TRIP-16 화합물의 베타세포 당지질독성 해독 기전 분석

Gradual deterioration of pancreatic beta cells is a conundrum still to be resolved in the diabetes field. The toxicity manifested by high level of glucose and saturated fatty acid (SFA), which is collectively termed as glucolipotoxicity, has been accepted as a predominant factor of beta cell dysfunction or failure. In this study, we examined the effect of TRIP (Triazolo[3,4-a]phthalazine)-16, a compound derivatized from TRIP which had been identified in a high throughput screening to discover chemicals protecting INS-1 cells from glucolipotoxicity. We also investigated its mode of action to reduce glucolipotoxicity, especially regarding modulation of lipid metabolism. From a series of cell-based experiments, we observed that TRIP-16 reduced fatty acid-induced triglyceride (TG) accumulation, whereas it increased oxidation rate of glucose or palmitate. The compound also reduced reactive oxygen species generated by palmitate and upregulated expression levels of carnitine palmitoyltransferase-1a (CPT-1a), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-$1{\alpha}$) and uncoupling protein 2 (UCP-2), implicating that it can facilitate mitochondrial energy metabolism to oxidize palmitate. In terms of beta cell functioning, TRIP-16 augmented glucose-stimulated insulin secretion (GSIS) per se. Taken together, our data strongly suggest that TRIP-16 can be a potential drug candidate for prevention of type 2 diabetes through beta cell protection.