Makar T K, Hungund B L, Cook G A, Kashfi K, Cooper A J
Department of Biochemistry, Cornell University Medical College, New York, NY 10021, USA.
J Neurochem. 1995 May;64(5):2159-68. doi: 10.1046/j.1471-4159.1995.64052159.x.
CBL/57 strain db/db mice exhibit type II (noninsulin-dependent) diabetes. The affected mice are markedly hyperinsulinemic, hyperglycemic, and hypercholesterolemic, and their serum K+ levels are decreased. The brains of the diabetic mice are significantly smaller than those of their lean, control littermates, but the protein concentration is normal. The low brain weight is accompanied by a loss of major fatty acid components within the whole brain, nerve endings, and mitochondrial membranes. Cholesterol levels are low in whole brain but are not significantly different from normal in the synaptosomal membranes. The phospholipid concentration is significantly decreased in whole brain homogenates, crude synaptosomal membranes, and crude mitochondrial membranes of the diabetic mice. In addition, the specific activities of membrane-bound synaptosomal acetylcholinesterase, Na+,K(+)-ATPase, and Mg(2+)-ATPase are decreased in crude synaptosomal membranes of the diabetic mice. The specific activities of carnitine palmitoyltransferase I and carnitine acetyltransferase are significantly increased in the crude mitochondrial fraction isolated from the brains of the type II diabetic mice, whereas the specific activity of pyruvate dehydrogenase complex is decreased. The specific activities of two other mitochondrial enzymes--monoamine oxidase B and citrate synthase--and a cytosolic enzyme--lactate dehydrogenase--are unaltered. The ability to synthesize cyclic AMP is markedly decreased in the brains of the diabetic mice. The concentrations of carnitine and of the amino acids, glutamate, aspartate, glutamine, and serine are unaltered, whereas glycine levels are significantly elevated in the brains of the db/db mice. The data suggest that in vivo the brains of the diabetic mice exhibit a decreased capacity for glucose oxidation and increased capacity for fatty acid oxidation. This hypothesis is supported by the finding that cerebral mitochondria isolated from the db/db mice oxidize [1-14C]palmitate to 14CO2 at a rate almost twice that of control mitochondria. The present findings emphasize the potentially serious alteration of brain metabolism in uncontrolled type II diabetes.
CBL/57品系的db/db小鼠表现出II型（非胰岛素依赖型）糖尿病。患病小鼠显著高胰岛素血症、高血糖和高胆固醇血症，且其血清钾离子水平降低。糖尿病小鼠的大脑明显小于其瘦的、作为对照的同窝小鼠，但蛋白质浓度正常。脑重量低伴随着全脑、神经末梢和线粒体膜内主要脂肪酸成分的损失。全脑中胆固醇水平低，但突触体膜中的胆固醇水平与正常水平无显著差异。糖尿病小鼠的全脑匀浆、粗突触体膜和粗线粒体膜中的磷脂浓度显著降低。此外，糖尿病小鼠粗突触体膜中膜结合的突触体乙酰胆碱酯酶、钠钾ATP酶和镁ATP酶的比活性降低。从II型糖尿病小鼠大脑中分离出的粗线粒体部分中，肉碱棕榈酰转移酶I和肉碱乙酰转移酶的比活性显著增加，而丙酮酸脱氢酶复合体的比活性降低。另外两种线粒体酶——单胺氧化酶B和柠檬酸合酶——以及一种胞质酶——乳酸脱氢酶——的比活性未改变。糖尿病小鼠大脑中合成环磷酸腺苷的能力显著降低。肉碱以及氨基酸谷氨酸、天冬氨酸、谷氨酰胺和丝氨酸的浓度未改变，而db/db小鼠大脑中甘氨酸水平显著升高。数据表明，在体内糖尿病小鼠大脑表现出葡萄糖氧化能力降低和脂肪酸氧化能力增加。从db/db小鼠分离出的脑线粒体氧化[1-14C]棕榈酸酯生成14CO2的速率几乎是对照线粒体的两倍，这一发现支持了该假说。目前的研究结果强调了未控制的II型糖尿病中脑代谢可能发生的严重改变。
