Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions

Abstract

AbstractChronic elevation of sphingolipids contributes to β-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic β-cell pathophysiology remains unclear. Here, we generated a mouse model lackingOrmdl3within pancreatic β-cells (Ormdl3β-/-). We show that loss of β-cellOrmdl3does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, whileOrmdl3β-/-mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss ofOrmdl3alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, but loss ofOrmdl3does alter specific sphingolipid levels.