J Korean Med Sci.  2016 Apr;31(4):547-552. 10.3346/jkms.2016.31.4.547.

The Glucotoxicity Protecting Effect of Ezetimibe in Pancreatic Beta Cells via Inhibition of CD36

• Yoon JS
• Moon JS
• Kim YW
• Won KC
• Lee HW

• KMID: 2363693
• DOI: http://doi.org/10.3346/jkms.2016.31.4.547

Abstract

Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36.

Keyword

Diabetes Mellitus; Beta Cells; Glucotoxicity; CD36; Ezetimibe

MeSH Terms

Animals
Anticholesteremic Agents/*pharmacology
Antigens, CD36/antagonists & inhibitors/genetics/*metabolism
Cells, Cultured
Ezetimibe/*pharmacology
Flow Cytometry
Glucose/toxicity
Insulin/genetics/metabolism/secretion
Insulin-Secreting Cells/cytology/*drug effects/metabolism
Male
Palmitic Acid/metabolism
RNA, Messenger/metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/metabolism
Real-Time Polymerase Chain Reaction
Anticholesteremic Agents
Antigens, CD36
Ezetimibe
Glucose
Insulin
Palmitic Acid
RNA, Messenger
Reactive Oxygen Species

Figure

• 

  Fig. 1 The effects of high glucose (30 mM) with or without ezetimibe on insulin secreting cells. The mRNA expression of insulin was decreased with high glucose (H-12h), which was reversed by ezetimibe (H+E-12h) in INS-1 cells (A) and rat islets (C). CD36 mRNA expression was increased with high glucose (H-12h), but decreased by ezetimibe (H+E) in INS-1 cells (B) and rat islets (D). Bars are mean ± SE of three separate experiments. * P < 0.05 vs. Control, † P < 0.05 vs. H-12h treated cells. 12h, 12 hours.

• 

  Fig. 2 The effects of three-day exposure of INS-1 cells to 30 mM glucose. Palmitate uptake (A) and intracellular peroxide levels (B) following an exposure to high glucose conditions (H-3d) for 3 days were significantly elevated, which were decreased by the ezetimibe (H-3d+E-12h) in INS-1 cells. Decreased glucose stimulated insulin secretion (GSIS) (C) by high glucose (H-3d) was reversed by ezetimibe (H-3d+E-12h). Bars are mean ± SE of three separate experiments. *P < 0.05 vs. Control, † P < 0.05 vs. H-3d. 3d, 3 days; 12h, 12 hours.

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