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

本应用程序的总体目标是更好地了解禁食环境在影响能力方面的作用 β-细胞对随后的进餐挑战做出反应。糖尿病前期是一种介于正常 糖代谢与2型糖尿病。糖尿病前期通常根据空腹血糖浓度进行分类。 以及摄取75g葡萄糖后2小时的葡萄糖浓度。这些小组的不同之处在于 空腹血糖和游离脂肪酸浓度、β细胞功能及其进展为2型的风险 糖尿病。有趣的是，β细胞对葡萄糖的反应依赖于空腹胰岛素的合成 而且，在游离脂肪酸浓度高和高血糖的受试者中，储存似乎受到了损害。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细胞的功能 合成，也许，推动了糖尿病前期向糖尿病的进展。此外，还有一个独特的子- 单纯性空腹血糖受损的糖尿病前期组。迄今获得的数据表明，这些受试者 表现得像葡萄糖激酶(GCK)基因突变的患者。此前，我们小组证明了 糖尿病患者存在肝脏葡萄糖激活酶功能障碍。在这一系列实验中，我们将确定 这一亚组确实单独或与β的整体缺陷一起表现出葡萄糖感觉受损- 细胞功能。这将有助于确定空腹和餐后胰岛素分泌缺陷是否会对 高血糖，独立发展。由于底物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度，并诱导了一种保护机制，称为 未折叠的蛋白质反应，意在恢复内质网的动态平衡。这在体内与此相关 反应未知--2型糖尿病患者胰岛素第一时相缺失，胰岛素原增多 释放暗示胰岛素合成有缺陷。然而，胰岛素原的浓度不太可能是 关于膳食β细胞功能的信息，因为其清除动力学尚不清楚。拟议中的实验将 阐明空腹游离脂肪酸和血糖的变化如何改变胰岛素和胰岛素原的分泌。自被提升以来 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 随着时间的推移而改变。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，并导致糖尿病前期发展为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.