Potential mechanism(s) of impaired pulsatile insulin secretion and action in Type

描述(申请人提供)：全球超过1亿人患有2型糖尿病(TTDM)或其前体空腹血糖受损。TTDM会导致严重的微血管和大血管并发症(失明、肾功能衰竭、心脏病发作、中风)和过早死亡，从而影响生活质量。TTDM的主要代谢异常包括胰岛素分泌受损和胰岛素抵抗。TTDM患者的胰岛以分泌胰岛素的“β”细胞缺乏约65%为特征。最近的研究表明，这种β细胞数量的减少导致了胰岛素分泌的异常模式，这本身可能导致胰岛素抵抗。胰岛素如何分泌的模式和这种模式对其工作效果的影响之间的这种联系是本申请的重点。在健康人群中，胰岛素以离散的胰岛素分泌方式分泌，每隔约5分钟进入门静脉，直接使肝脏暴露在胰岛素浓度波动的波前，波动幅度从禁食时的100-500pmol/L到进食后的1000-5000pmol/L。在TTDM患者中，这些振荡的大小明显减少(但频率没有变化)。在具体目标1中，我们将寻求建立导致胰岛素分泌暴发减少的潜在机制。我们将研究一种新开发的TTDM大鼠模型，通过直接测量糖尿病发生前后门静脉脉冲性胰岛素分泌，并同时从同一大鼠分离胰岛，目的是直接从这些胰岛建立导致体内观察到的胰岛素分泌缺陷的机制。初步研究表明，内质网压力和可用胰岛素储备量的减少共同导致了脉搏肿块的不足。在特定的目标2中，我们将试图确定TTDM中存在的胰岛素分泌的异常脉动模式的后果。为了实现这一点，我们将测量门静脉胰岛素输注后的肝脏葡萄糖产生，无论是1)正常脉动胰岛素输注，2)恒定胰岛素输注，3)选择胰岛素输注复制TTDM患者的观察结果。初步研究表明，TTDM中存在的胰岛素输送模式导致肝脏胰岛素抵抗。在具体目标3中，我们将寻求建立脉冲胰岛素传递增强肝脏胰岛素信号的潜在机制(S)。具体地说，我们将测试脉冲式胰岛素输送模式是否避免了对胰岛素信号的反馈抑制(避免了AKT对IRS-2激活的抑制)。具体目标3将在霍华德·休斯医学院的莫里斯·怀特博士的额外指导下进行。

DESCRIPTION (provided by applicant): More than 100 million people worldwide have Type 2 diabetes (TTDM) or its precursor impaired fasting glucose. TTDM compromises quality of life by causing serious microvascular and macrovascular complications (blindness, renal failure, heart attack, stroke) and premature death. Primary metabolic abnormalities in TTDM include impaired insulin secretion and insulin resistance. The pancreatic islet in people with TTDM is characterized by ~ 65% deficit in insulin secreting "beta" cells. Recent studies reveal hat this decreased number of beta cells leads to an abnormal pattern of insulin secretion which in of itself may contribute to insulin resistance. This link between the pattern of how insulin is secreted and the impact of this pattern on how well it works is the focus of the present application. In health insulin is secreted in discrete insulin secretory bursts occurring at ~5 minute intervals into the portal vein which directly exposes the liver to an insulin concentration wavefront of oscillations ranging in amplitude from 100-500 pmol/l at fasting to 1000-5000 pmol/l following meal ingestion. These oscillations are markedly decreased in size (but without change in frequency) in patients with TTDM. In Specific aim 1 we will seek to establish the underlying mechanisms leading to decreased insulin secretory bursts. We will study a newly developed rat model for TTDM by directly measuring pulsatile insulin secretion in the portal vein before and after development of diabetes and concurrently isolate islets from the same rats with the aim of establishing directly from these islets the mechanisms leading to the observed defective insulin secretion in vivo. Preliminary studies imply that a combination of endoplasmic reticulum stress and decreased available insulin stores leads to the deficit in pulse mass. In Specific Aim 2 we will seek to establish the consequences of the abnormal pulsatile pattern of linsulin secretion present in TTDM. To accomplish this we will measure hepatic glucose production following portal vein insulin delivery either in 1) normal pulsatile insulin infusion, 2) constant insulin infusion, 3) insulin infusion selected to reproduce that observed in patients with TTDM. Preliminary studies indicate that the pattern of insulin delivery present in TTDM leads to hepatic insulin resistance. In Specific Aim 3 we will seek to establish the potential mechanism(s) by which pulsatile insulin delivery enhances hepatic insulin signaling. Specifically, we will tests whether the pulsatile mode of insulin delivery avoids feedback inhibition of insulin signaling (avoiding AKT inhibition of IRS-2 activation). Specific Aim 3 will be undertaken with the additional guidance of Dr. Morris White at the Howard Hughes Medical Institute.