How does Mounjaro work inside the body?

-1 analogues stimulate glucose-dependent insulin secretion, dampen inappropriately high glucagon secretion, slow gastric emptying and reduce food intake. GLP-1 acts within the gut–brain axis; indeed, although it reaches the brain via endocrine mechanisms, it also acts locally by activating GLP-1R present on the dendritic terminals of the vagus nerve that innervate the gut, thus mediating the inhibition of food intake as well as relaying the satiety signal to the brain. In the brain, GLP-1R expression is found in several nuclei in the that are involved in controlling food intake and body weight. Recently, the combination of GLP-1–mediated signalling pathways and the adipocyte hormone leptin has raised interest. Indeed, leptin could be an important biological signal by which GLP-1 interacts additively or synergistically to reduce food intake and body weight. This leptin–GLP-1 action may be mediated in part by common and complementary intracellular signalling pathways (phosphorylated signal transducer and activator of transcription 3 [STAT3], PTP1B). Beyond their hypoglycemic and metabolic effects, GLP-1–based therapies have demonstrated anti-inflammatory effects, with in vitro and in vivo accumulating evidence demonstrating that GLP-1 reduces levels of inflammatory markers. GLP-1–based therapies downregulate pro-inflammatory responses in inflammatory chronic-related diseases such as diabetes, vascular diseases, neurodegenerative brain disorders, non-alcoholic steatohepatitis, nephropathy and OA.”


Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity?
2022 Journal of Orthopaedic Translation

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Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
Insight, 2020

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What is the “incretin effect” of Mounjaro? Why is it called an Incretin Mimetic and what do those drugs do? 

The incretin “effect is essential for normal glucose tolerance and is severely compromised in patients with type 2 diabetes. Recent research has documented that new pharmaceutical agents, based on the actions of the two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent the most effective therapy of the two major metabolic diseases, obesity and type 2 diabetes, improving not only metabolic parameters but also the risks of complications and mortality. … the effect, which is responsible for keeping up to 80% of ingested glucose away from the circulation (2), is essential for normal glucose tolerance. Several compounds are able to influence glucose-stimulated insulin secretion, including several peptides that can be extracted from the intestinal mucosa, but it is generally accepted that the peptides GIP and GLP-1 are the most important responsible factors.” 

Treatment of Type 2 Diabetes and Obesity on the Basis of the Incretin System: The 2021 Banting Medal for Scientific Achievement Award Lecture

ADA Award Lecture, published in Diabetes, 2021 


“The physiological role of the gastrointestinal tract was traditionally thought to involve nutrient digestion and absorption, but it is now known to be the source of a plethora of peptide hormones involved in the regulation of metabolism and other body functions… two major gastrointestinal tract‐derived hormones involved in regulation of postprandial glucose have been identified, namely, glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP), secreted from L‐cells and K‐cells of the gastrointestinal tract, respectively. Collectively, these two hormones account for 50%–70% of insulin secretion in response to a meal (Baggio & Drucker, 2007), with this action termed ‘the incretin effect’… GLP‐1 receptor mimetic therapy has consistently shown to improve liver disease, possibly indirectly via anti‐inflammatory and weight‐reducing actions…studies highlight the potential of GLP‐1 mimetics for the treatment of diseases and disorders driven by chronic inflammation.”

Metabolic responses and benefits of glucagon‐like peptide‐1 (GLP‐1) receptor ligands

British Journal of Pharmacology 


The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update

Diabetes obesity and Metabolism, July 2021 


The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update

Diabetes Obesity and Metabolism, June 2021