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

  • Life Sci. 2022 Jun 1;298:120515. doi: 10.1016/j.lfs.2022.120515.
Lei Fan  1 ,  Hong Yang  2 ,  Xiangnan Hu  3 ,  Juncheng Liu  2 ,  Yuehua You  2 ,  Xinyu Li  4 ,  Guangcheng Qin  5 ,  Qian Ge  6 ,  Yi Hou  7 ,  Xiaoqiu Xiao  8
Affiliations
  • 1. Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 2. Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3. College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 4. The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 5. The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6. Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 7. The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Experimental Teaching & Management Center, Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 8. Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; College of Pharmacy, Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 35367243 DOI: 10.1016/j.lfs.2022.120515
Abstract

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 β-cell function. Mouse pancreatic cell line MIN6 was used to evaluate β-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 β-cell-protective actions by preserving islet β-cell mass and increasing the expression of functional β-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 β-cell function might contribute to its anti-diabetic effects.

Keywords
DPP-4 inhibitor; GLP-1; Pancreatic β-cell; Type 2 diabetes; Vildagliptin.
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