GLUCOSE/SECRETAGOGUE METABOLISM IN PANCREATIC ISLETS

本研究的长期目标是获得胰岛素分泌代谢信号的新线索。该项目的直接目的是了解线粒体氢穿梭及其在胰腺β细胞中代谢分泌激素诱导的胰岛素分泌中的作用。我们的大部分工作将集中在线粒体甘油磷酸脱氢酶（mGPD）上，这是甘油磷酸穿梭的关键酶，以验证mGPD在细胞代谢脱氢酶（mGPD）中起重要作用的假设，这是甘油磷酸穿梭的关键酶，以验证mGPD在细胞代谢，包括胰岛素分泌中起重要作用的假设。mGPD在正常β细胞中丰富，但在糖尿病人和啮齿动物模型中减少。虽然存在一种小鼠品系（BALB/cHeA）具有自然发生的胞质甘油磷酸脱氢酶（穿梭的胞质一半）的零章动，但没有突变或有效抑制剂被描述为消除mGPD活性。第一个目标是使用最近生产的mGPD敲除小鼠和细胞质缺失动物来研究磷酸甘油穿梭及其组成酶在整个动物和分离的胰岛和线粒体中的作用。第二个目标是继续研究mGPD启动子，以确定β细胞中mGPD高表达及其在糖尿病中的减少的因素。该项目的第三个目的是验证胰腺细胞中除了苹果酸丙酮酸穿梭外还有NADP(H)穿梭的假设。最近的许多证据表明，丙酮酸苹果酸穿梭存在于胰岛中。这种梭子利用线粒体基质中的丙酮酸羧化酶作为维持梭子单向性的酶，细胞质溶胶中的苹果酸酶作为NADP(H)氧化还原酶。有人提出，β细胞中可能存在其他需要羧化酶的梭子，但与其他细胞质和细胞质脱氢酶结合。由于mGPD和丙酮酸羧化酶的水平，但与其他细胞质脱氢酶结合。由于β细胞中mGPD和丙酮酸羧化酶的水平在体内最高，但在非胰岛素依赖型糖尿病（NIDDM）中β细胞中水平降低，因此研究它们的调节将增加对NIDDM中燃料刺激胰岛素分泌及其缺陷的理解。

The broad long term objective of this research is to obtain new clues about metabolic signals for insulin secretion. The immediate purpose of this project is to gain an understanding of mitochondrial hydrogen shuttles and their role in metabolizable secretagogue-induced insulin secretion in the pancreatic beta cell. Much of our effort will focus on the mitochondrial glycerol phosphate dehydrogenase (mGPD), the key enzyme in the glycerol phosphate shuttle, to test the hypothesis that mGPD plays an important role in cellular metabolism dehydrogenase (mGPD), the key enzyme in the glycerol phosphate shuttle, to test the hypothesis that mGPD plays an important role in cellular metabolism, including insulin secretion. mGPD is abundant in the normal beta cell, but is reduced in diabetics humans and in rodent models. While a mouse strain (BALB/cHeA) exists that possesses a naturally-occurring null nutation of the cytosolic glycerol phosphate dehydrogenase (the cytosolic half of the shuttle), no mutations or potent inhibitors have been described to eliminate mGPD activity. The first aim is to use a recently produced mGPD knockout mouse and the cytosolic null animal to study the role of the glycerol phosphate shuttle and its component enzymes in the whole animals and in isolated islets and mitochondria. The second aim is to continue studies of the mGPD promoter to determine factors responsible for high mGPD expression in the beta cell and its decrease in diabetes. The third aim of this project is to test the hypothesis that there are NADP(H) shuttles in the pancreatic beta cells besides the pyruvate malate shuttle. Much recent evidence suggests that the pyruvate malate shuttle is present in islets. This shuttle utilizes pyruvate carboxylase in the mitochondrial matrix as the enzyme that maintains unidirectionality of the shuttle, and malic enzyme in the cytosol as the NADP(H) oxidoreductase. It is proposed that other shuttles may exist in the beta cell that require the carboxylase, but in combination with other cytosolic with the cytosolic dehydrogenases. Since the levels of both mGPD and pyruvate carboxylase, but in combination with other cytosolic dehydrogenases. Since the levels of both mGPD and pyruvate carboxylase in the beta cell are among the highest in the body, but are decreased in the beta cell in non-insulin dependent diabetes (NIDDM), studies of their regulation will increase the understanding of fuel-stimulated insulin secretion and its defects in NIDDM.