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

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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.