Tirzepatide (Mounjaro/Zepbound)

Tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Approved by the FDA under the brand names Mounjaro (for type 2 diabetes) and Zepbound (for weight management), it represents a significant advancement in incretin-based therapeutics. 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, extending its half-life to approximately 5 days and enabling once-weekly dosing. This dual mechanism provides complementary and potentially synergistic effects on glucose metabolism and body weight regulation.

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. The dual mechanism produces additive or synergistic effects on glycemic control and weight loss that exceed what either pathway achieves alone. The fatty acid modification enables albumin binding, protecting the peptide from degradation and extending its duration of action.