The role of amylin and GLP-1 mimetics in the treatment of children with T2DM

描述(由申请人提供)： 在过去的二十年里，2型糖尿病(T2 DM)在儿科人群中的发病率一直在上升。因此，并发症可能发生在较早的年龄，强调了改善儿科人群血糖控制的重要性。餐后高血糖是血糖控制不佳的主要原因。胰升糖素、胰淀素和胰升糖素样肽-1(GLP-1)等激素在糖尿病中调节失调。胰淀素和GLP-1作为胰高血糖素的抑制因子，有助于降低餐后高血糖。胰淀素和GLP-1的异常导致餐后高血糖。这些激素失调对儿童T2 DM的影响在很大程度上仍不清楚。这项建议的总体目标是研究胰淀素和GLP-1对T2 DM儿童血糖稳态的作用。这项建议的第一个具体目标是确定瘦、肥胖和T2 DM儿童在胃排空、底物和激素稳态(胰岛素、胰淀素、胰升糖素和GLP-1)方面的差异。第二个具体目的是以随机对照的方式观察单独应用胰淀素类似物普拉林肽和GLP-1受体激动剂埃塞那肽对接受胰岛素治疗的儿童餐后高血糖和高血糖素分泌的影响。在具体目标3中，我们将研究在抑制和非抑制的胰高血糖素条件下，普拉林肽和埃塞那肽的作用。这些研究将促进我们对餐后抑制胰高血糖素在儿童T2 DM治疗中的作用的认识。此外，我们还将考察普拉林肽和埃塞那肽作为次要终点对甘油三酯浓度和胃排空的影响。随着T2 DM在儿童人群中发病率的增加，呼吁对儿童T2 DM的代谢适应进行更多的研究。了解T2 DM患儿胰淀素和GLP-1缺乏的异常及其替代，以便以生理学的方式替代这些激素将是非常重要的。 我的长期目标是成为一名儿科T2 DM领域的独立研究者。通过贝勒医学院临床科学家培训计划指导的研究活动和这个奖项将为我提供实现目标所需的工具。

DESCRIPTION (provided by applicant): During the past two decades, the incidence of type 2 diabetes mellitus (T2DM) in the pediatric population has been on the rise. Consequently, complications may occur at an earlier age, underscoring the importance of improving glycemic control in the pediatric population. Postprandial hyperglycemia is a major contributor to poor glycemic control. Hormones such as glucagon, amylin and glucagon like peptide-1 (GLP-1) are dysregulated in diabetes. Amylin and GLP-1 act as glucagon suppressors helping to decrease postprandial hyperglycemia. Abnormalities in amylin and GLP-1 contribute to postprandial hyperglycemia. The effect of these hormonal dysregulations remains largely unknown in pediatric T2DM. The overall goal of this proposal is to study the role of amylin and GLP-1 on glucose homeostasis in children with T2DM. The first specific aim of this proposal is to determine the differences in gastric emptying, substrate and hormonal homeostasis (insulin, amylin, glucagon and GLP-1) between lean, obese and T2DM children. The second specific aim will examine in a randomized controlled fashion the effects of independent administration of the amylin analog, pramlintide and the incretomimetic effect of the GLP-1 receptor agonsit, exenatide on postprandial hyperglycemia and glucagon secretion in children with T2DM insulin treated. In specific aim 3 we will study the effect of pramlintide and exenatide under suppressed and unsuppressed glucagon conditions. These studies will advance our knowledge in the role of postprandial glucagon inhibition in the management of pediatric T2DM. In addition, we will examine the effect of pramlintide and exenatide on triglyceride concentrations and gastric emptying as a secondary end points. The increasing incidence of T2DM in the pediatric population, advocates for more studies looking at the metabolic adaptations in pediatric T2DM. Understanding abnormalities in amylin and GLP-1 deficiencies and their replacement in children with T2DM will be very important so as to replace these hormones in a physiologic manner. My long-term objective is to evolve into an independent investigator in the area of pediatric T2DM. The mentored research activities through the Clinical Scientist Training Program at Baylor College of Medicine and this award will provide me with the tools necessary to achieve my goal.