668219]

[10]
McIntyre, H.D.; Catalano, P.; Zhang, C.; Desoye, G.; Mathiesen, E.R.; Damm, P. Gestational diabetes mellitus. Nat. Rev. Dis. Primers,  2019, 5(1), 47.
 [http://dx.doi.org/10.1038/s41572-019-0098-8] [PMID:  31296866]

[11]
Broome, D.T.; Pantalone, K.M.; Kashyap, S.R.; Philipson, L.H. Approach to the patient with MODY-monogenic diabetes. J. Clin. Endocrinol. Metab.,  2021, 106(1), 237-250.
 [http://dx.doi.org/10.1210/clinem/dgaa710] [PMID:  33034350]

[12]
Holt, R.I.G.; DeVries, J.H.; Hess-Fischl, A.; Hirsch, I.B.; Kirkman, M.S.; Klupa, T.; Ludwig, B.; Nørgaard, K.; Pettus, J.; Renard, E.; Skyler, J.S.; Snoek, F.J.; Weinstock, R.S.; Peters, A.L. The management of Type 1 Diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care,  2021, 44(11), 2589-2625.
 [http://dx.doi.org/10.2337/dci21-0043] [PMID:  34593612]

[13]
Entezari, M.; Hashemi, D.; Taheriazam, A.; Zabolian, A.; Mohammadi, S.; Fakhri, F.; Hashemi, M.; Hushmandi, K.; Ashrafizadeh, M.; Zarrabi, A.; Ertas, Y.N.; Mirzaei, S.; Samarghandian, S. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomed. Pharmacother.,  2022, 146, 112563.
 [http://dx.doi.org/10.1016/j.biopha.2021.112563] [PMID:  35062059]

[14]
Hedrington, M.S.; Davis, S.N. Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes. Expert Opin. Pharmacother.,  2019, 20(18), 2229-2235.
 [http://dx.doi.org/10.1080/14656566.2019.1672660] [PMID:  31593486]

[15]
Deacon, C.F. Dipeptidyl peptidase 4 inhibitors in the treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol.,  2020, 16(11), 642-653.
 [http://dx.doi.org/10.1038/s41574-020-0399-8] [PMID:  32929230]

[16]
Wu, J.X.; Ding, D.; Wang, M.; Chen, L. Structural insights into the inhibitory mechanism of insulin secretagogues on the pancreatic ATP-sensitive potassium channel. Biochemistry,  2020, 59(1), 18-25.
 [http://dx.doi.org/10.1021/acs.biochem.9b00692] [PMID:  31566370]

[17]
Frkic, R.L.; Richter, K.; Bruning, J.B. The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes. J. Biol. Chem.,  2021, 297(3), 101030.
 [http://dx.doi.org/10.1016/j.jbc.2021.101030] [PMID:  34339734]

[18]
Palmer, S.C.; Tendal, B.; Mustafa, R.A.; Vandvik, P.O.; Li, S.; Hao, Q.; Tunnicliffe, D.; Ruospo, M.; Natale, P.; Saglimbene, V.; Nicolucci, A.; Johnson, D.W.; Tonelli, M.; Rossi, M.C.; Badve, S.V.; Cho, Y.; Nadeau-Fredette, A.C.; Burke, M.; Faruque, L.I.; Lloyd, A.; Ahmad, N.; Liu, Y.; Tiv, S.; Millard, T.; Gagliardi, L.; Kolanu, N.; Barmanray, R.D.; McMorrow, R.; Raygoza Cortez, A.K.; White, H.; Chen, X.; Zhou, X.; Liu, J.; Rodríguez, A.F.; González-Colmenero, A.D.; Wang, Y.; Li, L.; Sutanto, S.; Solis, R.C.; Díaz González-Colmenero, F.; Rodriguez-Gutierrez, R.; Walsh, M.; Guyatt, G.; Strippoli, G.F.M. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials. BMJ,  2021, 372, m4573.
 [http://dx.doi.org/10.1136/bmj.m4573] [PMID:  33441402]

[19]
Barbieri, M.; Cataldo, V.; Griffing, G.T.; Paolisso, G. New therapies for diabetes mellitus. Pathy’s Princi. Pract. Geri. Medi.,  2022, 2, 1108-1122.
 [http://dx.doi.org/10.1002/9781119484288.ch87]

[20]
Dungan, K. Amylin analogs for the treatment of diabetes mellitus.In: UpToDate; Basow, DS., Ed.; Waltham, MA, 2019; 11, pp. 12-19; 

[21]
Sauer, S. Ligands for the nuclear peroxisome proliferator-activated receptor gamma. Trends Pharmacol. Sci.,  2015, 36(10), 688-704.
 [http://dx.doi.org/10.1016/j.tips.2015.06.010] [PMID:  26435213]

[22]
Janani, C.; Ranjitha Kumari, B.D. PPAR gamma gene-a review. Diabetes Metab. Syndr.,  2015, 9(1), 46-50.
 [http://dx.doi.org/10.1016/j.dsx.2014.09.015] [PMID:  25450819]

[23]
Devchand, P.R.; Liu, T.; Altman, R.B.; FitzGerald, G.A.; Schadt, E.E. The pioglitazone trek via human PPAR gamma: From discovery to a medicine at the FDA and beyond. Front. Pharmacol.,  2018, 9, 1093.
 [http://dx.doi.org/10.3389/fphar.2018.01093] [PMID:  30337873]

[24]
Vaishnav, Y.; Dewangan, D.; Verma, S.; Mishra, A.; Thakur, A.S.; Kashyap, P.; Verma, S.K. PPAR gamma targeted molecular docking and synthesis of some new amide and urea substituted 1, 3, 4‐thiadiazole derivative as antidiabetic compound. J. Heterocycl. Chem.,  2020, 57(5), 2213-2224.
 [http://dx.doi.org/10.1002/jhet.3941]

[25]
Neyadi, S.S.A.; Adem, A.; Amir, N.; Abdou, I.M. Targeting PPAR<i>γ</i> Receptor using new phosphazene derivative containing thiazolidinedione: Design, synthesis, and glucose uptake. Open J. Med. Chem.,  2020, 10(2), 35-45.
 [http://dx.doi.org/10.4236/ojmc.2020.102003]

[26]
Kaur, P.; Bhat, Z.R.; Bhat, S.; Kumar, R.; Kumar, R.; Tikoo, K.; Gupta, J.; Khurana, N.; Kaur, J.; Khatik, G.L. Synthesis and evaluation of new 1,2,4-oxadiazole based trans- acrylic acid derivatives as potential PPAR-alpha/gamma dual agonist. Bioorg. Chem.,  2020, 100, 103867.
 [http://dx.doi.org/10.1016/j.bioorg.2020.103867] [PMID:  32353564]

[27]
Ren, Q.; Deng, L.; Zhou, Z.; Wang, X.; Hu, L.; Xie, R.; Li, Z. Design, synthesis, and biological evaluation of novel dual PPARα/δ agonists for the treatment of T2DM. Bioorg. Chem.,  2020, 101, 103963.
 [http://dx.doi.org/10.1016/j.bioorg.2020.103963] [PMID:  32480174]

[28]
Álvarez-Almazán, S.; Navarrete-Vázquez, G.; Padilla-Martínez, I.I.; Correa-Basurto, J.; Alemán-González-Duhart, D.; Tamay-Cach, F.; Mendieta-Wejebe, J.E. A new symmetrical thiazolidinedione derivative: In silico design, synthesis, and in vivo evaluation on a streptozotocin-induced rat model of diabetes. Processes,  2021, 9(8), 1294.
 [http://dx.doi.org/10.3390/pr9081294]

[29]
Sun, J.; Liu, H.Y.; Zhang, Y.H.; Fang, Z.Y.; Lv, P.C. Design, synthesis and bioactivity evaluation of thiazolidinedione derivatives as partial agonists targeting PPARγ. Bioorg. Chem.,  2021, 116, 105342.
 [http://dx.doi.org/10.1016/j.bioorg.2021.105342] [PMID:  34536928]

[30]
Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia,  2017, 60(9), 1577-1585.
 [http://dx.doi.org/10.1007/s00125-017-4342-z] [PMID:  28776086]

[31]
Umezawa, S.; Higurashi, T.; Nakajima, A. AMPK: Therapeutic target for diabetes and cancer prevention. Curr. Pharm. Des.,  2017, 23(25), 3629-3644.
 [PMID:  28714409]

[32]
Di Magno, L.; Di Pastena, F.; Bordone, R.; Coni, S.; Canettieri, G. The mechanism of action of biguanides: New answers to a complex question. Cancer,  2022, 14(13), 3220.
 [http://dx.doi.org/10.3390/cancers14133220] [PMID:  35804992]

[33]
Zhu, P.; Huang, W.; Li, J.; Ma, X.; Hu, M.; Wang, Y.; Xu, Q.; Wang, X. Design, synthesis chalcone derivatives as AdipoR agonist for type 2 diabetes. Chem. Biol. Drug Des.,  2018, 92(2), 1525-1536.
 [http://dx.doi.org/10.1111/cbdd.13319] [PMID:  29704399]

[34]
Ren, T.; Zhu, Y.; Kan, J. Zanthoxylum alkylamides activate phosphorylated AMPK and ameliorate glycolipid metabolism in the streptozotocin-induced diabetic rats. Clin. Exp. Hypertens.,  2017, 39(4), 330-338.
 [http://dx.doi.org/10.1080/10641963.2016.1259332] [PMID:  28513282]

[35]
Gu, Z.; Wu, L.; Duan, Y.; Wang, J.; Zhou, S.; Li, J.; Chen, K.; Li, J.; Liu, H. Design, synthesis, and structure-activity relationships of novel 4,7,12,12a-tetrahydro-5H-thieno[3′2′3,4]pyrido[1,2-b]isoquinoline and 5,8,12,12a-tetrahydro-6Hthieno[2′3′4,5]pyrido[2,1-a]isoquinoline derivatives as cellular activators of adenosine 5′-monophosphate-activated protein kinase (AMPK). Bioorg. Med. Chem.,  2018, 26(8), 2017-2027.
 [http://dx.doi.org/10.1016/j.bmc.2018.02.052] [PMID:  29545016]

[36]
Lu, Y.; Yao, J.; Gong, C.; Wang, B.; Zhou, P.; Zhou, S.; Yao, X. Gentiopicroside ameliorates diabetic peripheral neuropathy by modulating PPAR-Γ/AMPK/ACC signaling pathway. Cell. Physiol. Biochem.,  2018, 50(2), 585-596.
 [http://dx.doi.org/10.1159/000494174] [PMID:  30308492]

[37]
Liu, Y.; Deng, J.; Fan, D. Ginsenoside Rk3 ameliorates high-fat-diet/streptozocin induced type 2 diabetes mellitus in mice via the AMPK/Akt signaling pathway. Food Funct.,  2019, 10(5), 2538-2551.
 [http://dx.doi.org/10.1039/C9FO00095J] [PMID:  30993294]

[38]
Li, Y.; Liu, Y.; Liang, J.; Wang, T.; Sun, M.; Zhang, Z. Gymnemic acid ameliorates hyperglycemia through PI3K/AKT-and AMPK-mediated signaling pathways in type 2 diabetes mellitus rats. J. Agric. Food Chem.,  2019, 67(47), 13051-13060.
 [http://dx.doi.org/10.1021/acs.jafc.9b04931] [PMID:  31609623]

[39]
Jayachandran, M.; Wu, Z.; Ganesan, K.; Khalid, S.; Chung, S.M.; Xu, B. Isoquercetin upregulates antioxidant genes, suppresses inflammatory cytokines and regulates AMPK pathway in streptozotocin-induced diabetic rats. Chem. Biol. Interact.,  2019, 303, 62-69.
 [http://dx.doi.org/10.1016/j.cbi.2019.02.017] [PMID:  30817903]

[40]
Lu, X.; Wu, F.; Jiang, M.; Sun, X.; Tian, G. Curcumin ameliorates gestational diabetes in mice partly through activating AMPK. Pharm. Biol.,  2019, 57(1), 250-254.
 [http://dx.doi.org/10.1080/13880209.2019.1594311] [PMID:  30957612]

[41]
Tahrani, A.A.; Barnett, A.H.; Bailey, C.J. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat. Rev. Endocrinol.,  2016, 12(10), 566-592.
 [http://dx.doi.org/10.1038/nrendo.2016.86] [PMID:  27339889]

[42]
Grant, J.S.; Graven, L.J. Progressing from metformin to sulfonylureas or meglitinides. Workplace Health Saf.,  2016, 64(9), 433-439.
 [http://dx.doi.org/10.1177/2165079916644263] [PMID:  27621259]

[43]
Timmons; Boyle, J. Sulfonylureas and Meglitinides; Diabetes Drug Notes. 2022,  pp. 49-66.

[44]
Nauck, M.A.; Meier, J.J. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol.,  2016, 4(6), 525-536.
 [http://dx.doi.org/10.1016/S2213-8587(15)00482-9] [PMID:  26876794]

[45]
Boer, G.A.; Holst, J.J. Incretin hormones and type 2 diabetes—mechanistic insights and therapeutic approaches. Biology,  2020, 9(12), 473.
 [http://dx.doi.org/10.3390/biology9120473] [PMID:  33339298]

[46]
Seino, Y.; Kuwata, H.; Yabe, D. Incretin‐based drugs for type 2 diabetes: Focus on east asian perspectives. J. Diabetes Investig.,  2016, 7(S1)(Suppl. 1), 102-109.
 [http://dx.doi.org/10.1111/jdi.12490] [PMID:  27186364]

[47]
Andreadis, P.; Karagiannis, T.; Malandris, K.; Avgerinos, I.; Liakos, A.; Manolopoulos, A.; Bekiari, E.; Matthews, D.R.; Tsapas, A. Semaglutide for type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Obes. Metab.,  2018, 20(9), 2255-2263.
 [http://dx.doi.org/10.1111/dom.13361] [PMID:  29756388]

[48]
Chavda, V.P.; Ajabiya, J.; Teli, D.; Bojarska, J.; Apostolopoulos, V. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: A mini-review. Molecules,  2022, 27(13), 4315.
 [http://dx.doi.org/10.3390/molecules27134315] [PMID:  35807558]

[49]
Gallwitz, B. Clinical use of DPP-4 inhibitors. Front. Endocrinol.,  2019, 10, 389.
 [http://dx.doi.org/10.3389/fendo.2019.00389] [PMID:  31275246]

[50]
Makrilakis, K. The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: When to select, what to expect. Int. J. Environ. Res. Public Health,  2019, 16(15), 2720.
 [http://dx.doi.org/10.3390/ijerph16152720] [PMID:  31366085]

[51]
Luo, N.; Fang, X.; Su, M.; Zhang, X.; Li, D.; Li, H.; Li, S.; Zhao, Z. Design, synthesis and SAR studies of novel and potent Dipeptidyl Peptidase 4 inhibitors. Chin. J. Chem.,  2021, 39(1), 115-120.
 [http://dx.doi.org/10.1002/cjoc.202000342]

[52]
Dastjerdi, H.F.; Naderi, N.; Nematpour, M.; Rezaee, E.; Mahboubi-Rabbani, M.; Ebrahimi, M.; Hosseinipoor, S.; Hosseini, O.; Tabatabai, S.A. Design, synthesis and anti-diabetic activity of novel 1, 2, 3-triazole-5-carboximidamide derivatives as dipeptidyl peptidase-4 inhibitors. J. Mol. Struct.,  2020, 1221, 128745.
 [http://dx.doi.org/10.1016/j.molstruc.2020.128745]

[53]
Zhang, C.; Ye, F.; Wang, J.; He, P.; Lei, M.; Huang, L.; Huang, A.; Tang, P.; Lin, H.; Liao, Y.; Liang, Y.; Ni, J.; Yan, P. Design, synthesis, and evaluation of a series of novel super long-acting DPP-4 inhibitors for the treatment of type 2 diabetes. J. Med. Chem.,  2020, 63(13), 7108-7126.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c00374] [PMID:  32452679]

[54]
Emami, L.; Faghih, Z.; Sakhteman, A.; Rezaei, Z.; Faghih, Z.; Salehi, F.; Khabnadideh, S. Design, synthesis, molecular simulation, and biological activities of novel quinazolinone-pyrimidine hybrid derivatives as dipeptidyl peptidase-4 inhibitors and anticancer agents. New J. Chem.,  2020, 44(45), 19515-19531.
 [http://dx.doi.org/10.1039/D0NJ03774E]

[55]
Sever, B.; Soybir, H.; Görgülü, Ş.; Cantürk, Z.; Altıntop, M.D. Pyrazole incorporated new thiosemicarbazones: Design, synthesis and investigation of DPP-4 inhibitory effects. Molecules,  2020, 25(21), 5003.
 [http://dx.doi.org/10.3390/molecules25215003] [PMID:  33126761]

[56]
Narsimha, S.; Battula, K.S.; Ravinder, M.; Reddy, Y.N.; Nagavelli, V.R. Design, synthesis and biological evaluation of novel 1,2,3-triazole-based xanthine derivatives as DPP-4 inhibitors. J. Chem. Sci.,  2020, 132(1), 59.
 [http://dx.doi.org/10.1007/s12039-020-1760-0]

[57]
Syam, Y.M.; Anwar, M.M.; Abd El-Karim, S.S.; Elseginy, S.A.; Essa, B.M.; Sakr, T.M. New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: Design, synthesis, computational and bio-distribution studies. RSC Advances,  2021, 11(58), 36989-37010.
 [http://dx.doi.org/10.1039/D1RA06799K] [PMID:  35494381]

[58]
Fuh, M.T.; Tseng, C.C.; Li, S.M.; Tsai, S.E.; Chuang, T.J.; Lu, C.H.; Yang, Y.C.; Tsai, H.J.; Wong, F.F. Design, synthesis and biological evaluation of glycolamide, glycinamide, and β-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors. Bioorg. Chem.,  2021, 114, 105049.
 [http://dx.doi.org/10.1016/j.bioorg.2021.105049] [PMID:  34147879]

[59]
Mourad, A.A.E.; Khodir, A.E.; Saber, S.; Mourad, M.A.E. Novel potent and selective DPP-4 inhibitors: Design, synthesis and molecular docking study of Dihydropyrimidine Phthalimide hybrids. Pharmaceuticals,  2021, 14(2), 144.
 [http://dx.doi.org/10.3390/ph14020144] [PMID:  33670273]

[60]
Lee, Y.H.; Wang, M.Y.; Yu, X.X.; Unger, R.H. Glucagon is the key factor in the development of diabetes. Diabetologia,  2016, 59(7), 1372-1375.
 [http://dx.doi.org/10.1007/s00125-016-3965-9] [PMID:  27115412]

[61]
Okamoto, H.; Cavino, K.; Na, E.; Krumm, E.; Kim, S.Y.; Cheng, X.; Murphy, A.J.; Yancopoulos, G.D.; Gromada, J. Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice. Proc. Natl. Acad. Sci. USA,  2017, 114(10), 2753-2758.
 [http://dx.doi.org/10.1073/pnas.1621069114] [PMID:  28115707]

[62]
Thilagavathi, R.; Hosseini-Zare, M.S.; Malini, M.; Selvam, C. A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes. Chem. Biol. Drug Des.,  2022, 99(2), 247-263.
 [http://dx.doi.org/10.1111/cbdd.13979] [PMID:  34714587]

[63]
Charaya, N.; Pandita, D.; Grewal, A.S.; Lather, V. Design, synthesis and biological evaluation of novel thiazol-2-yl benzamide derivatives as glucokinase activators. Comput. Biol. Chem.,  2018, 73, 221-229.
 [http://dx.doi.org/10.1016/j.compbiolchem.2018.02.018] [PMID:  29518630]

[64]
Grewal, A.S.; Sharma, K.; Singh, S.; Singh, V.; Pandita, D.; Lather, V. Design, synthesis and antidiabetic activity of novel sulfamoyl benzamide derivatives as glucokinase activators. J. Adv. Pharm. Technol. Res. Manage.,  2018, 6(2), 115-124.

[65]
Khadse, S.C.; Amnerkar, N.D.; Dighole, K.S.; Dhote, A.M.; Patil, V.R.; Lokwani, D.K.; Ugale, V.G.; Charbe, N.B.; Chatpalliwar, V.A. Hetero-substituted sulfonamido-benzamide hybrids as glucokinase activators: Design, synthesis, molecular docking and in-silico ADME evaluation. J. Mol. Struct.,  2020, 1222, 128916.
 [http://dx.doi.org/10.1016/j.molstruc.2020.128916]

[66]
Singh Grewal, A.; Bhardwaj, S.; Pandita, D.; Lather, V.; Singh Sekhon, B. Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini Rev. Med. Chem.,  2015, 16(2), 120-162.
 [http://dx.doi.org/10.2174/1389557515666150909143737] [PMID:  26349493]

[67]
Thakur, S.; Gupta, S.K.; Ali, V.; Singh, P.; Verma, M. Aldose Reductase: A cause and a potential target for the treatment of diabetic complications. Arch. Pharm. Res.,  2021, 44(7), 655-667.
 [http://dx.doi.org/10.1007/s12272-021-01343-5] [PMID:  34279787]

[68]
ElGamal, H.; Munusamy, S. Aldose reductase as a drug target for treatment of diabetic nephropathy: Promises and challenges. Protein Pept. Lett.,  2017, 24(1), 71-77.
 [PMID:  27894247]

[69]
Bonora, B.M.; Avogaro, A.; Fadini, G.P. Extraglycemic effects of SGLT2 inhibitors: A review of the evidence. Diabetes Metab. Syndr. Obes.,  2020, 13, 161-174.
 [http://dx.doi.org/10.2147/DMSO.S233538] [PMID:  32021362]

[70]
Dardi, I.; Kouvatsos, T.; Jabbour, S.A. SGLT2 inhibitors. Biochem. Pharmacol.,  2016, 101, 27-39.
 [http://dx.doi.org/10.1016/j.bcp.2015.09.005] [PMID:  26362302]

[71]
Triplitt, C.; Cornell, S. Canagliflozin treatment in patients with type 2 diabetes mellitus. Clin. Med. Insi.: Endocrinology and. Diabetes,  2015, 8, 73-81.
 [http://dx.doi.org/10.4137/CMED.S31526]

[72]
Hossain, U.; Das, A.K.; Ghosh, S.; Sil, P.C. An overview on the role of bioactive α-glucosidase inhibitors in ameliorating diabetic complications. Food Chem. Toxicol.,  2020, 145, 111738.
 [http://dx.doi.org/10.1016/j.fct.2020.111738] [PMID:  32916220]

[73]
Dirir, A.M.; Daou, M.; Yousef, A.F.; Yousef, L.F. A review of alpha-glucosidase inhibitors from plants as potential candidates for the treatment of type-2 diabetes. Phytochem. Rev.,  2022, 21(4), 1049-1079.
 [http://dx.doi.org/10.1007/s11101-021-09773-1] [PMID:  34421444]

[74]
Hieronymus, L.; Griffin, S. Role of amylin in type 1 and type 2 diabetes. Diabetes Educ.,  2015, 41(1)(Suppl.), 47S-56S.
 [http://dx.doi.org/10.1177/0145721715607642] [PMID:  26424675]

[75]
Gadde, K.M.; Allison, D.B. Long-acting amylin analogue for weight reduction. Lancet,  2021, 398(10317), 2132-2134.
 [http://dx.doi.org/10.1016/S0140-6736(21)01999-1] [PMID:  34798059]

[76]
Kruse, T.; Hansen, J.L.; Dahl, K.; Schäffer, L.; Sensfuss, U.; Poulsen, C.; Schlein, M.; Hansen, A.M.K.; Jeppesen, C.B.; Dornonville de la Cour, C.; Clausen, T.R.; Johansson, E.; Fulle, S.; Skyggebjerg, R.B.; Raun, K. Development of cagrilintide, a long-acting amylin analogue. J. Med. Chem.,  2021, 64(15), 11183-11194.
 [http://dx.doi.org/10.1021/acs.jmedchem.1c00565] [PMID:  34288673]

[77]
Schwartz, S.S.; Zangeneh, F. Evidence-based practice use of quick-release bromocriptine across the natural history of type 2 diabetes mellitus. Postgrad. Med.,  2016, 128(8), 828-838.
 [http://dx.doi.org/10.1080/00325481.2016.1214059] [PMID:  27458683]

[78]
Kabir, M.T.; Ferdous Mitu, J.; Akter, R.; Akhtar, M.F.; Saleem, A.; Al-Harrasi, A.; Bhatia, S.; Rahman, M.S.; Damiri, F.; Berrada, M.; Rahman, M.H. Therapeutic potential of dopamine agonists in the treatment of type 2 diabetes mellitus. Environ. Sci. Pollut. Res. Int.,  2022, 29(31), 46385-46404.
 [http://dx.doi.org/10.1007/s11356-022-20445-1] [PMID:  35486279]

[79]
Kerru, N.; Singh-Pillay, A.; Awolade, P.; Singh, P. Current anti-diabetic agents and their molecular targets: A review. Eur. J. Med. Chem.,  2018, 152, 436-488.
 [http://dx.doi.org/10.1016/j.ejmech.2018.04.061] [PMID:  29751237]

[80]
Oh, D.Y.; Olefsky, J.M. G protein-coupled receptors as targets for anti-diabetic therapeutics. Nat. Rev. Drug Discov.,  2016, 15(3), 161-172.
 [http://dx.doi.org/10.1038/nrd.2015.4] [PMID:  26822831]

[81]
An, K.M.; Hong, C.H.; Kwak, H.J.; Cui, S.; Song, H.J.; Park, J.T.; Moon, A.N.; Kim, J.A.; Yang, J.H.; Yoon, J.; Lee, M.J.; Jeong, D-G.; Kim, D.; Lee, D-G.; Shin, J.C.; Je, I-G.; Lee, H-S.; Park, S.; Kang, J-H.; Ko, S.Y. Discovery of 2,3-Dihydro-1 H -indene derivatives as novel GPR40 agonists. Bull. Korean Chem. Soc.,  2017, 38(8), 861-868.
 [http://dx.doi.org/10.1002/bkcs.11185]

[82]
Chen, H.Y.; Plummer, C.W.; Xiao, D.; Chobanian, H.R.; DeMong, D.; Miller, M.; Trujillo, M.E.; Kirkland, M.; Kosinski, D.; Mane, J.; Pachanski, M.; Cheewatrakoolpong, B.; Di Salvo, J.; Thomas-Fowlkes, B.; Souza, S.; Tatosian, D.A.; Chen, Q.; Hafey, M.J.; Houle, R.; Nolting, A.F.; Orr, R.; Ehrhart, J.; Weinglass, A.B.; Tschirret-Guth, R.; Howard, A.D.; Colletti, S.L. Structure–activity relationship of novel and selective Biaryl-Chroman GPR40 AgoPAMs. ACS Med. Chem. Lett.,  2018, 9(7), 685-690.
 [http://dx.doi.org/10.1021/acsmedchemlett.8b00149] [PMID:  30034601]

[83]
Jiang, X.W.; Jiang, B.E.; Liu, H.; Liu, Z.T.; Hu, L.L.; Liu, M.; Lu, W.; Zhang, H.K. Design, synthesis, and biological evaluations of phenylpropiolic acid derivatives as novel GPR40 agonists. Eur. J. Med. Chem.,  2018, 158, 123-133.
 [http://dx.doi.org/10.1016/j.ejmech.2018.08.075] [PMID:  30212763]

[84]
Li, Z.; Xu, X.; Hou, J.; Wang, S.; Jiang, H.; Zhang, L. Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold. Bioorg. Chem.,  2018, 77, 429-435.
 [http://dx.doi.org/10.1016/j.bioorg.2018.01.039] [PMID:  29433092]

[85]
Furukawa, H.; Miyamoto, Y.; Hirata, Y.; Watanabe, K.; Hitomi, Y.; Yoshitomi, Y.; Aida, J.; Noguchi, N.; Takakura, N.; Takami, K.; Miwatashi, S.; Hirozane, Y.; Hamada, T.; Ito, R.; Ookawara, M.; Moritoh, Y.; Watanabe, M.; Maekawa, T. Design and identification of a GPR40 full agonist (SCO-267) possessing a 2-carbamoylphenyl piperidine moiety. J. Med. Chem.,  2020, 63(18), 10352-10379.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c00843] [PMID:  32900194]

[86]
Ye, Z.; Liu, C.; Zou, F.; Cai, Y.; Chen, B.; Zou, Y.; Mo, J.; Han, T.; Huang, W.; Qiu, Q.; Qian, H. Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents. Bioorg. Med. Chem.,  2020, 28(13), 115574.
 [http://dx.doi.org/10.1016/j.bmc.2020.115574] [PMID:  32546302]

[87]
Zhao, X.; Yoon, D.O.; Yoo, J.; Park, H.J. Structure–activity relationship study and biological evaluation of 2-(Disubstituted phenyl)-indole-5-propanoic acid derivatives as GPR40 full agonists. J. Med. Chem.,  2021, 64(7), 4130-4149.
 [http://dx.doi.org/10.1021/acs.jmedchem.1c00031] [PMID:  33769827]

[88]
Zhou, Y.; Zhu, X.; Zhang, L.; Tang, C.; Feng, B. Design, synthesis, and biological evaluation of 2-(4-(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists. Chem. Biol. Drug Des.,  2019, 93(1), 67-74.
 [http://dx.doi.org/10.1111/cbdd.13380] [PMID:  30120879]

[89]
Matsuda, D.; Kawamura, M.; Kobashi, Y.; Shiozawa, F.; Suga, Y.; Fusegi, K.; Nishimoto, S.; Kimura, K.; Miyoshi, M.; Takayama, N.; Kakinuma, H.; Ohtake, N. Design, synthesis and biological evaluation of novel 7-azaspiro[3.5]nonane derivatives as GPR119 agonists. Bioorg. Med. Chem.,  2018, 26(8), 1832-1847.
 [http://dx.doi.org/10.1016/j.bmc.2018.02.032] [PMID:  29486951]

[90]
Mach, M.; Bazydło-Guzenda, K.; Buda, P.; Matłoka, M.; Dzida, R.; Stelmach, F.; Gałązka, K.; Wąsińska-Kałwa, M.; Smuga, D.; Hołowińska, D.; Dawid, U.;  Gurba-Bryśkiewicz, L.; Wiśniewski, K.; Pieczykolan, J.; Wieczorek, M. Discovery and development of CPL207280 as new GPR40/FFA1 agonist. Eur. J. Med. Chem.,  2021, 226, 113810.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113810] [PMID:  34537444]

[91]
Kubo, O.; Takami, K.; Kamaura, M.; Watanabe, K.; Miyashita, H.; Abe, S.; Matsuda, K.; Tsujihata, Y.; Odani, T.; Iwasaki, S.; Kitazaki, T.; Murata, T.; Sato, K. Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives. Bioorg. Med. Chem.,  2021, 41, 116208.
 [http://dx.doi.org/10.1016/j.bmc.2021.116208] [PMID:  34010766]

[92]
Kyriakis, E.; Solovou, T.G.A.; Kun, S.; Czifrák, K.; Szőcs, B.; Juhász, L.; Bokor, É.; Stravodimos, G.A; Kantsadi, A.L; Chatzileontiadou, D.S.M; Skamnaki, V.T.; Somsák, L.; Leonidas, D.D  Probing the β-pocket of the active site of human liver glycogen phosphorylase with 3-(C-β-d-glucopyranosyl)-5-(4-substituted-phenyl)-1, 2, 4-triazole inhibitors. Bioorg. Chem.,  2018, 77, 485-493.
 [http://dx.doi.org/10.1016/j.bioorg.2018.02.008] [PMID:  29454281]

[93]
Szabó, K.E.; Kyriakis, E.; Psarra, A.M.G.; Karra, A.G.; Sipos, Á.; Docsa, T.; Stravodimos, G.A.; Katsidou, E.; Skamnaki, V.T.; Liggri, P.G.V.; Zographos, S.E.; Mándi, A.; Király, S.B.; Kurtán, T.; Leonidas, D.D.; Somsák, L. Glucopyranosylidene-spiro-imidazolinones, a new ring system: Synthesis and evaluation as glycogen phosphorylase inhibitors by enzyme kinetics and X-ray crystallography. J. Med. Chem.,  2019, 62(13), 6116-6136.
 [http://dx.doi.org/10.1021/acs.jmedchem.9b00356] [PMID:  31251604]

[94]
Kattimani, P.P.; Somagond, S.M.; Bayannavar, P.K.; Kamble, R.R.; Bijjaragi, S.C.; Hunnur, R.K.; Joshi, S.D. Novel 5‐(1‐aryl‐1 H ‐pyrazol‐3‐yl)‐1 H ‐tetrazoles as glycogen phosphorylase inhibitors: An in vivo antihyperglycemic activity study. Drug Dev. Res.,  2020, 81(1), 70-84.
 [http://dx.doi.org/10.1002/ddr.21606] [PMID:  31696542]

[95]
Chetter, B.A.; Kyriakis, E.; Barr, D.; Karra, A.G.; Katsidou, E.; Koulas, S.M.; Skamnaki, V.T.; Snape, T.J.; Psarra, A.M.G.; Leonidas, D.D.; Hayes, J.M. Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors. Bioorg. Chem.,  2020, 102, 104003.
 [http://dx.doi.org/10.1016/j.bioorg.2020.104003] [PMID:  32771768]

[96]
Miao, G.; Wang, Y.; Yan, Z.; Zhang, L. Synthesis, in vitro ADME profiling and in vivo pharmacological evaluation of novel glycogen phosphorylase inhibitors. Bioorg. Med. Chem. Lett.,  2020, 30(14), 127117.
 [http://dx.doi.org/10.1016/j.bmcl.2020.127117] [PMID:  32527535]

[97]
Goyard, D.; Kónya, B.; Czifrák, K.; Larini, P.; Demontrond, F.; Leroy, J.; Balzarin, S.; Tournier, M.; Tousch, D.; Petit, P.; Duret, C.; Maurel, P.; Docsa, T.; Gergely, P.; Somsák, L.; Praly, J.P.; Azay-Milhau, J.; Vidal, S. Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition. Org. Biomol. Chem.,  2020, 18(5), 931-940.
 [http://dx.doi.org/10.1039/C9OB01190K] [PMID:  31922157]

[98]
Xu, Y.; Huang, Y.; Song, R.; Ren, Y.; Chen, X.; Zhang, C.; Mao, F.; Li, X.; Zhu, J.; Ni, S.; Wan, J.; Li, J. Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes. Eur. J. Med. Chem.,  2020, 203, 112500.
 [http://dx.doi.org/10.1016/j.ejmech.2020.112500] [PMID:  32711108]

[99]
Han, X.; Huang, Y.; Wei, L.; Chen, H.; Guo, Y.; Tang, Z.; Hu, W.; Xia, Q.; Wang, Q.; Yan, J.; Ren, Y. Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase. Bioorg. Med. Chem.,  2020, 28(18), 115624.
 [http://dx.doi.org/10.1016/j.bmc.2020.115624] [PMID:  32828433]

[100]
Huang, Y.; Xu, Y.; Song, R.; Ni, S.; Liu, J.; Xu, Y.; Ren, Y.; Rao, L.; Wang, Y.; Wei, L.; Feng, L.; Su, C.; Peng, C.; Li, J.; Wan, J. Identification of the new covalent allosteric binding site of Fructose-1,6-bisphosphatase with disulfiram derivatives toward glucose reduction. J. Med. Chem.,  2020, 63(11), 6238-6247.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c00699] [PMID:  32375478]
Rights & Permissions Print Cite
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1389557523666230517113936	Print ISSN 1389-5575
Publisher Name Bentham Science Publisher	Online ISSN 1875-5607
Mini-Reviews in Medicinal Chemistry

An Insight into the Combat Strategies for the Treatment of Type 2 Diabetes Mellitus

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
