Tirzepatide (dual GIP/GLP-1 receptor agonist) is now approved for type 2 diabetes and obesity. How does GIP receptor agonism ADD to the benefits of GLP-1 receptor agonism?

• A GIP augments glucose-stimulated insulin secretion additively in beta cells, and in adipocytes promotes lipid uptake and storage when fed — providing a 'metabolic buffer' that reduces postprandial free fatty acid flux ✓
• B GIP receptor activates Gi protein in beta cells, hyperpolarizing them to prevent hypoglycaemia during fasting
• C GIP receptor agonism in the hypothalamus independently reduces AGRP/NPY neurons, providing additive anorectic effect to GLP-1
• D GIP increases glucagon secretion from alpha cells, which via portal signalling augments hepatic glucose production for anti-hypoglycaemic safety

Explanation

GIP (glucose-dependent insulinotropic polypeptide) receptor agonism in the context of tirzepatide provides several complementary effects. In pancreatic beta cells, GIP additively augments glucose-stimulated insulin secretion (both GIP and GLP-1 are incretins acting via Gs/cAMP in beta cells). In adipocytes, GIP receptors promote lipoprotein lipase activity and lipid deposition during the postprandial state — this 'nutrient buffering' reduces circulating free fatty acids and triglycerides, lessening lipotoxicity. In bone, GIP has anabolic effects. Importantly, unlike GLP-1 receptor agonists that cause nausea via vagal afferents and hypothalamic mechanisms, GIP may partially counteract GLP-1-induced nausea, improving tolerability. The SURPASS trials showed tirzepatide's superior glycaemic and weight reduction versus semaglutide.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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