Role of Pulsatile Insulin Secretion

描述(申请人提供)：1型和2型糖尿病的患病率都在增加。两者的特征都是分泌胰岛素的胰岛β细胞缺失。1型和2型糖尿病的特点都是胰岛素抵抗。虽然这可以通过注射更多的胰岛素来克服，但糖尿病的胰岛素抵抗会增加心脏病、中风和截肢的风险。在拟议的研究中，我们将检验这一假设，即糖尿病患者发生胰岛素抵抗的原因之一是当β细胞数量下降到正常水平的50%以下时，胰岛素分泌模式受到干扰。在健康中，几乎所有的胰岛素都是在离散的胰岛素分泌爆发中分泌的。在糖尿病患者中，胰岛素分泌不足是因为分泌爆发的大小太小。一旦β细胞数量降至正常的~50%以下，我们假设胰岛素脉冲的大小减少，因为剩余的β细胞无法产生足够的胰岛素来维持这些分泌爆发。然而，我们认为这并不明显，因为至少在一开始，随着胰岛素分泌的下降，肝脏对胰岛素的清除减少，因此循环中的胰岛素量保持相对正常。那么，这一切为什么重要呢？长期以来，人们一直认识到，随着人们接近发展成糖尿病(空腹血糖/葡萄糖耐量受损)，这种状态相对不稳定，并迅速发展为糖尿病。我们认为，这是因为IFG/IGT在许多情况下意味着β细胞质量下降到正常的~50%，脉动性胰岛素分泌下降，结果是胰岛素抵抗增加。我们认为，胰岛素需求的增加和维持胰岛素分泌的能力下降的集体影响会导致失代偿和糖尿病的发生。如果我们是正确的，那么针对促进β细胞质量下降的机制将是预防1型和2型糖尿病的最基本的方法。在拟议的研究中，我们将首先检查胰腺切除~50%的人和IFG/IGT患者与对照组的脉动性胰岛素分泌和胰岛素敏感性。其次，我们将直接在体内建立脉动胰岛素分泌的生理作用，最后，我们将研究脉动胰岛素分泌增强靶组织中胰岛素信号的机制。公共卫生相关性：在美国，2型糖尿病是导致2000多万人过早死亡的主要原因。目前的赠款建议继续资助旨在为患者从空腹血糖受损过渡到糖尿病的研究奠定基础。如果知道这一转变的基础，那么制定预防2型糖尿病的策略将更加现实。

DESCRIPTION (provided by applicant): Both type 1 and type 2 diabetes are increasing in prevalence. Both are characterized by a loss of insulin secreting pancreatic beta cells. Type1 and Type 2 diabetes are both characterized by insulin resistance. Although this can be overcome by administering more insulin, insulin resistance in diabetes confers increased risk for heart disease, strokes and amputation. In the proposed studies, we will test the hypothesis that one of the reasons people with diabetes develops insulin resistance is because the pattern of insulin secretion is disturbed when the number of beta cells decreases below ~50% of normal. In health, almost all insulin is secreted in discrete insulin secretory bursts. In people with diabetes insufficient insulin is secreted because the size of the secretory bursts is too small. Once the number of beta cells drops below ~50% of normal, we postulate the size of the insulin pulses decreases as the remaining beta cells are unable to generate sufficient insulin to sustain these secretory bursts. However, we propose that this is not obvious because, at least initially, hepatic insulin clearance of insulin decreases as insulin secretion declines, so that the amount of circulating insulin remains relatively normal. So why does all this matter? It has long been appreciated that as people get close to developing diabetes (Impaired fasting glucose/glucose intolerance) this state is relatively unstable with rapid progression to diabetes. We propose that the reason underpinning this is that IFG/IGT imply in many cases that the beta cell mass has declined to ~50% of normal, pulsatile insulin secretion declines and as a consequence insulin resistance is increased. We suggest that the collective impact of this increment in insulin demand and decreased capacity to sustain insulin secretion leads to decompensation and onset of diabetes. If we are correct, then targeting the mechanisms subserving the decline in beta cell mass will be the most rationale approach to preventing type 1 and 2 diabetes. In the proposed studies, we will first examine humans with an ~50% pancreatectomy and those with IFG/IGT compared to controls for pulsatile insulin secretion and insulin sensitivity. Second we will directly establish the physiological role of pulsatile insulin secretion in vivo and finally we will examine the mechanism by which pulsatile insulin secretion enhances insulin signaling in target tissues. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a leading cause of premature death in the USA involving more than 20 million people. The present grant proposes continued funding of studied designed to establish the basis for the transition of patients from impaired fasting glucose to diabetes. If the basis of this transition was known it would be more realistic to establish strategies to prevent type 2 diabetes.