Prolonged exposure to high levels of fatty acids impairs the insulin secretory capacity of pancreatic β-cells through mechanisms involving oxidative stress (lipotoxicity). Beta-cell lipotoxicity is thought to play an important role in the β-cell failure of type 2 diabetes. Antioxidants can protect β-cells from lipotoxicity by decreasing oxidative stress. Gammahydroxybutyrate (GHB), an endogenous neurotransmitter currently safely used as a treatment for narcolepsy, is also found in cells as an energy source and antioxidant. Previous studies have shown that GHB can protect mice from streptozotocin and alloxan induced diabetes; both compounds are generators of oxidative stress and yield models of type 1 diabetes. However, the effect of GHB in models of type 2 diabetes has not been investigated. We hypothesized that GHB can protect β-cells from lipotoxicity.

We first investigated the effectiveness of GHB in preventing β-cell dysfunction in high-fat treatment (palmitate) in an in vitro model with freshly isolated mouse islets. Beta-cell function was determined by glucose stimulated insulin secretion assays. Islets incubated with GHB were protected from β-cell lipotoxicity that resulted from the concurrent 48h exposure to palmitate. The antioxidant effects of GHB in lipotoxicity were further investigated by measuring reactive oxygen species (ROS) levels. GHB prevented the increase in ROS that was observed with the palmitate treatment while GHB by itself had no effects. While further studies need to be done to elucidate possible mechanisms of action of GHB beyond its antioxidant effect as well as GHB effectiveness in vivo, our findings suggest that GHB or potentially GHB derivatives may be of interest for their β-cell protective properties.


L. Yeung: None. A. Ivovic: None. Y. Tan: None. B. Batchuluun: None. M. Mamelak: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals.


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