The effect of the fasting milieu on beta-cell function in vivo

本申请的总体目的是更好地了解禁食环境在影响能力方面的作用。 以应对随后的膳食挑战。糖尿病前期是正常之间的过渡状态 糖代谢和2型糖尿病。糖尿病前期通常使用空腹血糖浓度进行分类 以及摄入75 g葡萄糖后2小时的葡萄糖浓度。这些小组在他们的 空腹血糖和游离脂肪酸浓度、其β细胞功能及其进展为2型糖尿病的风险 糖尿病有趣的是，依赖于空腹胰岛素合成的β细胞对葡萄糖的反应成分 并且在具有高游离脂肪酸浓度和高血糖症的受试者中储存似乎受损。这 提示这些底物的升高可能通过改变空腹胰岛素直接影响β细胞功能 合成，并可能推动前驱糖尿病发展为糖尿病。此外，还有一个独特的子- 单纯空腹血糖受损的糖尿病前期组。迄今为止的数据表明，这些受试者 表现得像葡萄糖激酶（GCK）基因突变的患者。此前，我们的团队证明， 糖尿病患者具有肝葡萄糖激酶功能障碍。在这一系列的实验中，我们将确定， 该亚组确实表现出单独的葡萄糖感知受损或与β-葡萄糖受体的整体缺陷相结合。 细胞功能这将有助于确定是否在空腹和餐后胰岛素分泌缺陷， 高血糖，独立发展。由于基质过剩增加了对合成机械的需求， 在β细胞中，它增加了蛋白质错误折叠的速率，并诱导了一种保护机制，称为 未折叠蛋白反应，旨在恢复内质网稳态。在体内相关的， 反应未知-2型糖尿病患者缺乏第1时相胰岛素，胰岛素原增加 这意味着胰岛素合成的缺陷。然而，胰岛素原的浓度不太可能 由于其清除动力学尚不清楚，因此可提供膳食β细胞功能的信息。拟议的实验将 阐明空腹FFA和血糖的变化如何改变胰岛素和胰岛素原的分泌。由于升高 胰岛素原与β细胞功能障碍有关，我们将研究胰岛素原分泌的变化 随时间变化。拟议的实验将有助于阐明禁食底物 过量会导致β-细胞功能障碍，并导致前驱糖尿病发展为2型糖尿病。

The overall aim of this application is to better understand the role of the fasting milieu in influencing the ability of the β-cell to respond to subsequent meal challenges. Prediabetes is the transitory state between normal glucose metabolism and type 2 diabetes. Prediabetes is often categorized using fasting glucose concentrations as well as glucose concentrations 2 hours after ingestion of 75g of glucose. These sub-groups differ in their fasting glucose and free fatty acid concentrations, their β-cell function and their risk of progression to type 2 diabetes. Intriguingly, the component of β-cell response to glucose that depends on fasting insulin synthesis and storage seems to be impaired in subjects with high free fatty acid concentrations and hyperglycemia. This suggests that elevation of these substrates might directly influence β-cell function by altering fasting insulin synthesis and, perhaps, drive the progression of prediabetes to diabetes. In addition, there is a unique sub- group of prediabetes with isolated, impaired fasting glucose. Data available to date suggest that these subjects behave like patients with a mutation in the glucokinase (GCK) gene. Previously, our group demonstrated that people with diabetes have hepatic glucokinase dysfunction. In this series of experiments we will ascertain if this subgroup does indeed exhibit impaired glucose sensing alone or in combination with a global defect in β- cell function. This will help to determine if defects in fasting and postprandial insulin secretion, in response to hyperglycemia, develop independently. Since substrate excess increases demand on the synthetic machinery of the β-cell, it increases the rate of protein misfolding and induces a protective mechanism, known as the unfolded protein response, intended to restore endoplasmic reticulum homeostasis. The in vivo correlate of this response is unknown – 1st phase insulin is absent in type 2 diabetes and there is an increase in proinsulin release implying defects in insulin synthesis. However, concentrations of proinsulin are unlikely to be informative of prandial β-cell function as its clearance kinetics are unknown. The proposed experiments will elucidate how changes in fasting FFA and glucose alter insulin and proinsulin secretion. Since elevated proinsulin has been associated with β-cell dysfunction, we will examine how changes in proinsulin secretion change over time. The proposed experiments will help elucidate the mechanisms by which fasting substrate excess contributes to β-cell dysfunction, and to the progression of prediabetes to type 2 diabetes.