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

描述（由申请人提供）：全球有超过1亿人患有2型糖尿病（TTDM）或其前驱空腹血糖受损。TTDM通过引起严重的微血管和大血管并发症（失明、肾衰竭、心脏病发作、中风）和过早死亡而损害生活质量。TTDM的主要代谢异常包括胰岛素分泌受损和胰岛素抵抗。TTDM患者的胰岛特征为约65%的胰岛素分泌“β”细胞缺陷。最近的研究表明，这种β细胞数量的减少导致胰岛素分泌的异常模式，其本身可能导致胰岛素抵抗。胰岛素如何分泌的模式与该模式对它如何工作的影响之间的这种联系是本申请的焦点。在健康状态下，胰岛素以约5分钟间隔发生的离散胰岛素分泌爆发的形式分泌到门静脉中，其直接使肝脏暴露于幅度范围为空腹时100-500 pmol/l至进餐后1000-5000 pmol/l的胰岛素浓度振荡波阵面。这些振荡的大小显着减少（但没有改变的频率）在TTDM患者。在具体目标1中，我们将寻求建立导致胰岛素分泌爆发减少的潜在机制。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中的脉动胰岛素分泌，同时从同一大鼠分离胰岛，目的是直接从这些胰岛中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，内质网应激和可用胰岛素储备减少的组合导致脉搏质量的不足。在具体目标2中，我们将寻求建立TTDM中存在的林舒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葡萄糖生成，1）正常脉冲胰岛素输注，2）恒定胰岛素输注，3）选择胰岛素输注以重现TTDM患者中观察到的结果。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式胰岛素给药增强肝脏胰岛素信号传导的潜在机制。具体而言，我们将测试胰岛素递送的脉动模式是否避免胰岛素信号传导的反馈抑制（避免IRS-2激活的AKT抑制）。具体目标3将在霍华德休斯医学研究所的Morris白色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.