The dual incretin coagonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice.

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG ). The 50min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose . Insulin sensitivity (SI ) and glucose effectiveness (SG ) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014±0.004 with glucose only to 0.099±0.016 (P<0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P<0.001). The increase in SG contributed to an increase in KG by 74±4% after glucose alone and by 67 ±8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26±4% and 33±8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.