LIPID-METABOLISM AND MEMBRANE-COMPOSITION ARE ALTERED IN THE BRAINS OF TYPE-II DIABETIC MICE

CBL/57 strain db/db mice exhibit type II (noninsulin-dependent) diabet es. The affected mice are markedly hyperinsulinemic, hyperglycemic, an d hypercholesterolemic, and their serum K+ levels are decreased. The b rains of the diabetic mice are significantly smaller than those of the ir lean, control littermates, but the protein concentration is normal. The low brain weight is accompanied by a loss of major fatty acid com ponents within the whole brain, nerve endings, and mitochondrial membr anes. Cholesterol levels are low in whole brain but are not significan tly different from normal in the synaptosomal[ membranes. The phosphol ipid concentration is significantly decreased in whole brain homogenat es, crude synaptosomal membranes, and crude mitochondrial membranes of the diabetic mice. In addition, the specific activities of membrane-b ound synaptosomal acetylcholinesterase, Na+,K+-ATPase, and Mg2+-ATPase are decreased in crude synaptosomal membranes of the diabetic mice. T he specific activities of carnitine palmitoyltransferase I and carniti ne acetyltransferase are significantly increased in the crude mitochon drial fraction isolated from the brains of the type II diabetic mice, whereas the specific activity of pyruvate dehydrogenase complex is dec reased. The specific activities of two other mitochondrial enzymes-mon oamine oxidase B and citrate synthase-and a cytosolic enzyme-lactate d ehydrogenase-are unaltered. The ability to synthesize cyclic AMP is ma rkedly decreased in the brains of the diabetic mice. The concentration s of carnitine and of the amino acids, glutamate, aspartate, glutamine , and serine are unaltered, whereas glycine levels are significantly e levated 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 gluc ose oxidation and increased capacity for fatty acid oxidation, This hy pothesis is supported by the finding that cerebral mitochondria isolat ed from the db/db mice oxidize [1-C-14] palmitate to (CO2)-C-14 at a r ate almost twice that of control mitochondria. The present findings em phasize the potentially serious alteration of brain metabolism in unco ntrolled type II diabetes.