EFFECT OF EXENTIDE ON INSULIN SECRETION AND BETA CELL MASS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项研究将利用狒狒。在人类中，只要在隔夜禁食后发现高血糖水平(超过100 mg/dl)，就可以诊断2型糖尿病(需要糖尿病的非胰岛素需求)和空腹血糖受损(糖尿病发作之前的一种状态)。2型糖尿病的原因是：1)胰岛素抵抗，即身体无法在正常的胰岛素浓度下通过降低血糖来做出反应，因此需要更高的胰岛素浓度来克服这种抵抗；2)在胰腺中产生胰岛素的细胞，即所谓的β细胞，胰岛素分泌不足。当身体不再能够产生足够数量的胰岛素来代谢葡萄糖时，血糖水平就会升高，临床上就会诊断为糖尿病。尽管进行了密集的研究，但我们并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，也就是在疾病的早期，使用某些促进再生的药物，将有可能预防2型糖尿病或至少阻止胰岛素治疗，能够保存和产生新的胰岛素产生细胞。我们建议测试的药物是埃克塞那肽，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是饭后在胃肠道产生的。GLP-1作用于胰岛素产生细胞，使它们在葡萄糖的作用下产生更多的胰岛素。此外，最近在小鼠和大鼠身上的研究表明，GLP-1可能促进胰岛素产生细胞的再生，即形成新的胰岛素产生细胞，并可能防止相同细胞的死亡。 为了准确测量胰岛素的分泌量，我们将在一段时间内静脉注射葡萄糖，使所有动物的葡萄糖水平达到预定的水平。这一过程被称为“高血糖钳夹”。这意味着血糖浓度维持(钳制)在高于正常浓度的(高血糖)。我们预计在艾塞那肽治疗后，血糖水平会下降，胰岛素浓度会上升。我们还预计会看到胰岛素产生细胞的数量增加，而显示出即将死亡的迹象的胰岛素产生细胞的数量减少(科学术语是细胞凋亡)。这类研究对于帮助开发新的、更好的治疗2型糖尿病非常有价值，2型糖尿病是一个世界性的巨大问题，特别是对其并发症，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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.