Aging And The Pancreas

我们在糖尿病部分的研究的一个主要组成部分是了解是什么控制了胰腺的β细胞质量。在年龄和2型糖尿病患者中，β细胞团的扩张失败。这可能是由于现有的贝塔细胞凋亡增加以及贝塔细胞新生减少所致。我们一直在研究胃肠激素GLP-1的作用，因为它们与胰岛素释放有关。我们发现，它不仅是一种强大的胰岛素促进剂，它还上调胰岛素的生物合成，增加PDX-1的转位，PDX-1是维持β细胞表型所必需的转录因子，它还增加葡萄糖激酶蛋白水平(β细胞中必不可少的葡萄糖感受器)。我们还发现，它通过促进朗格汉斯胰岛中的β细胞增殖来增加β细胞质量。其他研究人员证明了GLP-1在β细胞系和整个胰岛中的抗细胞凋亡作用。一种GLP-1受体(GLP-1R)激动剂exendin-4最近已可用于治疗2型糖尿病。 巴尔的摩老龄化纵向研究的数据显示，年龄在65岁或以上的人中，糖尿病在很大程度上是由于β细胞衰竭，胰岛素抵抗是一个次要因素。因此，exendin-4或任何通过GLP-1R发挥作用的化合物应该是治疗老年糖尿病的理想方法。另一个好处是GLP-1R激动剂不会引起低血糖，因为它们的胰岛素调节作用是葡萄糖依赖的。我们基础工作的一个组成部分是研究GLP-1是如何增加β细胞周转的。我们已经在成熟的胰岛中发现了Notch途径的所有原型组件。该途径的激活需要伽马分泌酶来裂解Notch受体(NICD)的C末端，然后NICD转位到细胞核。NiCd控制胰腺的内分泌分化，并决定胚胎胰腺中细胞的命运(内分泌、外分泌和导管细胞类型)。GLP-1R的激活，通过增加PKA的活性，进而导致诱导伽马分泌酶的活性。在体外和体内，伽玛分泌酶抑制剂抑制伽玛分泌酶可阻止GLP-1R介导的β细胞增殖。这提供了Notch信号通路激活、GLP-1R激活和β细胞增殖之间的直接联系。我们目前正在研究基于Notch配体受体激活部分的多肽，作为可能的药物来促进体内的β细胞增殖。我们还在调查Notch通路是否在衰老过程中受到负面干扰。

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.