Sphingolipids and Diabetes

Sphingolipid such as ceramide and sphingosine-1-phosphate (S1P) serve as signaling molecules and have been shown to regulate many processes in various cell types. Recent evidence suggests that ceramide levels are increased in human subjects with overt diabetes. Increases in ceramide levels are also associated with insulin resistance in skeletal muscle of animals. Sphingosine-1-phosphate (S1P) is made from the same precursor as ceramide by phosphorylation of sphingosine via sphingosine kinases (SphK) and appears to counteract the effects of ceramide. However, the exact role of S1P in regulation of glucose homeostasis and diabetes remains to be established. We have abolished the production of S1P by using a specific inhibitor of sphingosine kinases (SphKs) and found that inhibition of SphKs and thereby blocking the production of S1P in pancreatic beta cells impairs glucose-stimulated insulin secretion (GSIS). Consistent with this finding, treatment of pancreatic beta cells with siRNAs that inhibit SphK expression blocks GSIS. Increasing S1P levels by depletion of the S1P phosphatase Sgpp1 stimulates insulin secretion even in the absence of high glucose. Furthermore, we found that S1P levels are upregulated in response to high glucose and this is due to activation of sphingosine kinases by glucose. Inhibition of sphingosine kinase activity in mice by IP-injection of a specific inhibitor resulted in impaired glucose disposal due to decreased insulin secretion from pancreatic beta cells. Based on these preliminary data, we propose that increases in blood glucose levels stimulate SphK activity, thereby leading to elevated S1P levels. The glucose-induced increase in S1P levels is important for GSIS from pancreatic beta cells. The major goals of this application are to understand how S1P regulates insulin secretion and how glucose regulates SphK activity in pancreatic beta cells.