Diabetes Metab J.  2019 Apr;43(2):192-205. 10.4093/dmj.2018.0052.

Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5

Affiliations
  • 1Department of Biomedical Science, Graduate School of Medicine, Kyungpook National University, Daegu, Korea.
  • 2Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.
  • 3Institute of Medical Science, Yeungnam University College of Medicine, Daegu, Korea.
  • 4Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea. leei@knu.ac.kr
  • 5New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
  • 6Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu, Korea. jcim@cu.ac.kr

Abstract

BACKGROUND
Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced β-cell apoptosis and explored the relationship between myricetin and CDK5.
METHODS
To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis.
RESULTS
Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to β-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Δψm) loss.
CONCLUSION
Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.

Keyword

Apoptosis; Cyclin-dependent kinase 5; Endoplasmic reticulum stress; Insulin-secreting cells; Myricetin
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