हेपेटोलॉजी और अग्नाशय विज्ञान

The role of the prostaglandin PGE2 in pancreatic β- cell death in the context of type 2 diabetes

Abstract

Danielle Melloul

Type 2 diabetes (T2DM) could be a complex disease characterized by β-cell failure within the setting of insulin resistance. The underlying causes of β-cell failure are complex and result from the interplay between genetic and environmental factors. Consumption of foods high in saturated fatty acids (FFAs) and also the elevation of circulating FFAs are implicated as a crucial causative link among obesity, insulin resistance and β-cell dysfunction. Moreover, cumulative evidence indicates that there's a decrease in β-cell mass thanks to β-cell death in T2DM patients. FFAs can induce β-cell death by apoptosis, even within the absence of high glucose, whereas unsaturated fatty acids are usually protective. Several mechanisms are implicated in palmitate-induced β- cell death, including ceramide formation resulting in altered lipid partitioning, oxidative stress, and inflammation. Mild inflammation has been suggested to play a job within the pathogenesis of T2DM. Another family of molecules involved in inflammation is prostaglandins, but their role within the development of T2DM is poorly understood. this research aims at understanding the impact of prostaglandins (PGE2) on β-cell death. We show that PGE2-induced apoptosis is mediated by p38MAPK. To further elucidate the downstream signaling pathway of prostaglandins in β-cells, we studied the differential expression of PGE2 receptors (EP1-EP4) and located that the EP3 receptor is differentially upregulated in islets from T2DM patients. the importance of this receptor in β-cell apoptosis was tested by using EP3 specific siRNA or EP3 antagonist, and located that they led to a big rescue of those cells from apoptosis. In comparison to the opposite PGs, the role of PGE2 in β-cell function has been studied in greatest detail. this might stem from early reports demonstrating that the AA metabolite chargeable for decreased insulin secretion was PGE2 (Robertson 1988). However, several groups have called into question the solely inhibitory effect of PGE2 on insulin secretion. There are numerous lines of evidence in support of an inhibitory role of PGE2 on β-cell function in β-cell lines, isolated islets, and in vivo. In vitro studies have demonstrated that PGE2 treatment decreases GSIS in several different β-cell lines, including the HIT-T15, βHC13, and INS-1 (832/3) lines (Kimple et al. 2013; Meng et al. 2009; Robertson et al. 1987; Seaquist et al. 1989).