Prevention of Lipotoxicity in Pancreatic Islets with Gammahydroxybutyrate.

Justin Hou Ming Yung,Michael B Wheeler,Emelien Mariella Jentz,Adria Giacca,Battsetseg Batchuluun,Jamie W Joseph,Lucy Shu Nga Yeung,Mortimer Mamelak,Aleksandar Ivovic,Himaben Gohil,Yao Fang Tan

doi:10.3390/cells11030545

Abstract

Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH.

Highlights

Type 2 diabetes is characterized by insulin resistance and defective insulin secretion.Obesity is the major predisposing factor to type 2 diabetes and accounts for the excessive release of fatty acids from the expanded adipose tissue mass
High plasma levels of nonesterified fatty acids (NEFA) are known to cause insulin resistance, but the prolonged exposure of pancreatic ß-cells to high fatty acid levels impairs the insulin-producing capacity of these cells by a process that likely involves the generation of oxidative stress [1]. ß-cell damage by fatty acids and the subsequent reduction in insulin secretion appears to be an early event in the pathogenesis of hyperglycemia in type 2 diabetes
While reactive oxygen species (ROS) may be generated along the mitochondrial electron transport chain in the course of fatty acid oxidation or as a result of mitochondrial membrane damage, the major source of ROS generated in pancreatic ß-cells in response to NEFA appears to be the formation of superoxide by the cytoplasmic/plasma membrane NADPH oxidase complex

Summary

Introduction

Type 2 diabetes is characterized by insulin resistance and defective insulin secretion.Obesity is the major predisposing factor to type 2 diabetes and accounts for the excessive release of fatty acids from the expanded adipose tissue mass. SS-cell damage by fatty acids and the subsequent reduction in insulin secretion appears to be an early event in the pathogenesis of hyperglycemia in type 2 diabetes. There is good evidence that antioxidants can prevent the development of oxidative stress in ß-cells in response to fatty acids and that this can maintain the insulin-producing capacity of these cells [1,2]. Previous work in our laboratory has demonstrated that lipotoxicity is caused by the activation of islet NADPH oxidase by long-chain fatty acids and the ensuing formation of the superoxide radical and aldehydes. Antioxidants such as n-acetylcysteine, taurine, and tempol were shown to prevent the toxic effects of this oxidative stress [1,2]

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