Role of pulsatile insulin secretion.

描述(申请人提供)：2型糖尿病在#年呈上升趋势 以惊人的速度流行。这种疾病的根本原因仍然是 不知道。TTDM患者存在胰岛素抵抗和胰岛素缺陷 分泌物。近30年来，人们已经知道胰岛素在体内分泌 高频间歇脉冲。然而，由于这些脉冲仅导致 通常采血部位的胰岛素浓度会有微小的波动， 它们一直很难研究。国际和平研究所的实验室与 弗吉尼亚大学的Johannes Veldhuis开发并验证了 现在可以可靠地量化人类脉动性胰岛素分泌的方法。 这些方法的研究表明，几乎所有的胰岛素都是在体内分泌的。 这些间歇脉冲每隔6分钟出现一次。我们还展示了 实现了胰岛素分泌的调节(例如，餐后) 通过放大这些脉冲。此外，肝脏通常会暴露在 当这些脉冲分泌到门脉时，胰岛素浓度会发生巨大的变化 流入肝脏的静脉。在此之前，还没有任何研究考察过 这些肿块对胰岛素的作用产生脉冲作用。 在目前的研究中，我们计划首先 确定患者进餐后胰岛素分泌如何受到干扰 使用TTDM。我们怀疑它会有缺陷，因为胰岛素的大小 脉冲大大减少。此外，我们怀疑这是因为 分泌胰岛素的细胞数量减少。我们将通过以下方式进行测试 在狗模型中移除大约40%和70%的这些细胞 期望我们会制造出与TTDM相同的缺陷。我们 也将确定肝脏暴露在这些物质中有多么重要 较大的胰岛素浓度才能正常发挥作用。这一点很重要，因为 糖尿病患者必须在非常短的时间内接受胰岛素治疗。 不同的方式。未来替代患者胰岛素的系统的设计者 (例如通过移植或装置)需要评估 脉冲式胰岛素分泌胰岛素作用。

DESCRIPTION (Provided by applicant): Type-2 diabetes is increasing in prevalence at an alarming rate. The underlying cause of this disease is still not known. Patients with TTDM have insulin resistance and defective insulin secretion. It has been known for almost 30 years that insulin is secreted in high frequency intermittent pulses. However as these pulses result in only small oscillations in insulin concentration in the usual blood sampling sites, they have been hard to study. The laboratory of the PI in collaboration with Johannes Veldhuis at the University of Virginia have developed and validated methods that can now reliably quantify pulsatile insulin secretion in humans. Studies with these methods have revealed that almost all insulin is secreted in these intermittent pulses which occur at 6-minute intervals. We have also shown that the regulation of insulin secretion (for example after a meal) is achieved by the amplification of these pulses. Also, the liver is normally exposed to huge insulin concentration changes as these pulses are secreted into the portal vein that drains to the liver. No prior studies have examined the importance of these masses pulses on insulin action. In the present studies we plan to first establish how insulin secretion after meal ingestion is disturbed in patients with TTDM. We suspect that it will be deficient because the size of the insulin pulses is greatly decreased. Further, we suspect that this is because the number of cells that secrete insulin are decreased. We will test this by removing approximately 40 percent and 70 percent of these cells in a dog model with the expectation that we will create the same defect present in TTDM. We will also establish how important it is that the liver be exposed to these large insulin concentrations to function normally. This is important since patients with diabetes have to treat themselves with insulin in a very different manner. Designers of future systems to replace insulin in patients (e.g. by transplantation or devices) need to be appraised of the importance of pulsatile insulin secretion insulin action.