Aging of the beta cell and type 2 diabetes

这项应用侧重于了解衰老如何影响胰岛β细胞的功能，以及这是如何 有助于2型糖尿病(T2D)的发展。T2D与衰老有关，部分特征是 胰岛素分泌功能失调。AGE和改变的β细胞功能之间的重要相互作用进一步 随着糖尿病的进展，它的持续下降，加上β细胞群体的无力，就说明了这一点 通过促进增殖来控制高血糖。这种对有丝分裂刺激缺乏反应被认为是 细胞衰老，并与p16INK4a的表达有关。成人的β细胞是异质性的 在p16INK4a和功能的表达上，增加了β细胞功能与年龄和 在成人的任何时候，都有处于不同阶段的细胞：未成熟、成熟和衰老。然而， 这样的转变还有待研究。我们的初步数据表明，随着年龄的增长，存在衰老的β细胞亚群，表现出独特的衰老特征，并显示出功能衰退。我们的假设是，处于不同生命阶段的β细胞具有不同的标志物(如IGF-1R)和功能特征，年龄和环境因素都可以改变种群的组成。我们将研究定义明确的小鼠模型，以开发令人兴奋的新工具和见解，然后在人类胰岛上进行测试。我们的目标是确定不同生命阶段的β细胞亚群，了解它们的老化，并确定操作是否可以改变β细胞的功能寿命。具体目的1.确定衰老的β细胞的标志物，表征这一生命周期阶段的功能变化，以及IGF-1R是否可以调节这些变化。假设β细胞经历不同的生命阶段，随着动物年龄的增长，较老的细胞亚群得到丰富，从而能够识别衰老标记物、功能特征和潜在机制。这一目标将 确定与衰老的β细胞相关的标记，以获得特定的衰老基因签名(重点是细胞表面标记)，并探索IGF-1R在其衰老中的机制作用。具体目的2.分析成年β细胞葡萄糖反应性的异质性是否受其生命周期阶段的影响。假说是，已知的β细胞功能异质性反映了它们生命周期的不同阶段。将收集衰老和非衰老的β细胞亚群，分析它们的功能，并评估衰老细胞对邻近年轻β细胞功能的影响。具体目的3.测试在没有或存在高血糖的情况下，由年龄决定的异质性如何改变对胰岛素抵抗的反应。我们假设，在T2D之前的胰岛素抵抗状态会加速β细胞的衰老，从而加速疾病的发展。这一目标将测试代谢需求增加及其对β细胞衰老的拯救的影响。这些研究应该为β细胞如何应对胰岛素抵抗、糖耐量受损和T2D提供洞察力。

This application focuses on understanding how aging affects the function of pancreatic beta cells and how this contributes to the development of type 2 diabetes (T2D). T2D is related to aging and is partly characterized by dysfunctional insulin secretion. The important interaction between age and altered beta cell function is further illustrated by its continued decline as diabetes progresses coupled with an inability of the beta cell population to control hyperglycemia by enhanced proliferation. Such lack of response to mitogenic stimuli is considered cellular senescence and has been linked to the expression of p16Ink4a. Adult beta cells are heterogeneous both in expression of p16Ink4a and function, raising the possibility that beta cell function is related to age and that at any point in the adult there are cells at different stages: immature, mature and senescent. However, such transition remains to be studied. Our preliminary data suggest the existence of a senescent subpopulation of beta cells that accumulates with age, expresses a unique senescence signature and displays functional decline. Our hypothesis is that beta cells at various life stages have different markers (such as IGF-1R) and functional characteristics, and that both age and environmental factors can shift the composition of the population. We will study well-defined mouse models to develop exciting new tools and insights that will be tested then on human islets. Our goal is to identify the subpopulations of beta cells at different life stages, understand their aging and determine whether manipulations can alter beta cell functional longevity. Specific Aim 1. To identify markers of aged beta cells, the functional changes that characterize this life cycle stage and whether IGF-1R can mediate these changes. The hypothesis is that beta cells go through different life stages and as the animal ages the older subpopulation of cells is enriched, enabling the identification of aging markers, functional features and potential mechanisms. This aim will identify markers associated with aged beta cells to derive a specific senescence gene signature (with emphasis on cell surface markers) and explore a mechanistic role of IGF-1R in their aging. Specific Aim 2. To analyze whether the heterogeneity in glucose responsiveness of adult beta cells is determined by their lifecycle stage. The hypothesis is that the known functional heterogeneity of beta cells reflects the different stages of their lifecycle. Senescent and non-senescent subpopulations of beta cells will be collected, their function analyzed and the effects of aged cells upon the function of neighboring younger beta cells evaluated. Specific Aim 3. To test how the heterogeneity determined by aging changes in response to insulin resistance in the absence or presence of hyperglycemia. We hypothesize that insulin resistant states that precede T2D accelerate aging of the beta cells thus accelerating the development of disease. This aim will test the effects of increased metabolic demand and its rescue upon beta cell aging. These studies should provide insights into how beta cells respond to insulin resistance, impaired glucose tolerance and T2D.