Tirzepatide 10mg (Mounjaro)

Tirzepatide is a synthetic analogue of gastric inhibitory polypeptide (GIP) that was developed for its ability to stimulate insulin release and thus address both type 2 diabetes and non-alcoholic fatty liver disease. Made up of 39 amino acids, the relatively large Tirzepatide stimulates the release of insulin from the pancreas by binding to both GIP and GLP-1 (glucagon-like peptide-1) receptors. Taken over longer periods of time, Tirzepatide increases adiponectin levels by as much as 26% as well[1]. Research shows that Tirzepatide reduces feelings of hunger, lowers insulin levels, and increases insulin sensitivity. Taken together, these effects cause significant weight loss of 11 kg (25 lbs), improve glucose tolerance, decrease fat (adipose) tissue, and reduce cardiovascular risk.

Simply put, Tirzepatide increases the release of insulin from the pancreas resulting in improved glucose control. Research shows that, in individuals with Type 2 diabetes, Tirzepatide decreases hemoglobin A1c (HbA1c) levels by 2.4% after six months. The peptide also appears to aid in weight loss, showing a dose-dependent relationship and helping individuals lose as much as 11 kg (25 lbs) over six months[1], [2].

Research suggests that the peptide actually improves the function of pancreatic beta cells, the cells that make and release insulin. Studies suggest that Tirzepatide may actually make beta cells more effective at processing insulin, which leads not just to increases in insulin levels in the bloodstream, but decreased stress on the beta cells themselves. This may, in turn, help to slow the progressive nature of type 2 diabetes.

Tirzepatide appears to increase insulin levels only in response to increased blood glucose levels. During fasting, Tirzepatide actually decreases insulin levels and thus helps to increase insulin sensitivity over time. It also decreases fasting levels of glucagon, which are thought to exacerbate hyperglycemia by interfering with hepatic glucose metabolism[3].

Tirzepatide is a dual agonist of the gastric inhibitory polypeptide receptor and the glucagon-like peptide-1 receptor. Action at these receptors appears to have synergistic effects that make Tirzepatide more effective than strict GLP-1 agonists that are already approved for the treatment of type 2 diabetes.

Gastric inhibitory polypeptide is synthesized naturally in the small intestine. This polypeptide binds to the GIP receptor to inhibit gastric acid secretion and gastrin release while stimulating insulin release. The latter is the primary function of GIP-R and is the primary reason that insulin levels increase following a meal.

Glucagon-like peptide-1 receptors are found on beta cells as well as in neurons in the brain. Activation of GLP-1R increases both insulin synthesis and insulin release. In the brain, GLP-1R stimulation lowers appetite. GLP-1R stimulation also appears to increase beta cell density in the pancreas by enhancing beta cell survival[4].

Research shows that Tirzepatide favors cAMP production over beta-arrestin recruitment when acting at the GLP-1R. This difference in activity from endogenous GLP-1 appears to cause GLP-1R activation without increasing physiological internalization of the receptor, resulting in enhanced GLP-1R activity compared to both endogenous GLP-1 and other synthetic GLP-1R agonists[5].

Tirzepatide use is associated with substantial weight loss over a six-month time interval. A comparison of Tirzepatide to other GLP-1 analogues, like degludec, indicates a striking difference. Whereas Tirzepatide causes a dose-dependent decrease in weight over time, degludec and other GLP-1R agonists cause weight gain[12].

It appears that the GIP agonism caused by Tirzepatide is what is responsible for the peptide's long-term effects on weight. GIP appears to directly impact the insulin-sensitivity of adipocytes, which is likely the mechanism by which Tirzepatide impacts adiponectin levels.

Research shows that GIP signaling in the central nervous system regulates hypothalamic feeding centers leading to decreased food intake and improved glucose handling. This, in turn, leads to decreased body weight[13]. Thus, Tirzepatide impacts weight via adiponectin signaling directly in adipose tissue and via CNS alterations that reduce hunger levels via GIPR signaling in the brain.

Tirzepatide alters adiponectin levels. Low adiponectin has been associated with atherosclerosis, obesity, and heart disease while increased adiponectin levels have been associated with decreased risk of all of these things. Research in humans with type 2 diabetes has shown that Tirzepatide improves lipoprotein biomarkers, lowering levels of triglycerides, apoC-III, and a handful of other lipoproteins[8].

Increases in adiponectin levels increase HDL levels while decreasing triglyceride levels, both of which are associated with lower risk of heart disease. The peptide hormone appears to go further, reducing scavenger receptors in macrophages and increasing cholesterol efflux to greatly protect against atherosclerosis[9].

GLP-1 signaling has been shown to induce relaxation of blood vessels leading to decreased blood pressure and enhanced end organ perfusion. GLP-1 signaling also appears to decrease inflammation via reduced NF-kB signaling, decreased MMP-9 activity, and inhibited inflammatory cytokine synthesis. These effects appear to last as long as three months after a single dose of a GLP-1R agonist[10]. Tirzepatide is undergoing a clinical trial to further evaluate its medium-term effects on individuals with heart failure[11].