Abstract P038: Tissue-specific Regulation Of Ceramide De Novo Biosynthesis In Type 1 Diabetes. Role Of Metformin

Endothelial cell (EC) dysfunction precedes the onset of cardiovascular diseases (CVD), main complications of diabetes. Sphingolipids (SL) are essential components of cell membranes and bioactive lipids regulating different cellular functions in health and diseases. Dysregulation of SL, such as ceramides (Cer) accrual, has been implicated in diabetes and CVD, although specific mechanisms remain poorly understood. Whereas Cer accrual impairs endothelial nitric oxide synthase (eNOS) activity, low ceramides disrupt endothelial signal transduction and vascular tone regulation. To date, how Cer changes in diabetic EC in vivo is unknown. Metformin (Met), first-line therapy for diabetes, was shown to lower Cer in liver and muscle in mice. This study investigates the role of sphingolipid metabolism in diabetes and whether Met directly regulates this pathway.We discovered that Met can directly downregulate serine palmitoyltransferase activity, catalyzing the first step of the de novo biosynthesis of SL, thus refraining Cer from accrual. To assess this effect in vivo , we used non-obese diabetic mice, a model of type 1 diabetes, and nondiabetic mice as control. Diabetic mice were treated with Met (300mg/Kg/d) or vehicle for 5 weeks. Diabetic mesenteric arteries showed an impaired vasodilation to acetylcholine and exaggerated response to vasoconstrictors. Met treatment significantly improved endothelial function, by restoring acetylcholine-vasodilation and increasing phosphorylation of vasodilator stimulated phosphoprotein, index of eNOS-cGMP signaling. Interestingly, whereas Cer and sphingomyelins (SM) increased in the heart and liver, they were significantly decreased in myocardial EC, suggesting that in diabetes SL are differentially regulated. Met refrained Cer/SM from accrual in the heart and liver, while further decreased Cer/SM in EC. In conclusions, Met prevents Cer accrual in the heart and liver, thus limiting its deleterious effects. Contrary to the current believe, Cer are suppressed in diabetic EC in vivo , and might contribute to the progression of dysfunction. Most likely, Met downregulation of sphingolipid de novo biosynthesis, already suppressed in diabetic EC, does not underlie beneficial effects of Met on the endothelium.