What Are Insulinotropic Polypeptides? How Are They Regulated?

What Are Insulinotropic Polypeptides? 

Insulinotropic polypeptides regulate insulin secretion in response to meal consumption (Hammoud, 2024). GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (Glucagon-Like Peptide-1) are the two most well-known insulinotropic polypeptides (Vilsbøll, 2003). These peptides belong to the incretin hormone family and play an important role in glucose metabolism by stimulating insulin release from pancreatic beta cells in a glucose-dependent manner (Seino, 2023)

K-cells in the small intestine secrete GIP, whereas L-cells in the lower intestine generate GLP-1 (Rehfeld, 2018). Both hormones stimulate insulin secretion, whereas GLP-1 slows stomach emptying and decreases hunger (Jalleh, 2024). GIP, on the other hand, regulates lipid metabolism and may promote fat storage (Sachs, 2024). Insulinotropic polypeptides have been targeted for therapeutic interventions due to their glucose-regulating properties, particularly in the management of diabetes and obesity.

One of the most recent developments in this field is retatrutide, a new triple agonist that targets GIP, GLP-1, and glucagon receptors (Jastreboff, 2023). In clinical trials, this medication shown potential weight loss and metabolic improvements (Lilly, 2023; Sanyal, 2024).

How Are Insulinotropic Polypeptides Biologically Regulated? 

Dietary intake, metabolic condition, and hormone interactions all have a strong influence on insulinotropic polypeptide secretion and activity.

1. Nutrient Intake - Ingestion of carbs, lipids, and proteins causes the production of GIP and GLP-1. High-fat meals boost GIP production, while carbs largely promote GLP-1 release (Fukuda, 2021).

 2. Glucose-Dependent Action - Unlike insulin, which can be produced in response to a variety of stimuli, GIP and GLP-1 only increase insulin release when blood glucose levels rise. This lowers the risk of hypoglycemia (Christensen, 2015).

3. Enzymatic Breakdown - The enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades GIP and GLP-1, limiting its half-life. This has resulted in the creation of DPP-4 inhibitors, a type of diabetic drug that prolongs incretin action (Yin, 2022).

4. Receptor Interactions: GIP and GLP-1 activate their respective receptors on pancreatic beta cells (GIPR and GLP-1R), leading to increased insulin production (Zaïmia, 2023). However, GLP-1 has other effects, such as slowing stomach emptying and decreasing hunger, making it an important target for obesity therapy.

Retatrutide and Its Clinical Significance 

Retatrutide is an investigational triple receptor agonist that targets the GIP, GLP-1, and glucagon receptors, presenting a novel approach to metabolic illness management. A 48-week phase 2 obesity study found significant weight reductions of 22.8% and 24.2% at 8 mg and 12 mg doses, respectively (Lilly, 2023) (Sanyal, 2024). 

A substudy of metabolic dysfunction-associated steatotic liver disease (MASLD) discovered that retatrutide significantly reduced liver fat (Kaur, 2024). Participants with at least 10% liver fat at baseline received once-weekly subcutaneous injections of retatrutide (1 mg, 4 mg, 8 mg, or 12 mg) or placebo. After 24 weeks, liver fat reductions were (Lilly, 2023) (Sanyal, 2024):

- 1 mg dose: −42.9%

- 4 mg dose: −57.0%

- 8 mg dose: −81.4%  

- 12 mg dose: −82.4%  

- Placebo: +0.3%   

These findings show that retatrutide not only increases weight loss but also dramatically improves metabolic indicators, insulin sensitivity, and lipid metabolism, giving it a promising treatment option for obesity and MASLD (Lilly, 2023) (Sanyal, 2024).

Regulation of Insulinotropic Polypeptides and Related Therapies 

The United States Food and Drug Administration (FDA) regulates insulinotropic polypeptide-based medicines (CFR Title 21). Incretin-based medications, such as GLP-1 receptor agonists and DPP-4 inhibitors, must go through rigorous clinical trials to prove their safety, effectiveness, and long-term metabolic advantages. 1. Clinical Trial Phases - Incretin-based medicines, like all new pharmaceuticals, must go through preclinical investigations, then Phase 1, 2,  surveillance programs, which document adverse events and long-term risks. 3. Combination Therapies - As with retatrutide, multi-receptor agonists (targeting GIP, GLP-1, and glucagon) are emerging and necessitate extra regulatory considerations. 4. Special FDA Considerations – Incretin therapies require extensive cardiovascular outcome trials (CVOTs) before widespread use due to potential risks such as pancreatitis, thyroid tumors, and cardiovascular effects (Ibrahim, 2011).

 The European Medicines Agency (EMA) and other global agencies, such as Japan's PMDA and China's NMPA, have their own approval processes for incretin-based drugs.

Future Directions and Market Growth

With the popularity of GLP-1 receptor agonists such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro), the market for incretin-based medicines is fast growing. The development of multi-receptor agonists, such as retatrutide, represents the next generation of metabolic therapy.

The global demand for obesity and diabetes treatments is rising, with the market for incretin-based insulinotropic medicines likely to expand dramatically over the next decade (Pardeshi, 2023). Future research will investigate the long-term safety and efficacy of multi-receptor agonists.- The potential cardiovascular benefits of combo treatments. - New medicine formulations with extended half-lives to decrease injection frequency.

As regulatory agencies improve approval processes for next-generation metabolic medications, polypeptides will continue to be an important area of innovation in the treatment of diabetes, obesity, and metabolic diseases.

References

Adkison, J. (2024, April 1). Comparing ozempic, Wegovy and other GLP-1 drugs. GoodRx. https://www.goodrx.com/classes/glp-1-agonists/glp-1-drugs-comparison

Christensen, M., Calanna, S., Sparre-Ulrich, A. H., Kristensen, P. L., Rosenkilde, M. M., Faber, J., Purrello, F., van Hall, G., Holst, J. J., Vilsbøll, T., & Knop, F. K. (2015). Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes. Diabetes, 64(1), 72–78. doi: 10.2337/db14-0440

Hammoud, R., Kaur, K. D., Koehler, J. A., Baggio, L. L., Wong, C. K., Advani, K. E., Yusta, B., Efimova, I., Gribble, F. M., Reimann, F., Fishman, S., Varol, C., & Drucker, D. J. (2024). Glucose-dependent insulinotropic polypeptide receptor signaling alleviates gut inflammation in mice. JCI Insight, 9(12), e174825. doi: 10.1172/jci.insight.174825

FBI. (2021). Incretin-based therapies market size, share & COVID-19 impact analysis, by type (GLP-1 agonists, DPP-4 inhibitors), by application, and regional forecast, 2021–2028. Fortune Business Insights.

Fukuda, M. (2021). The role of GIP receptor in the CNS for the pathogenesis of obesity. Diabetes, 70(9), 1929–1937. doi: 10.2337/dbi21-0001

Ibrahim, J. G., Chen, M.-H., Xia, H. A., & Liu, T. (2011). Bayesian meta‐experimental design: Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Biometrics, 68(2), 578–586. https://doi.org/10.1111/j.1541-0420.2011.01679.x

Jalleh, R. J., Plummer, M. P., Marathe, C. S., Umapathysivam, M. M., Quast, D. R., Rayner, C. K., Jones, K. L., Wu, T., Horowitz, M., & Nauck, M. A. (2024). Clinical consequences of delayed gastric emptying with GLP-1 receptor agonists and tirzepatide. The Journal of Clinical Endocrinology & Metabolism, 110(1), 1–15. doi: 10.1210/clinem/dgae719

Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., Hartman, M. L., & Retatrutide Phase 2 Obesity Trial Investigators (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. The New England journal of medicine, 389(6), 514–526. 10.1056/NEJMoa2301972

Kaur, M., & Misra, S. (2024). A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity. European Journal of Clinical Pharmacology, 80(5), 669–676. doi: 10.1007/s00228-024-03646-0

Lilly. (2023, June 26). Lilly’s Phase 2 retatrutide results published in the New England Journal of Medicine Show the Investigational Molecule achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight. PR Newswire: press release distribution, targeting, monitoring and marketing. https://www.prnewswire.com/news-releases/lillys-phase-2-retatrutide-results-published-in-the-new-england-journal-of-medicine-show-the-investigational-molecule-achieved-up-to-17-5-mean-weight-reduction-at-24-weeks-in-adults-with-obesity-and-overweight-301863690.html 

Pardeshi, M., & Deshmukh, R. (2023, December). Incretin-based drugs market statistics, forecast - 2032. Allied Market Research. https://www.alliedmarketresearch.com/incretin-based-drugs-marketb

Rehfeld, J. F. (2018). The origin and understanding of the incretin concept. Frontiers in Endocrinology, 9, 387. doi: 10.3389/fendo.2018.00387

Sachs, S., Götz, A., Finan, B., Feuchtinger, A., DiMarchi, R. D., Döring, Y., Weber, C., Tschöp, M. H., Müller, T. D., & Hofmann, S. M. (2024). Correction: GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease. Cardiovascular Diabetology, 23(1), 341.

Sanyal, A. J., Kaplan, L. M., Frias, J. P., Brouwers, B., Wu, Q., Thomas, M. K., Harris, C., Schloot, N. C., Du, Y., Mather, K. J., Haupt, A., & Hartman, M. L. (2024). Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: A randomized phase 2a trial. Nature Medicine, 30(7), 2037–2048. doi: 10.1038/s41591-024-03018-2

Seino, Y., Fukushima, M., & Yabe, D. (2010). GIP and GLP-1, the two incretin hormones: Similarities and differences. Journal of Diabetes Investigation, 1(1-2), 8–23. doi: 10.1111/j.2040-1124.2010.00022.x

Vilsbøll, T., Krarup, T., Madsbad, S., & Holst, J. J. (2003). Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regulatory Peptides, 114(2), 115–121. doi: 10.1016/S0167-0115(03)00111-3

Yin, R., Xu, Y., Wang, X., Yang, L., & Zhao, D. (2022). Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules, 27(10), 3055. doi: 10.3390/molecules27103055

Zaïmia, N., Obeid, J., Varrault, A., Sabatier, J., Broca, C., Gilon, P., Costes, S., Bertrand, G., & Ravier, M. A. (2023). GLP-1 and GIP receptors signal through distinct β-arrestin 2-dependent pathways to regulate pancreatic β cell function. Cell Reports, 42(11), 113326. doi: 10.1016/j.celrep.2023.113326