Studies of Tirzepatide in Obesity and Type 2 Diabetes

Tirzepatide is a novel peptide that is a modified version of the incretins called glucose-dependent insulinotropic polypeptide (GIP), formerly known as gastric inhibitory peptide and GLP-1 (Glucagon-like peptide-1).The duodenum and small intestines may produce incretins following caloric intake, and an incretin’s function is to stimulate insulin production.^[1] This may help the organism produce enough insulin before glucose is released into the bloodstream.

Tirzepatide peptide has 14 unique amino acids (engineered from the GIP sequence) and an amidated exenatide-like (GLP-1 agonist) C terminus. It is made of 39 amino acids and has a sequence of YXEGTFTSDY SIXLDKIAQK AFVQWLIAGG PSSGAPPPS. Tirzepatide was developed to activate both the GLP-1 and GIP receptors. In general, it potentially activates GIP more significantly than GLP-1. Furthermore, Tirzepatide peptide may also be also lipidated, which is suggested to improve its bioavailability and stability.

 

Research on Tirzepatide

 

Tirzepatide Peptide and Type 2 Diabetes

Tirzepatide appears to help control blood sugar levels by activating both the GIP and GLP-1 receptors. Both receptors can be found in the pancreas and other organs such as the gut, heart, and brain.^[2,3] Activating the receptors in the pancreas may lead to the release of insulin and improved control over blood sugar levels. Tirzepatide peptide is under active study as to its efficacy in triggering these receptors.

The potential of Tirzepatide peptide appears to be glucose-dependent, so the peptide may not trigger insulin secretion if glucose levels are low or average. Therefore, Tirzepatide may have an advantage over many other anti-diabetic research compounds as it is not likely to cause hypoglycemia.

Another possible advantage of the dual-agonist potential characteristics of Tirzepatide peptide is that it may lead to better glycemic control than GLP-1 agonists. A meta-analysis of 26 randomized control studies observed that Tirzepatide may have higher efficacy than similar research compounds, like Semaglutide, Liraglutide, Sitagliptin, Canagliflozin, and Empagliflozin.^[4][5]

Further studies suggest that Tirzepatide has the potential to reduce appetite and calorie intake, leading to weight loss and improved insulin sensitivity.^[6] Some scientists suggest that a significant part of the improvement in insulin sensitivity may be independent of weight loss.

For example, one study reported that about 15-20% of the improvement in insulin sensitivity appeared to be weight loss related, while the other 80-85% was apparently attributed to the potential action of the peptide.^[7] Moreover, the researchers noted that the beneficial action on insulin resistance and glucose control appeared to be greater than other experimental peptides which appear to activate GLP-1 alone, such as Dulaglutide, potentially.

 

Tirzepatide Peptide and Obesity

The largest study on obese non-diabetic research models was conducted in 2022.^[9] In 17 months of study, the research models averaged a 20% or more loss in body weight. Tirzepatide may also lead to a significant reduction of visceral fat. In contrast to subcutaneous fat, visceral fat is the adipose tissue that deposits around and inside the internal organs. Small amounts of visceral fats are essential for the normal functioning of the organs. However, obese research models often exhibit increased levels of visceral fat. This is called visceral obesity, which may lead to severe metabolic problems. This is potentially because visceral fat appears to be more metabolically active than subcutaneous fat and releases significant amounts of proinflammatory cytokines and triglycerides in the bloodstream.^[10] As a result, an elevated level of inflammation and triglycerides may lead to insulin resistance, unfavorable lipid profile, etc.

Ultimately, research suggests visceral obesity is a significant risk factor for chronic conditions such as type 2 diabetes, heart disease, and cancer.^[11] Studies hypothesize that Tirzepatide may help with weight loss and visceral fat reduction. One study in obese research models of fatty liver suggested that for 12 months of exposure, the peptide led to an average of 8% reduction in liver fat.^[12] The researchers concluded that “Tirzepatide peptide showed a significant reduction in LFC and VAT and ASAT volumes compared with insulin degludec in this subpopulation … with type 2 diabetes in the SURPASS-3 study. ” Despite the research suggesting the significant potential of the peptide on weight loss, as of 2023, the peptide is still in testing and is under research within the context of obesity with related comorbidities.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References

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1. Thorens B. (1995). Glucagon-like peptide-1 and control of insulin secretion. Diabete & metabolisme, 21(5), 311–318.
2. Usdin, T. B., Mezey, E., Button, D. C., Brownstein, M. J., & Bonner, T. I. (1993). Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology, 133(6), 2861–2870. https://doi.org/10.1210/endo.133.6.8243312
3. Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D. Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides. J Clin Endocrinol Metab. 2009 Jun;94(6):1843-52. doi: 10.1210/jc.2008-1296. Epub 2009 Mar 31. PMID: 19336511; PMCID: PMC2690432.
4. Zaazouee, M. S., Hamdallah, A., Helmy, S. K., Hasabo, E. A., Sayed, A. K., Gbreel, M. I., Elmegeed, A. A., Aladwan, H., Elshanbary, A. A., Abdel-Aziz, W., Elshahawy, I. M., Rabie, S., Elkady, S., Ali, A. S., Ragab, K. M., & Nourelden, A. Z. (2022). Semaglutide for the treatment of type 2 Diabetes Mellitus: A systematic review and network meta-analysis of safety and efficacy outcomes. Diabetes & metabolic syndrome, 16(6), 102511. https://doi.org/10.1016/j.dsx.2022.102511
5. Permana, H., Yanto, T. A., & Hariyanto, T. I. (2022). Efficacy and safety of tirzepatide as novel treatment for type 2 diabetes: A systematic review and meta-analysis of randomized clinical trials. Diabetes & metabolic syndrome, 16(11), 102640. https://doi.org/10.1016/j.dsx.2022.102640
6. Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, Milicevic Z, Urva S, Haupt A, Robins DA. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes Metab. 2020 Jun;22(6):938-946. doi: 10.1111/dom.13979. Epub 2020 Feb 11. PMID: 31984598; PMCID: PMC7318331.
7. Thomas, M. K., Nikooienejad, A., Bray, R., Cui, X., Wilson, J., Duffin, K., Milicevic, Z., Haupt, A., & Robins, D. A. (2021). Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. The Journal of clinical endocrinology and metabolism, 106(2), 388–396. https://doi.org/10.1210/clinem/dgaa863
8. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4. PMID: 35658024.
9. Heerspink HJL, Sattar N, Pavo I, Haupt A, Duffin KL, Yang Z, Wiese RJ, Tuttle KR, Cherney DZI. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022 Nov;10(11):774-785. doi: 10.1016/S2213-8587(22)00243-1. Epub 2022 Sep 21. PMID: 36152639.
10. Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013 Jan;93(1):359-404. doi: 10.1152/physrev.00033.2011. PMID: 23303913.
11. Dhawan D, Sharma S. Abdominal Obesity, Adipokines and Non-communicable Diseases. J Steroid Biochem Mol Biol. 2020 Oct;203:105737. doi: 10.1016/j.jsbmb.2020.105737. Epub 2020 Aug 18. PMID: 32818561; PMCID: PMC7431389.
12. Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022 Jun;10(6):393-406. doi: 10.1016/S2213-8587(22)00070-5. Epub 2022 Apr 22. PMID: 35468325.