Tirzepatide

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. It was developed by Eli Lilly and is studied as a model of combined incretin receptor signalling.

The peptide is engineered based on the native GIP sequence with modifications that enable GLP-1 receptor activation. A C20 fatty diacid moiety is attached, which binds albumin and extends its half-life to approximately 5 days. The dual mechanism makes it a reference compound for studying how GIP and GLP-1 signalling combine.

Tirzepatide acts through simultaneous activation of two incretin hormone receptors:

GIP Receptor Agonism GIP is released from K-cells in the duodenum in response to nutrient ingestion. Tirzepatide's GIP activity enhances glucose-dependent insulin secretion, improves insulin sensitivity particularly in adipose tissue, and may directly influence lipid metabolism and fat storage.

GLP-1 Receptor Agonism GLP-1 is secreted by L-cells in the ileum and colon. Activation of GLP-1 receptors stimulates insulin secretion, suppresses glucagon release from pancreatic alpha cells, delays gastric emptying, and activates satiety centers in the brain to reduce appetite.

Published studies compare its combined receptor activity with selective GLP-1 agonists. The fatty acid modification enables albumin binding, protecting the peptide from degradation and extending its duration of action.