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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Review Article

Molecular Pathology and Therapeutic Strategies of Type 2 Diabetes

Author(s): Helen Ziqing Liao, Yanting Liang, Ye Wang and Chun Liang*

Volume 23, Issue 11, 2023

Published on: 09 June, 2023

Page: [1392 - 1399] Pages: 8

DOI: 10.2174/1871530323666230320162753

Price: $65

Abstract

Diabetes Mellitus (DM) is a metabolic disorder characterized by hyperglycemia. Over the years, scientists have identified many factors that may have causal relationships with DM development. Identified factors are either genetic or environmental, and they may promote or prevent DM development. This review discusses various factors that are involved in the molecular pathogenesis, development, and therapeutic strategies of type 2 diabetes. DM is caused by interactions between multiple factors and triggers. Altered metabolic pathways and cellular functions, primarily in organs involved in glucose metabolisms, such as the pancreas and liver, often result in metabolic dysfunction, leading to DM. Additionally, abnormal levels of some factors, the presence of some pathogens, or the use of some types of medicine, such as immuno-inflammatory mediators, glucagon, apolipoprotein E4, chromogranin-A, exosomes, vitamin D, viruses, glucocorticoid medication, and antipsychotic drugs, may play roles in the development of DM. Some of these factors and mechanisms are well-studied, while others are more controversial and have contradicting experimental results. Further research is needed to confirm the roles of these factors in DM and fully understand how they contribute to DM development. Numerous medications for diabetics have been developed to help alleviate the symptoms of hyperglycemia and its complications. Several types of small compounds or peptide drugs with anti-diabetic effects can decrease blood glucose levels, improve insulin resistance, and inhibit key enzymes involved in the development and progression of diabetes. Here, we review the commonly used effective antidiabetic drugs, including the most recent innovative ones, such as GLP- 1R/GIPR and GLP-1R/GCGR agonists, and Chinese medicine.

« Previous Next »
[1]
Blair, M. Diabetes mellitus review. Urol. Nurs., 2016, 36(1), 27-36.
[http://dx.doi.org/10.7257/1053-816X.2016.36.1.27] [PMID: 27093761]
[2]
Kahn, S.E.; Cooper, M.E.; Del Prato, S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet, 2014, 383(9922), 1068-1083.
[http://dx.doi.org/10.1016/S0140-6736(13)62154-6] [PMID: 24315620]
[3]
Classification and diagnosis of diabetes. Diabetes care, American Diabetes Association, 25(38 Suppl), S8-S166.
[http://dx.doi.org/10.2337/dc15-5005]
[4]
Takiishi, T.; Gysemans, C.; Bouillon, R.; Mathieu, C. Vitamin D and diabetes. Rheum. Dis. Clin. North Am., 2012, 38(1), 179-206.
[http://dx.doi.org/10.1016/j.rdc.2012.03.015] [PMID: 22525851]
[5]
Álvarez-Almazán, S.; Filisola-Villaseñor, J.G.; Alemán-González-Duhart, D.; Tamay-Cach, F.; Mendieta-Wejebe, J.E. Current molecular aspects in the development and treatment of diabetes. J. Physiol. Biochem., 2020, 76(1), 13-35.
[http://dx.doi.org/10.1007/s13105-019-00717-0] [PMID: 31925679]
[6]
Forbes, J.M.; Cooper, M.E. Mechanisms of diabetic complications. Physiol. Rev., 2013, 93(1), 137-188.
[http://dx.doi.org/10.1152/physrev.00045.2011] [PMID: 23303908]
[7]
Sarıkaya, E.; Doğan, S. Glutathione peroxidase in health and diseases. IntechOpen. Available from: https://www.intechopen.com/chapters/70955
[http://dx.doi.org/10.5772/intechopen.91009]
[8]
Acheson, K.J.; Schutz, Y.; Bessard, T.; Anantharaman, K.; Flatt, J.P.; Jéquier, E. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am. J. Clin. Nutr., 1988, 48(2), 240-247.
[http://dx.doi.org/10.1093/ajcn/48.2.240] [PMID: 3165600]
[9]
Alwahsh, S.; Dwyer, B.; Forbes, S.; van Thiel, D.; Starkey Lewis, P.; Ramadori, G. Insulin production and resistance in different models of diet-induced obesity and metabolic syndrome. Int. J. Mol. Sci., 2017, 18(2), 285.
[http://dx.doi.org/10.3390/ijms18020285] [PMID: 28134848]
[10]
Butler, A.E.; Janson, J.; Bonner-Weir, S.; Ritzel, R.; Rizza, R.A.; Butler, P.C. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 2003, 52(1), 102-110.
[http://dx.doi.org/10.2337/diabetes.52.1.102] [PMID: 12502499]
[11]
Gromada, J.; Chabosseau, P.; Rutter, G.A. The α-cell in diabetes mellitus. Nat. Rev. Endocrinol., 2018, 14(12), 694-704.
[http://dx.doi.org/10.1038/s41574-018-0097-y] [PMID: 30310153]
[12]
Lee, Y.; Wang, M.Y.; Du, X.Q.; Charron, M.J.; Unger, R.H. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes, 2011, 60(2), 391-397.
[http://dx.doi.org/10.2337/db10-0426] [PMID: 21270251]
[13]
Moore, B.; Edie, E.S.; Abram, J.H. On the treatment of Diabetus mellitus by acid extract of duodenal mucous membrane. Biochem. J., 1906, 1(1), 28-38.
[http://dx.doi.org/10.1042/bj0010028] [PMID: 16742013]
[14]
Gutniak, M.K.; Svartberg, J.; Hellström, P.M.; Holst, J.J.; Adner, N.; Ahrén, B. Antidiabetogenic action of glucagon-like peptide-1 related to administration relative to meal intake in subjects with type 2 diabetes. J. Intern. Med., 2001, 250(1), 81-87.
[http://dx.doi.org/10.1046/j.1365-2796.2001.00862.x] [PMID: 11454146]
[15]
Moore, M.C.; Coate, K.C.; Winnick, J.J.; An, Z.; Cherrington, A.D. Regulation of hepatic glucose uptake and storage in vivo. Adv. Nutr., 2012, 3(3), 286-294.
[http://dx.doi.org/10.3945/an.112.002089] [PMID: 22585902]
[16]
Seino, Y.; Fukushima, M.; Yabe, D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J. Diabetes Investig., 2010, 1(1-2), 8-23.
[http://dx.doi.org/10.1111/j.2040-1124.2010.00022.x] [PMID: 24843404]
[17]
Koren-Iton, A.; Salomon-Zimri, S.; Smolar, A.; Shavit-Stein, E.; Dori, A.; Chapman, J.; Michaelson, D.M. Central and peripheral mechanisms in apoe4-driven diabetic pathology. Int. J. Mol. Sci., 2020, 21(4), 1289.
[http://dx.doi.org/10.3390/ijms21041289] [PMID: 32075060]
[18]
Mahapatra, N.R.; O’Connor, D.T.; Vaingankar, S.M.; Hikim, A.P.S.; Mahata, M.; Ray, S.; Staite, E.; Wu, H.; Gu, Y.; Dalton, N.; Kennedy, B.P.; Ziegler, M.G.; Ross, J., Jr; Mahata, S.K. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J. Clin. Invest., 2005, 115(7), 1942-1952.
[http://dx.doi.org/10.1172/JCI24354] [PMID: 16007257]
[19]
Gayen, J.R.; Saberi, M.; Schenk, S.; Biswas, N.; Vaingankar, S.M.; Cheung, W.W.; Najjar, S.M.; O’Connor, D.T.; Bandyopadhyay, G.; Mahata, S.K. A novel pathway of insulin sensitivity in chromogranin A null mice: a crucial role for pancreastatin in glucose homeostasis. J. Biol. Chem., 2009, 284(42), 28498-28509.
[http://dx.doi.org/10.1074/jbc.M109.020636] [PMID: 19706599]
[20]
Tang, K.; Pasqua, T.; Biswas, A.; Mahata, S.; Tang, J.; Tang, A.; Bandyopadhyay, G.K.; Sinha-Hikim, A.P.; Chi, N.W.; Webster, N.J.G.; Corti, A.; Mahata, S.K. Muscle injury, impaired muscle function and insulin resistance in Chromogranin A-knockout mice. J. Endocrinol., 2017, 232(2), 137-153.
[http://dx.doi.org/10.1530/JOE-16-0370] [PMID: 27799464]
[21]
Herold, Z.; Doleschall, M.; Kovesdi, A.; Patocs, A.; Somogyi, A. Chromogranin A and its role in the pathogenesis of diabetes mellitus. Endokrynol. Pol., 2018, 69(5), 598-610.
[http://dx.doi.org/10.5603/EP.a2018.0052] [PMID: 30074235]
[22]
Colombo, M.; Raposo, G.; Théry, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol., 2014, 30(1), 255-289.
[http://dx.doi.org/10.1146/annurev-cellbio-101512-122326] [PMID: 25288114]
[23]
homou, T.; Mori, M.A.; Dreyfuss, J.M.; Konishi, M.; Sakaguchi, M.; Wolfrum, C. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature, 2017, 542(7642), 450-455.
[24]
Mori, M.A.; Raghavan, P.; Thomou, T.; Boucher, J.; Robida-Stubbs, S.; Macotela, Y.; Russell, S.J.; Kirkland, J.L.; Blackwell, T.K.; Kahn, C.R. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab., 2012, 16(3), 336-347.
[http://dx.doi.org/10.1016/j.cmet.2012.07.017] [PMID: 22958919]
[25]
Deng, Z.; Poliakov, A.; Hardy, R.W.; Clements, R.; Liu, C.; Liu, Y.; Wang, J.; Xiang, X.; Zhang, S.; Zhuang, X.; Shah, S.V.; Sun, D.; Michalek, S.; Grizzle, W.E.; Garvey, T.; Mobley, J.; Zhang, H.G. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes, 2009, 58(11), 2498-2505.
[http://dx.doi.org/10.2337/db09-0216] [PMID: 19675137]
[26]
Grammatiki, M.; Karras, S.; Kotsa, K. The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: A narrative review. Hormones, 2019, 18(1), 37-48.
[http://dx.doi.org/10.1007/s42000-018-0063-z] [PMID: 30255482]
[27]
Li, L.; Wu, B.; Liu, J.Y.; Yang, L.B. Vitamin D receptor gene polymorphisms and type 2 diabetes: A meta-analysis. Arch. Med. Res., 2013, 44(3), 235-241.
[http://dx.doi.org/10.1016/j.arcmed.2013.02.002] [PMID: 23506721]
[28]
Repaske, D.R. medication‐induced diabetes mellitus. Pediatr. Diabetes, 2016, 17(6), 392-397.
[http://dx.doi.org/10.1111/pedi.12406] [PMID: 27492964]
[29]
Henderson, D.C.; Cagliero, E.; Gray, C.; Nasrallah, R.A.; Hayden, D.L.; Schoenfeld, D.A.; Goff, D.C. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am. J. Psychiatry, 2000, 157(6), 975-981.
[http://dx.doi.org/10.1176/appi.ajp.157.6.975] [PMID: 10831479]
[30]
Chathoth, V.; Ramamurthy, P.; Solomon, S. Clozapine-induced insulin-resistant hyperglycemia in a diabetic patient. Indian J. Psychol. Med., 2018, 40(4), 375-377.
[http://dx.doi.org/10.4103/IJPSYM.IJPSYM_373_17] [PMID: 30093751]
[31]
Vigneri, R.; Goldfine, I.D. Role of metformin in treatment of diabetes mellitus. Diabetes Care, 1987, 10(1), 118-122.
[http://dx.doi.org/10.2337/diacare.10.1.118] [PMID: 3552509]
[32]
Hawley, S.A.; Ross, F.A.; Chevtzoff, C.; Green, K.A.; Evans, A.; Fogarty, S.; Towler, M.C.; Brown, L.J.; Ogunbayo, O.A.; Evans, A.M.; Hardie, D.G. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab., 2010, 11(6), 554-565.
[http://dx.doi.org/10.1016/j.cmet.2010.04.001] [PMID: 20519126]
[33]
Fiévet, C.; Fruchart, J.; Staels, B. PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. Curr. Opin. Pharmacol., 2006, 6(6), 606-614.
[http://dx.doi.org/10.1016/j.coph.2006.06.009] [PMID: 16973418]
[34]
Puls, W. Pharmacology of glucosidase inhibitors. In: Oral antidiabetics; kuhlmann, J.; Puls, W., Eds.; Oral antidiabeties Handbook of experimental pharmacology, vol 1119. Springer, berlin, Heidelberg., 1996; pp. 497-534.
[http://dx.doi.org/10.1007/978-3-662-09127-2_17]
[35]
Derosa, G.; Maffioli, P. Mini-special issue paper management of diabetic patients with hypoglycemic agents α-glucosidase inhibitors and their use in clinical practice. Arch. Med. Sci., 2012, 5(5), 899-906.
[http://dx.doi.org/10.5114/aoms.2012.31621] [PMID: 23185202]
[36]
Proks, P.; Reimann, F.; Green, N.; Gribble, F.; Ashcroft, F. Sulfonylurea stimulation of insulin secretion. Diabetes, 2002, 51(S3), S368-S376.
[http://dx.doi.org/10.2337/diabetes.51.2007.S368] [PMID: 12475777]
[37]
Chen, M.; Hu, C.; Jia, W. Pharmacogenomics of glinides. Pharmacogenomics, 2015, 16(1), 45-60.
[http://dx.doi.org/10.2217/pgs.14.152] [PMID: 25560470]
[38]
Shubrook, J.; Baradar-Bokaie, B.; Adkins, S. Empagliflozin in the treatment of type 2 diabetes: Evidence to date. Drug Des. Devel. Ther., 2015, 9, 5793-5803.
[http://dx.doi.org/10.2147/DDDT.S69926] [PMID: 26586935]
[39]
Lee, Y.S.; Shin, S.; Shigihara, T.; Hahm, E.; Liu, M.J.; Han, J.; Yoon, J.W.; Jun, H.S. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes, 2007, 56(6), 1671-1679.
[http://dx.doi.org/10.2337/db06-1182] [PMID: 17369525]
[40]
Zheng, S.L.; Roddick, A.J.; Aghar-Jaffar, R.; Shun-Shin, M.J.; Francis, D.; Oliver, N.; Meeran, K. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes. JAMA, 2018, 319(15), 1580-1591.
[http://dx.doi.org/10.1001/jama.2018.3024] [PMID: 29677303]
[41]
Abrahami, D.; Douros, A.; Yin, H.; Yu, O.H.Y.; Renoux, C.; Bitton, A.; Azoulay, L. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: Population based cohort study. BMJ, 2018, 360, k872.
[http://dx.doi.org/10.1136/bmj.k872] [PMID: 29563098]
[42]
Al-Zamel, N.; Al-Sabah, S.; Luqmani, Y.; Adi, L.; Chacko, S.; Schneider, T.D.; Krasel, C. A dual GLP-1/GIP receptor agonist does not antagonize glucagon at its receptor but may act as a biased agonist at the GLP-1 receptor. Int. J. Mol. Sci., 2019, 20(14), 3532.
[http://dx.doi.org/10.3390/ijms20143532] [PMID: 31330984]
[43]
Pocai, A.; Carrington, P.E.; Adams, J.R.; Wright, M.; Eiermann, G.; Zhu, L.; Du, X.; Petrov, A.; Lassman, M.E.; Jiang, G.; Liu, F.; Miller, C.; Tota, L.M.; Zhou, G.; Zhang, X.; Sountis, M.M.; Santoprete, A.; Capito’, E.; Chicchi, G.G.; Thornberry, N.; Bianchi, E.; Pessi, A.; Marsh, D.J.; SinhaRoy, R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes, 2009, 58(10), 2258-2266.
[http://dx.doi.org/10.2337/db09-0278] [PMID: 19602537]
[44]
Jastreboff, A.M.; Aronne, L.J.; Ahmad, N.N.; Wharton, S.; Connery, L.; Alves, B.; Kiyosue, A.; Zhang, S.; Liu, B.; Bunck, M.C.; Stefanski, A. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med., 2022, 387(3), 205-216.
[http://dx.doi.org/10.1056/NEJMoa2206038] [PMID: 35658024]
[45]
Chen, Y.; Song, S.; Shu, A.; Liu, L.; Jiang, J.; Jiang, M.; Wu, Q.; Xu, H.; Sun, J. The herb pair radix rehmanniae and cornus officinalis attenuated testicular damage in mice with diabetes mellitus through butyric acid/glucagon-like peptide-1/glucagon-like peptide-1 receptor pathway mediated by gut microbiota. Front. Microbiol., 2022, 13, 831881.
[PMID: 35273587]
[46]
Zeng, H.; Li, X.; Zhou, D.; Wang, N.; Yu, X.; Long, L.; Cheng, H.; Zhou, S.; Shen, Z.; Zhou, W. Qihu preparation ameliorates diabetes by activating the ampk signaling pathway in db/db mice. Diabetes Metab. Syndr. Obes., 2021, 14, 3229-3241.
[http://dx.doi.org/10.2147/DMSO.S312137] [PMID: 34285530]

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