Diabetes Studies and Tirzepatide Peptide

Tirzepatide, a synthetic analog of gastric inhibitory polypeptide (GIP), has emerged as a promising research compound designed to address the complex interplay of type 2 diabetes and liver disease. Comprising 39 amino acids, this relatively sizable peptide appears to exhibit a unique mechanism of action, potentially simultaneously targeting GIP and GLP-1 receptors, and it is thereby speculated to trigger a robust release of insulin from the pancreatic beta cells.^[1]

The intricate interplay between Tirzepatide peptide and its receptor targets extends beyond insulin modulation. Extensive research has unveiled its probable capacity to elevate adiponectin levels, emphasizing its possible multifaceted impact on metabolic processes.^[1] Prolonged exposure to Tirzepatide peptide is suggested to yield a cascade of impacts, possibly including a reduction in hunger hormone signaling, a decrease in insulin levels, and an enhancement of insulin sensitivity.^[1] Notably, this cumulative physiological response is speculated to translate into weight loss, concurrent improvements in glucose tolerance, diminished adipose tissue mass, and a consequential reduction in cardiovascular risk.

 

Mechanism of Action

Tirzepatide, functioning as a dual agonist for the gastric inhibitory polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), appears to exhibit a distinctive mechanism of action that may surpass conventional GLP-1 agonists typically employed in type 2 diabetes cases. Notably, Tirzepatide’s suggested higher affinity for the GIP receptor appears to amplify its impact, establishing a unique peptide profile.^[2]

Gastric inhibitory polypeptide, synonymous with glucose-dependent insulinotropic polypeptide, is indicated as an endogenously synthesized in the small intestine. By binding to the GIP receptor, this polypeptide appears to orchestrate a dual role of inhibiting gastric acid secretion and gastrin release while concurrently stimulating insulin release. This pivotal potential underlies the postprandial increase in insulin levels.^[3]

The glucagon-like peptide-1 receptor, present on beta cells and neurons, appears to be activated by both endogenous agonists such as glucagon and GLP-1, as well as synthetic agonists like dulaglutide, lithium, and oxyntomodulin. Beyond insulin synthesis and release, stimulation of GLP-1R is also speculated to be associated with intriguing effects, including an increase in beta cell density in the pancreas. This occurs through the modulation of genes like bcl-2, bax, and caspase-3, resulting in heightened beta-cell survival and elevated insulin levels.^[3]

Furthermore, Tirzepatide appears to exhibit a remarkable ability to modulate adiponectin levels, possibly elevating the concentration of fat cell dissolution. The suggested resultant reduction in fat cell differentiation and increased energy expenditure, mediated by inefficient mitochondria, positions Tirzepatide as a multifaceted compound in disease research such as type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease.^[5] Elevated adiponectin levels appear to further contribute to enhanced insulin sensitivity, underscoring Tirzepatide’s multifaceted potential on metabolic regulation.

 

Research and Scientific Studies

 

Tirzepatide Peptide and Hunger Hormone Signaling

Tirzepatide’s influence on hunger is speculated through its modulation of gastric emptying kinetics, as illuminated by research findings. Initially, during the early phases of introduction, Tirzepatide appears to exhibit a possible delay in gastric emptying, a phenomenon that, however, exhibits a diminishing trend over time due to the onset of tachyphylaxis.^[5] Intriguingly, these proposed actions align closely with those observed in the context of pure GLP-1 receptor (GLP-1R) agonists, suggesting that Tirzepatide’s impact on gastric emptying may be predominantly governed by GLP-1 activity, possibly with minimal influence from gastric inhibitory polypeptide (GIP) activity.

The speculated delayed gastric emptying induced by Tirzepatide assumes significance in the context of appetite regulation. By fostering an extended sense of satiety and mitigating hunger hormone signaling and food intake, this impact appears to complement Tirzepatide’s speculated broader impact on glucose levels. Consequently, the cumulative influence on eating patterns over the long term underscores the potential of Tirzepatide as a multifaceted compound in research related to hunger and associated metabolic dynamics.

 

Tirzepatide Peptide and Diabetes Research

Tirzepatide’s potential for synergistic agonistic activity on both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIP-R) introduces a dimension of impact that may surpass that of conventional GLP-1R agonists. Observations from research propose that Tirzepatide’s affinity for GIP-R exceeds that for GLP-1R, amplifying its physiological influence.^[3]

GIP, naturally synthesized in the small intestine, assumes a pivotal role upon binding to GIP-R. This interaction orchestrates a dual effect of inhibiting gastric acid secretion and gastrin release while concurrently instigating insulin release. On the other hand, GLP-1R, distributed in beta cells and neurons within the brain, is considered to respond to activation by stimulating insulin synthesis and release, concurrently suppressing appetite. Moreover, GLP-1R activation appears to contribute to increased beta cell density in the pancreas through upregulation of the anti-apoptotic bcl-2 gene and downregulation of apoptosis, possibly culminating in heightened insulin levels.

Tirzepatide’s potential parity with GIP at GIP-R is juxtaposed with its distinctive potential at GLP-1R, where researchers suggest it exhibits a propensity for cyclic adenosine monophosphate (cAMP) production over β-arrestin recruitment. This nuanced distinction translates into heightened GLP-1R activity without escalating the physiological internalization of the receptor, positioning Tirzepatide as a candidate with potential superiority over other synthetic GLP-1R agonists.^[3]

The ramifications of this distinction include the prospect of Tirzepatide inducing insulin secretion, fostering satiety, and mitigating inflammation in adipose tissue.

 

Tirzepatide Peptide and Weight

Tirzepatide’s influence on weight appears to stem from its GIP agonistic activity, particularly through the modulation of insulin sensitivity in adipocytes. This mechanism is postulated as the driver behind Tirzepatide’s impact on adiponectin levels. Researchers propose that Tirzepatide may engage GIP receptors in fat cells, thereby augmenting insulin sensitivity. This cascade potential could contribute to a reduction in adipose inflammation and an elevation in adiponectin levels, resulting in associated metabolic action.

Furthermore, additional investigations^[6] suggest that Tirzepatide’s “lowers body weight and food intake”.^[6]

Notably, the peptide hormone may engage in GIP signaling within the central nervous system, exerting regulatory action on hypothalamic feeding centers. This regulatory influence holds the potential to decrease food intake and enhance glucose handling, consequently culminating in a reduction in body weight. Consequently, Tirzepatide is posited to impact weight by both directly influencing adiponectin signaling in adipose tissue and by modulating hunger levels through GIPR signaling in the brain.

 

Tirzepatide Peptide and Cardiac System

Tirzepatide’s impact on cardiac function is discerned through its potential to modulate adiponectin levels, a critical factor associated with atherosclerosis, obesity, and cardiovascular issues.

The existing correlation between higher adiponectin levels and a decreased risk of these ailments underscores the importance of Tirzepatide’s influence in this context. Notably, research^[8] in models of type 2 diabetes indicates that Tirzepatide may exert a positive effect on lipoprotein biomarkers, possibly resulting in reduced levels of triglycerides, apoC-III, and other lipoproteins. This, in turn, may translate to a lowered risk of heart-related issues. Additionally, Tirzepatide has been proposed by researchers to exhibit a multifaceted impact on cardiovascular function by decreasing scavenger receptors in macrophages, enhancing cholesterol efflux, and elevating adiponectin levels. These combined potential actions may contribute to increased levels of high-density lipoprotein (HDL) and reduced levels of triglycerides, collectively correlating with a diminished risk of cardiovascular issues.

Moreover, investigations underscore the critical role of glucagon-like peptide-1 (GLP-1) activity as it “exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling.”^[7]

Indirectly, GLP-1 activity may also influence factors such as inflammation and endothelial cell dysfunction. GLP-1’s direct impact on inflammation and endothelial function is considered to be mediated through various mechanisms. In terms of endothelial function, GLP-1 signaling is proposed to induce blood vessel relaxation, leading to decreased blood pressure and improved end-organ perfusion. This effect is attributed to an increase in the expression of endothelial nitric oxide synthase (eNOS), the enzyme responsible for nitric oxide generation and subsequent vascular relaxation. Furthermore, GLP-1 signaling appears to exert anti-inflammatory potential by inhibiting NF-κB signaling, reducing matrix metalloproteinase-9 (MMP-9) activity, inhibiting inflammatory cytokine synthesis, and diminishing inflammatory macrophage activity. Importantly, these impacts have been observed by researchers to persist for up to three months following a single presentation of a GLP-1 receptor agonist, such as Tirzepatide.

 

In Summary

Tirzepatide, a synthetic analog derived from gastric inhibitory polypeptide (GIP), is speculated to possess dual functionality, concurrently acting as a glucagon-like peptide-1 (GLP-1) analog. This unique combination is expected to cause the peptide to reduce blood glucose levels, enhance insulin sensitivity, promote satiety, and facilitate weight loss. Originally designed for research in type 2 diabetes, studies indicate that Tirzepatide may also exhibit additional potential characteristics, including cardiovascular protection.

 

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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. Francis S. Willard, et al., Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist, JCI Insight, Published July 30, 2020. https://insight.jci.org/articles/view/140532
3. Resurrecting the Beta Cell in Type 2 Diabetes, Medscape. http://www.medscape.org/viewarticle/544820
4. L. Hartman et al., “Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes,” Diabetes Care, vol. 43, no. 6, pp. 1352–1355, Jun. 2020, doi: 10.2337/dc19-1892. https://diabetesjournals.org/care/article/43/6/1352/35649/Effects-of-Novel-Dual-GIP-and-GLP-1-Receptor
5. Urva, Shweta, et al. 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, Obesity and Metabolism, vol. 22, no. 10, 13 July 2020, pp. 1886–1891, 10.1111/dom.14110. https://pubmed.ncbi.nlm.nih.gov/32519795/
6. 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/
7. 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/
8. Jonathan M Wilson 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 MetabolismVolume 22, Issue 12 p. 2451-2459, 16 August 2020. https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.14174