Aging And The Pancreas

我们在糖尿病科研究的一个主要组成部分是了解是什么控制了胰腺中的β细胞功能和质量。随着年龄的增长和2型糖尿病，β细胞对升高的血糖水平的反应失败（β细胞功能障碍）变得明显，β细胞群的扩张似乎失败。这可能是由于现有β细胞的凋亡增加以及新生细胞的减少。我们一直在研究GLP-1（一种肠道激素）的作用机制，因为它们与胰岛素释放有关。我们发现，GLP-1不仅是一种有效的胰岛素促胰岛素剂，它还能上调胰岛素的生物合成，增加pdx-1（维持β细胞表型所必需的转录因子）向细胞核的易位，并增加葡萄糖激酶蛋白水平（β细胞中必不可少的葡萄糖传感器）。我们还发现它通过增加朗格汉斯岛的β细胞增殖来增加啮齿动物的β细胞质量。其他研究者证实了GLP-1在β细胞系和整个胰岛中的抗凋亡作用。一种GLP-1受体激动剂exendin-4现在可用于治疗2型糖尿病。我们基础工作的一个组成部分是研究GLP-1如何增加β细胞的更新。与衰老相关，我们发现GLP-1受体激动剂增加β细胞周转的能力在老年啮齿动物的胰岛中降低：然而，用GLP-1受体激动剂持续不懈地治疗动物可以克服这一点。除了β细胞功能和增殖缺陷外，我们还发现α细胞增加了。这使我们推测需要适当的β细胞功能来控制α细胞的功能和数量。此外，游离脂肪水平在衰老和2型糖尿病中增加。我们假设一个统一的机制涵盖β细胞功能障碍，α细胞过度活跃，胰岛素抵抗和细胞因子水平升高。最终，我们希望在这个概念中勾勒出新的治疗靶点。

A major component of our research in the Diabetes Section is to understand what controls beta cell function and mass in the pancreas. With age and type 2 diabetes failure of beta cells to respond to rising blood glucose levels (beta cell dysfunction) becomes evident and there appears to be a failure of expansion of beta cell mass. This is possibly due to increased apoptosis of existing beta cells as well as decreased neogenesis. We have been studying the mechanisms of action of GLP-1, a gut hormone, as they relate to insulin release. We found that not only is GLP-1 a potent insulinotropic agent, it upregulates insulin biosynthesis, increases translocation of pdx-1, a transcription factor necessary for maintenance of the beta cell phenotype, to the nucleus and it increases glucokinase protein levels (the essential glucose sensor in beta cells). We also found that it increases beta cell mass in rodents by increasing beta cell proliferation in islets of Langerhans. Other investigators demonstrated antiapoptotic effects of GLP-1 in beta cell lines and whole islets. A GLP-1 receptor agonist, exendin-4, is now available for treating type 2 diabetes. A component of our basic work is investigating how GLP-1 increases beta cell turnover. Of relevance to aging, we have found that the ability of GLP-1 receptor agonists to increase beta cell turnover is reduced in islets from old rodents: however, continuous, unremitting treatment of the animals with GLP-1 receptor agonists can overcome this. In addition to defective beta cell function and proliferation, we have found that alpha cells are increased. This led us to speculate that proper beta cell function is needed to control alpha cell function and numbers. Additionally, free fatty levels are increased in aging and type 2 diabetes. We are hypothesizing a unifying mechanism covering beta cell dysfunction, alpha cell hyperactivity, insulin resistance and increased cytokine levels. Eventually, we hope to outline novel therapeutic targets within this concept.