METABOLIC REGULATION OF INSULIN SECRETION

胰岛素分泌的代谢调节

基本信息

批准号：
2734040
负责人：
BARBARA E. CORKEY
金额：
$ 29.54万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-01-01 至 1999-06-30
项目状态：
已结题

项目摘要

The first step in resolving abnormalities in insulin secretion is to understand how the beta-cell is normally stimulated by glucose to secrete insulin. Data obtained during the preceding grant period led us to propose a model linking oscillatory release of insulin from the pancreatic beta- cell with glucose metabolism. According to the model an increase in the ambient glucose concentration causes oscillatory changes in glucose phosphorylation and glycolysis leading to oscillations in the ATP/ADP ratio and O2 consumption. Peaks in ATP/ADP close ATP-sensitive K+-channels depolarizing the cell and causing opening of voltage regulated Ca2+- channels. As a consequence of the latter, oscillatory increases in cytosolic free Ca2+ occur in the beta-cell. A second change caused by enhanced glucose metabolism is an increase in malonyl CoA which leads to increases in diacylglycerol and cytosolic long chain acyl CoA. According to our model these may activate protein kinase C or cause the acylation of regulatory proteins. Finally, we have found that increases in glucose concentration increase the amplitude of oscillations in metabolism, cytosolic free Ca2+ and insulin release. This appears to be due to a synchronous recruitment of responding cells suggesting communication among cells and islets. The proposed studies will use methods and collaborative arrangements that have been established during the current grant period to test and extend the metabolic model and examine the phenomena of recruitment and synchronization. We will attempt to 1, substantiate that changes in the ATP/ADP ratio and O2 consumption precede those in cytosolic Ca2+; 2, identify the physiological changes in oscillating metabolites that regulate beta-cell ion channel activity; 3, establish whether isolated beta-cells are recruited to respond to glucose through cell contact, intracellular metabolites, or extracellular ions; 4, document how cells and islets are synchronized to respond to glucose in an oscillatory manner; 5, determine whether protein kinase C and GTP binding protein activity is regulated by acyl CoA esters in beta-cells; and 6, discover how fuels such as alpha-keto-isocaproic acid and glyceraldehyde cause ionic and metabolic changes in the beta-cell similar to those caused by glucose. These studies will address fundamental questions concerning metabolic events, electrical activity and Ca2+ levels in the framework of a complex model that includes both first and second phase insulin secretion.

解决胰岛素分泌异常的第一步是了解葡萄糖通常如何刺激β细胞分泌胰岛素。在之前的资助期内获得的数据使我们提出将胰腺β-胰岛素振荡释放联系起来的模型具有葡萄糖代谢的细胞。根据模型，增加环境葡萄糖浓度导致葡萄糖振荡变化磷酸化和糖酵解导致 ATP/ADP 比率波动和氧气消耗量。 ATP/ADP 峰值关闭 ATP 敏感 K+ 通道使细胞去极化并导致电压调节的 Ca2+- 打开渠道。由于后者，振荡增加胞质游离 Ca2+ 出现在 β 细胞中。引起的第二个变化葡萄糖代谢的增强是丙二酰辅酶 A 的增加，从而导致二酰基甘油和胞质长链酰基辅酶A增加。根据根据我们的模型，这些可能会激活蛋白激酶 C 或导致调节蛋白。最后，我们发现血糖升高浓度增加新陈代谢的振荡幅度，胞质游离 Ca2+ 和胰岛素释放。这似乎是由于反应细胞的同步募集表明细胞之间的交流细胞和胰岛。拟议的研究将使用方法和协作在当前赠款期内已制定的安排测试和扩展代谢模型并检查以下现象招募和同步。我们将尝试 1、证实 ATP/ADP 比率和 O2 消耗的变化先于细胞质中的变化钙2+； 2、识别振荡代谢物的生理变化调节 β 细胞离子通道活性； 3、确定是否隔离 β细胞被招募来通过细胞接触对葡萄糖做出反应，细胞内代谢物或细胞外离子； 4、记录细胞如何胰岛以振荡方式同步响应葡萄糖； 5、确定蛋白激酶 C 和 GTP 结合蛋白活性是否受 β 细胞中酰基 CoA 酯的调节； 6、了解如何推动这样的因为α-酮异己酸和甘油醛会导致离子和代谢 β细胞的变化与葡萄糖引起的变化类似。这些研究将解决有关代谢事件、电学等基本问题复杂模型框架中的活性和 Ca2+ 水平，包括第一相和第二相胰岛素分泌。

项目成果

期刊论文数量（44）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glucose-induced toxicity in insulin-producing pituitary cells that coexpress GLUT2 and glucokinase. Implications for metabolic engineering.

葡萄糖诱导的共表达 GLUT2 和葡萄糖激酶的产生胰岛素的垂体细胞的毒性。

DOI：
10.1074/jbc.m102542200
发表时间：
2001
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Faradji,RN;Havari,E;Chen,Q;Gray,J;Tornheim,K;Corkey,BE;Mulligan,RC;Lipes,MA
通讯作者：
Lipes,MA

Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus.

DOI：
10.1161/circulationaha.110.014506
发表时间：
2011-07-26
期刊：
Circulation
影响因子：
37.8
作者：
Shenouda SM;Widlansky ME;Chen K;Xu G;Holbrook M;Tabit CE;Hamburg NM;Frame AA;Caiano TL;Kluge MA;Duess MA;Levit A;Kim B;Hartman ML;Joseph L;Shirihai OS;Vita JA
通讯作者：
Vita JA

Glucose-stimulated increase in cytoplasmic pH precedes increase in free Ca2+ in pancreatic beta-cells. A possible role for pyruvate.

葡萄糖刺激细胞质 pH 值的增加先于胰腺 β 细胞中游离 Ca2 的增加。