REGULATION OF METABOLISM BY AKT/PKB IN BETA CELLS AND BRAIN

了解β细胞生长和功能的调节是我们希望实现的关键目标 1型糖尿病和2型糖尿病的合理治疗。在前者中，自身免疫性攻击 胰岛消除了β细胞，导致胰岛素的绝对严重缺乏。的一种方法 有一些热情的治疗方法是实验性的β细胞群扩增， 体外或体内。在2型糖尿病中，胰岛素抵抗的增加（通常与肥胖有关）会增加胰岛素抵抗， 对胰腺的需求是增加胰岛素的分泌。然而，共识是，这并不 出现症状，直到β细胞增生和胰岛素分泌不再同步增加， 胰岛素相对不足。同样，这种疾病可能会得到改善， 通过增强功能性β细胞质量的增加而显著增加。一条通道， 近年来对β细胞生长的控制的相当大的关注是胰岛素信号传导途径本身。 该途径中的关键中间体是丝氨酸/苏氨酸蛋白激酶Akt，也称为蛋白激酶B。 这种酶以PI 3 '-激酶依赖性方式被激活，现在被认为调节细胞生长， 在许多组织类型中的增殖和分化。在上一个融资期，我们表明， β细胞中活性Akt的过表达导致β细胞群的大量扩增，这是由以下引起的： 细胞数量的增加以及β细胞的大小。此外，表达激活Akt的动物 在β细胞中，它被保护免受许多类型的实验性糖尿病的影响。在本提案中，我们 描述了旨在了解Akt产生的分子细节机制的实验， 这些影响，并阐明Akt在正常β细胞发育和神经元控制中的作用， 新陈代谢.该补助金分为三个目标。目的一是进一步调控Akt的表达 暂时在小鼠的β细胞中，以进一步阐明激酶的作用，并评估几种 下游信号分子。目的二是确定Akt在β细胞中的生理作用， 生长和功能，通过选择性消融β细胞中的各种Akt亚型。在目标3中，我们将 扩展我们对β细胞中Akt功能的了解，以探索其在能量控制中的作用 和下丘脑神经元的葡萄糖代谢。

Understanding the regulation of beta cell growth and function is a goal critical to our hopes of achieving rationale therapies for both Type 1 and Type 2 diabetes mellitus. In the former, an autoimmune attack on the islet eliminates beta cells, leading to an absolute, severe deficiency of insulin. One approach to treatment for which there has been some enthusiasm is the experimental expansion of beta cell mass, either in vitro or in vivo. In Type 2 diabetes, increasing insulin resistance, often associated with obesity, boosts the demands on the pancreas for enhanced secretion of insulin. However, the consensus is that this does not become symptomatic until the increased beta cell hyperplasia and insulin secretion can no longer keep pace, and there is a relative deficiency of insulin. Again, it is likely that the disease would be ameliorated considerably by an enhanced increase in functional beta cell mass. A pathway that has received considerable attention in recent years for the control of beta cell growth is the insulin signaling pathway itself. A key intermediate in this pathway is the serine/threonine protein kinase Akt, also known as protein kinase B. This enzyme is activated in a PI 3'-kinase-dependent manner and is now recognized to regulate cell growth, proliferation and differentiation in a number of tissue types. In the previous funding period we showed that overexpression of an active Akt in beta cells leads to a substantial expansion of beta cell mass, caused by an increase in cell number as well as the size of the beta cells. Moreover, animals expressing activated Akt in the beta cells are protected from a number of types of experimental diabetes. In this proposal, we describe experiments aimed at understanding in molecular detail the mechanism by which Akt produces these effects, and clarifying Akt's role in normal beta cell development and the neuronal control of metabolism. The grant is divided into three aims. Aim one is to further manipulate the expression of Akt temporally in the beta cell of the mouse to further clarify the role of the kinase, and to evaluate several downstream signaling molecules. In aim two, we will determine the physiological role of Akt in beta cell growth and function, by selectively ablating the various Akt isoforms in the beta cell. Lastly, in aim 3, we will extend what we have learned about Akt function in the beta cell to explore its role in the control of energy and glucose metabolism by hypothalamic neurons.