Metformin prevents glucotoxicity by alleviating oxidative and ER stress-induced CD36 expression in pancreatic beta cells.

Abstract:

AIM/HYPOTHESIS:Cluster determinant 36 (CD36), a fatty acid transporter, was reported to have a pivotal role in glucotoxicity-induced beta cell dysfunction. However, little is known about how glucotoxicity influences CD36 expression, and it is unknown whether this action can be counteracted by metformin. In the present study, we showed that metformin counteracts glucotoxicity by alleviating oxidative and endoplasmic reticulum (ER) stress-induced CD36 expression. METHODS:We used primary rat islets as well as INS-1 cells for 72h to 24h with 30mM glucose, respectively. Thapsigargin was used as strong ER stressor, and Sulfo-N-succinimidyl oleate (SSO) and RNA interference were chosen for CD36 inhibition. Free fatty acid uptake was measured by radioisotope tracing technique. RESULTS:Exposure of isolated rat islets to high glucose (HG) for 3days decreased insulin and pancreatic duodenal homeobox1 (Pdx1) mRNA expression, with the suppression of glucose-stimulated insulin secretion (GSIS) along with elevation of reactive oxygen species (ROS) levels. Incubation with metformin restored insulin and Pdx1 mRNA expression with significant improvements in GSIS and decrease in ROS production. HG exposure in INS-1 cells increased free fatty acid uptake via induction of CD36 along with impaired insulin and Pdx1 mRNA expression. Moreover, thapsigargin also increased the induction of CD36 expression. Metformin blocked HG- and thapsigargin-induced CD36 expression. In addition, the simultaneous inhibition of intracellular ROS production by metformin or CD36 activation by SSO or CD36 siRNA significantly decreased the apoptotic response in HG-treated INS-1 cells. CONCLUSION/INTERPRETATION:In conclusion, metformin conferred protection against HG-induced apoptosis of pancreatic beta cells, largely by interfering with ROS production, and inhibited the CD36-mediated free fatty acid influx. This report provides evidence that the inhibition of CD36 may have potential therapeutic effects against hyperglycemia-induced beta cell damage in diabetes.

authors

Moon JS,Karunakaran U,Elumalai S,Lee IK,Lee HW,Kim YW,Won KC

doi

10.1016/j.jdiacomp.2016.09.001

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

21-30

issue

1

eissn

1056-8727

issn

1873-460X

pii

S1056-8727(16)30507-4

journal_volume

31

pub_type

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