Metabolism of Islets of Langerhans and Hormone Release

描述(由申请者提供)：本次拨款支持的研究计划的长期目标是深入了解胰岛β细胞的中间代谢在燃料刺激的胰岛素释放中的作用。葡萄糖和谷氨酰胺的代谢及其相互关系是研究的主要焦点。该计划受到男性明确的、遗传性的、低血糖和高血糖综合征的相关临床研究的强烈影响，包括葡萄糖激酶病和葡萄糖脱氢酶或SUR-1/KIR 6.2关联低血糖。我们制定了以下项目。项目1.使用葡萄糖激酶(GK)的自发突变体和设计突变体继续该酶的结构/活性研究，重点是不明原因的MODY-2和PNDM-GK病例，选定的新发现的GK病例，以及GK的非必需异位变构激活的分子基础和生理相关性。项目2：通过研究葡萄糖和/或其他燃料分子的直接控制以及激素和神经递质的可能修饰，特别是胰岛素在这一过程中间接自分泌作用的可能性，来研究GK在β细胞中的表达控制。 研究谷氨酰胺代谢及其葡萄糖对胰岛β细胞功能的调节作用，重点研究谷氨酰胺酶、谷氨酰胺合成酶、谷氨酸脱氢酶和转氨酶的分子调控机制，并探讨谷氨酰胺作为燃料和辅因子在刺激胰岛素释放中的双重作用。

DESCRIPTION (provided by applicant): The long-term goal of the research program supported by the present grant is to understand in depth the role of intermediary metabolism of pancreatic beta-cells in fuel stimulated insulin release. Glucose and glutamine metabolism and their interconnections are the primary focus. This program is strongly influenced by relevant clinical studies of well-defined, inherited, hypo- and hyperglycemia syndromes in men, including Glucokinase Disease and GDH or SUR-1/Kir 6.2 linked hypoglycemia. We have formulated the following projects. Project 1. Continue structure/activity studies of glucokinase (GK) using spontaneous and designer mutants of the enzyme with emphasis on the unexplained MODY-2 and PNDM-GK cases, on selected newly-discovered cases of GK disease and on the molecular basis and physiological relevance of nonessential heterotopic allosteric activation of GK. Project 2. Investigate expression control of GK in beta-cells by focusing on the direct control of glucose and/or other fuel molecules and possible modifications by hormones and neurotransmitters, in particular on the possibility of an indirect autocrine role of insulin in the process. Project 3. Study the role of glutamine metabolism and its regulation by glucose in beta-cell function by focusing on the molecular mechanisms that regulate glutaminase, glutamine synthetase, glutamate dehydrogenase and transaminases, and exploring a hypothetical dual role of glutamine as fuel and as cofactor in stimulated insulin release.