Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, exhibits favourable effects on pancreatic β-cells and hepatic steatosis in obese type 2 diabetic db/db mice.

Abstract

Tirzepatide, a dual agonist of glucagon-like peptide receptor and glucose-dependent insulinotropic polypeptide receptor, is expected to exhibit high clinical efficacy in obese type 2 diabetic patients. We evaluated the effects of tirzepatide on pancreatic β-cells and the liver, an insulin-target organ, in a mouse model of obese type 2 diabetes mellitus. Obese type 2 diabetic db/db mice (BKS.Cg-/+ Leprdb/+ Leprdb/Jcl*) were used in this study. Starting at 7 weeks of age, mice were treated with tirzepatide (30 nmol/kg, subcutaneous injection twice a week) or semaglutide (200 nmol/kg, subcutaneous injection twice a week). The control group received phosphate-buffered saline (40-50 μL/subcutaneous injection twice a week). After 4 weeks of drug administration, pancreatic β-cells and the liver were removed and examined. Compared to the control group, blood glucose and body weight were significantly reduced in the group that received either tirzepatide or semaglutide (p < 0.001 and p < 0.05, respectively). Fasting insulin was significantly higher in the semaglutide and tirzepatide groups compared to the control group (p < 0.001). β-Cell mass and quality of insulin granules in β-cells similarly increased in the semaglutide and tirzepatide groups compared to the control group (p < 0.05 and p < 0.001, respectively). The fat staining area in the liver in oil red O staining and the liver-spleen ratio in computed tomography showed improvement only in the tirzepatide group (p < 0.001 and p < 0.005, respectively). Liver macrophage M1/M2 ratio similarly improved with semaglutide and tirzepatide (p < 0.05). Tirzepatide and semaglutide exhibited similar potent glucose-lowering effects. At concentrations used in the present experiments, tirzepatide exhibited more beneficial effects on β-cell-related gene expression, insulin granule count and glucose-stimulated insulin secretion compared to semaglutide. In addition, tirzepatide exhibited a stronger favourable effect on hepatic fat deposition and improved inflammation in the liver. This is the first report showing that tirzepatide, a novel diabetes drug, exhibits a superior effect on pancreatic β-cells and the liver of obese type 2 diabetic mice.