Glycosylphosphatidylinositol-specific phospholipase D improves glucose tolerance

Insulin regulation of energy metabolism is complex and involves numerous signaling cascades. Insulin has been suggested to stimulate a phospholipase that cleaves glycosylphosphatidylinositols resulting in the generation of an inositol glycan that serves as an insulin mediator. To determine if glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) may play a role in glucose metabolism, we examined the effect of overexpressing GPI-PLD using adenovirus-mediated gene transfer in C57BL/6 mice. Overexpressing GPI-PLD was associated with a decrease in fasting glucose as well as an improvement in glucose tolerance as determined by an intraperitoneal glucose tolerance test. This effect to improve glucose tolerance does not result from an increase in insulin sensitivity, as overexpressing GPI-PLD does not alter the response to insulin. In contrast, the insulin response during the glucose tolerance test in GPI-PLD-overexpressing mice was increased. Overexpressing GPI-PLD in an insulinoma cell line enhanced glucose-stimulated insulin secretion, suggesting that enhanced insulin secretion in vivo may have contributed to the improved glucose tolerance.