TRIP-16 화합물의 베타세포 당지질독성 해독 기전 분석
A Triazolo[3,4-a]phthalazine Derivative Protects INS-1 beta cells from Glucolipotoxicity Induced by High Glucose and Palmitate
박선미(경기과학기술진흥원 바이오센터); 정대연(경기과학기술진흥원 바이오센터); 구진모(경기과학기술진흥원 바이오센터); 황윤정(아주대학교 의과대학); 최성이(아주대학교); 강엽(아주대학교); 정귀완(재단법인 경기과학기술진흥원)
60권 6호, 327~334쪽
초록
Gradual deterioration of pancreatic beta cells is a conundrum still to be resolved in the diabetes field. The toxicitymanifested by high level of glucose and saturated fatty acid (SFA), which is collectively termed as glucolipotoxicity, hasbeen 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 screeningto 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 observedthat TRIP-16 reduced fatty acid-induced triglyceride (TG) accumulation, whereas it increased oxidation rate of glucose orpalmitate. The compound also reduced reactive oxygen species generated by palmitate and upregulated expression levelsof carnitine palmitoyltransferase-1a (CPT-1a), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) 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, ourdata strongly suggest that TRIP-16 can be a potential drug candidate for prevention of type 2 diabetes through beta cell protection.
Abstract
Gradual deterioration of pancreatic beta cells is a conundrum still to be resolved in the diabetes field. The toxicitymanifested by high level of glucose and saturated fatty acid (SFA), which is collectively termed as glucolipotoxicity, hasbeen 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 screeningto 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 observedthat TRIP-16 reduced fatty acid-induced triglyceride (TG) accumulation, whereas it increased oxidation rate of glucose orpalmitate. The compound also reduced reactive oxygen species generated by palmitate and upregulated expression levelsof carnitine palmitoyltransferase-1a (CPT-1a), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) 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, ourdata strongly suggest that TRIP-16 can be a potential drug candidate for prevention of type 2 diabetes through beta cell protection.
- 발행기관:
- 대한약학회
- 분류:
- 약학