Kash S F, Condie B G, Baekkeskov S
Department of Medicine, and Hormone Research Institute, University of California San Francisco, 94143-0534, USA.
Horm Metab Res. 1999 May;31(5):340-4. doi: 10.1055/s-2007-978750.
The GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) is expressed in pancreatic beta-cells and GABA has been suggested to play a role in islet cell development and function. Mouse beta-cells predominantly express the larger isoform of the enzyme, GAD67, and very low levels of the second isoform, GAD65. Yet GAD65 has been shown to be a target of very early autoimmune T-cell responses associated with beta-cell destruction in the non-obese diabetic (NOD) mouse model of Type 1 diabetes. Mice deficient in GAD67, GAD65 or both were used to assess whether GABA is important for islet cell development, and whether GAD65 is required for initiation of insulitis and progression to Type 1 diabetes in the mouse. Lack of either GAD65 or GAD67 did not effect the development of islet cells and the general morphology of islets. When GAD65-/-(129/Sv) mice were backcrossed into the NOD strain for four generations, GAD65-deficient mice developed insulitis similar to GAD65+/+ mice. Furthermore, at the low penetrance of diabetes in this backcross, GAD65-deficient mice developed disease at the same rate and incidence as wildtype mice. The results suggest that GABA generated by either GAD65 or GAD67 is not critically involved in islet formation and that GAD65 expression is not an absolute requirement for development of autoimmune diabetes in the NOD mouse.
γ-氨基丁酸合成酶谷氨酸脱羧酶（GAD）在胰腺β细胞中表达，并且有人提出γ-氨基丁酸在胰岛细胞的发育和功能中发挥作用。小鼠β细胞主要表达该酶的较大异构体GAD67，而第二种异构体GAD65的表达水平非常低。然而，在1型糖尿病的非肥胖糖尿病（NOD）小鼠模型中，GAD65已被证明是与β细胞破坏相关的非常早期自身免疫性T细胞反应的靶点。利用缺乏GAD67、GAD65或两者的小鼠来评估γ-氨基丁酸对胰岛细胞发育是否重要，以及GAD65对于小鼠胰岛炎的起始和向1型糖尿病的进展是否是必需的。缺乏GAD65或GAD67均不影响胰岛细胞的发育以及胰岛的总体形态。当将GAD65-/-（129/Sv）小鼠与NOD品系回交四代时，GAD65缺陷小鼠发生的胰岛炎与GAD65+/+小鼠相似。此外，在该回交中糖尿病的低发病率情况下，GAD65缺陷小鼠与野生型小鼠以相同的速率和发病率发病。结果表明，由GAD65或GAD67产生的γ-氨基丁酸对胰岛形成并非至关重要，并且GAD65的表达对于NOD小鼠自身免疫性糖尿病的发展不是绝对必需的。
