1. Academic Validation
  2. Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4

Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4

  • Int J Mol Sci. 2019 Jan 27;20(3):530. doi: 10.3390/ijms20030530.
Po-Kai Huang 1 Shian-Ren Lin 2 Jirawat Riyaphan 3 Yaw-Syan Fu 4 Ching-Feng Weng 5
Affiliations

Affiliations

  • 1 Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan. kevin7699402@hotmail.com.
  • 2 Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan. d9813003@gms.ndhu.edu.tw.
  • 3 Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan. 810254005@gms.ndhu.edu.tw.
  • 4 Departmental of Biomedical Science and Environmental Biology, Kaoshiung Medical University, Kaoshiung 80708, Taiwan. m805004@kmu.edu.tw.
  • 5 Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan. cfweng@gms.ndhu.edu.tw.
Abstract

Serine protease Dipeptidyl Peptidase 4 (DPP-4) is involved in self/non-self-recognition and Insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus Infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

Keywords

clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide; dipeptidyl peptidase 4; hyperglycemia; molecular docking; natural compound inhibitors.

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