GLUCOREGULATORY PEPTIDE HORMONES

这些研究旨在确定脂肪酸(FFA)是如何刺激 肥胖症早期的β细胞代偿，但会导致功能障碍 代偿性β细胞死亡和NIDDM在肥胖晚期。我们发现了 PPARpha在胰岛中起FFA“受体”的作用。补偿性的 FFA升高引起的高胰岛素血症可在体外复制 由PPARpha配体，氯贝特(CF)+9-顺式维甲酸(RA)。 ZDF大鼠无法补偿高水平的脂肪酸， PPARα在其胰岛中显著减少，而CF/RA则无影响。胖的 在他们的胰岛中积聚，最终导致β细胞的凋亡 还有糖尿病。为了证明这一点，我们将在β细胞中过度表达PPARpha 并确定这是否将β细胞从细胞毒中拯救出来 脂肪酸的影响。要确定低PPARAlpha是否次于 OB-R受体突变，PPARpha mRNA将在胰岛中定量 用来过度表达野生型OBR。最后，我们将评估 归一化PPARpha在FFA和On诱导细胞凋亡中的作用 减少FFA进入神经酰胺和DAG的流量，关键信号 细胞凋亡途径。这些研究应该指出FFA通过什么机制 在肥胖的早期引起β细胞的代偿性变化 导致晚期胰岛β细胞功能障碍、细胞凋亡和糖尿病 好几年了。

These studies are designed to determine how fatty acids (FFA) stimulate beta-cell compensation early in obesity and yet cause dysfunction and death of compensated beta-cells and NIDDM late in obesity. We have found that PPARalpha serves as the FFA "receptor" in islets. Compensatory hyperinsulinemia induced by elevations of FFA can be duplicated in vitro by the PPARalpha ligands, clofibrate (CF) plus 9-cis retinoic acid (RA). ZDF rats are unable to compensate for high levels of fatty acids, PPARalpha is markedly reduced in their islets and CF/RA has no effect. Fat accumulates in their islets and ultimately causes apoptosis of beta cells and diabetes. To prove this, we will over-express PPARalpha in beta cells of ZDF rats and determine if this rescues beta-cells from the cytotoxic effects of fatty acids. To determine if the low PPARalpha is secondary to the OB-R receptor mutation, PPARalpha mRNA will be quantified in islets made to over-express wild type OBR. Finally, we will assess the effects of normalizing PPARalpha expression on apoptogenic effects of FFA and on reducing the flux of FFA into ceramide and DAG, key signals in the apoptotic pathway. The studies should indicate the mechanisms by which FFA cause compensatory changes in beta-cells in the early years of obesity but cause dysfunction apoptosis of beta-cells, and diabetes, in the late years.