What is the mechanism of action of Tirzepatide (Dual GIP (Glucose-Dependent Insulinotropic Polypeptide) and GLP-1 (Glucagon-Like Peptide-1) receptor agonist)?

Mechanism of Action of Tirzepatide

Tirzepatide is a dual GIP/GLP-1 receptor agonist that activates both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, though it binds with approximately five times less affinity to the GLP-1 receptor compared to endogenous GLP-1. 1

Dual Receptor Activation

GLP-1 Receptor Mechanism

• When tirzepatide activates the G-protein coupled GLP-1 receptor on pancreatic β cells, it increases intracellular calcium, leading to insulin exocytosis in a glucose-dependent manner 1, 2
• GLP-1 receptor activation inhibits glucagon secretion from pancreatic α cells, reducing hepatic glucose production 2
• The glucose-dependent nature of insulin stimulation explains the low risk of hypoglycemia with tirzepatide 1, 2
• GLP-1 receptor agonism may promote β cell proliferation and protect against apoptosis, potentially preserving pancreatic β cell mass 2

GIP Receptor Mechanism

• Tirzepatide binds to the GIP receptor on pancreatic β cells, stimulating insulin secretion when blood glucose levels are elevated 1, 2
• GIP receptor activation has a dual effect on glucagon: it augments glucagon secretion during euglycemia or hypoglycemia and inhibits glucagon secretion during hyperglycemia 2
• GIP receptors do not significantly affect gastric emptying, unlike GLP-1 receptors 2

Metabolic and Appetite Regulation

Central Nervous System Effects

• Both GLP-1 and GIP receptors are located in the hypothalamus and brainstem nuclei (arcuate nucleus, area postrema, nucleus tractus solitarius), where they mediate appetite, satiety, energy intake, and expenditure 1, 2
• These central pathways suppress the arcuate nucleus and induce meal termination in parabrachial neurons, contributing to weight loss 1

Gastrointestinal Effects

• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, reducing gastric contractions and gastric acid secretion 2
• This delayed gastric emptying contributes to increased satiety and reduced food intake 2

Superior Efficacy Through Dual Agonism

• Tirzepatide produced greater reductions in HbA1c and body weight compared with selective GLP-1 receptor agonists like semaglutide and dulaglutide 1, 3
• The dual receptor agonism improves insulin sensitivity and insulin secretory responses to a greater extent than selective GLP-1 agonists, associated with lower prandial insulin and glucagon concentrations 3
• Improvements in insulin resistance with tirzepatide are only partly attributable to weight loss (13-21%), suggesting the dual receptor agonism confers distinct mechanisms of glycemic control beyond weight reduction 4

Molecular Structure and Pharmacology

• Tirzepatide is a synthetic linear peptide consisting of 39 amino acids based on the GIP sequence 5
• It has been molecularly modified with acylation technology that allows it to bind to albumin, enabling once-weekly dosing 6, 5
• This modification prevents rapid cleavage and inactivation by dipeptidyl peptidase-4 (DPP-4), unlike endogenous GLP-1 which has a half-life of only 2 minutes 1, 2

Clinical Implications

• The glucose-dependent mechanism of both GIP and GLP-1 receptor activation means insulin secretion is significantly attenuated when plasma glucose is not elevated, minimizing hypoglycemia risk 1, 2
• Tirzepatide's effects on insulin sensitivity include increased adiponectin, IGFBP-1, and IGFBP-2 levels, markers of improved metabolic function 4
• The combination of enhanced insulin secretion, reduced glucagon release, delayed gastric emptying, and central appetite suppression creates a comprehensive mechanism for glycemic control and weight reduction 5