Del Monte M A, Rabbani R, Diaz T C, Lattimer S A, Nakamura J, Brennan M C, Greene D A
Department of Ophthalmology, University of Michigan, Ann Arbor 48109.
Diabetes. 1991 Oct;40(10):1335-45.
The "myo-inositol depletion hypothesis" remains a leading but still controversial contender among proposed pathogenetic mechanisms for the chronic complications of diabetes. The multifaceted interrelationships among altered tissue myo-inositol content and metabolism and tissue function have been difficult to elucidate in diabetic animal models due in part to the complex, heterogeneous nature of tissues prone to diabetic complications. The retinal pigment epithelium consists of a homogenous cell monolayer that exhibits related alterations in myo-inositol metabolism and function in diabetic animals. Nontransformed human retinal pigment epithelial (hRPE) cells, which retain their general phenotypic and morphological characteristics during monolayer culture in vitro, were examined for parallel alterations in myoinositol metabolism and cell function when grown under carefully controlled conditions in medium containing hyperglycemic concentrations of glucose. Exposure of hRPE cells to 20-40 mM glucose produced time- and dose-dependent increases in sorbitol content and decreases in myo-inositol content that were partially blocked by the aldose reductase inhibitor sorbinil. myo-Inositol was taken up by two Na-dependent transport systems, at least one of which was competitively inhibited by glucose. Exposure to 20 mM glucose impaired the ability of hRPE cells to take up human retinal rod outer segments, an important physiological function of these cells. The impairment of rod outer segment uptake by high glucose levels was prevented by an aldose reductase inhibitor or elevated medium myo-inositol that corrected the fall in myo-inositol content. Thus, hRPE cells provide a new in vitro model in which to examine the biochemical-functional interrelationships of the myo-inositol depletion hypothesis.
“肌醇耗竭假说”在糖尿病慢性并发症的发病机制中仍是一个主要但仍存在争议的观点。在糖尿病动物模型中，组织肌醇含量和代谢改变与组织功能之间多方面的相互关系难以阐明，部分原因是易患糖尿病并发症的组织具有复杂、异质性的特点。视网膜色素上皮由单层同质细胞组成，在糖尿病动物中其肌醇代谢和功能呈现相关改变。非转化的人视网膜色素上皮（hRPE）细胞在体外单层培养时保留其一般表型和形态特征，当在含有高血糖浓度葡萄糖的培养基中在严格控制的条件下生长时，研究其肌醇代谢和细胞功能的平行改变。将hRPE细胞暴露于20 - 40 mM葡萄糖会使山梨醇含量呈时间和剂量依赖性增加，肌醇含量降低，醛糖还原酶抑制剂索比尼尔可部分阻断这种变化。肌醇通过两种钠依赖性转运系统摄取，其中至少一种被葡萄糖竞争性抑制。暴露于20 mM葡萄糖会损害hRPE细胞摄取人视网膜杆状体外段的能力，这是这些细胞的一项重要生理功能。高糖水平导致的杆状体外段摄取受损可通过醛糖还原酶抑制剂或提高培养基中的肌醇来预防，后者可纠正肌醇含量的下降。因此，hRPE细胞提供了一个新的体外模型，用于研究肌醇耗竭假说的生化 - 功能相互关系。
