J Korean Diabetes.  2024 Jun;25(2):82-88. 10.4093/jkd.2024.25.2.82.

Mechanisms of Glucagon Receptor Agonism and GLP-1/Glucagon/GIP Receptor Triple Agonism for Treatment of Diabetes and Obesity

• Min SH

• KMID: 2556758
• DOI: http://doi.org/10.4093/jkd.2024.25.2.82

Abstract

With an increasing prevalence of diabetes and its complications, there is a need for new therapies to improve glycemic control and weight management. Multireceptor agonists may be a means to address this unmet need. A novel triple agonist peptide at the glucagon receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, and the glucagon-like peptide-1 (GLP-1) receptor exhibits balanced glucagon and GLP-1 activity but greater GIP activity. In preclinical research, administration of a triple agonist decreased body weight and enhanced glycemic control. The addition of glucagon receptor-mediated increases in energy expenditure to GIP and GLP-1 receptors-driven calorie restriction promotes body weight loss. In clinical studies, the triple agonist demonstrated an acceptable safety profile, and its pharmacokinetics suggest a once-weekly administration schedule. This discovery, along with the pharmacodynamic findings of robust reductions in body weight and increased glycemic control, indicates a new era of treatment for obesity and type 2 diabetes. This review discusses the metabolic effects of glucagon agonism and the clinical significance of a triple agonist.

Keyword

Diabetes mellitus; Glucagon; Obesity; Triple agonist

Reference

1.Murlin JR., Clough HD., Gibbs CBF., Stokes AM. Aqueous extracts of pancreas: I. Influence on the carbohydrate me-tabolism of depancreatized animals. J Biol Chem. 1923. 56:253–96.

2.Wewer Albrechtsen NJ., Holst JJ., Cherrington AD., Finan B., Gluud LL., Dean ED, et al. 100 years of glucagon and 100 more. Diabetologia. 2023. 66:1378–94.

3.Rix I., Nexøe-Larsen C., Bergmann NC., Lund A., Knop FK. Glucagon physiology. Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, editors. Endotext. South Dartmouth (MA): MDText.com, Inc.;2000.

4.Stern JH., Smith GI., Chen S., Unger RH., Klein S., Scherer PE. Obesity dysregulates fasting-induced changes in glucagon secretion. J Endocrinol. 2019. 243:149–60.

5.Guan HP., Yang X., Lu K., Wang SP., Castro-Perez JM., Previs S, et al. Glucagon receptor antagonism induces increased cholesterol absorption. J Lipid Res. 2015. 56:2183–95.

6.Cheng C., Jabri S., Taoka BM., Sinz CJ. Small molecule glucagon receptor antagonists: an updated patent review (2015-2019). Expert Opin Ther Pat. 2020. 30:509–26.

7.Al-Massadi O., Fernø J., Diéguez C., Nogueiras R., Quiñones M. Glucagon control on food intake and energy balance. Int J Mol Sci. 2019. 20:3905.

8.Conceição-Furber E., Coskun T., Sloop KW., Samms RJ. Is glucagon receptor activation the thermogenic solution for treating obesity? Front Endocrinol (Lausanne). 2022. 13:868037.

9.Kleinert M., Sachs S., Habegger KM., Hofmann SM., Müller TD. Glucagon regulation of energy expenditure. Int J Mol Sci. 2019. 20:5407.

10.Samols E., Marri G., Marks V. Promotion of insulin secretion by glucagon. Lancet. 1965. 2:415–6.

11.Holter MM., Saikia M., Cummings BP. Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion. Front Endocrinol (Lausanne). 2022. 13:934775.

12.Stockinger Z., Geary N. Pancreatic glucagon does not alter intrameal gastric emptying of milk in the rat. Physiol Be-hav. 1989. 45:1259–61.

13.Jakubowska A., Roux CWL., Viljoen A. The road towards triple agonists: glucagon-like peptide 1, glucose-depen-dent insulinotropic polypeptide and glucagon receptor - an update. Endocrinol Metab (Seoul). 2024. 39:12–22.

14.Novikoff A., Müller TD. The molecular pharmacology of glucagon agonists in diabetes and obesity. Peptides. 2023. 165:171003.

15.Habegger KM., Stemmer K., Cheng C., Müller TD., Hep-pner KM., Ottaway N, et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes. 2013. 62:1453–63.

16.Klein T., Augustin R., Hennige AM. Perspectives in weight control in diabetes - survodutide. Diabetes Res Clin Pract. 2024. 207:110779.

17.Pocai A., Carrington PE., Adams JR., Wright M., Eiermann G., Zhu L, et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes. 2009. 58:2258–66.

18.Liu YL., Ford HE., Druce MR., Minnion JS., Field BC., Shillito JC, et al. Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents. Int J Obes (Lond). 2010. 34:1715–25.

19.Tan TM., Field BC., McCullough KA., Troke RC., Cham-bers ES., Salem V, et al. Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyper-glycemia. Diabetes. 2013. 62:1131–8.

20.Ambery PD., Klammt S., Posch MG., Petrone M., Pu W., Rondinone C, et al. MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, phase 1 study. Br J Clin Pharmacol. 2018. 84:2325–35.

21.Nahra R., Wang T., Gadde KM., Oscarsson J., Stumvoll M., Jermutus L, et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care. 2021. 44:1433–42.

22.Ambery P., Parker VE., Stumvoll M., Posch MG., Heise T., Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018. 391:2607–18.

23.Melson E., Ashraf U., Papamargaritis D., Davies MJ. What is the pipeline for future medications for obesity? Int J Obes (Lond). 2024. doi: 10.1038/s41366-024-01473-y. [Epub ahead of print].

24.Di Prospero NA., Yee J., Frustaci ME., Samtani MN., Alba M., Fleck P. Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with type 2 diabetes mellitus and obesity: a randomized dose-ranging study. Clin Obes. 2021. 11:e12433.

25.Finan B., Yang B., Ottaway N., Smiley DL., Ma T., Clem-mensen C, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015. 21:27–36.

26.Coskun T., Urva S., Roell WC., Qu H., Loghin C., Moyers JS, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022. 34:1234–47.e9.

27.Rosenstock J., Frias J., Jastreboff AM., Du Y., Lou J., Gurbuz S, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, dou-ble-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023. 402:529–44.

28.Jastreboff AM., Kaplan LM., Frías JP., Wu Q., Du Y., Gurbuz S., Retatrutide Phase 2 Obesity Trial Investigators, et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. N Engl J Med. 2023. 389:514–26.