Gao Zhiyong, Young Robert A, Li Guizhu, Najafi Habiba, Buettger Carol, Sukumvanich Siam S, Wong Ryan K, Wolf Bryan A, Matschinsky Franz M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and The Children's Hospital, Philadelphia, Pennsylvania 19104, USA.
Endocrinology. 2003 May;144(5):1949-57. doi: 10.1210/en.2002-0072.
Culturing rat islets in high glucose (HG) increased 1-(14)C-alpha-ketoisocaproate (KIC) oxidation compared with culturing them in low glucose. Leucine caused insulin secretion (IS) in low glucose but not in HG rat islets, whereas KIC did so in both. Pretreatment with HG for 40 min abolished leucine stimulation of IS by mouse islets and prevented the cytosolic Ca(2+) rise without inhibiting IS and Ca(2+) increments caused by KIC. When islets were pretreated without glucose and glutamine, aminooxyacetic acid (AOA) markedly decreased KIC effects. When islets were pretreated without glucose and with glutamine, AOA potentiated leucine effects but attenuated KIC effects. AOA stimulated glutamine oxidation in the presence but not the absence of +/-2-amino-2-norbornane-carboxylic acid, a nonmetabolized leucine analog. Pretreatment with HG and glutamine partially reversed AOA inhibition of KIC effects. Glucose increased intracellular ATP and GTP, whereas it decreased ADP and GDP in beta HC9 cells. Glutamate dehydrogenase activity of beta HC9 cell extracts was increased by leucine and attenuated by GTP, but it was potentiated by ADP. In conclusion, leucine and KIC stimulated beta-cells via distinct mechanisms. Glutamate dehydrogenase is the sensor of leucine, whereas transamination plays an important role in KIC stimulation of pancreatic beta-cells.
与在低糖环境中培养相比，在高糖（HG）环境中培养大鼠胰岛可增加1-（14）C-α-酮异己酸（KIC）氧化。亮氨酸在低糖环境中可引起胰岛素分泌（IS），但在高糖大鼠胰岛中则不然，而KIC在两种环境中均可引起胰岛素分泌。用高糖预处理40分钟可消除亮氨酸对小鼠胰岛胰岛素分泌的刺激作用，并防止细胞溶质Ca（2+）升高，同时不抑制KIC引起的胰岛素分泌和Ca（2+）增加。当胰岛在无葡萄糖和谷氨酰胺的情况下进行预处理时，氨氧基乙酸（AOA）可显著降低KIC的作用。当胰岛在无葡萄糖但有谷氨酰胺的情况下进行预处理时，AOA可增强亮氨酸的作用，但减弱KIC的作用。在存在而非不存在±2-氨基-2-降冰片烷羧酸（一种非代谢性亮氨酸类似物）的情况下，AOA可刺激谷氨酰胺氧化。用高糖和谷氨酰胺预处理可部分逆转AOA对KIC作用的抑制。葡萄糖可增加β HC9细胞内的ATP和GTP，而降低ADP和GDP。亮氨酸可增加β HC9细胞提取物的谷氨酸脱氢酶活性，GTP可使其减弱，但ADP可使其增强。总之，亮氨酸和KIC通过不同机制刺激β细胞。谷氨酸脱氢酶是亮氨酸的传感器，而转氨作用在KIC刺激胰腺β细胞中起重要作用。
