Metabolic Interactions Between Carbohydrate and Fat Metabolism in Human Subjects Robert R. Wolfe, Ph.D. (University of Texas Medical Branch, Department of Surgery Shriners Hospital for Children) Carbohydrate (glucose) and fat are the only non-protein sources of energy for ATP production, so their rates of metabolism are inextricably linked. The metabolic relationship between fat and carbohydrate oxidation is at the heart of the response to hypocaloric diets containing different amounts of the substrate. However, controversy remains regarding the exact nature of that relationship. The “glucose-fatty acid cycle”, proposed by Randle and associates in 1963, was a seminal proposal relating carbohydrate (glucose) and fat (free fatty acids – FFA) metabolism. The centerpiece of this proposal was that the availability of FFA determined the relative rate of fat and carbohydrate oxidation, i.e., increased availability of FFA directly inhibited the oxidation of glucose. Glucose, on the other hand, putatively acted only to prevent fatty acid oxidation by inhibiting its release from adipose tissue triglyceride (TG) via lipolysis. This hypothesis was developed on the basis of in vitro data from rat diaphragm muscle. In vivo experiments in our laboratory have demonstrated that in human subjects the relationship between fat and carbohydrate oxidation is actually reversed from the traditional proposal. Thus, the availability of glucose determines the rate of oxidation of fatty acids. The regulation of fatty acid oxidation by glucose is mediated by the intracellular concentration of malonyl CoA, which inhibits the enzyme system carnitine acyl transferase I that is responsible for fatty acids entering the mitochondria for oxidation. The relevance of substrate interactions to the response to hypocaloric diets can be appreciated by quantitively examining the role of glucose availability in controlling the response of energy substrate metabolism to fasting. With complete fasting, carbohydrate stores are reduced. As a result, the proportional contribution of glucose to energy production falls, and fat oxidation increases. Provision of only 50 gm of glucose per day, infused continuously throughout fasting, prevents the drop in blood glucose that otherwise occurs. Insulin concentration remains below basal when euglycemia is maintained during fasting, and the rate of lipolysis remains elevated. Nonetheless, the increase in FFA oxidation that normally occurs during fasting is blocked, presumably by the mechanism described above. Therefore, the percent of REE derived from fat oxidation is reduced from the fasting value to approximately the normal basal rate. The contribution of glucose oxidation to total energy production rises in this circumstance, but even if utilization of the exogenous glucose is completely efficient (i.e., all 50 gm are oxidized), that amount of glucose is insufficient to make up for the decrement in energy production resulting from the inhibition of fat oxidation. Consequently, the oxidation of endogenous protein (amino acids) must be accelerated, thereby increasing the proportion of energy production from protein oxidation. In the case of fasting, this means that endogenous protein stores, predominantly muscle, will be oxidized at an accelerated rate.