Recent Developments in Diabetes Management: Exploring Receptors, Pathways, and Compounds

Abstract

Diabetes mellitus (DM) is a widespread metabolic disorder with profound effects on vital organs. Often referred to as a “systemic” or “multi-organ” disorder due to the impact on key organs, such as the kidneys, pancreas, eyes, and heart, DM is characterized by elevated blood glucose levels due to insufficient insulin production. DM consists of three subtypes (type 1 DM, type 2 DM, and gestational DM). Approximately 537 million adults are living with DM, a number predicted to increase to 643 million by 2030, according to the International Diabetes Federation (IDF) data. With the rising prevalence of DM, the Pan American Health Organization and World Health Organization estimate an age-standardized mortality rate of 20.9 deaths per 100,000 people. Therefore, it is important to study the prevention and cure of DM and determine the underlying mechanism and regulation. Numerous receptors and pathways help to regulate DM. This article delves into the intricate regulatory mechanisms underlying DM involving receptors and pathways, such as K_ATP (sulfonylurea), 5′AMP-activated protein kinase enzyme (biguanides), PPAR gamma, alpha-glucosidase, Glucose transporters (GLUT4), dipeptide peptidase-4 (DPP-4), and sodium-glucose co-transporters type 2 (SGLT2). The article highlights recent advances from 2020–2024 in synthesizing compounds targeting specific receptors for diabetes management. In so doing, insights into newly synthesized compounds, marketed drugs, phytoconstituents, and drugs currently in clinical trials will be provided. The role of each receptor in maintaining glucose homeostasis is reviewed in detail and various compounds with potential as effective antidiabetic agents are evaluated. This comprehensive review presents the pharmacologic mechanisms underlying these receptors and an in-depth analysis of promising new drug candidates.

Keywords

biguanides / DM / DPP-4 / GLUT4 / PPARγ / SGLT2 / sulfonylureas

References

[1] Matoori S. Diabetes and its complications. ACS Pharmacol Transl Sci 2022; 5(8): 513- 5. [DOI: 10.1021/acsptsci.2c00122]

[2] Pal D, Kumar S, Saha S. Antihyperglycemic activity of phenyl and ortho-hydroxy phenyl linked imidazolyl triazolo hydroxamic acid derivatives. Int J Pharm Pharm Sci 2017; 9(12): 247-51. [DOI: 10.22159/ijpps.2017v9i12.22086]

[3] Pories WJ, Albrecht RJ. Etiology of type II diabetes mellitus: role of the foregut. World J Surg 2001; 25(4): 527-31. [PMID: 11344408 DOI: 10.1007/s002680020348]

[4] Mishra V, Nayak P, Sharma M, Albutti A, Alwashmi AS, et al. Emerging treatment strategies for diabetes mellitus and associated complications: an update. Pharmaceutics 2021; 13(10): 1568. [PMID: 34683861 DOI: 10.3390/pharmaceutics13101568]

[5] IDF Diabetes Atlas, 10^th edition 2022. Available from: https://diabetesatlas.org/ [accessed on 31 July 2023].

[6] Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, et al. Type 1 diabetes mellitus. Nat Rev Dis Primers 2017; 3: 17016. [PMID: 28358037 DOI: 10.1038/nrdp.2017.16]

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

[8] American Diabetes Association . Gestational diabetes mellitus. Diabetes Care 2004; 27: S88-90. [PMID: 14693936 DOI: 10.2337/diacare.27.2007.S88]

[9] Rahati S, Shahraki M, Arjomand G, Shahraki T. Food pattern, lifestyle and diabetes mellitus. Int J High Risk Behav Addict 2014; 3(1): e8725. [PMID: 24971303 DOI: 10.5812/ijhrba.8725]

[10] Saha S, Pal D. Role of histone deacetylase inhibitors on viral replication: a review. Biointerface Res Appl Chem 2023; 13(6): 589. [DOI: 10.33263/BRIAC136.589]

[11] Haas B, Hass MDS, Voltz A, Vogel M, Walther J, et al. Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation. Mol Metab 2024; 85: 101956. [PMID: 38735390 DOI: 10.1016/j.molmet.2024.101956]

[12] Lang V, Light PE. The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes. Pharmacogenomics Pers Med 2010; 3: 145-61. [PMID: 23226049 DOI: 10.2147/PGPM.S6969]

[13] Muller AA. Managing pediatric ingestions of the new antidiabetic agents. J Emerg Nurs 2004; 30(2): 183-4. [PMID: 15039680 DOI: 10.1016/j.jen.2003.12.011]

[14] Reynaldo F, Fayed R . Religious fasting, diabetes management, and medication dosage adjustments. Medsurg Nursing 2022; 31(1): 4498. [DOI: 10.62116/msj.2022.31.1.44]

[15] Sahin I, Bakiner O, Demir T, Sari R, Atmaca A. Current position of gliclazide and sulfonylureas in the contemporary treatment paradigm for type 2 diabetes: a scoping review. Diabetes Ther 2024; 15(8): 1687-716. [PMID: 38935188 DOI: 10.1007/s13300-024-01612-8]

[16] El-Zahabi MA, Bamanie FH, Ghareeb S, Alshaeri HK, Alasmari MM, et al. Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazoline-sulfonylurea hybrids as peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) agonists. Int J Mol Sci 2022; 23(17): 9605. [PMID: 36077003 DOI: 10.3390/ijms23179605]

[17] Khamees Thabet H, Ammar YA, Imran M, Hamdy Helal M, Ibrahim Alaqel S, et al. Unveiling anti-diabetic potential of new thiazole-sulfonamide derivatives: design, synthesis, in vitro bio-evaluation targeting DPP-4, α-glucosidase, and α-amylase with in-silico ADMET and docking simulation. Bioorg Chem 2024; 151: 107671. [PMID: 39067419 DOI: 10.1016/j.bioorg.2024.107671]

[18] Ahmed A, Zaib S, Bhat MA, Saeed A, Altaf MZ, et al. Acyl pyrazole sulfonamides as new antidiabetic agents: synthesis, glucosidase inhibition studies, and molecular docking analysis. Front Chem 2024; 12: 1380523. [PMID: 38694406 DOI: 10.3389/fchem.2024.1380523]

[19] Ayoup MS, Khaled N, Abdel-Hamid H, Ghareeb DA, Nasr SA, et al. Novel sulfonamide derivatives as multitarget antidiabetic agents: design, synthesis, and biological evaluation. RSC Adv 2024; 14(11): 7664-75. [PMID: 38440282 DOI: 10.1039/D4RA01060D]

[20] Ranade SD, Alegaon SG, Khatib NA, Gharge S, Kavalapure RS, et al. Design, synthesis, molecular dynamic simulation, DFT analysis, computational pharmacology and decoding the antidiabetic molecular mechanism of sulphonamide-thiazolidin-4-one hybrids. J Mol Struct 2024; 1311: 138359. [DOI: 10.1016/j.molstruc.2024.138359]

[21] Khamees Thabet H, Ragab A, Imran M, Helal MH, Ibrahim Alaqel S, et al. Discovery of new anti-diabetic potential agents based on paracetamol incorporating sulfa-drugs: design, synthesis, α-amylase and α-glucosidase inhibitors with docking simulation. Eur J Med Chem 2024; 275: 116589. [PMID: 38878516 DOI: 10.1016/j.ejmech.2024.116589]

[22] Campbell RK, White Jr JR, Saulie BA. Metformin: a new oral biguanide. Clin Ther 1996; 18(3): 360-71. [PMID: 8829014 DOI: 10.1016/S0149-2918(96)80017-8]

[23] Bailey CJ. Metformin: effects on micro and macrovascular complications in type 2 diabetes. Cardiovasc Drugs Ther 2008; 22: 215-24. [PMID: 18288595 DOI: 10.1007/s10557-008-6092-0]

[24] Di Magno L, Di Pastena F, Bordone R, Coni S, Canettieri G. The mechanism of action of biguanides: new answers to a complex question. Cancers 2022; 14(13): 3220. [PMID: 35804992 DOI: 10.3390/cancers14133220]

[25] Yi H, Huang C, Shi Y, Cao Q, Chen J, et al. Metformin attenuates renal fibrosis in a mouse model of adenine-induced renal injury through inhibiting TGF-β1 signaling pathways. Front Cell Dev Biol 2021; 9: 603802. [PMID: 33614642 DOI: 10.3389/fcell.2021.603802]

[26] Demaré S, Kothari A, Calcutt NA, Fernyhough P. Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system. Expert Rev Neurother 2021; 21(1): 45-63. [PMID: 33161784 DOI: 10.1080/14737175.2021.1847645]

[27] Corleto KA, Strandmo JL, Giles ED. Metformin and breast cancer: current findings and future perspectives from preclinical and clinical studies. Pharmaceuticals 2024; 17(3): 396. [PMID: 38543182 DOI: 10.3390/ph17030396]

[28] Li W, Wang Y, Liu C, Yu Y, Xu L, et al. Evaluation of the regulatory effect of the pan-PPAR agonist chiglitazar on the dawn phenomenon. Diabetes Ther 2025; 16(4): 731-48. [DOI: 10.1007/s13300-025-01708-9]

[29] Barb D, Kalavalapalli S, Leiva EG, Bril F, Huot-Marchand P, et al. Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD. J Hepatol 2025. [PMID: 39824443 DOI: 10.1016/j.jhep.2024.12.045]

[30] Deeks ED. Chiglitazar: first approval. Drugs 2022; 82(1): 87-92. [PMID: 34846697 DOI: 10.1007/s40265-021-01648-1]

[31] Sheng R, Li Y, Wu Y, Liu C, Wang W, et al. A pan-PPAR agonist E17241 ameliorates hyperglycemia and diabetic dyslipidemia in KKAy mice via up-regulating ABCA1 in islet, liver, and white adipose tissue. Biomed Pharmacother 2024; 172: 116220. [PMID: 38308968 DOI: 10.1016/j.biopha.2024.116220]

[32] Iltz JL, Baker DE, Setter SM, Keith Campbell R . Exenatide: an incretin mimetic for the treatment of type 2 diabetes mellitus. Clin Ther 2006; 28(5): 652-65. [PMID: 16861088 DOI: 10.1016/j.clinthera.2006.05.006]

[33] Inoue Y, Emoto M, Inoue H, Kaku K, Kaneko T. Characterization of the binding sites for [3H]glibenclamide in rat liver membranes. Eur J Pharmacol 1995; 284(1-2): 77-82. [PMID: 8549639 DOI: 10.1016/0014-2999(95)00368-u]

[34] Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, et al. Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol 2003; 43(1): 84-91. [PMID: 12520632 DOI: 10.1177/0091270002239710]

[35] Qaoud MT, Almasri I, Önkol T. Peroxisome proliferator-activated receptors as superior targets for treating diabetic disease, design strategies - review article. Turk J Pharm Sci 2022; 19(3): 353-70. [PMID: 35775494 DOI: 10.4274/tjps.galenos.2021.70105]

[36] Bosenberg LH, Van Zyl DG. The mechanism of action of oral antidiabetic drugs: a review of recent literature. J Endocrinol Metab Diabetes South Afr 2008; 13(3): 80-8. [DOI: 10.1080/22201009.2008.10872177]

[37] Sangeetha R. Luteolin in the management of type 2 diabetes mellitus. Curr Res Nutr Food Sci J 2019; 7(2): 393-8. [DOI: 10.12944/CRNFSJ.7.2.09]

[38] Mueller M, Jungbauer A . Culinary plants, herbs and spices - a rich source of PPARγ ligands. Food Chem 2009; 117(4): 660-7. [DOI: 10.1016/j.foodchem.2009.04.063]

[39] Mueller M, Lukas B, Novak J, Simoncini T, Genazzani AR, et al. Oregano: a source for peroxisome proliferator-activated receptor γ antagonists. J Agric Food Chem 2008; 56(24): 11621-30. [PMID: 19053389 DOI: 10.1021/jf802298w]

[40] Ansari P, Choudhury ST, Seidel V, Rahman AB, Aziz MA, et al. Therapeutic potential of quercetin in the management of type-2 diabetes mellitus. Life 2022; 12(8): 1146. [PMID: 36013325 DOI: 10.3390/life12081146]

[41] Shi GJ, Li Y, Cao QH, Wu HX, Tang XY, et al. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: a systematic review of the literature. Biomed Pharmacother 2019; 109: 1085-99. [PMID: 30551359 DOI: 10.1016/j.biopha.2018.10.130]

[42] Fang XK, Gao J, Zhu DN. Kaempferol and quercetin isolated from Euonymus alatus improve glucose uptake of 3T3-L1 cells without adipogenesis activity. Life Sci 2008; 82(11-12): 615-22. [PMID: 18262572 DOI: 10.1016/j.lfs.2007.12.021]

[43] Alnuaimi S, Reljic T, Abdulla FS, Memon H, Al-Ali S, et al. PPAR agonists as add-on treatment with metformin in management of type 2 diabetes: a systematic review and meta-analysis. Sci Rep 2024; 14(1): 8809. [PMID: 38627464 DOI: 10.1038/s41598-024-59390-z]

[44] Skoczyńska A, Ołdakowska M, Dobosz A, Adamiec R, Gritskevich S, et al. PPARs in clinical experimental medicine after 35 years of Worldwide Scientific Investigations and medical experiments. Biomolecules 2024; 14(7): 786. [PMID: 39062500 DOI: 10.3390/biom14070786]

[45] Vaishnav Y, Dewangan D, Verma S, Mishra A, Thakur AS, et al. 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): 2213-24. [DOI: 10.1002/jhet.3941]

[46] Najmi A, Alam MS, Thangavel N, Taha MME, Meraya AM, et al. Synthesis, molecular docking, and in vivo antidiabetic evaluation of new benzylidene-2, 4-thiazolidinediones as partial PPAR-γ agonists. Sci Rep 2023; 13(1): 19869. [PMID: 37963936 DOI: 10.1038/s41598-023-47157-x]

[47] Al Neyadi SS, Adem A, Amir N, Abdou IM. Targeting PPARγ receptor using new phosphazene derivative containing thiazolidinedione: design, synthesis, and glucose uptake. Open J Med Chem 2020; 10(2): 35-45. [DOI: 10.4236/ojmc.2020.102003]

[48] Ali IH, Hassan RM, El Kerdawy AM, Abo-Elfadl MT, Abdallah HMI, et al. Novel thiazolidin-4-one benzenesulfonamide hybrids as PPARγ agonists: design, synthesis and in vivo anti-diabetic evaluation. Eur J Med Chem 2024; 269: 116279. [PMID: 38460271 DOI: 10.1016/j.ejmech.2024.116279]

[49] Thabet HK, Abusaif MS, Imran M, Helal MH, Alaqel SI, et al. Discovery of novel 6-(piperidin-1-ylsulfonyl)-2H-chromenes targeting α-glucosidase, α-amylase, and PPAR-γ: Design, synthesis, virtual screening, and anti-diabetic activity for type 2 diabetes mellitus. Comput Biol Chem 2024; 111: 108097. [PMID: 38772048 DOI: 10.1016/j.compbiolchem.2024.108097]

[50] Thabet HK, Ragab A, Imran M, Hamdy Helal M, Ibrahim Alaqel S, et al. Innovation of 6-sulfonamide-2 H-chromene derivatives as antidiabetic agents targeting α-amylase, α-glycosidase, and PPAR-γ inhibitors with in silico molecular docking simulation. RSC Adv 2024; 14(22): 15691-705. [PMID: 38746843 DOI: 10.1039/D4RA02143F]

[51] Patchipala SB, Pasupuleti VR, Audipudi AV, Bollikolla HB. Synthesis, in-vivo anti-diabetic & anticancer activities and molecular modelling studies of tetrahydrobenzo[d]thiazole tethered nicotinohydrazide derivatives. Arab J Chem 2022; 15(2): 103546. [DOI: 10.1016/j.arabjc.2021.103546]

[52] Fadaly WAA, Elshewy A, Nemr MTM, Abdou K, Sayed AM, et al. Discovery of novel thiazole derivatives containing pyrazole scaffold as PPAR-γ agonists, α-glucosidase, α-amylase and COX-2 inhibitors; design, synthesis and in silico study. Bioorg Chem 2024; 152: 107760. [DOI: 10.1016/j.bioorg.2024.107760]

[53] Fayed EA, Thabet A, Abd El-Gilil SM, Elsanhory HHM, Ammar YA. Fluorinated thiazole-thiosemicarbazones hybrids as potential PPAR-γ agonist and α-amylase, α-glucosidase antagonists: design, synthesis, in silico ADMET and docking studies and hypoglycemic evaluation. J Mol Struct 2024; 1301: 137374 [DOI: 10.1016/j.molstruc.2023.137374]

[54] Gharge S, Alegaon SG, Ranade SD, Khatib NA, Kavalapure RS, et al. Design, synthesis of new 2, 4-thiazolidinediones: in-silico, in-vivo anti-diabetic and anti-inflammatory evaluation. Eur J Med Chem Rep 2024; 11: 100151. [DOI: 10.1016/j.ejmcr.2024.100151]

[55] Amin S, Sheikh KA, Iqubal A, Ahmed Khan M, Shaquiquzzaman M, et al. Synthesis, in-silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent. Bioorg Chem 2023; 134: 106449. [PMID: 36889200 DOI: 10.1016/j.bioorg.2023.106449]

[56] Safithri M, Sari YP. Inhibition of α-glucosidase activity by ethanolic extract of Melia azedarach L. leaves. IOP Conf Ser Earth Environ Sci 2016; 31(1): 012025. [DOI: 10.1088/1755-1315/31/1/012025]

[57] Nakamura S, Takahira K, Tanabe G, Muraoka O, Nakanishi I. Homology modeling of human alpha-glucosidase catalytic domains and SAR study of salacinol derivatives. Open J Med Chem 2012; 2(3): 50-60. [DOI: 10.4236/ojmc.2012.23007]

[58] Mauldina MG, Sauriasari R, Elya B. α-Glucosidase inhibitory activity from ethyl acetate extract of Antidesma bunius (L.) Spreng stem bark containing triterpenoids. Pharmacogn Mag 2017; 13(52): 590-4. [PMID: 29200718 DOI: 10.4103/pm.pm_25_17]

[59] Dabhi AS, Bhatt NR, Shah MJ. Voglibose: an alpha glucosidase inhibitor. J Clin Diagn Res 2013; 7(12): 3023- 7. [PMID: 24551718 DOI: 10.7860/JCDR/2013/6373.3838]

[60] Xie X, Wu C, Hao Y, Wang T, Yang Y, et al. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol 2023; 14: 1301093. [DOI: 10.3389/fendo.2023.1301093]

[61] Broome DT, Kodali A, Phillips D, Makin V, Mendlovic D, et al. Combined dipeptidyl peptidase 4 inhibitor and α-glucosidase inhibitor treatment in postprandial hypoglycemia. Clin Diabetes 2022; 40(1): 116-9. [PMID: 35221483 DOI: 10.2337/cd21-0042]

[62] Usman B, Sharma N, Satija S, Mehta M, Vyas M, et al. Recent developments in alpha-glucosidase inhibitors for management of type-2 diabetes: an update. Curr Pharm Des 2019; 25(23): 2510-25. [PMID: 31333110 DOI: 10.2174/1381612825666190717104547]

[63] Tavaf Z, Dangolani SK, Yousefi R, Panahi F, Shahsavani MB, et al. Synthesis of new curcumin derivatives as influential antidiabetic α-glucosidase and α-amylase inhibitors with anti-oxidant activity. Carbohydr Res 2020; 494: 108069. [PMID: 32563890 DOI: 10.1016/j.carres.2020.108069]

[64] Ritu, Sharma P, Gupta GD, Asati V . Design, synthesis and antidiabetic study of triazole clubbed indole derivatives as α-glucosidase inhibitors. Bioorg Chem 2023; 139: 106750. [PMID: 37499530 DOI: 10.1016/j.bioorg.2023.106750]

[65] Khan S, Iqbal S, Rahim F, Shah M, Hussain R, et al. New biologically hybrid pharmacophore thiazolidinone-based indole derivatives: synthesis, in vitro alpha-amylase and alpha-glucosidase along with molecular docking investigations. Molecules 2022; 27(19): 6564. [PMID: 36235098 DOI: 10.3390/molecules27196564]

[66] Khan SA, Ali M, Latif A, Ahmad M, Khan A, et al. Mercaptobenzimidazole-based 1,3-thaizolidin-4-ones as antidiabetic agents: synthesis, in vitro α-glucosidase inhibition activity, and molecular docking studies. ACS Omega 2022; 7(32): 28041-51. [PMID: 35990459 DOI: 10.1021/acsomega.2c01969]

[67] Ullah H, Khan S, Rahim F, Taha M, Iqbal R, et al. Benzimidazole bearing thiosemicarbazone derivatives act as potent α-amylase and α-glucosidase inhibitors; synthesis, bioactivity screening and molecular docking study. Molecules 2022; 27(20): 6921. [PMID: 36296520 DOI: 10.3390/molecules27206921]

[68] Abdullah MA, Lee YR, Mastuki SN, Leong SW, Wan Ibrahim WN, et al. Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis. Bioorg Chem 2020; 104: 104277. [PMID: 32971414 DOI: 10.1016/j.bioorg.2020.104277]

[69] Hussain R, Rehman W, Khan S, Maalik A, Hefnawy M, et al. Imidazopyridine-based thiazole derivatives as potential antidiabetic agents: synthesis, in vitro bioactivity, and in silico molecular modeling approach. Pharmaceuticals 2023; 16(9): 1288. [PMID: 37765096 DOI: 10.3390/ph16091288]

[70] Shayegan N, Iraji A, Bakhshi N, Moazzam A, Faramarzi MA, et al. Design, synthesis, and in silico studies of benzimidazole bearing phenoxyacetamide derivatives as α-glucosidase and α-amylase inhibitors. J Mol Struct 2022; 1268: 133650. [DOI: 10.1016/j.molstruc.2022.133650]

[71] Hu C, Liang B, Sun J, Li J, Xiong Z, et al. Synthesis and biological evaluation of indole derivatives containing thiazolidine-2, 4-dione as α-glucosidase inhibitors with antidiabetic activity. Eur J Med Chem 2024; 264: 115957. [PMID: 38029465 DOI: 10.1016/j.ejmech.2023.115957]

[72] Khan S, Rahim F, Rehman W, Nawaz M, Taha M, et al. New benzoxazole-based sulphonamide hybrids analogs as potent inhibitors of α-amylase and α-glucosidase: Synthesis and in vitro evaluation along with in silico study. Arab J Chem 2022; 15(12): 104341. [DOI: 10.1016/j.arabjc.2022.104341]

[73] Khan I, Rehman W, Rahim F, Hussain R, Khan S, et al. Synthesis, in vitro biological analysis and molecular docking studies of new thiadiazole-based thiourea derivatives as dual inhibitors of a-amylase and a-glucosidase. Arab J Chem 2023; 16(9): 105078. [DOI: 10.1016/j.arabjc.2023.105078]

[74] Aroua LM, Alosaimi AH, Alminderej FM, Messaoudi S, Mohammed HA, et al. Synthesis, molecular docking, and bioactivity study of novel hybrid benzimidazole urea derivatives: a promising α-amylase and α-glucosidase inhibitor candidate with antioxidant activity. Pharmaceutics 2023; 15(2): 457. [PMID: 36839780 DOI: 10.3390/pharmaceutics15020457]

[75] Hussain R, Rehman W, Rahim F, Khan S, Taha M, et al. Discovery of imidazopyridine derived oxadiazole-based thiourea derivatives as potential anti-diabetic agents: synthesis, in vitro antioxidant screening and in silico molecular modeling approaches. J Mol Struct 2023; 1293: 136185. [DOI: 10.1016/j.molstruc.2023.136185]

[76] Hussain R, Iqbal S, Shah M, Rehman W, Khan S, et al. Synthesis of novel benzimidazole-based thiazole derivatives as multipotent inhibitors of α-amylase and α-glucosidase: in vitro evaluation along with molecular docking study. Molecules 2022; 27(19): 6457. [PMID: 36234994 DOI: 10.3390/molecules27196457]

[77] Jiménez-Martí E, Hurtado-Genovés G, Aguilar-Ballester M, Martínez-Hervás S, González-Navarro H . Novel therapies for cardiometabolic disease: recent findings in studies with hormone peptide-derived g protein coupled receptor agonists. Nutrients 2022; 14(18): 3775. [PMID: 36145148 DOI: 10.3390/nu14183775]

[78] Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C. Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science 1993; 261(5120): 466-9. [PMID: 8101391 DOI: 10.1126/science.8101391]

[79] Röhrborn D, Wronkowitz N, Eckel J. DPP4 in diabetes. Front Immunol 2015; 6: 386. [PMID: 26284071 DOI: 10.3389/fimmu.2015.00386]

[80] Green BD, Flatt PR, Bailey CJ. Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes. Diab Vasc Dis Res 2006; 3(3): 159-65. [PMID: 17160910 DOI: 10.3132/dvdr.2006.024]

[81] Rashmi R, Bojan Magesh S, Mohanram Ramkumar K, Suryanarayanan S, Venkata SubbaRao M . Antioxidant potential of naringenin helps to protect liver tissue from streptozotocin-induced damage. Rep Biochem Mol Biol 2018; 7(1): 76-84. [PMID: 30324121]

[82] Liu F, Wang TTY, Tang Q, Xue C, Li RW, et al. Malvidin 3-glucoside modulated gut microbial dysbiosis and global metabolome disrupted in a murine colitis model induced by dextran sulfate sodium. Mol Nutr Food Res 2019; 63(21): e1900455. [PMID: 31444937 DOI: 10.1002/mnfr.201900455]

[83] Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, et al. Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull 2015; 119: 1-11. [PMID: 26361743 DOI: 10.1016/j.brainresbull.2015.09.002]

[84] Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schäfer B, et al. Safety aspects of the use of quercetin as a dietary supplement. Mol Nutr Food Res 2018; 62(1). [PMID: 29127724 DOI: 10.1002/mnfr.201700447]

[85] Magnani C, Isaac VL, Correa MA, Salgado HR. Caffeic acid: a review of its potential use in medications and cosmetics. Anal Methods 2014; 6(10): 3203- 10. [DOI: 10.1039/C3ay41807C]

[86] Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? An analysis based on the current literature. Front Mol Biosci 2023; 10: 1130625. [PMID: 37287751 DOI: 10.3389/fmolb.2023.1130625]

[87] Kalra S, Bhattacharya S, Dhingra A, Das S, Kapoor N, et al. Expert consensus on dipeptidyl peptidase-4 inhibitor-based therapies in the modern era of type 2 diabetes mellitus management in India. Cureus 2024; 16(6): e61766. [PMID: 38975525 DOI: 10.7759/cureus.61766]

[88] Lyu YS, Oh S, Kim JH, Kim SY, Jeong MH. Comparison of SGLT2 inhibitors with DPP-4 inhibitors combined with metformin in patients with acute myocardial infarction and diabetes mellitus. Cardiovasc Diabetol 2023; 22(1): 185. [PMID: 37481509 DOI: 10.1186/s12933-023-01914-4]

[89] Kazeem IM, Awenegieme NO. Apple and banana displayed better inhibition of dipeptidyl peptidase IV activity than vildagliptin. In: Proceedings of the Annual Meeting of the Japanese Pharmacological Society, WCP2018 (18th World Congress of Basic and Clinical Pharmacology). Japanese Pharmacol Soc 2018; PO1-5-8. [DOI: 10.1254/jpssuppl.WCP2018.0_PO1-5-8]

[90] Bindu B, Vijayalakshmi S, Manikandan A. Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities. Eur J Med Chem 2020; 187: 111912. [DOI: 10.1016/j.ejmech.2019.111912]

[91] Ngoc Toan V, Son Hai D, Thi Kim Van H, Minh Tri N, Ngoc Toan D, et al. Design, synthesis, inhibitory activity, and molecular simulations study for d-glucose-conjugated thioureas containing pyrimidine ring as multitarget inhibitors against α-amylase, α-glucosidase, DDP-4, and PTP1B in type 2 diabetes mellitus. RSC Med Chem 2024; 15(10): 3395-417. [PMID: 39185455 DOI: 10.1039/d4md00334a]

[92] Huneif MA, Mahnashi MH, Jan MS, Shah M, Almedhesh SA, et al. New succinimide-thiazolidinedione hybrids as multitarget antidiabetic agents: design, synthesis, bioevaluation, and molecular modelling studies. Molecules 2023; 28(3): 1207. [PMID: 36770873 DOI: 10.3390/molecules28031207]

[93] Meurot C, Martin C, Sudre L, Breton J, Bougault C, et al. Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis. Sci Rep 2022; 12(1): 1567. [PMID: 35091584 DOI: 10.1038/s41598-022-05323-7]

[94] Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11(3): 76-98. [PMID: 33274014 DOI: 10.4331/wjbc.v11.i3.76]

[95] Chong K, Chang JK, Chuang LM. Recent advances in the treatment of type 2 diabetes mellitus using new drug therapies. Kaohsiung J Med Sci 2024; 40(3): 212-20. [PMID: 38183334 DOI: 10.1002/kjm2.12800]

[96] Oh H, Nguyen HD, Yoon IM, Ahn BR, Kim MS. Antidiabetic effect of gemigliptin: a systematic review and meta-analysis of randomized controlled trials with Bayesian inference through a quality management system. Sci Rep 2021; 11(1): 20938. [PMID: 34686738 DOI: 10.1038/s41598-021-00418-z]

[97] Kasamatsu H, Chino T, Oyama N, Nakaya T, Hasegawa M. Bullous pemphigoid receiving a novel long-acting dipeptidyl-peptidase-4 (DPP-4) inhibitor omarigliptin in a patient with type 2 diabetes: a case report. J Cutan Immunol Allergy 2021; 4(4): 89-91. [DOI: 10.1002/cia2.12162]

[98] Patel BD, Ghate MD. Recent approaches to medicinal chemistry and therapeutic potential of dipeptidyl peptidase-4 (DPP-4) inhibitors. Eur J Med Chem 2014; 74: 574-605. [PMID: 24531198 DOI: 10.1016/j.ejmech.2013.12.038]

[99] Madar DJ, Kopecka H, Pireh D, Yong H, Pei Z, et al. Discovery of 2-[4-{{2-(2S, 5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl] amino]-4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes. J Med Chem 2006; 49(21): 6416-20. [PMID: 17034148 DOI: 10.1016/B978-0-12-409547-2.12443-6]

[100] Kuthati Y, Rao VN, Busa P, Wong CS. Teneligliptin exerts antinociceptive effects in rat model of partial sciatic nerve transection induced neuropathic pain. Antioxidants 2021; 10(9): 1438. [PMID: 34573072 DOI: 10.3390/antiox10091438]

[101] Hall A, Neelamkavil S, Jones R. CNS, pain, metabolic syndrome, cardiovascular, tissue, fibrosis and urinary incontinence. 2017. Available from: https://www.alkemlabs.com/pdf/adverse/Evogliptin.pdf

[102] Singla RK, Kumar R, Khan S, Mohit Kumari K, Garg A. Natural products: potential source of DPP-IV inhibitors. Curr Protein Pept Sci 2019; 20(12): 1218-25. [PMID: 31057098 DOI: 10.2174/1389203720666190502154129]

[103] Chayah M, Luque-González A, Gómez-Pérez V, Salagre D, Al-Shdaifat A, et al. Synthesis and anti-diabetic activity of an 8-purine derivative as a novel DPP-4 inhibitor in obese diabetic Zücker rats. Drug Des Devel Ther 2024; 18: 1133-41. [PMID: 38618281 DOI: 10.2147/DDDT.S450917]

[104] Dastjerdi HF, Naderi N, Nematpour M, Rezaee E, Mahboubi-Rabbani M, et al. 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. [DOI: 10.1016/j.molstruc.2020.128745]

[105] Narsimha S, Battula KS, Ravinder M, Reddy YN, Nagavelli VR. Design, synthesis and biological evaluation of novel 1,2,3-triazole-based xanthine derivatives as DPP-4 inhibitors. J Chem Sci 2020; 132: 1-9. [DOI: 10.1007/s12039-020-1760-0]

[106] Katiyar S, Ahmad S, Kumar A, Ansari A, Bisen AC, et al. Design, synthesis, and biological evaluation of 1,4-dihydropyridine-indole as a potential antidiabetic agent via GLUT4 translocation stimulation. J Med Chem 2024; 67(14): 11957-74. [PMID: 39013034 DOI: 10.1021/acs.jmedchem.4c00570]

[107] Colin-Lozano B, Torres-Gomez H, Hidalgo-Figueroa S, Chávez-Silva F, Estrada-Soto S, et al. Synthesis, in vitro, in vivo and in silico antidiabetic bioassays of 4-nitro (thio) phenoxyisobutyric acids acting as unexpected PPARγ modulators: an in combo study. Pharmaceuticals 2022; 15(1): 102. [PMID: 35056159 DOI: 10.3390/ph15010102]

[108] Wright EM. SGLT2 inhibitors: physiology and pharmacology. Kidney360. 2021; 2(12): 2027-37. [PMID: 35419546 DOI: 10.34067/KID.0002772021]

[109] Uitrakul S, Aksonnam K, Srivichai P, Wicheannarat S, Incomenoy S. The incidence and risk factors of urinary tract infection in patients with type 2 diabetes mellitus using SGLT2 inhibitors: a real-world observational study. Medicines 2022; 9(12): 59. [PMID: 36547992 DOI: 10.3390/medicines9120059]

[110] Bhattacharya S, Asati V, Mishra M, Das R, Kashaw V, et al. Integrated computational approach on sodium-glucose co-transporter 2 (SGLT2) Inhibitors for the development of novel antidiabetic agents. J Mol Struct 2021; 1227: 129511. [DOI: 10.1016/j.molstruc.2020.129511]

[111] Wakisaka M, Nagao T. Sodium glucose cotransporter 2 in mesangial cells and retinal pericytes and its implications for diabetic nephropathy and retinopathy. Glycobiology 2017; 27(8): 691-5. [PMID: 28535208 DOI: 10.1093/glycob/cwx047]

[112] Tupas GD, Otero MC, Ebhohimen IE, Egbuna C, Aslam M. Antidiabetic lead compounds and targets for drug development. Phytochem Lead Compounds N Drug Discov 2020; 127-41. [DOI: 10.1016/B978-0-12-817890-4.00008-1]

[113] Ritzel R, Roussel R, Bolli GB, Vinet L, Brulle-Wohlhueter C, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab 2015; 17(9): 859-67. [PMID: 25929311 DOI: 10.1111/dom.12485]

[114] Holden SE, Jenkins-Jones S, Morgan CL, Schernthaner G, Currie CJ . Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association with all-cause mortality, cardiovascular events and cancer. Diabetes Obes Metab 2015; 17(4): 350-62. [PMID: 25399739 DOI: 10.1111/dom.12412]

[115] Mashraqi MM, Chaturvedi N, Alam Q, Alshamrani S, Bahnass MM, et al. Biocomputational prediction approach targeting FimH by natural SGLT2 inhibitors: a possible way to overcome the uropathogenic effect of SGLT2 inhibitor drugs. Molecules 2021; 26(3): 582. [PMID: 33499241 DOI: 10.3390/molecules26030582]

[116] Dias TR, Alves MG, Casal S, Oliveira PF, Silva BM. Promising potential of dietary (poly)phenolic compounds in the prevention and treatment of diabetes mellitus. Curr Med Chem 2017; 24(4): 334-54. [PMID: 27593957 DOI: 10.2174/0929867323666160905150419]

[117] Li C, Luo J, Jiang M, Wang K. The efficacy and safety of the combination therapy with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes mellitus: a systematic review and meta-analysis. Front Pharmacol 2022; 13: 838277. [PMID: 35185588 DOI: 10.3389/fphar.2022.838277]

[118] Pan HC, Chen JY, Chen HY, Yeh FY, Huang TT, et al. Sodium-glucose cotransport protein 2 inhibitors in patients with type 2 diabetes and acute kidney disease. JAMA Netw Open 2024; 7(1): e2350050. [PMID: 38170522 DOI: 10.1001/jamanetworkopen.2023.50050]

[119] Feng GJ, Guo YF, Tang Y, Li M, Jia Y, et al. Design, synthesis, and biological evaluation of thioglucoside analogues of gliflozin as potent new gliflozin drugs. J Med Chem 2023; 66(17): 12536-43. [PMID: 37608596 DOI: 10.1021/acs.jmedchem.3c01138]

[120] Sipos Á, Szennyes E, Hajnal NÉ, Kun S, Szabó KE, et al. Dual-target compounds against type 2 diabetes mellitus: proof of concept for sodium dependent glucose transporter (SGLT) and glycogen phosphorylase (GP) inhibitors. Pharmaceuticals 2021; 14(4): 364. [PMID: 33920838 DOI: 10.3390/ph14040364]

[121] Kong YK, Song KS, Jung ME, Kang M, Kim HJ, et al. Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes. Bioorg Med Chem Lett 2022; 56: 128466. [PMID: 34813882 DOI: 10.1016/j.bmcl.2021.128466]

[122] Wang S, Chen K, Guo F, Zhu W, Liu C, et al. C-H Glycosylation of native carboxylic acids: discovery of antidiabetic SGLT-2 inhibitors. ACS Cent Sci 2023; 9(6): 1129-39. [DOI: 10.1021/acscentsci.3c00201]

[123] Powell D, Zambrowicz B, Morrow L, Beysen C, Hompesch M, et al. OR22-5 Sotagliflozin decreases postprandial glucose and insulin by delaying intestinal glucose absorption. J Endocr Soc 2019; 3(suppl 1): OR22-5. [DOI: 10.1210/js.2019-OR22-5]

[124] Clinical Trial report. Antidiabetic Drugs for Steatotic Liver Disease. Available from: https://clinicaltrials.gov/ct2/show/NCT03646292?term=drugs&cond=diabetic+sglt2&draw=2&rank=9 [Last accessed on 15 Aug 2023].

[125] Pioglitazon. Available from: https://www.drugbank.ca/drugs/DB01132 [Last accessed on 15 Aug 2023].

[126] Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012; 35(7): 1473-8. [PMID: 22446170 DOI: 10.2337/dc11-1693]

[127] Dobbins RL, O’Connor-Semmes R, Kapur A, Kapitza C, Golor G, et al. Remogliflozin etabonate, a selective inhibitor of the sodium-dependent transporter 2 reduces serum glucose in type 2 diabetes mellitus patients. Diabetes Obes Metab 2012; 14(1): 15-22. [PMID: 21733056 DOI: 10.1111/j.1463-1326.2011.01462.x]

[128] Varney MJ, Benovic JL. The role of G protein-coupled receptors and receptor kinases in pancreatic β-cell function and diabetes. Pharmacol Rev 2024; 76(2): 267-99. [PMID: 38351071 DOI: 10.1124/pharmrev.123.001015]

[129] Pocai A. G protein-coupled receptors and obesity. Front Endocrinol 2023; 14: 1301017. [PMID: 38161982 DOI: 10.3389/fendo.2023.1301017]

[130] Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9(1): 234. [PMID: 39289339 DOI: 10.1038/s41392-024-01931-z]

[131] Pola S, Shah SR, Pingali H, Zaware P, Thube B, et al. Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes. Bioorg Med Chem 2021; 35: 116071. [PMID: 33611013 DOI: 10.1016/j.bmc.2021.116071]

[132] Wang X, Li X, Wei S, Wang M, Xu Y, et al. Discovery of novel and selective G-protein coupled receptor 120 (GPR120) Agonists for the treatment of type 2 diabetes mellitus. Molecules 2022; 27(24): 9018. [PMID: 36558150 DOI: 10.3390/molecules27249018]

[133] Drzazga A, Okulus M, Rychlicka M, Biegała Ł, Gliszczyńska A, et al. Lysophosphatidylcholine containing anisic acid is able to stimulate insulin secretion targeting G protein coupled receptors. Nutrients 2020; 12(4): 1173. [PMID: 32331428 DOI: 10.3390/nu12041173]

[134] Bazydlo-Guzenda K, Buda P, Matloka M, Mach M, Stelmach F, et al. CPL207280, a novel G protein-coupled receptor 40/free fatty acid receptor 1-specific agonist, shows a favorable safety profile and exerts antidiabetic effects in type 2 diabetic animals. Mol Pharmacol 2021; 100(4): 335-47. [PMID: 34349026 DOI: 10.1124/molpharm.121.000260]

[135] Juárez-Cruz S, Estrada-Soto S, Colín-Lozano B, Marquina-Rodríguez H, Delgado-Aguilar T, et al. Design and synthesis of barbiturates and hydantoins with multitarget antidiabetic effect. J Mex Chem Soc 2024; 68(4): 609-23. [DOI: 10.29356/jmcs.v68i4.2284]

[136] Hidalgo-Figueroa S, Rodríguez-Luévano A, Almanza-Pérez JC, Giacoman-Martínez A, Ortiz-Andrade R, et al. Synthesis, molecular docking, dynamic simulation and pharmacological characterization of potent multifunctional agent (dual GPR40-PPARγ agonist) for the treatment of experimental type 2 diabetes. Eur J Pharmacol 2021; 907: 174244. [PMID: 34116041 DOI: 10.1016/j.ejphar.2021.174244]

[137] Ye Z, Liu C, Zou F, Cai Y, Chen B, et al. Discovery of novel potent GPR40 agonists containing imidazo[1,2- a]pyridine core as antidiabetic agents. Bioorg Med Chem 2020; 28(13): 115574. [DOI: 10.1016/j.bmc.2020.115574]

[138] Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021; 384(2): 129-39. [PMID: 33200891 DOI: 10.1056/NEJMoa2030186]

[139] Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 2024; 331(1): 38-48. [PMID: 38078870 DOI: 10.1001/jama.2023.24945]

[140] Ueki K, Tanizawa Y, Nakamura J, Yamada Y, Inagaki N, et al. Long-term safety and efficacy of alogliptin, a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry). BMJ Open Diabetes Res Care 2021; 9(1): e001787. [PMID: 33441417 DOI: 10.1136/bmjdrc-2020-001787]

[141] Sass F, Ma T, Ekberg JH, Kirigiti M, Ureña MG, Dollet L, et al. NK2R control of energy expenditure and feeding to treat metabolic diseases. Nature 2024; 635: 1-4. [PMID: 39537932 DOI: 10.1038/s41586-024-08207-0]

[142] Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, et al. G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. J Am Soc Nephrol 2016; 27(5): 1362-78. [PMID: 26424786 DOI: 10.1681/ASN.2014121271]