GLUCOKINASE GENE EXPRESSION IN PANCREATIC BETA CELL

葡萄糖激酶（GK）在葡萄糖稳态中起重要作用。在 在人类中，这种酶的突变会导致成熟型糖尿病， 青年2型（MODY-2）和持续性高胰岛素血症性低血糖 婴儿期（PHHI）。 虽然GK基因突变是少数几个 糖尿病的遗传学定义的原因，我们还没有完全理解 这个基因的突变是如何改变血糖的 浓度. 这是利用转基因和基因- 改变小鼠以了解更多关于葡萄糖激酶的细胞特异性作用 (GK)葡萄糖稳态和适应性反应， 对急性和慢性血糖变化的反应 浓度. 目的1明确GK的组织特异性功能 在葡萄糖稳态中通过选择性地将其从不同细胞中除去 使用Cre/LoxP策略。 Aim 2将开发具有可诱导 肝脏葡萄糖利用和/或β细胞胰岛素缺陷 分泌，并表征响应于 肝脏或胰岛GK的急性丧失。所有这些 研究将为分子生物学提供新的基本见解， 发病机制MODY-2以及适应发生在响应 高血糖症 因此，这些研究也与 2型糖尿病的发病机制和治疗。

Glucokinase (GK) plays an essential role in glucose homeostasis. In humans, mutations in this enzyme cause both maturity onset diabetes of youth, type 2 (MODY-2) and persistant hyperinsulinemic hypoglycemia of infancy (PHHI). Although GK gene mutations are one of only a few genetically-defined causes of diabetes, we do not yet fully understood how mutations in this gene actually alter the plasma glucose concentration. This is a proposal to make use of novel lines transgenic and gene- altered mice to learn more about the cell-specific roles of glucokinase (GK) in glucose homeostasis and about adaptive responses that occur in response to acute and chronic alternations in the plasma glucose concentration. Aim 1 will define the tissue-specific functions of GK in glucose homeostasis by selectively removing it from different cell types using a Cre/LoxP strategy. Aim 2 will develop mice with inducible defects in either hepatic glucose utilization and/or beta cell insulin secretion, and characterize the adaptations that occur in response to both an acute loss of either hepatic or islet GK. Together, these studies will provide fundamental new insights into the molecular pathogenesis MODY-2 as well adaptations that occur in response to hyperglycemia. Thus, these studies are also relevant to the pathogenesis and treatment of Type 2 diabetes mellitus.