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...

No abstract

A B S T R A C T Although alcoholism is a leading cause of morbidity and mortality of middle-aged Americans, there are no data available pertaining to the consequences of Laennec's cirrhosis on total body energy requirements or mechanisms for maintaining fuel homeostasis in this patient population. Therefore, we simultaneously used the techniques of indirect calorimetry and tracer analyses of ["4C]palmitate to measure the nature and quantity of fuels oxidized by patients with biopsy-proven alcoholic cirrhosis and compared the results with values obtained from healthy volunteers. Cirrhotic patients were studied after an overnight fast (10-12 h). Normal volunteers were studied after an overnight fast (12 h) or after a longer period of starvation (36-72 h).Total basal metabolic requirements were similar in overnight fasted cirrhotic patients (1.05±0.06 kcal/ min per 1.73 m2), overnight fasted normal subjects (1.00±0.05 kcal/min per 1.73 m2), and 36-72-h fasted normal volunteers (1.10±0.06 kcal/min per 1.73 m2).Indirect calorimetry revealed that in cirrhotic patients the percentages of total calories derived from fat (69±3%), carbohydrate (13±2%), and protein (17±4%) were comparable to those found in 36-72-h fasted subjects, but were clearly different from those of overnight fasted normal individuals who derived 40±6, 39±4, and 21±2% from fat, carbohydrate, and protein, respectively.These data are strikingly similar to data obtained through tracer analyses of ['4C]palmitate, which showed that in overnight fasted patients with alcoholic cir-

To study the mechanism of the diabetogenic action of ethanol, ethanol (0.75 g/kg over 30 min) and then glucose (0.5 g/kg over 5 min) were infused intravenously into six normal males. During the 4-h study, 21.8±2.1 g of ethanol was metabolized and oxidized to CO2 and H20. Ethanol decreased total body fat oxidation by 79% and protein oxidation by 39%, and almost completely abolished the 249% rise in carbohydrate (CHO) oxidation seen in controls after glucose infusion. Ethanol decreased the basal rate of glucose appearance (GR.) by 30% and the basal rate of glucose disappearance (GR,) by 38%, potentiated glucose-stimulated insulin release by 54%, and had no effect on glucose tolerance. In hyperinsulinemic-euglycemic clamp studies, ethanol caused a 36% decrease in glucose disposal. We conclude that ethanol was a preferred fuel preventing fat, and to lesser degrees, CHO and protein, from being oxidized. It also caused acute insulin resistance which was compensated for by hypersecretion of insulin.

Although it is an established concept that the liver is important in the disposition of glucose, the quantitative contribution of the splanchnic and peripheral tissues, respectively, to the disposal of an oral glucose load is still controversial. In the present investigation, we have employed the hepatic venous catheter technique in combination with a double-tracer approach (in which the glucose pool is labeled with 3H-glucose and the oral glucose load is labeled with 14C-glucose) to quantitate the four determinants of oral glucose tolerance: rate of oral glucose appearance, splanchnic glucose uptake, peripheral glucose uptake, and suppression of hepatic glucose production. Studies were carried out in 11 normal volunteers in the overnight-fasted state and for 3.5 h after the ingestion of glucose (1 g/kg body wt; range, 55-93 g). In the postabsorptive state, the rate of endogenous (hepatic) glucose production, evaluated from the 3H-glucose infusion, was 2.34 +/- 0.06 mg/min X kg. Glucose ingestion was accompanied by a prompt reduction of endogenous glucose output, which reached a nadir of 0.62 +/- 0.23 mg/min X kg at 45 min and remained suppressed after 3.5 h (0.85 +/- 0.22 mg/min X kg). The average inhibition of hepatic glucose output during the absorptive period was 53 +/- 5%. The appearance of ingested glucose in arterial blood, as derived from the 14C-glucose measurements after correction for recycling 14-C radioactivity, reached a peak after 15-30 min, and 14C-glucose continued to enter the systemic circulation throughout the observation period. The rate of appearance of ingested glucose was 2.47 +/- 0.45 mg/min X kg at 3.5 h. A total of 73 +/- 4% of the oral load was recovered in the systemic circulation within 3.5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

A B S T R A C T Forearm muscle metabolism was studied in eight obese subjects after an overnight, 3 and 24 day fast. Arterio-deep-venous differences of oxygen, carbon dioxide, glucose, lactate, pyruvate, free fatty acids, acetoacetate, and P-hydroxybutyrate with simultaneous forearm blood flow were measured. Rates of metabolite utilization and production were thus estimated. Oxygen consumption and lactate and pyruvate production remained relatively constant at each fasting period. Glucose, initially the major substrate consumed, showed decreased consumption after 3 and 24 days of fasting. Acetoacetate and P-hydroxybutyrate consumption after an overnight fast was low. At 3 days of fasting with increased arterial concentrations of acetoactate and P-hydroxybutyrate, consumption of these substrates rose dramatically. At 24 days of fasting, despite further elevation of arterial levels of acetoacetate and P-hydroxybutyrate, the utilization of acetoacetate did not increase further and if anything decreased, while five out of eight subjects released P-hydroxybutyrate across the forearm. Acetoacetate was preferentially extracted over P-hydroxybutyrate. At 24 days of starvation, free fatty acids were the principal fuels extracted by forearm muscle; at this time there was a decreased glucose and also ketone-body consumption by skeletal muscle.

A B S T R A C T The metabolism of acetone was studied in lean and obese humans during starvation ketosis. Acetone concentrations in plasma, urine, and breath; and rates of endogenous production, elimination in breath and urine, and in vivo metabolism were determined. There was a direct relationship between plasma acetone turnover (20-77 ,Umol/m2 per min) and concenitration (0.19-1.68 mM). Breath and urinary excretion of acetone accounted for a 2-30% of the endogenous production rate, and in vivo metabolism accounted for the remainder. Plasma acetone oxidation accounted for -60% of the production rate in 3-d fasted subjects and about 25% of the production rate in 21-d fasted subjects. About 1-2% ofthe total CO2 production was derived from plasma acetone oxidation and was not related to the plasma concentration or production rate. Radioactivity from [14C]acetone was not detected in plasma free fatty acids, acetoacetate, ,-hydroxybutyrate, or other anionic compounds, but was present in plasma glucose, lipids, and proteins. If glucose synthesis from acetone is possible in humans, this process could account for 11% of the glucose production rate and 59% of the acetone production rate in 21-d fasted subjects. During maximum acetonemia, acetone productioni from acetoacetate could account for 37% of the anticipated acetoacetate production, which implies that a significant fraction of the latter compound does not undergo immediate terminal oxidation.

A B S T R A C T Plasma acetate turnover and oxidation were determined in 11 healthy subjects by the constant infusion of a trace amount of [1_-4C]acetate for 6 h. The subjects ages ranged from 22 to 57 yr. There was a positive correlation (P < 0.001) between plasma acetate concentration and turnover rate, and a negative correlation (P < 0.001) between turnover and age. The plasma acetate concentration in the subjects 22-28 yr old was 0.17 vs. 0.13 mM (P < 0.02) in subjects 40-57 yr old. The plasma acetate turnover rate was also greater in the younger age group (8.23+0.66 vs. 4.98+0.64 ,umol/ min -kg, P < 0.01). Approximately 90% of the plasma acetate turnover was immediately oxidized to CO2 in both age groups, however, 13.2±+0.89% of the CO2 output in the younger group was derived from plasma acetate oxidation compared to 7.9+0.94% in the older group (P < 0.01). The mean plasma acetate concentration, turnover, and oxidation in six cancer patients 47-63 yr old were similar to the values observed in the age-matched healthy subjects.