Metabolic Control Analysis in Defining the Phenotype of Disease. Richard Veech, M.D., D.Phil. (NIH, Bethesda, MD) Low carbohydrate diets can induce ketosis, depending upon the amounts of carbohydrate and protein they contain. The blood levels of ketone bodies achieved with the classical Mayo clinic ketogenic diet or by prolonged fasting approach a mean of 5-7 mM. This level of ketone bodies improves hydraulic efficiency in a working perfused heart by about 25% compared with the metabolism of glucose alone. A detailed analysis of the metabolic effects of ketone bodies on fluxes through the glycolytic pathway and of the energetics of mitochondrial energy production define the basic biochemical changes from which flow the inference that mild ketosis may be of therapeutic benefit in a number of disease phenotypes including: 1) insulin resistant states or states of substrate deficiency, 2) hypoxic states and 3) diseases involving free radical toxicity. On the other hand, low carbohydrate ketotic diets with associated low insulin levels can lead to elevation of plasma free fatty acids which can have a number of detrimental effects and produce inefficiency in the generation of metabolic energy. The toxicity of elevated free fatty acids can induce significant complications in individuals with a variety of underlying pathology. Administration of low carbohydrate ketogenic diets should therefore only be used under careful medical supervision.