Mitogenic Signal Transduction in Pancreatic Beta-Cells

现在已经认识到2型糖尿病是一种胰岛素不足的疾病。2型糖尿病是 与功能性胰腺SS细胞群的减少相关， 胰岛素抵抗因此，维持胰岛素分泌需求的最佳ss细胞群， 特别是通过促进β-细胞存活，是延迟2型和1型糖尿病发病的关键。在 在这方面，IRS-2已被证明在ss细胞生长和生存中发挥关键作用。增加IRS-2 IRS-2表达促进ss细胞生长和存活，而IRS-2表达不足导致自发性 ss细胞凋亡。虽然IRS-2蛋白和mRNA在胰岛β细胞中的半衰期很短，但这可以通过有效的胰岛素抵抗来抵消。 和IRS-2表达的高度调节控制，主要在转录水平介导。下 在基础条件下，ss细胞IRS-2基因的转录由FoxO转录因子通过胰岛素受体调控。 IRS-2启动子中的反应元件（IRE）。当IRS-2/PI 3 K/PKB信号在ss细胞中被激活时，FoxO 因此，转录因子失活，IRS-2表达减少，这似乎是一个新的机制。 时间负反馈机制，以防止IRS-2信号持续。IRS-2 可以通过替代方法独立地控制SS细胞中的表达。葡萄糖，在生理上 相关范围，是ss细胞IRS-2基因转录的主要调节因子。这需要葡萄糖代谢， Ca 2+依赖。它可能提供了一种机制，以保持ss细胞的健康在急性变化， 这一点很重要，因为其他因素，如肠促胰岛素，只增加ss细胞中IRS-2的表达。 以葡萄糖依赖的方式。然而，这些早期发现需要证实。这一提议意味着， 在分子水平上更好地了解胰腺ss细胞中IRS-2表达的控制。是 旨在更好地表征基础条件下IRS-2基因转录的控制，重点是 鉴定PI 3 K/PKB信号传导下游的哪种特定FoxO转录因子增加IRS-2 表情此外，我们将查明葡萄糖增加发出哪些特定的二级信号 β-细胞中的代谢与IRS-2表达增加有关（尤其是通过Ca 2 +/CaMK）。它旨在定义一个 IRS-2基因启动子中的葡萄糖调节顺式元件（GRES），然后鉴定反式作用因子 与GRE葡萄糖调节方式相关的基因。因此，更深入地了解 控制IRS-2在正常、肥胖和2型糖尿病原代ss细胞中表达的分子机制将 从这些研究中得出的结论。 肥胖相关的2型糖尿病在美国是一个主要的健康问题，是由胰腺ss细胞丢失引起的 产生胰岛素的细胞需要新的治疗方法，旨在保护内源性 ss细胞群产生足够的胰岛素来延迟，也许是无限期地，糖尿病的发病。IRS-2是一种 基因的关键ss细胞生存，预计新的见解控制IRS-2的表达将导致 一种在体内维持足够的β细胞数量和足够的胰岛素产生的新方法， 缓解，甚至可能预防2型糖尿病的症状。

It has now been realized that type-2 diabetes is a disease of insulin insufficiency. Type-2 diabetes is associated with a decrease in functional pancreatic ss-cell mass that no longer compensates for the peripheral insulin resistance. As such, maintaining an optimal ss-cell population for the insulin secretory demand, especially by promoting ss-cell survival, is key for delaying the onset of type-2, as well as type-1, diabetes. In this regard, IRS-2 has been shown to play a pivotal role in ss-cell growth and survival. Increased IRS-2 expression promotes ss-cell growth and survival, whereas insufficient IRS-2 expression leads to spontaneous ss-cell apoptosis. Although IRS-2 protein and mRNA half-life is short in islet ss-cells, this is countered by efficient and highly regulated control of IRS-2 expression, predominately mediated at the transcriptional level. Under basal conditions, ss-cell IRS-2 gene transcription is controlled by a FoxO transcription factor via an insulin response element (IRE) in the IRS-2 promoter. When IRS-2/PI3K/PKB signaling is activated in ss-cells, FoxO transcription factors are consequently inactivated and IRS-2 expression is reduced, in what appears to be a temporal negative feedback mechanism to prevent IRS-2 signaling from being sustained. However, IRS-2 expression can be independently controlled in ss-cells by alternative means. Glucose, in the physiologically relevant range, is a major regulator of ss-cell IRS-2 gene transcription. This requires glucose metabolism and is Ca2+-dependent. It likely provides a mechanism to preserve ss-cell well-being during acute changes in metabolic demand, and is important since other factors, like incretins, only increae IRS-2 expression in ss-cells in a glucose-dependent fashion. However, these early findings need substantiating. This proposal means to gain a better insight into the control of IRS-2 expression in pancreatic ss-cells at the molecular level. It is intended to better characterize control of IRS-2 gene transcription under basal conditions with an emphasis on identifying which particular FoxO transcription factor downstream of PI3K/PKB signaling increases IRS-2 expression. In addition, we will pinpoint which particular secondary signals emanating from increased glucose metabolism in ss-cells link to increased IRS-2 expression (especially via Ca2+/CaMK). It is intended to define a glucose-regulatory cis-element(s) (GREs) in the IRS-2 gene promoter and then identify a trans-acting factor(s) that specifically associates with the GRE glucose-regulatory manner. Thus, a much deeper insight into the molecular mechanism that controls IRS-2 expression in normal, obese and type-2 diabetic primary ss-cells will emerge from these proposed studies. Obesity-linked type-2 diabetes is a major health problem in the US and caused by loss of pancreatic ss-cells that produce insulin. Novel therapeutic approaches are needed which are aimed at protecting the endogenous ss-cell population to produce enough insulin to delay, perhaps indefinitely, the onset of diabetes. IRS-2 is a gene key to ss-cell survival, and it is anticipated that new insight into the control of IRS-2 expression will lead to a novel means of maintaining adequate ss-cell numbers and sufficient insulin production in vivo, that in turn will alleviate, or perhaps even prevent, symptoms of type-2 diabetes.