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的细胞质量。随着年龄的增长和2型糖尿病的发生，β细胞群的扩张出现了失败。这可能是由于现有β细胞凋亡增加以及β细胞新生减少。我们一直在研究肠道激素GLP-1的作用，因为它们与胰岛素释放有关。我们发现它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细胞增殖来增加细胞质量。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。GLP-1受体（GLP-1R）激动剂exendin-4最近被用于治疗2型糖尿病。

A major component of our research in the Diabetes Section is understanding what controls beta cell mass of the pancreas. With age and type 2 diabetes, there is a failure of expansion of beta cell mass. This is possibly due to increased apoptosis of existing beta cells as well as decreased beta cell neogenesis. We have been investigating the actions of GLP-1, a gut hormone, as they relate to insulin release. We found that not only is it 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 by increasing beta cell proliferation in islets of Langerhans. Other investigators demonstrated antiapototic effects of GLP-1 in beta cell lines and whole islets. A GLP-1 receptor (GLP-1R) agonist, exendin-4, has recently become available for treating type 2 diabetes. Data from the Baltimore Longitudinal Study of Aging shows us that diabetes, in people whose ages are sixty-five years or older, is, to a large extent, due to beta cell failure, with insulin resistance being a minor component. Therefore, exendin-4 or any compound which works through the GLP-1R should be an ideal way to treat the elderly with diabetes. An added benefit is that GLP-1R agonists will not cause hypoglycemia because their insulinotropic effect is glucose dependent. A component of our basic work is investigating how GLP-1 increases beta cell turnover. We have uncovered all of the prototypic components of the Notch pathway in mature islets. Activation of the pathway requires gamma-secretase to cleave the C-terminus of the Notch receptor (NICD), which then translocates to the nucleus. NICD controls pancreatic endocrine differentiation and determines cell fate (endocrine vs. exocrine vs. duct cell type) in the embryonal pancreas. GLP-1R activation, by increasing PKA activity results, in turn, in inducing gamma-secretase activity. Inhibition of gamma-secretase in vitro and in vivo by gamma-secretase inhibitors prevents GLP-1R mediated proliferation of beta cells. This provides a direct link between activation of the Notch signaling pathway, GLP-1R activation and beta cell proliferation. We are currently working with peptides based on the receptor activation moieties of Notch ligands as possible agents to increase beta cell proliferation in vivo. We are also investigating if the Notch pathway is negatively perturbed in aging.