 |
Publisher: Peytchinski Publishing Ltd.
ISSN: 1312-773X (Online)
Issue: 2026, vol. 32, issue2
Subject Area: Medicine
-
DOI: 10.5272/jimab.2026322.6901
Published online: 08 June 2026
Review article
J of IMAB. 2026 Apr-Jun;32(2):6901-6907
AMYLIN AND AMYLIN ANALOGS – FUTURE THERAPEUTIC STRATEGIES FOR THE TREATMENT OF TYPE 2 DIABETES AND OBESITY
Nikolinka Koleva1
, Boris Dinkov1, 2
, Galya Stavreva1,
1) Department of Pharmacology and Toxicology, Medical University of Pleven, Bulgaria.
2) Clinic of Endocrinology and Metabolic Diseases, University Hospital "Dr Georgi Stranski" - Pleven, Bulgaria.
ABSTRACT:
Amylin is a peptide hormone co-synthesized with insulin in pancreatic beta cells at a ratio of 1:100. Notably, amylin has a pronounced tendency to form toxic amyloid fibrils, a characteristic relevant to its pathological role.
Purpose: This study aims to review both approved amylin analogs (AAs) and those currently in preclinical and clinical development, with a focus on their molecular structure, pharmacokinetics, receptor activity, and metabolic outcomes.
Methods: A comprehensive literature review was conducted using PubMed and clinical trial databases. The analysis focused on structure-function relationships of AAs, biotechnological modifications influencing pharmacokinetics, receptor pharmacology (AMY 1-3), and their effects on glycemic control and appetite.
Results: Pramlintide, approved by the FDA in 2005, delays gastric emptying, suppresses postprandial glucagon secretion, improves HbA1c, and induces modest weight loss. Dual amylin-calcitonin receptor agonists (DACRAs) represent next-generation drugs. Davalintide, in phase II trials, has demonstrated reductions in food intake, body weight, and HbA1c. It was ultimately discontinued due to insufficient efficacy and an unfavorable tolerability profile. KBP-089 and KBP-088 have shown favorable metabolic and hepatic effects in preclinical studies. Cagrilintide, a long-acting amylin analog combined with semaglutide (CagriSema), is currently in phase III clinical trials, showing significantly greater weight loss and improved glycemic control compared to monotherapy. Novel investigational agents, including NN1213, eloralintide, petrelintide, MET-233i, and amycretin, have demonstrated substantial weight loss, signaling a new era in amylin-based obesity pharmacotherapy.
Conclusion: Amylin analogs present a compelling dual-targeted approach for managing T2D and obesity by improving both glycemic control and weight outcomes. Ongoing clinical trials will further define their long-term therapeutic role.
Keywords: amylin, amylin analogs, diabetes, obesity,
- Download FULL TEXT /PDF 771 KB/
Please cite this article as: Koleva N, Dinkov B, Stavreva G. Amylin and Amylin Analogs – Future Therapeutic Strategies for the Treatment of Type 2 Diabetes and Obesity. J of IMAB. 2026 Apr-Jun;32(2):6901-6907. [Crossref - 10.5272/jimab.2026322.6901]
Correspondence to: Boris Dinkov, Department of Pharmacology and Toxicology, Medical University of Pleven; 1, Kliment Ohridski Str., 5800 Pleven, Bulgaria; E-mail: Boris.Dinkov@mu-pleven.bg
REFERENCES:
1. Marzban L, Soukhatcheva G, Verchere CB. Role of carboxypeptidase E in processing of pro-islet amyloid polypeptide in {beta}-cells. Endocrinology. 2005 Apr;146(4):1808-17. [PubMed]
2. Higham CE, Hull RL, Lawrie L, Shennan KI, Morris JF, Birch NP, et al. Processing of synthetic pro-islet amyloid polypeptide (proIAPP) 'amylin' by recombinant prohormone convertase enzymes, PC2 and PC3, in vitro. Eur J Biochem. 2000 Aug;267(16):4998-5004. [PubMed]
3. Wickbom J, Herrington MK, Permert J, Jansson A, Arnelo U. Gastric emptying in response to IAPP and CCK in rats with subdiaphragmatic afferent vagotomy. Regul Pept. 2008 Jun 5;148(1-3):21–5. [PubMed]
4. Coester B, Pence SW, Arrigoni S, Boyle CN, Le Foll C, Lutz TA. RAMP1 and RAMP3 Differentially Control Amylin's Effects on Food Intake, Glucose and Energy Balance in Male and Female Mice. Neuroscience. 2020 Nov 1;447:74-93. [PubMed]
5. Fernandes-Santos C, Zhang Z, Morgan DA, Guo DF, Russo AF. Rahmouni K. Amylin acts in the central nervous system to increase sympathetic nerve activity. Endocrinology. 2013 Jul;154(7):2481–88. [PubMed]
6. Mietlicki-Baase EG. Amylin-mediated control of glycemia, energy balance, and cognition. Physiol Behav. 2016 Aug 1;162:130-40. [PubMed]
7. Boccia L, Gamakharia S, Coester B, Whiting L, Lutz TA, Le Foll C. Amylin brain circuitry. Peptides. 2020 Oct;132:170366. [PubMed]
8. Coester B, Koester-Hegmann C, Lutz TA, Le Foll C. Amylin/Calcitonin Receptor-Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice. Diabetes. 2020 Jun;69(6):1110-1125. [PubMed]
9. Liberini CG, Boyle CN, Cifani C, Venniro M, Hope BT, Lutz TA. Amylin receptor components and the leptin receptor are co-expressed in single rat area postrema neurons. Eur J Neurosci. 2016 Mar;43(5):653-61. [PubMed]
10. Mathai ML, Sosa Leon LA, May CN, Thomson CE, McKinley MJ. Amylin induces natriuresis by a central angiotensin-dependent mechanism. Regul Pept. 2005 Aug 15;130(1-2):91-6. [PubMed]
11. Chien V, Aitken J, Zhang S, Buchanan C, Hickey A, Brittain T, et al. The chaperone proteins HSP70, HSP40/DnaJ and GRP78/BiP suppress misfolding and formation of β-sheet-containing aggregates by human amylin: a potential role for defective chaperone biology in Type 2 diabetes. Biochem J. 2010 Nov 15;432(1):113-21. [PubMed]
12. Singh S, Bhowmick DC, Pany S, Joe M, Zaghlula N, Jeremic AM. Apoptosis signal regulating kinase-1 and NADPH oxidase mediate human amylin evoked redox stress and apoptosis in pancreatic beta-cells. Biochim Biophys Acta Biomembr. 2018 Sep;1860(9):1721-1733. [PubMed]
13. Abedini A, Cao P, Plesner A, Zhang J, He M, Derk J, et al. RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity. J Clin Invest. 2018 Feb 1;128(2):682-698. [PubMed]
14.Westermark P, Engström U, Johnson KH, Westermark GT, Betsholtz C. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5036-40. [PubMed]
15. Westwell-Roper C, Dunne A, Kim M, Verchere CB, Masters SL Activating the NLRP3 inflammasome using the amyloidogenic peptide IAPP. Methods Mol Biol. 2013 Jun;1040:9-18. [Crossref]
16. Raleigh D, Zhang X, Hastoy B, Clark A. The β-cell assassin: IAPP cytotoxicity. J Mol Endocrinol. 2017 Oct;59(3):R121-40. [Crossref]
17. Zhang XX, Pan YH, Huang YM, Zhao HL Neuroendocrine hormone amylin in diabetes. World J Diabetes. 2016 May 10;7(9):189-97. [PubMed]
18. Bower RL, Hay DL. Amylin structure-function relationships and receptor pharmacology: implications for amylin mimetic drug development. Br J Pharmacol. 2016 Jun;173(12):1883-98. [PubMed]
19. Westermark GT, Krogvold L, Dahl-Jørgensen K, Ludvigsson J. Islet amyloid in recent-onset type 1 diabetes-the DiViD study. Ups J Med Sci. 2017 Aug;122(3):201-203[PubMed]
20. Mazzini G, Le Foll C, Boyle CN, Garelja ML, Zhyvoloup A, Miller MET, et al. The processing intermediate of human amylin, pro-amylin(1–48), has in vivo and in vitro bioactivity. Biophys Chem. 2024 May:308:107201. [Crossref]
21. Blackard WG, Clore JN, Kellum JM. Amylin/insulin secretory ratios in morbidly obese man: inverse relationship with glucose disappearance rate. J Clin Endocrinol Metab. 1994 May;78(5):1257-60. [PubMed]
22. Kailasam MT, Parmer RJ, Tyrell EA, Henry RR, O'Connor DT. Circulating amylin in human essential hypertension: heritability and early increase in individuals at genetic risk. J Hypertens. 2000 Nov;18(11):1611-20. [PubMed]
23. Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, et al. β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol. 2011 Jun;178(6):2632-40. [PubMed]
24. Boyle CN, Zheng Y, Lutz TA. Mediators of Amylin Action in Metabolic Control. J Clin Med. 2022 Apr 15;11(8):2207. [PubMed]
25. Gurlo T, Kim S, Butler AE, Liu C, Pei L, Rosenberger M, Butler PC. Pregnancy in human IAPP transgenic mice recapitulates beta cell stress in type 2 diabetes. Diabetologia. 2019 Jun;62(6):1000-10. [PubMed]
26. Maianti JP, McFedries A, Foda ZH, Kleiner RE, Du XQ, Leissring MA, et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature. 2014 Jul 3;511(7507):94-8. [PubMed]
27. Larsen AT, Sonne N, Andreassen KV, Karsdal MA, Henriksen K. The Calcitonin Receptor Plays a Major Role in Glucose Regulation as a Function of Dual Amylin and Calcitonin Receptor Agonist Therapy. J Pharmacol Exp Ther. 2020 Jul;374(1):74-83. [PubMed]
28. Bartelt A, Jeschke A, Müller B, Gaziano I, Morales M, Yorgan T, et al. Differential effects of Calca-derived peptides in male mice with diet-induced obesity. PLoS One. 2017 Jun 30;12(6):e0180547. [PubMed]
29. Gydesen S, Hjuler ST, Freving Z, Andreassen KV, Sonne N, Hellgren LI, et al. A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference. Br J Pharmacol. 2017 Apr;174(7):591-602. [PubMed]
30. D'Ascanio AM, Mullally JA, Frishman WH. Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity. Cardiol Rev. 2024 Jan-Feb 01;32(1):83-90. [PubMed]
31. Kruse T, Hansen JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. J Med Chem. 2021 Aug 12;64(15):11183-11194. [PubMed]
32. Garvey WT, Blüher M, Osorto Contreras CK, Davies MJ, Winning Lehmann E, Pietiläinen KH, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025 Aug 14;393(7):635-647. Jun 22. [PubMed]
33. Dahl K, Raun K, Hansen JL, Poulsen C, de la Cour CD, Clausen TR, et al. NN1213 - A Potent, Long-Acting, and Selective Analog of Human Amylin. J Med Chem. 2024 Jul 25;67(14):11688-11700. [PubMed ]
34. Zealand Pharma. ZUPREME-1 Phase 2 topline results. GlobeNewswire; 2026 Mar 5. [Internet]
35. Briere DA, Qu H, Lansu K, He MM, Moyers JS, Coskun T, et al., Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept. Mol Metab. 2025 Dec;102:102271. [PubMed]
36. Bailey CJ, Flatt PR, Conlon JM. Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes. Peptides. 2026 Mar;196:171480. [PubMed]
37. Dahl K, Toubro S, Dey S, Duque do Vale R, Flint A, Gasiorek A, et al., Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet. 2025 Jul 12;406(10499):149-162. [PubMed]
Received: 18 September 2025
Published online: 08 June 2026