INSULYSIN INHIBITORS AS NOVEL ANTI-DIABETIC AGENTS: FROM COMPUTATIONAL DESIGN TO PRE-CLINICAL VALIDATION
Main Article Content
Keywords
Insulysin inhibitors, Insulin-degrading enzyme, Anti-diabetic, In-silico drug design, STZ-NAD diabetic model, Type 2 diabetes
Abstract
Background: Diabetes mellitus is a health crisis that has been increasing worldwide in prevalence and has fewer treatment options. The enzyme insulysin (also called insulin-degrading enzyme, IDE) is also important in insulin metabolism and glucose homeostasis. New insulysin inhibitors are coming up as effective therapeutic agents in the management of diabetes.
Objective: This review assesses the potential to use novel insulinase inhibitors as anti-diabetic agents using an integrated approach involving computational and experimental methods in streptozotocin-nicotinamide induced diabetic rat models.
Methods: An extensive literature review was done with the help of such databases as PubMed, Scopus, and Web of Science that included publications dated 2015-2024. Inlay terms were insulin degrading enzyme, insulin-degrading enzyme, in-silico and STZ-NAD diabetic model.
Results: The existing data indicates that insulinase inhibitors show great anti-diabetic effects in a variety of mechanisms such as the increased insulin sensitivity, improved β-cell act, and decreased insulin degradation. In-silico research indicates potential binding affinities and pharmacokinetic characteristics whereas in-vivo research in STZ-NAD models demonstrates better glycemic control and morphology of the pancreas.
Conclusion: Novel insulinase inhibitors offer a perspective in treating diabetes and a combination of in- Silico and in-vivo studies offers a great strength to the clinical efficacy of the compound.
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13. Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med. 2012;237(5):481-490.
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15. Im H, Manolopoulou M, Malito E, et al. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch. J Biol Chem. 2007;282(35):25453-25463.
16. Shen Y, Joachimiak A, Rosner MR, Tang WJ. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature. 2006;443(7113):870-874.
17. Fernandez-Gacio A, Ugarte M, Espinosa JF. Insulin degrading enzyme: structure-function relationship and its possible roles in health and disease. Curr Pharm Des. 2003;9(4):321-334.
18. Duckworth WC, Hamel FG, Peavy DE. Hepatic metabolism of insulin. Am J Med. 1988;85(5A):71-76.
19. Groves JT, Song Y. Enzymatic catalysis. Models for insulin degrading enzyme and the insulin-degrading enzyme mechanism. J Biol Inorg Chem. 2007;12(7):1015-1025.
20. Zhao L, Teter B, Morihara T, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. J Neurosci. 2004;24(49):11120-11126.
21. Camberos MC, Pérez AA, Udrisar DP, et al. ATP inhibits insulin-degrading enzyme activity. Exp Biol Med. 2001;226(4):334-341.
22. Kurochkin IV. Insulin-degrading enzyme: embarking on amyloid destruction. Trends Biochem Sci. 2001;26(7):421-425.
23. Mukherjee A, Song E, Kihiko-Ehmann M, et al. Insulin degrading enzyme is negatively regulated by protein kinase B/Akt. J Biol Chem. 2000;275(26):20282-20287.
24. Kuo WL, Montag AG, Rosner MR. Insulin-degrading enzyme is differentially expressed and developmentally regulated in various rat tissues. Endocrinology. 1993;132(2):604-611.
25. Fakhrai-Rad H, Nikoshkov A, Kamel A, et al. Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats. Hum Mol Genet. 2000;9(14):2149-2158.
26. Villa-Pérez P, Merino B, Fernández-Díaz CM, et al. Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice. Metabolism. 2018;88:1-11.
27. Pivovarova O, Höhn A, Grune T, et al. Insulin-degrading enzyme: new therapeutic target for type 2 diabetes? Diabetologia. 2016;59(9):1827-1834.
28. Neant-Fery M, Garcia-Ordonez RD, Logan TP, et al. A small-molecule inhibitor of insulin degrading enzyme enhances memory in APP/PS1 mice. Neuropsychopharmacology. 2008;33(13):3016-3026.
29. Karamohamed S, Latourelle JC, Racette BA, et al. LRRK2 G2019S penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol. 2005;4(10):591-594.
30. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701.
31. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-1585.
32. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017;389(10085):2239-2251.
33. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281(21):2005-2012.
34. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-2443.
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Sep 30, 2025
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Divanshi Suryavanshi, Dr.Pragnesh Patani, Milan Jadav, & Dr. Nishkruti R. Mehta. (2025). INSULYSIN INHIBITORS AS NOVEL ANTI-DIABETIC AGENTS: FROM COMPUTATIONAL DESIGN TO PRE-CLINICAL VALIDATION. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1242-1257. https://doi.org/10.53555/npva0c18
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Author Biographies
Divanshi Suryavanshi
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr.Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
Milan Jadav
Assitant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
Professor & Head, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Divanshi Suryavanshi, Dr.Pragnesh Patani, Milan Jadav, & Dr. Nishkruti R. Mehta. (2025). INSULYSIN INHIBITORS AS NOVEL ANTI-DIABETIC AGENTS: FROM COMPUTATIONAL DESIGN TO PRE-CLINICAL VALIDATION. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1242-1257. https://doi.org/10.53555/npva0c18