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Tirzepatide: Research in Weight, Insulin Sensitivity, and Cardiac Function

by | Jun 7, 2023 | peptides

Tirzepatide: Research in Weight, Insulin Sensitivity, and Cardiac Function
Comprised of 39 amino acids, Tirzepatide, a synthetic analog of the gastric inhibitory polypeptide (GIP), stands as a comparatively large peptide that appears to exert physiological potential through targeting and binding to GIP and GLP-1 (glucagon-like peptide-1) receptors. 

Through this possible binding mechanism, Tirzepatide may stimulate insulin release from pancreatic cells, potentially enhancing glucose metabolism. Notably, the long-term presentation of Tirzepatide has been reported by researchers to elicit an apparent increase in adiponectin levels.1 Scientific investigations have indicated that Tirzepatide may exhibit an array of actions, including possible suppression of appetite, reduction of circulating insulin levels, and possible improvement of insulin sensitivity. 

How does the Tirzepatide peptide produce action?

By engaging the GIP and GLP-1 receptors, Tirzepatide may possibly initiate a signaling cascade, culminating in the stimulation of insulin secretion from the pancreatic beta cells. This augmentation of insulin release may possibly enhance glucose utilization and improve glycemic.(2) 

Tirzepatide’s potential to bind to GLP-1 receptors may contribute to its possible impact on weight and adipose tissue modulation. Activation of GLP-1 receptors by Tirzepatide might lead to the inhibition of gastric emptying, slowing down the rate at which nutrients are absorbed from the gastrointestinal tract. This deceleration of nutrient absorption would attenuate postprandial glucose excursions and contribute to satiety. Collectively, the complex mechanism of action of Tirzepatide as suggested by research teams, involving engagement with GIP and GLP-1 receptors, may orchestrate a cascade of potential physiological responses, including augmented insulin secretion, appetite suppression, weight loss, improved insulin sensitivity, and modulation of adipose tissue function.

Extensive research has suggested that Tirzepatide may have the potential to exhibit GIP-like activity at the GIPR. At the same time, at the GLP-1R, it may exert a possible preference for cyclic adenosine monophosphate (cAMP) production rather than β-arrestin recruitment. Although these intricate details may appear somewhat arcane, this disparity in activity compared to endogenous GLP-1 appears to confer GLP-1R activation, possibly without concurrent elevation of physiological receptor internalization. Consequently, Tirzepatide has the potential to manifest possible enhanced GLP-1R activity in comparison to both endogenous GLP-1 and other synthetic GLP-1R agonists.(2)

These subtle modifications engender a possibly substantial augmentation of insulin secretion, satiety induction, and adipose tissue inflammation mitigation. 

 

Research Studies on Tirzepatide Peptide

Tirzepatide Peptide and Appetite

According to research findings, the initial introduction of Tirzepatide in test models appears to cause a delay in gastric emptying, which gradually diminishes over time, possibly due to the development of tachyphylaxis. These observations mirror the potential action observed with pure glucagon-like peptide-1 receptor (GLP-1R) agonists, indicating that Tirzepatide’s potential impact on gastric emptying may primarily be governed by GLP-1 activity, rather than any gastric inhibitory polypeptide (GIP) activity.(3)

However, researchers have noted that the potential of Tirzepatide on gastric emptying may be extended if the peptide is introduced at a low concentration for four weeks, followed by a subsequent escalation in concentration. Any possible delayed gastric emptying induced by Tirzepatide may have the potential to enhance sensations of satiety and alleviate hunger in test subjects.

Tirzepatide and Cardiac System

Researchers have suggested that Tirzepatide may modulate adiponectin levels. Low adiponectin levels have been associated with atherosclerosis, obesity, and heart disease, while elevated adiponectin levels have been correlated with a reduced risk of such conditions. Studies conducted on test models with type 2 diabetes have suggested that Tirzepatide may improve lipoprotein biomarkers by reducing triglyceride levels, apoC-III, and several other lipoproteins.(4)

Collectively, these potential actions may contribute to reduced adiposity. Increased adiponectin levels have been linked to favorable outcomes such as higher levels of high-density lipoprotein (HDL) and lower levels of triglycerides, both of which are associated with a diminished risk of heart dysfunction. 

Moreover, Tirzepatide appears to exert additional potential via reducing macrophage scavenger receptors and augmenting cholesterol efflux. As per researchers, “Adiponectin has various molecular anti-atherosclerotic properties, such as reduction of scavenger receptors in macrophages and increase of cholesterol efflux. These findings suggest that high levels of circulating adiponectin can protect against atherosclerosis. Weight loss, exercise, nutritional factors, anti-diabetic drugs, lipid-lowering drugs, and anti-hypertensive drugs have been associated with an increase of serum adiponectin level,” and Tirzepatide appears to exhibit similar potential.(5)

Tirzepatide Peptide and Inflammation

Research suggests that Tirzepatide may play a role in indirectly regulating factors such as inflammation and endothelial cell dysfunction.(6)

GLP-1 signaling appears to have a direct impact on endothelial function. Activation of GLP-1 signaling has been suggested to induce vasodilation, resulting in decreased blood pressure and improved perfusion of end organs. This action is attributed to increased expression of endothelial nitric oxide synthase (eNOS), an enzyme responsible for nitric oxide generation and subsequent vascular relaxation. 

Inflammation is also considered by researchers to be influenced by GLP-1 signaling. Although the precise mechanisms are still under investigation, GLP-1 signaling has been associated with reduced NF-κB signaling, decreased matrix metalloproteinase-9 (MMP-9) activity, inhibition of inflammatory cytokine synthesis, and attenuation of inflammatory macrophage activity. Research suggests that these anti-inflammatory actions appear to persist for up to three months following a single presentation of a GLP-1 receptor (GLP-1R) agonist, such as Tirzepatide.(6)

Researchers state that based on these results, GLP-1 receptor agonists such as Tirzepatide “exerts specific cardiovascular actions in diabetes and may attenuate the development and progression of associated cardiovascular complications.”(6)

Tirzepatide Peptide and Weight

 A comparative analysis between Tirzepatide and other glucagon-like peptide-1 (GLP-1) analogs suggests a remarkable distinction. While Tirzepatide appeared to yield a concentration-dependent reduction in weight over time, other GLP-1 receptor agonists (GLP-1R) reportedly induced weight gain, according to comparative research studies.(7)

The underlying mechanism potentially responsible for Tirzepatide’s possible action on weight appears to stem from its agonistic activity on gastric inhibitory polypeptide (GIP) receptors. GIP has been suggested to directly influence the insulin sensitivity of adipocytes directly, thereby modulating adiponectin levels. Research teams suggest that Tirzepatide appears to activate GIP receptors in adipose tissue, potentially leading to heightened insulin sensitivity. Consequently, this process may contribute to alleviating adipose tissue inflammation, elevation of adiponectin levels, and associated properties. However, this represents only part of the comprehensive explanation.

Emerging research indicates that GIP signaling in the central nervous system (CNS) may possibly regulate hypothalamic feeding centers, resulting in decreased food intake and possibly improved glucose regulation.(8) Therefore, researchers suggest, Tirzepatide seems to exert influence on weight through adiponectin signaling directly in adipose tissue and via central nervous system modifications, which appear to diminish hunger levels through GIP receptor (GIPR) signaling in the brain.

 

Synopsis

Tirzepatide, a synthetic analog of gastric inhibitory polypeptide (GIP) with concurrent glucagon-like peptide-1 (GLP-1) activity, may possess multifaceted mechanisms of action. Its potential dual functionality may enable Tirzepatide to lower blood glucose levels, enhance insulin sensitivity, promote satiety, and facilitate weight loss. Researchers have suggested Tirzepatide may host additional cardiovascular protective potential as well.

 

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References:

  1. Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, Milicevic Z, Haupt A, Robins DA. Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab. 2021 Jan 23;106(2):388-396. doi: 10.1210/clinem/dgaa863. PMID: 33236115; PMCID: PMC7823251. https://pubmed.ncbi.nlm.nih.gov/33236115/ 
  2. Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, Capozzi ME, van der Velden WJ, Stutsman C, Cardona GR, Urva S, Emmerson PJ, Holst JJ, D’Alessio DA, Coghlan MP, Rosenkilde MM, Campbell JE, Sloop KW. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020 Sep 3;5(17):e140532. doi: 10.1172/jci.insight.140532. PMID: 32730231; PMCID: PMC7526454.
  3. Urva S, Coskun T, Loghin C, Cui X, Beebe E, O’Farrell L, Briere DA, Benson C, Nauck MA, Haupt A. The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists. Diabetes Obes Metab. 2020 Oct;22(10):1886-1891. doi: 10.1111/dom.14110. Epub 2020 Jul 13. PMID: 32519795; PMCID: PMC7539915. https://pubmed.ncbi.nlm.nih.gov/32519795/ 
  4. Wilson, Jonathan M., et al, The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes. Diabetes, Obesity, and Metabolism, vol.22, no.12, 15 Sept. 2020, pp. 2451-2459. https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.14174 
  5. H. Yanai and H. Yoshida. Beneficial Effects of Adiponectin on Glucose and Lipid Metabolism and Atherosclerotic Progression: Mechanisms and Perspectives. Int. J Mol. Sci, vol.20, no.5, p.1190, Mar.2019. https://www.mdpi.com/1422-0067/20/5/1190
  6. Tate M, Chong A, Robinson E, Green BD, Grieve DJ. Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes. Br J Pharmacol. 2015 Feb;172(3):721-36. doi: 10.1111/bph.12943. Epub 2014 Dec 1. PMID: 25231355; PMCID: PMC4301685. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301685/ 
  7. Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, Bray R, Rodríguez Á. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021 Aug 14;398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4. Epub 2021 Aug 6. PMID: 34370970. https://pubmed.ncbi.nlm.nih.gov/34370970/
  8. Zhang Q, Delessa CT, Augustin R, Bakhti M, Colldén G, Drucker DJ, Feuchtinger A, Caceres CG, Grandl G, Harger A, Herzig S, Hofmann S, Holleman CL, Jastroch M, Keipert S, Kleinert M, Knerr PJ, Kulaj K, Legutko B, Lickert H, Liu X, Luippold G, Lutter D, Malogajski E, Medina MT, Mowery SA, Blutke A, Perez-Tilve D, Salinno C, Sehrer L, DiMarchi RD, Tschöp MH, Stemmer K, Finan B, Wolfrum C, Müller TD. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab. 2021 Apr 6;33(4):833-844.e5. doi: 10.1016/j.cmet.2021.01.015. Epub 2021 Feb 10. PMID: 33571454; PMCID: PMC8035082. https://pubmed.ncbi.nlm.nih.gov/33571454/ 
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