Over 50 years ago, Benedict (2) published his extensive monograph on the metabolism of fasting in man, in which he demonstrated that carbohydrate stores provide a small but significant component of the body's fuel for only the first few days. Thereafter, protein and fat are the sole sources of fuel, the former contributing 15 % of the calories and the latter the balance.The primary role of fat as fuel was apparent to Benedict and his contemporaries; it is plentiful and expendable. The significance of the protein requirement, however, was less clear; in fact, it was not fully understood until nearly 20 years later when the obligatory dependence of the central nervous system on glucose was firmly established (3). Since glycogen stores in man were known to approximate only 200 g, it was readily apparent that glucose has to be derived from protein in order to maintain cerebral metabolism during a prolonged fast. More recently, our understanding of the fasted state has been further clarified by the demonstration that free fatty acid is both the major transport form of lipid leaving adipose tissue (4, 5) and a substrate that is * Submitted for publication January 26, 1966; accepted August 4, 1966. Supported in part by grants from the U. readily utilized by liver, muscle, and many other tissues.Although the above findings provide a basis for understanding the metabolism of fasting, certain areas such as the physiologic role of hormones and the mechanisms controlling glucose production and utilization remain poorly defined. In addition, estimates of glucose turnover (6)(7)(8)(9)(10)(11)(12) or splanchnic glucose production (13-15) during a short fast all greatly exceed the amount that can be contributed by gluconeogenesis (as reflected by urinary nitrogen loss). This study was, therefore, designed to obtain base-line information concerning the metabolic and hormonal response to fasting in normal subjects and in two subjects with mild diabetes in the hope that such information would provide at least partial insight into some of these problems. In brief, we found in the normal subjects that the well-integrated release of peripheral fuels and the maintenance of blood glucose concentrations were probably related to insulin concentrations, suggesting but not necessarily proving that insulin is the primary signal responsible for fuel control during starvation. The studies also suggested that glu-, cose metabolism, particularly by brain, must be decreased in order for man to survive prolonged periods of caloric deprivation. MethodsSubjects. Six normal male subjects were selected to provide a diverse spectrum of body size and shape (Table I). Five (N1, Ns, N4, N5, and N.) were divinity students, and the sixth (N2) was a sporting-goods salesman. All were in perfect health and had been consuming an average diet estimated to contain over 250 g of carbohydrate and 80 g of protein with variable amounts of fat. Subjects N2 and N4 were intentionally selected because of a family history of diabetes; their mothers had maturity-onset...

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