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

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

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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