Volume 27, Issue S1 p. 1010.10-1010.10
Biochemistry/Molecular Biology
Free Access

Inhibition of Mono-Acyl-Glycerol Lipase by JZL-184 Results in Glucolipotoxicity in Pancreatic β-Cells

Charles Berdan

Charles Berdan

Department of Medicine, Boston University Medical Center, Boston, MA

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Barbara E Corkey

Barbara E Corkey

Department of Medicine, Boston University Medical Center, Boston, MA

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Jude T Deeney

Jude T Deeney

Department of Medicine, Boston University Medical Center, Boston, MA

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Abstract

Objective

Chronic exposure of pancreatic β-cells to elevated glucose and fatty acid (FA) levels (24–48 hrs) results in glucolipoxity (GLT), a condition mimicking type 2 diabetes with elevated basal secretion and impaired glucose stimulated insulin secretion (GSIS). Acute exposure to mono-oleoyl-glycerol (MOG) results in rapid onset (<1hr) of GLT in both clonal β-cells and dissociated rat islets. Our goal was to determine the effect of altered lipid cycling on β-cell function using JZL, a mono-acyl-glycerol (MAG) lipase inhibitor.

Methods

Acute and chronic incubations of clonal β-cells (INS-1 832/13) and dissociated rat islets with the MAG lipase inhibitor JZL-184 were performed. Insulin secretion (HTRF), glycerol release (NADH luciferase) and intracellular lipid accumulation (Nile red) were measured.

Results

JZL (1–10uM) acutely inhibited GSIS and KCl/diazoxide-stimulated insulin secretion in both dissociated rat islets and INS-1 cells. Chronic JZL (10uM) exposure in the presence of FA (0.1 mM) increased intracellular lipid droplets and accelerated the development of GLT in INS-1 cells. Under these same conditions JZL reduced glycerol release indicating MAG lipase was inhibited.

Conclusion

Inhibition of MAG lipase resulted in altered insulin secretion mimicking chronic effects of elevated glucose and FA.

Funded by NIH.