Unlocking the Potential of Receptor-Based Approaches in Diabetes Treatment

Abstract

Diabetes, a common metabolic condition, poses a substantial health burden worldwide. To revolutionize diabetes management, enhance glycemic control, and decrease the risk of complications, recent research has revealed innovative targets and therapeutic options. A thorough examination of modern drugs that target particular receptors and metabolic pathways for glucose and fat metabolism is presented. Recent research has revealed innovative targets and therapeutic options. Liraglutide, a GLP-1 receptor agonist, has been shown to effectively lower glucagon levels and promote weight loss. Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor with substantial promise in decreasing blood glucose levels, and providing cardiovascular and renal advantages. Pegbelfermin (BMS-986036), a fibroblast growth factor 21 (FGF21) analogue, is being investigated for its ability to regulate glucose and lipid metabolism, and potentially enhance glycemic control and lipid profiles. Additionally, G-protein-coupled receptor (GPCR) agonists and adenosine monophosphate-activated protein kinase (AMPK) activators are emerging as potential medicines to improve insulin sensitivity, glucose uptake, and insulin signaling pathways. Despite being in early research stages, bile acid receptor agonists and mitochondrial uncouplers have promising potential for modifying lipid and glucose metabolism. The long-acting insulin analogue insulin glargine, which replaces basal insulin, continues to be a cornerstone of advanced diabetes management. In the future, these medications are expected to be improved through the use of combination therapy and personalized, precision medicine. Gene therapies show promise as novel strategies to address genetic defects and provide potential treatments. Additionally, patient monitoring, adherence, and self-management will be greatly aided by the integration of digital health technology, telemedicine, and artificial intelligence (AI), thus leading to better treatment outcomes and patient quality of life. Healthcare professionals, researchers, politicians, and patients working together will pave the way to substantial improvements in the management of metabolic disorders including diabetes. In conclusion, hope for more efficient, individualized, and secure therapies may come from continuing research and breakthroughs in novel diabetes treatment targets. These developments are at the forefront of offering people with diabetes and related metabolic disorders a better and healthier future, by revolutionizing diabetes management.

Keywords

Diabetes / GLP-1 agonists / metabolic disorders / receptors / SGLT2 inhibitors / therapeutic targets

References

[1] Kaul K, Tarr JM, Ahmad SI, Kohner EM, Chibber R. Introduction to diabetes mellitus. In: Ahmad SI, editor. Diabetes: an old disease, a new insight. New York, NY: Springer; 2013. pp. 1- 1. [DOI: 10.1007/978-1-4614-5441-0_1]

[2] Yedjou CG, Grigsby J, Mbemi A, Nelson D, Mildort B, et al. The management of diabetes mellitus using medicinal plants and vitamins. Int J Mol Sci 2023; 24(10): 9085. [PMID: 37240430 DOI: 10.3390/ijms24109085]

[3] Quazi A, Patwekar M, Patwekar F, Alghamdi S, Rajab BS, et al. In vitro alpha-amylase enzyme assay of hydroalcoholic polyherbal extract: proof of concept for the development of polyherbal teabag formulation for the treatment of diabetes. Evid Based Complement Alternat Med 2022; 2022: 1577957. [PMID: 35600963 DOI: 10.1155/2022/1577957]

[4] Saraon P, Pathmanathan S, Snider J, Lyakisheva A, Wong V, et al. Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches. Oncogene 2021; 40(24): 4079-93. [PMID: 34079087 DOI: 10.1038/s41388-021-01841-2]

[5] Saltiel AR. Insulin signaling in health and disease. J Clin Invest 2021; 131(1): e142241. [PMID: 33393497 DOI: 10.1172/JCI142241]

[6] Wang D, Zhou W, Chen J, Wei W. Upstream regulators of phosphoinositide 3-kinase and their role in diseases. J Cell Physiol 2019; 234(9): 14460-72. [PMID: 30710358 DOI: 10.1002/jcp.28215]

[7] White MF, Kahn CR. Insulin action at a molecular level-100 years of progress. Mol Metab 2021; 52: 101304. [PMID: 34274528 DOI: 10.1016/j.molmet.2021.101304]

[8] Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. Int J Mol Sci 2020; 21(12): 4507. [DOI: 10.3390/ijms21124507]

[9] Wen X, Zhang B, Wu B, Xiao H, Li Z, et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther 2022; 7(1): 298. [PMID: 36031641 DOI: 10.1038/s41392-022-01149-x]

[10] Patwekar M, Quazi A, Faheem IP, Kamal MA, Mukim M, et al. In vitro inhibitory effect on alpha amylase enzyme by polyherbal dip tea in diabetes. Indo Glob J Pharm Sci 2022; 12(1): 156-65. [DOI: 10.35652/IGJPS.2022.12018]

[11] Helmstädter J, Keppeler K, Küster L, Münzel T, Daiber A, et al. Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-the role of the GLP-1 receptor. Br J Pharmacol 2022; 179(4): 659-76. [PMID: 33764504 DOI: 10.1111/bph.15462]

[12] Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: implications for neurodegenerative disease treatment. Pharmacol Res 2022; 186: 106550. [PMID: 36372278 DOI: 10.1016/j.phrs.2022.106550]

[13] Ikonomidis I, Pavlidis G, Thymis J, Birba D, Kalogeris A, et al. Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and their combination on endothelial glycocalyx, arterial function, and myocardial work index in patients with type 2 diabetes mellitus after 12-month treatment. J Am Heart Assoc 2020; 9(9): e015716. [PMID: 32326806 DOI: 10.1161/JAHA.119.015716]

[14] Lv X, Dong Y, Hu L, Lu F, Zhou C, et al. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): a systematic review. Endocrinol Diabetes Metab 2020; 3(3): e00163. [PMID: 32704576 DOI: 10.1002/edm2.163]

[15] Xu D, Nair A, Sigston C, Ho C, Li J, et al. Potential roles of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in nondiabetic populations. Cardiovasc Ther 2022; 2022: 6820377. [PMID: 36474714 DOI: 10.1155/2022/6820377]

[16] Urva S, Coskun T, Loghin C, Cui X, Beebe E, et al. The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists. Diabetes Obes Metab 2020; 22(10): 1886-91. [PMID: 32519795 DOI: 10.1111/dom.14110]

[17] Kumar S, Khatik GL, Mittal A. In silico molecular docking study to search new SGLT2 inhibitor based on dioxabicyclo[3.2.1] octane scaffold. Curr Comput Aided Drug Des 2020; 16(2): 145-54. [PMID: 30345926 DOI: 10.2174/1573409914666181019165821]

[18] Palapra H, Viswam SK, Kalaiselvan V, Undela K. SGLT2 inhibitors associated pancreatitis: signal identification through disproportionality analysis of spontaneous reports and review of case reports. Int J Clin Pharm 2022; 44(6): 1425-33. [PMID: 36224513 DOI: 10.1007/s11096-022-01476-7]

[19] Sinha B, Ghosal S. Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure. Diabetes Res Clin Pract 2019; 150: 8-16. [PMID: 30794833 DOI: 10.1016/j.diabres.2019.02.014]

[20] Moinul M, Amin SA, Kumar P, Patil UK, Gajbhiye A, et al. Exploring sodium glucose cotransporter (SGLT2) inhibitors with machine learning approach: a novel hope in anti-diabetes drug discovery. J Mol Graph Model 2022; 111: 108106. [PMID: 34923429 DOI: 10.1016/j.jmgm.2021.108106]

[21] Suijk DL, van Baar MJ, van Bommel EJ, Iqbal Z, Krebber MM, et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Clin J Am Soc Nephrol 2022; 17(5): 663-71. [PMID: 35322793 DOI: 10.2215/CJN.11480821]

[22] Singh M, Sharma R, Kumar A. Safety of SGLT2 inhibitors in patients with diabetes mellitus. Curr Drug Saf 2019; 14(2): 87-93.

[23] Tian Q, Guo K, Deng J, Zhong Y, Yang L. Effects of SGLT2 inhibitors on haematocrit and haemoglobin levels and the associated cardiorenal benefits in T2DM patients: a meta-analysis. J Cell Mol Med 2022; 26(2): 540-7. [PMID: 34878225 DOI: 10.1111/jcmm.17115]

[24] Moeckli B, Pham TV, Slits F, Latrille S, Peloso A, et al. FGF21 negatively affects long-term female fertility in mice. Heliyon 2022; 8(11): e11490. [PMID: 36406708 DOI: 10.1016/j.heliyon.2022.e11490]

[25] Chikamatsu M, Watanabe H, Shintani Y, Murata R, Miyahisa M, et al. Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease. J Control Release 2023; 355: 42-53. [PMID: 36690035 DOI: 10.1016/j.jconrel.2023.01.039]

[26] Tan H, Yue T, Chen Z, Wu W, Xu S, et al. Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine. Int J Biol Sci 2023; 19(1): 66-88. [PMID: 36594101 DOI: 10.7150/ijbs.73936]

[27] Claflin KE, Sullivan AI, Naber MC, Flippo KH, Morgan DA, et al. Pharmacological FGF21 signals to glutamatergic neurons to enhance leptin action and lower body weight during obesity. Mol Metab 2022; 64: 101564. [PMID: 35944896 DOI: 10.1016/j.molmet.2022.101564]

[28] Watanabe H, Miyahisa M, Chikamatsu M, Nishida K, Minayoshi Y, et al. Development of a long acting FGF21 analogue-albumin fusion protein and its anti-diabetic effects. J Control Release 2020; 324: 522-31. [PMID: 32450094 DOI: 10.1016/j.jconrel.2020.05.036]

[29] Guo C, Zhao L, Li Y, Deng X, Yuan G. Relationship between FGF21 and drug or nondrug therapy of type 2 diabetes mellitus. J Cell Physiol 2021; 236(1): 55-67. [PMID: 32583417 DOI: 10.1002/jcp.29879]

[30] Lam CS, Xia YX, Chen BS, Du YX, Liu KL, et al. Dihydro-resveratrol attenuates oxidative stress, adipogenesis and insulin resistance in in vitro models and high-fat diet-induced mouse model via AMPK activation. Nutrients 2023; 15(13): 3006. [PMID: 37447331 DOI: 10.3390/nu15133006]

[31] Yoon KJ, Zhang D, Kim SJ, Lee MC, Moon HY. Exercise-induced AMPK activation is involved in delay of skeletal muscle senescence. Biochem Biophys Res Commun 2019; 512(3): 604-10. [PMID: 30910357 DOI: 10.1016/j.bbrc.2019.03.086]

[32] Steele HE, Guo Y, Li BY, Na S. Mechanotransduction of mitochondrial AMPK and its distinct role in flow-induced breast cancer cell migration. Biochem Biophys Res Commun 2019; 514(2): 524-9. [PMID: 31060777 DOI: 10.1016/j.bbrc.2019.04.191]

[33] Chen H, Nie T, Zhang P, Ma J, Shan A. Hesperidin attenuates hepatic lipid accumulation in mice fed high-fat diet and oleic acid induced HepG2 via AMPK activation. Life Sci 2022; 296: 120428. [PMID: 35218767 DOI: 10.1016/j.lfs.2022.120428]

[34] Feng TY, Lv DL, Zhang X, Du YQ, Yuan YT, et al. Rosmarinic acid improves boar sperm quality, antioxidant capacity and energy metabolism at 17°C via AMPK activation. Reprod Domest Anim 2020; 55(12): 1714-24. [PMID: 32969084 DOI: 10.1111/rda.13828]

[35] Watkins LR, Orlandi C. In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity. Br J Pharmacol 2021; 178(15): 2963-75. [PMID: 33784795 DOI: 10.1111/bph.15468]

[36] Grisshammer R. The quest for high-resolution G protein-coupled receptor-G protein structures. Proc Natl Acad Sci U S A 2020; 117(13): 6971-3. [PMID: 32179692 DOI: 10.1073/pnas.2002665117]

[37] Ren H, Li J, Zhang N, Hu LA, Ma Y, et al. Function-based high-throughput screening for antibody antagonists and agonists against G protein-coupled receptors. Commun Biol 2020; 3(1): 146. [PMID: 32218528 DOI: 10.1038/s42003-020-0867-7]

[38] Shi Y, Chen Y, Deng L, Du K, Lu S, et al. Structural understanding of peptide-bound G protein-coupled receptors: peptide-target interactions. J Med Chem 2023; 66(2): 1083-111. [PMID: 36625741 DOI: 10.1021/acs.jmedchem.2c01309]

[39] van Gastel J, Leysen H, Boddaert J, Luttrell LM, Martin B, et al. Aging-related modifications to G protein-coupled receptor signaling diversity. Pharmacol Ther 2021; 223: 107793. [PMID: 33316288 DOI: 10.1016/j.pharmthera.2020.107793]

[40] Kimura T, Pydi SP, Pham J, Tanaka N. Metabolic functions of G protein-coupled receptors in hepatocytes-potential applications for diabetes and NAFLD. Biomolecules 2020; 10(10): 1445. [PMID: 33076386 DOI: 10.3390/biom10101445]

[41] Smits MM, Fluitman KS, Herrema H, Davids M, Kramer MH, et al. Liraglutide and sitagliptin have no effect on intestinal microbiota composition: a 12-week randomized placebo-controlled trial in adults with type 2 diabetes. Diabetes Metab 2021; 47(5): 101223. [PMID: 33429063 DOI: 10.1016/j.diabet.2021.101223]

[42] Lee JS, Han P, Chaudhury R, Khan S, Bickerton S, et al. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin. Nat Biomed Eng 2021; 5(9): 983-97. [PMID: 34616050 DOI: 10.1038/s41551-021-00791-0]

[43] Song Y, Sun L, Ma P, Xu L, Xiao P. Dihydromyricetin prevents obesity via regulating bile acid metabolism associated with the farnesoid X receptor in ob/ ob mice. Food Functi 2022; 13(5): 2491-503. [PMID: 35147634 DOI: 10.1039/d1fo03971g]

[44] Ito K, Okumura A, Takeuchi JS, Watashi K, Inoue R, et al. Dual agonist of farnesoid X receptor and takeda G protein-coupled receptor 5 inhibits hepatitis B virus infection in vitro and in vivo. Hepatology 2021; 74(1): 83-98. [PMID: 33434356 DOI: 10.1002/hep.31712]

[45] Shi M, Tang J, Zhang T, Han H. Swertiamarin, an active iridoid glycoside from Swertia pseudochinensis H. Hara, protects against alpha-naphthylisothiocyanate-induced cholestasis by activating the farnesoid X receptor and bile acid excretion pathway. J Ethnopharmacol 2022; 291: 115164. [PMID: 35278607 DOI: 10.1016/j.jep.2022.115164]

[46] Kårhus ML, Sonne DP, Thomasen M, Ellegaard AM, Holst JJ, et al. Enterohepatic, gluco-metabolic, and gut microbial characterization of individuals with bile acid malabsorption. Gastro Hep Adv 2022; 1(3): 299-312. [PMID: 39131668 DOI: 10.1016/j.gastha.2021.12.007]

[47] Wagle SR, Kovacevic B, Walker D, Ionescu CM, Jones M, et al. Pharmacological and advanced cell respiration effects, enhanced by toxic human-bile nano-pharmaceuticals of probucol cell-targeting formulations. Pharmaceutics 2020; 12(8): 708. [PMID: 32751051 DOI: 10.3390/pharmaceutics12080708]

[48] Okamoto T, Shimada T, Matsumura C, Minoshima H, Ban T, et al. New approach to drug discovery of a safe mitochondrial uncoupler: OPC-163493. ACS Omega 2021; 6(26): 16980-8. [PMID: 34250356 DOI: 10.1021/acsomega.1c01993]

[49] Ramesh T. Oxidative stress and hepatocellular mitochondrial dysfunction attenuated by Asiatic acid in streptozotocin-induced diabetic rats. J King Saud Univ Sci 2021; 33(3): 101369. [DOI: 10.1016/j.jksus.2021.101369]

[50] Xiong Y, He YL, Li XM, Nie F, Zhou XK. Endogenous asymmetric dimethylarginine accumulation precipitates the cardiac and mitochondrial dysfunctions in type 1 diabetic rats. Eur J Pharmacol 2021; 902: 174081. [PMID: 33901463 DOI: 10.1016/j.ejphar.2021.174081]

[51] Dorighello GG, Rovani JC, Paim BA, Rentz T, Assis LH, et al. Mild mitochondrial uncoupling decreases experimental atherosclerosis, a proof of concept. J Atheroscler Thromb 2022; 29(6): 825-38. [PMID: 34092712 DOI: 10.5551/jat.62796]

[52] Lu H, Buchan RJ, Cook SA. MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovasc Res 2010; 86(3): 410-20. [PMID: 20080987 DOI: 10.1093/cvr/cvq010]

[53] Nikzamir A, Palangi A, Kheirollaha A, Tabar H, Malakaskar A, et al. Expression of glucose transporter 4 (GLUT4) is increased by cinnamaldehyde in C2C12 mouse muscle cells. Iran Red Crescent Med J 2014; 16(2): e13426. [PMID: 24719730 DOI: 10.5812/ircmj.13426]

[54] Atkinson BJ, Griesel BA, King CD, Josey MA, Olson AL. Moderate GLUT4 overexpression improves insulin sensitivity and fasting triglyceridemia in high-fat diet-fed transgenic mice. Diabetes 2013; 62(7): 2249-58. [PMID: 23474483 DOI: 10.2337/db12-1146]

[55] Dehghan F, Hajiaghaalipour F, Yusof A, Muniandy S, Hosseini SA, et al. Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in-vitro and in-vivo. Sci Rep 2016; 6(1): 25139. [PMID: 27122001 DOI: 10.1038/srep25139]

[56] Zheng S, Rollet M, Pan YX. Protein restriction during gestation alters histone modifications at the glucose transporter 4 (GLUT4) promoter region and induces GLUT4 expression in skeletal muscle of female rat offspring. J Nutr Biochem 2012; 23(9): 1064-71. [PMID: 22079207 DOI: 10.1016/j.jnutbio.2011.05.013]

[57] McCoull W, Addie MS, Birch AM, Birtles S, Buckett LK, et al. Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes. Bioorg Med Chem Lett 2012; 22(12): 3873-8. [PMID: 22608962 DOI: 10.1016/j.bmcl.2012.04.117]

[58] Meyers CD, Tremblay K, Amer A, Chen J, Jiang L, et al. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis 2015; 14(1): 8. [PMID: 25889044 DOI: 10.1186/s12944-015-0006-5]

[59] Shih CC, Ciou JL, Lin CH, Wu JB, Ho HY. Cell suspension culture of Eriobotrya japonica regulates the diabetic and hyperlipidemic signs of high-fat-fed mice. Molecules 2013; 18(3): 2726-53. [PMID: 23455665 DOI: 10.3390/molecules18032726]

[60] Xiao C, Dash S, Morgantini C, Hegele RA, Lewis GF. Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol. Diabetes 2016; 65(7): 1767-78. [PMID: 27329952 DOI: 10.2337/db16-0046]

[61] Banerji MA, Dunn JD. Impact of glycemic control on healthcare resource utilization and costs of type 2 diabetes: current and future pharmacologic approaches to improving outcomes. Am Health Drug Benefits 2013; 6(7): 382. [PMID: 24991370]

[62] NamKoong C, Kim MS, Jang BT, Lee YH, Cho YM, et al. Central administration of GLP-1 and GIP decreases feeding in mice. Biochem Biophys Res Commun 2017; 490(2): 247-52. [PMID: 28610922 DOI: 10.1016/j.bbrc.2017.06.031]

[63] Jiang N, Jing L, Li Q, Su S, Yang Q, et al. Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists. Eur J Med Chem 2021; 212: 113118. [PMID: 33422984 DOI: 10.1016/j.ejmech.2020.113118]

[64] Willard FS, Bueno AB, Sloop KW. Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp Diabetes Res 2012; 2012: 709893. [PMID: 22611375 DOI: 10.1155/2012/709893]

[65] Cao Y, Hölscher C, Hu MM, Wang T, Zhao F, et al. DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer’s disease. Eur J Pharmacol 2018; 827: 215-26. [PMID: 29551659 DOI: 10.1016/j.ejphar.2018.03.024]

[66] Mirzaei F, Khodadadi I, Majdoub N, Vafaei SA, Tayebinia H, et al. Role of glucagon-like peptide-1 (GLP-1) agonists in the management of diabetic patients with or without COVID-19. Open Med Chem J 2022; 16(1): e187410452212130. [DOI: 10.2174/18741045-v16-e2212130]

[67] Jones AB. Peroxisome proliferator-activated receptor (PPAR) modulators: diabetes and beyond. Med Res Rev 2001; 21(6): 540-52. [PMID: 11607934 DOI: 10.1002/med.1025]

[68] Ram VJ. Therapeutic significance of peroxisome proliferator-activated receptor modulators in diabetes. Drugs Today (Barc) 2003; 39(8): 609-32. [PMID: 14566384 DOI: 10.1358/dot.2003.39.8.799408]

[69] Patsouris D, Müller M, Kersten S. Peroxisome proliferator activated receptor ligands for the treatment of insulin resistance. Curr Opin Investig Drugs 2004; 5(10): 1045-50. [PMID: 15535425]

[70] Moore-Carrasco R, Poblete Bustamante M, Gonzalez Guerra O, Leiva Madariaga E, Mujica Escudero V, et al. Peroxisome proliferator-activated receptors: targets for the treatment of metabolic illnesses (Review). Mol Med Rep 2008; 1(3): 317-24. [PMID: 21479412]

[71] Wagner KD, Wagner N. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) acts as regulator of metabolism linked to multiple cellular functions. Pharmacol Ther 2010; 125(3): 423-35. [PMID: 20026355 DOI: 10.1016/j.pharmthera.2009.12.001]

[72] Kim HW, Lee JE, Cha JJ, Hyun YY, Kim JE, et al. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology 2013; 154(9): 3366-76. [PMID: 23825123 DOI: 10.1210/en.2012-2276]

[73] Schwenk BM, Hartmann H, Serdaroglu A, Schludi MH, Hornburg D, et al. TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. EMBO J 2016; 35(21): 2350-70. [PMID: 27621269 DOI: 10.15252/embj.201694221]

[74] Kim HW, Lee JE, Cha JJ, Hyun YY, Kim JE, et al. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology 2013; 154(9): 3366-76. [PMID: 23825123 DOI: 10.1210/en.2012-2276]

[75] Arifa I, Aditsania A, Kurniawan I. The implementation of genetic algorithm-ensemble learning on QSAR study of diacylglycerol acyltransferase-1 (DGAT1) inhibitors as anti-diabetes. In: The International Conference on Data Science and Emerging Technologies. Singapore: Springer Nature Singapore; 2022. pp. 282-92.

[76] Kellerer M, Kaltoft MS, Lawson J, Nielsen LL, Strojek K, et al. Effect of once-weekly semaglutide versus thrice-daily insulin aspart, both as add-on to metformin and optimized insulin glargine treatment in participants with type 2 diabetes (SUSTAIN 11): a randomized, open-label, multinational, phase 3b trial. Diabetes Obes Metab 2022; 24(9): 1788-99. [PMID: 35546450 DOI: 10.1111/dom.14765]

[77] Heller SR, DeVries JH, Wysham C, Hansen CT, Hansen MV, et al. Lower rates of hypoglycaemia in older individuals with type 2 diabetes using insulin degludec versus insulin glargine U100: results from SWITCH 2. Diabetes Obes Metab 2019; 21(7): 1634-41. [PMID: 30891886 DOI: 10.1111/dom.13708]

[78] Yuan X, Guo X, Zhang J, Dong X, Lu Y, et al. Improved glycaemic control and weight benefit with iGlarLixi versus insulin glargine 100 U/mL in Chinese people with type 2 diabetes advancing their therapy from basal insulin plus oral antihyperglycaemic drugs: results from the LixiLan-L-CN randomized controlled trial. Diabetes Obes Metab 2022; 24(11): 2182-91. [PMID: 35762489 DOI: 10.1111/dom.14803]

[79] Battelino T, Danne T, Edelman SV, Choudhary P, Renard E, et al. Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: the head-to-head randomized controlled InRange trial. Diabetes Obes Metab 2023; 25(2): 545-55. [PMID: 36263928 DOI: 10.1111/dom.14898]

[80] Chou CA, Chuang SF. Evaluation of the efficacy of low-dose liraglutide in weight control among Taiwanese non-diabetes patients. J Diabetes Investig 2020; 11(6): 1524-31. [PMID: 32506681 DOI: 10.1111/jdi.13314]

[81] Ramadan NM, Malek HA, Abd-El Rahman K, El-Kholy E, Shaalan D, et al. Liraglutide effect on ventricular transient outward K+ channel and Connexin-43 protein expression. Exp Clin Endocrinol Diabetes 2021; 129(12): 899-907. [PMID: 32559789 DOI: 10.1055/a-1162-8196]

[82] Kahal H, Kilpatrick E, Rigby A, Coady A, Atkin S. The effects of treatment with liraglutide on quality of life and depression in young obese women with PCOS and controls. Gynecol Endocrinol 2019; 35(2): 142-5. [PMID: 30599799 DOI: 10.1080/09513590.2018.1505848]

[83] Yu DN, Wang LJ, Cheng B, Li M, Pan Q, et al. [The effects of liraglutide on body composition and muscle strength in adult obese patients with type 2 diabetes mellitus]. Zhonghua Nei Ke Za Zhi 2021; 60(11): 982-6. [PMID: 34689519 DOI: 10.3760/cma.j.cn112138-20210205-00105]

[84] Kochar IS, Sethi A. Efficacy and safety of liraglutide in Indian adolescents with obesity. Obes Sci Pract 2019; 5(3): 251-7. [PMID: 31275599 DOI: 10.1002/osp4.328]

[85] Sedky AA. Improvement of cognitive function, glucose and lipid homeostasis and serum osteocalcin levels by liraglutide in diabetic rats. Fundam Clin Pharmacol 2021; 35(6): 989-1003. [PMID: 33683755 DOI: 10.1111/fcp.12664]

[86] Omar M, Jensen J, Ali M, Frederiksen PH, Kistorp C, et al. Associations of empagliflozin with left ventricular volumes, mass, and function in patients with heart failure and reduced ejection fraction: a substudy of the empire HF randomized clinical trial. JAMA Cardiol 2021; 6(7): 836-40. [PMID: 33404637 DOI: 10.1001/jamacardio.2020.6827]

[87] Ku EJ, Lee DH, Jeon HJ, Oh TK. Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study. Diabetes Res Clin Pract 2021; 182: 109123. [PMID: 34740742 DOI: 10.1016/j.diabres.2021.109123]

[88] Pasqua MR, Jafar A, Kobayati A, Tsoukas MA, Haidar A. Low-dose empagliflozin as adjunct to hybrid closed-loop insulin therapy in adults with suboptimally controlled type 1 diabetes: a randomized crossover controlled trial. Diabetes Care 2023; 46(1): 165-72. [PMID: 36331522 DOI: 10.2337/dc22-0490]

[89] Mason T, Coelho-Filho OR, Verma S, Chowdhury B, Zuo F, et al. Empagliflozin reduces myocardial extracellular volume in patients with type 2 diabetes and coronary artery disease. JACC Cardiovasc Imaging 2021; 14(6): 1164-73. [PMID: 33454272 DOI: 10.1016/j.jcmg.2020.10.017]

[90] Verzijl CR, Van De Peppel IP, Struik D, Jonker JW. Pegbelfermin (BMS-986036): an investigational PEGylated fibroblast growth factor 21 analogue for the treatment of nonalcoholic steatohepatitis. Expert Opin Investig Drugs 2020; 29(2): 125-33. [PMID: 31899984 DOI: 10.1080/13543784.2020.1708898]

[91] Brown EA, Minnich A, Sanyal AJ, Loomba R, Du S, et al. Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial. JHEP Rep 2023; 5(4): 100661. [PMID: 36866389 DOI: 10.1016/j.jhepr.2022.100661]

[92] Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity (Silver Spring) 2019; 27(1): 41-9. [PMID: 30520566 DOI: 10.1002/oby.22344]

[93] Thompson KE, Guillot M, Graziano MJ, Mangipudy RS, Chadwick KD. Pegbelfermin, a PEGylated FGF21 analogue, has pharmacology without bone toxicity after 1-year dosing in skeletally-mature monkeys. Toxicol Appl Pharmacol 2021; 428: 115673. [PMID: 34364948 DOI: 10.1016/j.taap.2021.115673]

[94] Patwekar M, Patwekar F, Mezni A, Sanaullah S, Fatema SR, et al. Assessment of antioxidative and alpha-amylase potential of polyherbal extract. Evid Based Complement Alternat Med 2022; 2022: 7153526. [PMID: 35685725 DOI: 10.1155/2022/7153526]

[95] Ma T, Tian X, Zhang B, Li M, Wang Y, et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature 2022; 603(7899): 159-65. [PMID: 35197629 DOI: 10.1038/s41586-022-04431-8]

[96] Quazi A, Mohsina FP, Faheem IP, Priya S. In silico ADMET analysis, molecular docking and in vivo anti diabetic activity of polyherbal tea bag formulation in Streptozotocin-nicotinamide induced diabetic rats. Int J Health Sci 2022; 6: 343-72. [DOI: 10.53730/ijhs.v6nS3.5189]

[97] Szymczak-Pajor I, Wenclewska S, Śliwińska A. Metabolic action of metformin. Pharmaceuticals (Basel) 2022; 15(7): 810. [PMID: 35890109 DOI: 10.3390/ph15070810]

[98] Mohsina FP, Faheem IP, Priya S, Husain SM. Evaluation OF anti diabetic activity OF ichnocarpus frutescens L. Int J Adv Pharm Biotechnol 2018; 4: 1-2. [DOI: 10.38111/ijapb.20180402001]

[99] Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med 2022; 387(7): 599-610. [PMID: 36070710 DOI: 10.1056/NEJMoa2201662]

[100] Faheem IP, Gopalakrishna B, Mohsina FP, Priya S . Antidiabetic potential of ethanolic leaf extract of Crataeva magna in streptozotocin-induced diabetic model. Innov Pharmaceutical Pharm 2021; 9: 1-7.

[101] Ameen O, Samaka RM, Abo-Elsoud RA. Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway. Sci Rep 2022; 12(1): 17084. [PMID: 36224264 DOI: 10.1038/s41598-022-20945-7]

[102] Faheem IP, Gopalakrishana B, Mohsina FP, Ahmad N . Antidiabetic activity OF FICUS dalhousiae miq leaves ethanolic extract ON streptozotocin induced diabtes IN wistar albino rats. World J Pharm Res 2020; 10(1): 1258.

[103] Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, et al. Effect of metformin vs placebo on invasive disease-free survival in patients with breast cancer: the MA.32 randomized clinical trial. JAMA 2022; 327(20): 1963-73. [PMID: 35608580 DOI: 10.1001/jama.2022.6147]

[104] Quazi A, Patwekar M, Patwekar F, Mezni A, Ahmad I, et al. Evaluation of wound healing activity (excision wound model) of ointment prepared from infusion extract of polyherbal tea bag formulation in diabetes-induced rats. Evid Based Complement Alternat Med 2022; 2022: 1372199. [PMID: 35707477 DOI: 10.1155/2022/1372199]

[105] Hasanvand A. The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases. Inflammopharmacology 2022; 30(3): 775-88. [PMID: 35419709 DOI: 10.1007/s10787-022-00980-6]

[106] Goel S, Singh R, Singh V, Singh H, Kumari P, et al. Metformin: activation of 5′ AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action. Front Genet 2022; 13: 1022739. [PMID: 36386794 DOI: 10.3389/fgene.2022.1022739]

[107] Di Folco U, Vallecorsa N, Nardone MR, Pantano AL, Tubili C. Effects of semaglutide on cardiovascular risk factors and eating behaviors in type 2 diabetes. Acta Diabetol 2022; 59(10): 1287-94. [PMID: 35842847 DOI: 10.1007/s00592-022-01936-6]

[108] Stretton B, Kovoor J, Bacchi S, Chang S, Ngoi B, et al. Weight loss with subcutaneous semaglutide versus other glucagon-like peptide 1 receptor agonists in type 2 diabetes: a systematic review. Intern Med J 2023; 53(8): 1311-20. [PMID: 37189293 DOI: 10.1111/imj.16126]

[109] Ahmed NR, Kulkarni VV, Pokhrel S, Akram H, Abdelgadir A, et al. Comparing the efficacy and safety of obeticholic acid and semaglutide in patients with non-alcoholic fatty liver disease: a systematic review. Cureus 2022; 14(5): e24829. [PMID: 35693370 DOI: 10.7759/cureus.24829]

[110] Liu SY, Huang CC, Yang YY, Huang SF, Lee TY, et al. Obeticholic acid treatment ameliorates the cardiac dysfunction in NASH mice. PLoS One 2022; 17(12): e0276717. [PMID: 36490253 DOI: 10.1371/journal.pone.0276717]

[111] Inoue Y, Wada Y, Sato M, Sato S, Okamoto T, et al. Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone-induced toxicities in rats: comparative study with other mitochondrial uncouplers (2,4-dinitrophenol, OPC-163493 and tolcapone). Toxicol Res 2023; 39(4): 611-23. [PMID: 37779591 DOI: 10.1007/s43188-023-00189-x]

[112] Tingle SJ, Thompson ER, Bates L, Ibrahim IK, Govaere O, et al. Pharmacological testing of therapeutics using normothermic machine perfusion: a pilot study of 2,4-dinitrophenol delivery to steatotic human livers. Artif Organs 2022; 46(11): 2201-14. [PMID: 35546070 DOI: 10.1111/aor.14309]

[113] Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022; 21(3): 201-23. [PMID: 34815532 DOI: 10.1038/s41573-021-00337-8]

[114] Zhang Z, Zhou D, Luan X, Wang X, Zhu Z, et al. Biodegradable hollow nanoscavengers restore liver functions to reverse insulin resistance in type 2 diabetes. ACS Nano 2023; 17(10): 9313-25. [PMID: 37155357 DOI: 10.1021/acsnano.3c00875]

[115] Halim SA, Lodhi HW, Waqas M, Khalid A, Abdalla AN, et al. Targeting α-amylase enzyme through multi-fold structure-based virtual screening and molecular dynamic simulation. J Biomol Struct Dyn 2024; 42(11): 5617-30. [PMID: 37378513 DOI: 10.1080/07391102.2023.2227721]

[116] Jones-Tabah J. Targeting G protein-coupled receptors in the treatment of Parkinson’s disease. J Mol Biol 2023; 435(12): 167927. [PMID: 36563742 DOI: 10.1016/j.jmb.2022.167927]

[117] Zhang D, Zhang Y, Sun B. The molecular mechanisms of liver fibrosis and its potential therapy in application. Int J Mol Sci 2022; 23(20): 12572. [PMID: 36293428 DOI: 10.3390/ijms232012572]

[118] Ikegami H, Hiromine Y, Noso S. Insulin-dependent diabetes mellitus in older adults: current status and future prospects. Geriatr Gerontol Int 2022; 22(8): 549-53. [PMID: 35711119 DOI: 10.1111/ggi.14414]

[119] Yin W, Zhang Z, Xiao Z, Li X, Luo S, et al. Circular RNAs in diabetes and its complications: current knowledge and future prospects. Front Genet 2022; 13: 1006307. [PMID: 36386812 DOI: 10.3389/fgene.2022.1006307]