ZD-2, a novel DPP4 inhibitor, protects islet β-cell and improves glycemic control in high-fat-diet-induced obese mice

Aims: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been extensively used for the treatment of type 2 diabetes mellitus. Nevertheless, side effects like sore throat and diarrhea also occur in DPP-4 inhibitors treatment. The study aims to identify and develop novel DPP-4 inhibitors with better therapeutic profiles. Materials and methods: Here we synthesized a series of vildagliptin analogs, and among which, ZD-2 showed the moderate inhibition of DPP-4 activity compared with vildagliptin. High-fat-diet (HFD) mice were treated with ZD-2 (4.5 and 7.5 mg/kg) or vildagliptin (6 mg/kg) for 7 weeks following the examinations of metabolic index and pancreatic beta-cell function. Mouse pancreatic cell line MIN6 was used to evaluate beta-cell function, and intestinal enteroendocrine cell line STC-1 was used to evaluate the expression of gut hormones. Key findings: The IC50 of ZD-2 was over 30-fold higher than vildagliptin. However, both ZD-2 and vildagliptin treatment showed comparable effects on improving glucose tolerance and reducing the steatosis of liver and fat mass in HFD mice. Moreover, ZD-2 exerted beta-cell-protective actions by preserving islet beta-cell mass and increasing the expression of functional beta-cell-related genes. Additionally, ZD-2 also stimulated the expression of gut hormones in STC-1 cells. Significance: ZD-2 showed comparable anti-diabetic activities in HFD-fed mice although its lower potency on inhibition of DPP-4 compared with vildagliptin. Protection of beta-cell function might contribute to its anti-diabetic effects.

Automated summary

This study synthesized a series of vildagliptin analogs, among which ZD-2 showed moderate inhibition of DPP-4. Both ZD-2 and vildagliptin showed similar effects on improving glucose tolerance and reducing fat accumulation in high-fat-diet mice. ZD-2 also protected beta-cell function and stimulated gut hormone expression.