Abstract
Recent studies suggest that sphingolipid metabolism is altered during type 2 diabetes. Increased levels of the sphingolipid ceramide are associated with insulin resistance. However, a role for sphingolipids in pancreatic beta cell function, or insulin production, and release remains to be established. Our studies in MIN6 cells and mouse pancreatic islets demonstrate that glucose stimulates an intracellular rise in the sphingolipid, sphingosine 1-phosphate (S1P), whereas the levels of ceramide and sphingomyelin remain unchanged. The increase in S1P levels by glucose is due to activation of sphingosine kinase 2 (SphK2). Interestingly, rises in S1P correlate with increased glucose-stimulated insulin secretion (GSIS). Decreasing S1P levels by treatment of MIN6 cells or primary islets with the sphingosine kinase inhibitor reduces GSIS. Moreover, knockdown of SphK2 alone results in decreased GSIS, whereas knockdown of the S1P phosphatase, Sgpp1, leads to a rise in GSIS. Treatment of mice with the sphingosine kinase inhibitor impairs glucose disposal due to decreased plasma insulin levels. Altogether, our data suggest that glucose activates SphK2 in pancreatic beta cells leading to a rise in S1P levels, which is important for GSIS.
Highlights
Sphingolipids play an important role in glucose homeostasis
Exposure of MIN6 cells to high glucose (25 mM) for 1 h resulted in about 2-fold increase in sphingosine 1-phosphate (S1P) levels when compared with 1 mM glucose incubated cells (Fig. 1A), whereas there were no significant changes in the levels of other sphingolipids, such as sphingomyelin and ceramide
We found that sphingosine kinases (SphKs) activity was increased over 4-fold in MIN6 cells incubated with high glucose (Fig. 2)
Summary
Results: High glucose induces SphK activity, leading to increases in S1P levels and stimulation of insulin secretion. Our studies in MIN6 cells and mouse pancreatic islets demonstrate that glucose stimulates an intracellular rise in the sphingolipid, sphingosine 1-phosphate (S1P), whereas the levels of ceramide and sphingomyelin remain unchanged. Our data suggest that glucose activates SphK2 in pancreatic beta cells leading to a rise in S1P levels, which is important for GSIS. In support of the idea that S1P may be involved in promoting beta cell viability, SphK activity is increased in the presence of cytokines in INS-1 cells and mouse pancreatic islets [14]. We investigated the role of S1P in pancreatic beta cell function and discovered that exposure to high glucose increases S1P levels by activation of sphingosine kinase isoform
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