EFFECT OF EXENTIDE ON INSULIN SECRETION AND BETA CELL MASS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本研究将使用狒狒。2型糖尿病（不需要胰岛素的糖尿病）和空腹血糖受损（在时间上先于糖尿病发作的状态）通过在人类中简单地发现过夜禁食后的高葡萄糖水平（超过100 mg/dl）来诊断。2型糖尿病是由以下原因引起的：1）胰岛素抵抗，即身体不能通过在正常胰岛素浓度下降低葡萄糖来响应，因此需要更高的胰岛素浓度来克服这种抵抗，以及2）胰腺中产生胰岛素的细胞（称为β细胞）的胰岛素分泌不足。当身体不再能够产生足够量的胰岛素来代谢葡萄糖时，葡萄糖水平高，临床上诊断为糖尿病。尽管进行了深入的研究，但我们不知道导致人类产生胰岛素的细胞死亡的分子机制。我们假设，在某些条件下，即在疾病的早期并使用某些促进再生的药物，有可能预防2型糖尿病或至少预防胰岛素治疗，能够保存并产生新的胰岛素产生细胞。我们建议测试的药物是艾司那肽，它与一种名为GLP-1（胰高血糖素样肽1）的激素非常相似，GLP-1在餐后胃肠道中产生。GLP-1作用于胰岛素产生细胞，使其响应于葡萄糖产生更多胰岛素。此外，最近在小鼠和大鼠中的研究表明，GLP-1可能促进胰岛素产生细胞的再生，即新胰岛素产生细胞的形成，也可能防止相同细胞的死亡。 为了精确测量胰岛素分泌量，我们将静脉注射葡萄糖，使所有动物在一定时间内达到预定的葡萄糖水平。这个过程被称为“高血糖钳夹”。这意味着葡萄糖浓度被维持（钳制）在高于正常浓度（高血糖）的水平。我们预计在exenglycine治疗后，葡萄糖水平会降低，胰岛素浓度会升高。我们还期望看到产生胰岛素的细胞数量增加，  产生显示即将死亡（细胞凋亡）迹象的细胞  科学术语）。这种研究对于帮助开发新的更好的2型糖尿病治疗方法非常有价值，这是一个全球性的巨大问题，特别是对于其并发症，如心脏病发作，中风和截肢，每年有数百万人。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This study will utilize baboons. Type 2 diabetes (non-insulin requiring diabetes) and impaired fasting glucose (a state that precedes temporally the onset of diabetes) are diagnosed by simply finding high glucose levels (over 100mg/dl) after overnight fasting, in humans. Type 2 diabetes is caused by: 1) insulin resistance, that is the inability of the body to respond by lowering glucose at normal insulin concentration and therefore requiring higher insulin concentrations to overcome this resistance and 2) insufficient insulin secretion by the cells that produce insulin in the pancreas, that are called beta-cells. When the body is no longer capable of producing insulin in sufficient amounts to metabolize glucose, glucose levels are high and diabetes is diagnosed clinically. Despite intensive research we do not know the molecular mechanisms that cause the death of the cells that produce insulin in humans. We hypothesize that under certain conditions, that is very early in the disease and employing certain medications that promote regeneration, it would be possible to prevent type 2 diabetes mellitus or at least to prevent insulin therapy, be being able to preserve and to generate new insulin producing cells. The drug that we propose to test is EXENATIDE, which is very similar to a hormone called GLP-1 (Glucagon like peptide 1), that is produced in the gastrointestinal tract following a meal. GLP-1 acts on the insulin producing cells causing them to produce more insulin in response to glucose. Also, recent studies in mice and rats suggest that GLP-1 might promote regeneration of insulin producing cells, that is the formation of new insulin producing cells and also might prevent the death of the same cells. In order to precisely measure the amount of insulin secreted, we will administer glucose intravenously to reach a predefined glucose level in all animals for a certain period of time. This procedure is called "hyperglycemic clamp". It means that the glucose concentration is maintained (clamped) at a higher (hyperglycemic) than normal concentration. We expect to see a decrease in glucose levels and an increase in insulin concentration after exenatide treatment. We also expect to see an increase in the number of insulin producing cells and a reduced number of insulin  producing cells that show sign of imminent death (apoptosis  scientific term). This kind of research is extremely valuable for helping to develop new and better treatments for type 2 diabetes, which is an enormous problem worldwide, especially for its complications, such as heart attacks, strokes and amputations, which are several millions every year.