Metabolism

Abstract: This article marks the beginning of Rodbell's interest in cell receptors. In it, he related his discovery that fat cells could be isolated from other cells by treating them with preparations of collagenase, and also found that insulin could stimulate glucose uptake. This had far-reaching implications for the treatment of various diseases, as it was the first demonstration that insulin acted on individual cells.

Abstract: This is a record of the concentrations of the nonenzyme components of the Embden-Meyerhof system in mouse brain measured at brief intervals after the production of complete ischemia by decapitation. All of the 18 recognized active components were looked for. Of these, 1,3-diphosphoglycerate did not reach levels measurable by the procedures used. Additional substances determined were glycogen, phosphocreatine, creatine, adenosine 5’-phosphate, cu-glycerophosphate, and triphosphopyridinenucleotide and its reduced form. The pyridine nucleotide values are only provisional. Considerable attention is devoted to methodology, since there are numerous possibilities for serious errors in preparation of samples as well as in the analyses for individual substrates. The substances measured account for all the known significant sources of energy available to the brain after its blood supply is cut off. Therefore it is possible to calculate the metabolic rate during the brief period of survival, as well as the time sequence according to which the brain taps its reserve sources of energy. Ischemia resulted in increases in glycolytic rates of at least 4to 7-fold in different experimental groups of mice. The coincident changes in substrate concentrations show which steps were facilitated to make this increase in flux take place, i.e. which steps control glycolysis in brain. These steps are the phosphorylations of glucose and fructose 6-phosphate, and the phosphorolysis of glycogen. There is no evidence that facilitation occurs at any other step in the glycolytic pathway.

Abstract: Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13C NMR spectroscopy to examine the metabolism of glioblastoma cells exhibiting aerobic glycolysis. In these cells, the tricarboxylic acid (TCA) cycle was active but was characterized by an efflux of substrates for use in biosynthetic pathways, particularly fatty acid synthesis. The success of this synthetic activity depends on activation of pathways to generate reductive power (NADPH) and to restore oxaloacetate for continued TCA cycle function (anaplerosis). Surprisingly, both these needs were met by a high rate of glutamine metabolism. First, conversion of glutamine to lactate (glutaminolysis) was rapid enough to produce sufficient NADPH to support fatty acid synthesis. Second, despite substantial mitochondrial pyruvate metabolism, pyruvate carboxylation was suppressed, and anaplerotic oxaloacetate was derived from glutamine. Glutamine catabolism was accompanied by secretion of alanine and ammonia, such that most of the amino groups from glutamine were lost from the cell rather than incorporated into other molecules. These data demonstrate that transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools. Rather, glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.