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

Aim: 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.

Materials and methods: 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.

Results: 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).

Conclusion: 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.

Keywords: GIP receptor; GLP‐1 receptor; pancreatic β‐cells; steatosis; type 2 diabetes mellitus.