Therapeutic Peptides for the Treatment of Type 2 Diabetes and Weight Loss

Therapeutic peptides have emerged as promising drugs for treating various medical conditions, including type 2 diabetes and weight loss. 

The chronic metabolic disorder Type 2 diabetes is distinguished by insulin resistance and impaired insulin secretion, resulting in elevated blood sugar levels. Obesity often coexists with type 2 diabetes and worsens its complications, making weight management a crucial aspect of diabetes treatment.

Peptides play significant roles in various physiological processes within the body. In the context of type 2 diabetes and weight loss, therapeutic peptides offer several advantages over traditional medications, including high specificity, low toxicity, and reduced risk of adverse effects.

One of the most well-known therapeutic peptides for type 2 diabetes treatment is a glucagon-like peptide-1 (GLP-1) agonist. The intestine secretes the hormone peptide GLP-1 in response to food intake. GLP-1 induces insulin secretion from pancreatic beta cells, inhibits glucagon secretion, slows gastric emptying, and promotes satiety. Synthetic GLP-1 agonists, such as exenatide, liraglutide, and dulaglutide, mimic the actions of endogenous GLP-1. In patients with type 2 diabetes, GLP-1 helps to regulate blood sugar levels. Additionally, GLP-1 agonists are associated with weight loss due to their effects on appetite suppression and delayed gastric emptying.

In recent years, the commercial approval of peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor for type II diabetes treatment has marked a significant milestone in the field. The FDA's approval of liraglutide (Victoza®; Novo Nordisk), semaglutide (Ozempic®, Rybelsus®; Novo Nordisk), and dulaglutide (Trulicity®; Eli Lilly), and semaglutide (Wegovy®; Novo Nordisk) for weight loss has not only expanded the range of treatment options but also sparked a new wave of interest in this type of peptide.

Another class of therapeutic peptides used in treating type 2 diabetes are amylin analogs. Amylin is a hormone co-secreted with insulin by pancreatic beta cells. It regulates glucose metabolism by suppressing glucagon secretion, slowing gastric emptying, and promoting satiety. Pramlintide, the synthetic analog of amylin, allows the treatment of patients for whom other medications have failed. Pramlintide helps to reduce glucose levels after a meal, which can result in weight loss by reducing food intake.

In addition to targeting glucose metabolism, therapeutic peptides for weight loss aim to regulate appetite and energy expenditure. One example is the melanocortin-4 receptor (MC4R) agonist setmelanotide. MC4R is involved in regulating food intake and energy balance. Setmelanotide stimulates MC4R signaling, leading to reduced appetite and increased energy expenditure. Setmelanotide allows the treatment of rare genetic disorders associated with severe obesity, such as pro-opiomelanocortin (POMC) deficiency and leptin receptor (LEPR) deficiency.

Despite their therapeutic potential, therapeutic peptides for type 2 diabetes and weight loss may have limitations, including the need for injection and high cost. Also, there are potential side effects, such as nausea, vomiting, and hypoglycemia. However, a significant goal of ongoing research is to overcome these challenges by developing novel peptide-based therapies with improved efficacy, safety, and convenience of administration. 

Overall, therapeutic peptides represent promising drugs to manage type 2 diabetes and obesity, offering targeted approaches to address underlying metabolic dysregulation and promote better health outcomes.

Weight loss peptides targeting the glucagon-like peptide-1 (GLP-1) receptor interact with multiple organs and tissues (See Figure 1).

Figure 1: Physiological actions of glucagon-like peptide-1 (GLP-1) 

(Source: wikimedia commons)

Therapeutic peptide drugs are pharmaceuticals that selectively target biological molecules. The FDA has approved over 80 peptide drugs, and many more are enrolled in preclinical studies and clinical development. Moreover, the versatility of therapeutic peptides is now being harnessed in a wide range of medical areas, from cancer and metabolism to respiratory, cardiovascular, urology, autoimmune, pain, and antimicrobial applications. This broad spectrum of applications not only demonstrates the adaptability of therapeutic peptides but also underscores their immense potential in revolutionizing modern medicine, inspiring a new era of treatment possibilities.

Drugs to treat type 2 diabetes and chronic obesity target the glucagon-like peptide-1 receptor (GLP-1R). Therapeutic peptides such as glucagon, liraglutide, and semaglutide are peptide hormone mimetics targeting GLP-1R. The introduction of side chain modifications avoids degradation and increases the pharmacokinetics of the peptides.

Standard automated solid-phase peptide synthesis allows timely synthesis of these peptide analogs in mg to gram amounts. However, cost-efficient methods for larger quantities are now available for combining solid-phase synthesis with liquid-phase synthesis. Proprietary synthetic approaches developed by Biosynthesis Inc. now allow the synthesis of these peptides ranging from mgs to kgs.

Table 1: Therapeutic GLP-1 Peptide Analogs

Peptide Drug

Model and Sequence

Approval Date


Glucagon is a 29 amino acid hormone used as a diagnostic aid in radiologic exams to temporarily inhibit the gastrointestinal tract's movement and treat severe hypoglycemia. Glucagon raises blood sugar by activating hepatic glucagon receptors, stimulating glycogenolysis and the release of glucose. The alpha cells of the pancreatic islets of Langerhans secret glucagon. drugbank

Glucagon Physiology




 >Glucagon for Injection Sequence  HSQGTFTSDYSKYLDSRRAQDFVQWLMNT

  US 1960

Glucagon like peptide 1 (GLP-1)


GLP-1 (glucagon-like peptide-1) is a gut-derived peptide hormone released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic β-cells in a glucose-dependent manner. Gut-derived peptides are also known as incretins. Incretins are a group of metabolic hormones stimulating a decrease in blood glucose levels. PMC



 >pdb|3IOL|B Chain B, Glucagon




Exenatide is a glucagon-like peptide-1 (GLP-1) analog sold under the brand names Bydureon BCise and Byetta. It activates the GLP-1 receptor and increases insulin secretion, decreases glucagon secretion, and slows gastric emptying to improve glycemic control. It is used in the management of type 2 diabetes mellitus.

drugbank, Exenatide





 US 2005


Pramlintide (Symlin®) The amylin analog Pramlintide allows the management of type 1 and type 2 diabetes mellitus as an adjunct to prior to dinner insulin therapy in patients without adequate glycemic control of insulin therapy.

Amylin is a glucoregulatory hormone synthesized by pancreatic β-cells and released into the bloodstream after a meal. Like insulin, amylin is deficient in individuals with diabetes. The drug is provided as an acetate salt. Pramlintide is a 37-amino acid polypeptide that differs structurally from human amylin by replacing alanine, serine, and serine at positions 25, 28, and 29, respectively, with proline.

drugbank, Pramlintide, 8F2B


 >pdb|8F2B|P Chain P, pramlintide analogue San45






Liraglutide is sold under the brand names Victoza and Saxenda. Liraglutide is used to treat type 2 diabetes, obesity, and chronic weight management. In diabetes, it is a less preferred agent than metformin. Its effects on long-term health outcomes like heart disease and life expectancy are unclear. Liraglutide is injected under the skin. The fatty acid side chain and the resulting self-association and albumin binding protect against dipeptidyl peptidase IV (DPP-IV)-mediated degradation. Liraglutide, drugbank


 Liraglutide Sequence (gamma-E-palmitoyl at K20)


 EU 2009

 US 2010


Eli Lilly markets Dulaglutide under the brand name Trulicity. It is a once-weekly subcutaneous glucagon-like peptide-1 (GLP-1) receptor agonist designed using recombinant DNA technology.

It was approved as an adjunct therapy to diet and exercise in the management of type 2 diabetes (T2DM). The FDA initially approved dulaglutide in 2014 and, in February 2020, approved it for use in patients with T2DM and multiple cardiovascular risk factors for the prevention of cardiovascular events. It is the first T2DM drug approved to reduce major adverse cardiovascular events (MACE) risk in primary and secondary prevention populations.

drugbank, Dulaglutide


> Dulaglutide Sequence 


 US 2014


Semaglutide is sold under the brand names Ozempic and Rybelsus for diabetes and Wegovy for weight loss. The GLP-1 analog semaglutide treats type 2 diabetes, obesity, and chronic weight management. For weight loss, semaglutide is recommended to be used together with a modified diet and exercise for long-term weight loss. Semaglutide, drugbank


  >pdb|7KI0|P Chain P, Semaglutide


  US 2017


Setmelanotide is sold under the brand name Imcivree. It is a medication for the treatment of genetic obesity caused by a rare single-gene mutation.

Setmelanotide can treat obesity caused by genetic POMC, PCSK1, LEPR deficiencies, or Bardet-Biedl syndrome.

Setmelanotide is an agonist of the melanocortin 4 receptor.

Earlier attempts at agonizing MC4R (such as LY2112688) led to successful weight loss but also an increase in blood pressure and heart rate. Other earlier treatments for these patients included gastric bypass surgery. Patients taking setmelanotide experienced an average weight loss of 0.6 kg/week.

drugbank, Setmelanotide



 US 2020

 US 2021



Al-Majed, A. A., Bakheit, A. H., Abdel‐Aziz, H. A., Alharbi, H. F., & Al-Jenoobi, F. I. (2016). Pioglitazone. Profiles of Drug Substances, Excipients and Related Methodology. Science Direct

Andersen, A., Lund, A., Knop, F. K. & Vilsbøll, T. Glucagon-like peptide 1 in health and disease. Nat. Rev. Endocrinol. 14, 390–403 (2018). PubMed

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. doi: 10.1111/bph.13496. Epub 2016 May 18. PMID: 27061187; PMCID: PMC4882495. PMC

Cao J, Belousoff MJ, Gerrard E, Danev R, Fletcher MM, Dal Maso E, Schreuder H, Lorenz K, Evers A, Tiwari G, Besenius M, Li Z, Johnson RM, Wootten D, Sexton PM. Structural insight into selectivity of amylin and calcitonin receptor agonists. Nat Chem Biol. 2024 Feb;20(2):162-169. doi: 10.1038/s41589-023-01393-4. Epub 2023 Aug 3. PMID: 37537379. NIH

Collins & Costello; Glucagone-Like Peptide-1 Receptor Agonists NIH

Drucker, D J.; The Glucagon-Like Peptides, Endocrinology, Volume 142, Issue 2, 1 February 2001, Pages 521-527,  Endocrinology

Frederick MO, Boyse RA, Braden TM, Calvin JR, Campbell BM, Changi SM, et al. (2021). "Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing". Organic Process Research & Development25 (7): 1628–1636. ACS

Gao Y, Yuan X, Zhu Z, Wang D, Liu Q, Gu W. Research and prospect of peptides for use in obesity treatment (Review). Exp Ther Med. 2020 Dec;20(6):234. PMC

Gross, J. L., Kramer, C. K., Leitão, C. B., Hawkins, N., Viana, L. V., Schaan, B. D., Pinto, L. C., Rodrigues, T. C., & Azevedo, M. J. (2011). Effect of antihyperglycemic agents added to metformin and a sulfonylurea on glycemic control and weight gain in type 2 diabetes: A network meta-analysis. Annals of Internal Medicine

Holst JJ (October 2007). "The physiology of glucagon-like peptide 1". Physiological Reviews87 (4): 1409-39.  Physiological Review

Hoogwerf BJ, Doshi KB, Diab D. Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk. Vasc Health Risk Manag. 2008;4(2):355-62. PMC

Li, C. M. et al. Novel peptide therapeutic approaches for cancer treatment. Cells 10, 2908 (2021). PMC

Li, S. et al. Therapeutic peptides for treatment of lung diseases: infection, fibrosis, and cancer. Int. J. Mol. Sci. 24, 8642 (2023). PMC

Liu HK, Green BD, Gault VA, McCluskey JT, McClenaghan NH, O’Harte FPM, et al.. N-Acetyl-GLP-1: A Dpp IV-resistant Analogue of Glucagon-Like Peptide-1 (GLP-1) With Improved Effects on Pancreatic β-Cell-Associated Gene Expression. Cell Biol Int (2004) 28:69–73.   10.1016/j.cellbi.2003.10.004 PubMed

Muttenthaler, M., King, G. F., Adams, D. J. & Alewood, P. F. Trends in peptide drug discovery. Nat. Rev. Drug Discov. 20, 309–325 (2021). PubMed

Raffort J, Lareyre F, Massalou D, Fénichel P, Panaïa-Ferrari P, Chinetti G. Insights on glicentin, a promising peptide of the proglucagon family. Biochem Med (Zagreb). 2017 Jun 15;27(2):308-324. PMC

Ryan DH. Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice? J Obes Metab Syndr. 2021 Sep 30;30(3):196-208. PMC

Sasaki K, Dockerill S, Adamiak DA, Tickle IJ, Blundell T. X-ray analysis of glucagon and its relationship to receptor binding. Nature. 1975 Oct 30;257(5529):751-7. NIH; pdb/1GCN

Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S. Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. J Biol Chem. 2010 Jan 1;285(1):723-30. PMC; pdb/3IOL

Underwood, C. R. (2013). Ligand binding and activation mechanism og the glucagon-like peptide-1 receptor. Thesis 2013.pdf

US Food and Drug Administration. FDA approves new drug treatment for chronic weight management, first since 2014. [Press release]. 2021. www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014 Available at: (accessed 26 June 2023).

US patent 9474780, Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, "GIP and GLP-1 co-agonist compounds", issued 2016-10-25, assigned to Eli Lilly and Co.

Vadevoo, S. M. P. et al. Peptides as multifunctional players in cancer therapy. Exp. Mol. Med. 55, 1099–1109 (2023). PMC

Wang, L. et al. Therapeutic peptides: current applications and future directions. Sig Transduct. Target Ther. 7, 48 (2022). Nature

Zhao F, Zhou Q, Cong Z, Hang K, Zou X, Zhang C, Chen Y, Dai A, Liang A, Ming Q, Wang M, Chen LN, Xu P, Chang R, Feng W, Xia T, Zhang Y, Wu B, Yang D, Zhao L, Xu HE, Wang MW. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun. 2022 Feb 25;13(1):1057. PMC; Tirzepatide pdb/7VAB