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A deficit of K+ of close to 300 mmol develops in the first 2 wk of fasting, but little further excretion of K+ occurs, despite high levels of aldosterone and the delivery of ketoacid anions that are not reabsorbed in the distal nephron. Our purpose was to evaluate how aldosterone could have primarily NaCl-retaining, rather than kaliuretic, properties in this setting. To evaluate the role of distal delivery of Na+, four fasted subjects received an acute infusion of NaCl to induce a natriuresis. To assess the role of distal delivery of HCO3-, five fasted subjects were given an infusion containing NaHCO3. The natriuresis induced by an infusion of NaCl caused only a small rise in the rate of excretion of K+ (0.8 +/- 0.1 to 1.9 +/- 0.3 mmol/h); in contrast, when HCO3- replaced Cl- in the infusate, K+ excretion rose to 8.3 +/- 2.2 mmol/h, despite little excretion of HCO3- (urine, pH 5.8) and similar rates of excretion of Na+. The transtubular K+ concentration gradient was 19 +/- 3 with HCO3- and 6 +/- 2 with NaCl. We conclude that the infusion of NaHCO3 led to an increase in K+ excretion, likely reflecting an increased rate of distal K+ secretion. With a low distal delivery of HCO3-, aldosterone acts as a NaCl-retaining, rather than a kaliuretic, hormone.

Objective: To determine the changes in the plasma level of acylation stimulating protein (ASP) during a one month total fast in female subjects with marked obesity., Design: Patients with marked obesity underwent a month total fast, before, during (2 weeks), and at the end of which, a variety of relevant metabolic parameters were measured., Setting: A metabolic unit of a teaching hospital., Subjects: 10 women with marked obesity were studied and the results compared with those in 16 age-matched controls., Main Outcome Measures: Plasma ASP, lipoprotein lipids, apoB, free fatty acid, and ketone levels., Results: At baseline, fasting levels of ASP in the obese group were double that in control subjects (116 +/- 26 vs 53 +/- 30 nM P < 0.001). During the fast, ASP levels dropped progressively and were within the normal range at the end of the study (63 +/- 16 vs 53 +/- 30 nM pNS). In addition, there was a strong correlation between the plasma ASP at baseline before beginning the fast and the 4 week drop in ASP. That is, those subjects who had the highest starting ASP also had the largest 4 week drop in ASP (r2 = 0.644, P < 0.005). Of interest, as plasma ASP levels dropped, plasma free fatty acid and ketone levels rose and when all timepoints were considered, there was a significant inverse relation between plasma ASP and plasma free fatty acid (r2 = 0.295, P < 0.0002)., Conclusions: The pattern of responses during the fast is that of increasing mobilization of fatty acids from adipose tissue coincident with decreased activity of the pathway responsible for the storage of adipocyte triglyceride mass. The data are consistent, therefore, with the role proposed for ASP as a major determinant of the rate of triglyceride synthesis in human adipocytes and thus a potentially important factor in the pathophysiology of obesity.

We tested whether sodium restriction would counteract the decrease in sympathetic nervous system activity usually associated with marked energy restriction. The effects of two levels of energy restriction, with different sodium intakes, on plasma norepinephrine (NE) levels while supine and in response to standing were studied. Twenty-two healthy normotensive obese female subjects (body mass index, 34 +/- 1 kg/m2; weight, 90 +/- 2 kg) followed one of three 3-week protocols: 1) total fasting with 80 mmol/day NaCl, 2) a very low energy diet (VLED) containing 1.7 MJ, 93 g protein, and 90 mmol Na/day, with an additional 60 mmol/day NaCl supplement, or 3) total fasting without NaCl (0 Na fast). At the end of the baseline isocaloric diet and of total fasts or VLED, pulse, blood pressure, and plasma NE were measured after 4 h of recumbency and 5 and 10 min after assuming the upright posture. These measurements were repeated after 1 L physiological saline was infused into the 0 Na fast subjects. Cumulative negative sodium balance was observed only in the 0 Na fasting subjects. Supine blood pressure decreased from baseline with fasting, but not with the VLED. The decreases in systolic pressure and increases in heart rate on standing observed with all diets were greatest with the 0 Na fast. Supine plasma NE (vs. baseline value) declined (P less than 0.05) with the VLED, remained unchanged with the Na supplemented fast, but increased with the 0 Na fast (P less than 0.05). The upright plasma NE values were highest in the 0 Na fast subjects, but lower after the saline infusion as well as in the subjects on the VLED. Thus, the decrease in NE due to energy restriction with normal sodium intake was counteracted by moderate sodium restriction, and levels increased with zero sodium intake. Therefore, sodium depletion can override the suppressive effect of energy restriction and, instead, increase the activity of the sympathetic nervous system, as reflected by plasma NE.

In an attempt to minimize fluid retention and obtain a gradual return to the pre-fast metabolic state, 14 nondiabetic obese subjects, who had fasted totally for 32 +/- 3 days, were fed a hypocaloric diet that incorporated stepwise increments in carbohydrate beginning at 20 g/day. During the refeeding period of 14 days, the total caloric intake for the first 9 days was 800 kcal/day and 1000 kcal/day thereafter. No untoward clinical events occurred. A weight regain of 2.2 +/- 0.4 kg during the first 7 days was accounted for by fluid retention. The return to pre-fast postabsorptive plasma glucose levels (82 +/- 3 to 93 +/- 3 mg dl-1) and a rise in immunoreactive insulin (0.5 +/- 0.1 to 0.8 +/- 0.1 ng ml-1) occurred by day 7. Blood 3-hydroxybutyrate and acetoacetate concentrations (4.1 and 0.6 mM, respectively) declined more slowly to reach pre-fast values by day 14; urinary excretion of 3-hydroxybutyrate dropped from 64 mmol/day to pre-fast levels by day 10. Urinary nitrogen excretion increased from 2.6 to a plateau of 5.5-6.0 g/day from day 3 onward; nitrogen balance was at least +3 g/day throughout refeeding. This approach to refeeding is associated with acceptable clinical response and may be appropriate after other states of marked caloric deprivation.

Splanchnic metabolism was studied to quantify changes underlying the fatty liver, hyperlipemia, and hypoglycemia produced by ethanol. Four subjects fasted for 15 h were compared with five subjects fasted for 69 h under basal conditions and during continuous intravenous infusion of sufficient ethanol to give a concentration of 3-5 mM in arterial blood plasma. Splanchnic storage of fatty acids was estimated from the difference between uptake of FFA and secretion of derived products. Basal values for splanchnic uptake of FFA were twofold higher after the 69-h fast while splanchnic storage of fatty acids and production of ketone bodies increased threefold. Values for basal secreation into the blood of triglycerides derived from FFA were similar in the two groups. In both nutritional states, the fraction of FFA taken up in the splanchnic region oxidized to ketone bodies and to CO2 fell when ethanol was given because of preferential oxidation of ethanol to acetate, and the fraction esterified rose. However, systemic transport and splanchnic uptake of FFA fell with ethanol in subjects fasted 15 h, so that neither storage of triglycerides in splanchnic tissues nor secretion into the blood increased. In subjects fasted 69 h, ethanol increased transport of FFA and splanchnic storage of fat. In all but one subject it also increased secretion of triglycerides into the blood. The concentration of glucose in blood fell during ethanol infusion in all five subjects undergoing the 69-h fast. Mean splanchnic glucose production was maintained at about one-half of the pre-ethanol value, despite virtual cessation of splanchnic uptake of lactate and of those amino acids that are metabolized via malate. Quantitative estimates of extrasplanchnic metabolism suggest that enhanced formation of alpha-glycerophosphate from glucose, in addition to impaired hepatic gluconeogenesis, may contribute to ethanol-induced hypoglycemia in man.

Eleven obese subjects (body mass index, 41.3 kg/m2) were examined to determine their metabolic and acid-base responses during two hypoenergetic diets, and the diets' influence on subsequent responses to prolonged total fasting. Subjects were first treated for 2 wk with 400-kcal/d (1.67-MJ/d) diets of either protein (13.2 g nitrogen, 23 mmol potassium) or glucose with 16 mmol potassium chloride and a multivitamin supplement. Mild acidosis developed during the protein diet as well as greater excretions of urinary ammonium and urea N, a greater degree of ketosis, and significantly better N balance (-42.7 vs -80.4 g, p less than 0.05) than during the glucose diet. The subsequent fast was associated with greater negative N balance after protein (-129 vs 83 g), mainly as urea N, but despite similar ketosis there was a greater acidosis after glucose and greater ammonium N excretion and cumulative K losses. These data support the concept of a labile N pool, depleted during a glucose diet and resulting in a decreased loss with the subsequent fast. We suggest a role for K depletion in augmenting fasting ammonium excretion.

The hormone-substrate milieu has been investigated in male fasted lean (C57BL/6-+/+) mice and mutant obese mice of the same strain (C57BL/6-obob). The lean mouse, in winter, mobilized insufficient fat (due to inadequate stores) to permit survival beyong 3 days and was unable to achieve any degree of conservation of vital protein stores. By contrast, in summer, the same animals survived 7 days and showed evidence of greater and more sustained fat mobilization and ketosis and the ability to conserve protein. The insulin, glucagon, and insulin/glucagon molar ratios changed in both groups in a direction consistent with conversion to a catabolic state, and hence were probably largely responsible for the mobilization of substrates and stimulation of gluconeogenesis and ketogenesis. The seasonal difference in response is unexplained. The obob mice, generally employed as a model for obesity, hyperglycemia, and hyperinsulinemia showed these features but also adapted to fasting in a fashion permitting prolonged survival during this state. In a fashion analogous to that known to occur in man, these animals developed fall in glycemia, rise in circulating fat-derived substrates, and marked protein conservation. Profound fall in insulinemia was associated with a fall in glucagonemia, the latter from normal levels. Thus the initial markedly "anabolic" insulin/glucagon molar ratio diminished, but nevertheless remained higher than at any time in the lean mice. Pancreatic contents of insulin showed markedly different changes with fasting in obob compared with lean mice. The ability of the obese mouse to adapt to prolonged fasting in a fashion largely analogous to that of man renders it a useful model for the study of metabolism in this state, with the potential of applicability of findings to man.

Skeletal muscle function and standard nutritional assessment parameters were measured in six obese patients. Base-line measurements were made on a weight-maintaining diet, and further measurements after 2 wk of a 400-cal diet, followed by 2 wk of fasting and then after 2 wk of refeeding. The function of the adductor pollicis muscle was assessed by electrical stimulation of the ulnar nerve. The objective parameters of muscle function measured were: 1) force of contraction expressed as a percentage of the maximal force obtained with electrical stimulation at 10, 20, 30, 50, and 100 Hz. 2) Maximal relaxation rate expressed as percentage force loss/10 ms. 3) Endurance expressed as percentage force loss/30 s. Standard nutritional assessment parameters (serum albumin and transferrin, creatinine height index, anthropometry and total body nitrogen and potassium) were also measured. There was a significant increase in the force of contraction at 10 Hz from a base-line of 29.6 +/- 1.0% to 49.0 +/- 2.8% (mean +/- SEM) after 2 wk of a 400-cal diet (p less than 0.01). These was a significant slowing of the maximal relaxation rate from a base-line of 9.8 +/- 0.03% force loss/10 ms to 8.2 +/0 0.3% force loss/10 ms (mean +/- SEM) (p less than 0.01) after 2 wk of a 400-cal diet. After a further 2 wk of fasting these abnormalities in muscle function persisted. There was a significant increase in muscle force loss from a base-line of 3.9 +/- 0.8% force loss/30 s to 13.7 +/- 3.4% force loss/30 s (mean +/- SEM) after fasting (P less than 0.01). After 2 wk of refeeding all aspects of muscle function measured were normal. During the study the standard nutritional assessment parameters did not change significantly.

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylation fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.

Rapidly induced systemic alkalinization due to either sodium-lactate or sodium-bicarbonate infusion in prolonged-fasted subjects with steady-state ketoacidosis was associated with a decrease in urine pH. This decrease in urine pH from 5.50 to 5.20 was the result of a significant decrease in urinary ammonium excretion from 8.40 to 6.35 mEg/hr and was not accompanied by an increase in net acid excretion (11.3 vs. 10.6 mEg/hr). The decreased ammonium excretion is attributed to the raised pH of the proximal tubular fluid resulting in a less favorable pH gradient for gaseous ammonia entry. This would decrease gaseous ammonia generated in the loop of Henle for collecting duct buffering of secreted hydrogen ions.

The effect of prolonged (3-5 wk) fasting on tracer-determined glucose turnover and of recycling radioactive glucose has been examined. We followed the specific activity of plasma glucose after the simultaneous administration of 1-14C-glucose and 3-3H-glucose. The rate of glucose turnover decreased during prolonged fasting. Recycling of radioactive glucose was estimated by two different techniques: (1) the appearance of 14C in positions 2 to 6 glucose was measured; (2) the difference in the slopes of specific activity decline for 1-14C-glucose and for 3-3H-glucose was calculated. The two methods of estimating the radioactive recycling gave results similar to each other. The amount of glucose recycled did not change during prolonged fasting. However, in view of the decline in glucose production during fasting, the proportion of glucose production which was represented by recycling increased. Based on weight and urinary nitrogen loss an estimate of the glucose production from amino acids and glycerol was obtained. The difference between the rate of glucose production from the contribution of amino acids and glycerol and that estimated by radioisotopic techniques was much larger than the measured rate of recycling. This finding suggests that either a large exchange of 12C with 14C occurred in some glycolytic intermediates or that a hitherto unknown source of carbon for glucose production appeared during prolonged fasting.

Newborn rabbits delivered by Caesarean section at term were fasted for 72 h at 36 degrees C. Despite the abrupt interruption of maternal supply of energy substrates, glycaemia remains stable for 4 h after birth. This can be related to glucose production via rapid liver glycogenolysis; however, indirect evidence suggests that gluconeogenesis could also contribute to glucose production during this period. There is a selective decrease in the concentrations of gluconeogenic substrates and a suitable hormonal environment for gluconeogenesis as decreased insulin and increased glucagon concentration just after birth. The relative hypoglycaemia which develops after 6 h of life (2.6 mM at 72 h), despite high blood concentrations of non-esterified fatty acids and ketone bodies is not due to a deficient gluconeogenesis per se, as injection of gluconeogenic substrates to 72 h fasted newborns produces a three-fold increase in plasma glucose concentration. It is suggested that this relative hypoglycaemia is secondary to limited gluconeogenic substrate availability in the form of low circulting concentrations of gluconeogenic amino acids.

Studies were undertaken to examine triglyceride turnover in obese humans on isocaloric balanced diets and during prolonged (3-5 wk) fasting. The data were related to plasma concentrations of insulin (IRI), glucagon (IRG), and free fatty acids (FFA) and to blood ketone concentrations. The triglyceride turnover rates were also related to the plasma triglyceride concentration. This relationship was the same in the obese on isocaloric balanced diets as that we have previously observed in lean humans on similar diets. The relationship between triglyceride turnover and concentration changed during prolonged fasting in a way that suggested that triglyceride removal was impaired. This viewpoint is consistent with the known effects of fasting on adipose tissue lipoprotein lipase activity. In another group of fasted obese, refed with a hypocaloric diet, the relationship returned toward normal. In addition to the impaired triglyceride removal, prolonged fasting resulted in a decrease in triglyceride production. This decrease occurred despite an increase in plasma FFA. After 3-5 wk of fasting the IRI was about 50% of the initial value, while the IRG was the same as the initial value. While triglyceride production fell during fasting, the blood ketone concentration rose. Others have seen similar changes in ketones and triglycerides in livers perfused with medium in which the ratio of insulin to glucagon fell. The rate of triglyceride production was not related to body weight. However, regardless of nutritional state, it was positively related to the basal plasma insulin levels. These data indicate that, in man as in animal preparations, insulin may regulate hepatic triglyceride production.

Catecholamines have multiple metabolic and fluid-electrolyte as well as cardiovascular effects, and their levels in plasma respond to alterations in nutrient and sodium intakes. Plasma norepinephrine, epinephrine, and dopamine were measured in 12 obese nondiabetic subjects before and after 400 kcal/day diets of either protein or glucose, followed by total fasting, and then by hypocaloric refeeding, each for 14-day periods. Measurements were made in the supine and upright posture and during and after 6-10 min of exhaustive exercise at 80% maximal VO2. Sodium intake varied with the nutrients ingested, being markedly decreased with the 400 kcal/day diets and fasting. Norepinephrine levels were higher in fasting than base line while subjects were lying or standing and after recovery from exercise. Those of epinephrine were elevated on standing. No differences were found after the 400 kcal/day diets, with protein and glucose yielding equivalent results. In contrast, refeeding was associated with lower norepinephrine levels than all other diets while subjects were lying or standing and after recovery from exercise. Peak levels of norepinephrine and epinephrine with exercise were indistinguishable among diets. Fasting was associated with lower systolic and diastolic blood pressures and lower responses to standing and exercise than base line, whereas upright heart rate was greater and that during exercise less than base line. Significant though less extensive changes occurred with the other diets. Thus both electrolyte status and nutrient intakes interact to determine net catecholamine responses, and the former seem to override the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

During a total fast in obese subjects, the daily rate of nitrogen excretion undergoes only a small further decline after 2 wk, the excretion rate being about 5 g N/day. At this time, ammonium and urea each constitute about one-half of this excretion. The purpose of this study was to consider two alternative hypotheses: first, that the near plateau in nitrogen excretion represents an irreducible minimum rate of net protein breakdown in order to supply essential organs with calories in the form of glucose; second, that protein breakdown could be further reduced by minimizing the requirement to provide nitrogen for ammonium excretion during the ketoacidosis of fasting. Because ammonium excretion is largely controlled by acid-base balance, 150 mmol of sodium bicarbonate plus 60 mmol of potassium chloride were administered daily to decrease ammonium excretion in eight obese subjects who were totally fasting for more than 14 days. Urine ammonium nitrogen fell with this treatment (from 3.8 +/- 0.4 to 2.0 +/- 0.4 g N/g creatinine). In addition, there was a smaller fall in the rate of urea excretion (from 2.5 +/- 0.2 to 2.1 +/- 0.3 g N/g creatinine) together with a fall in the blood urea nitrogen. Therefore, it appears that ammonium excretion contributes to the negative nitrogen balance of a prolonged total fast, as assessed over a 3-day period of observation, is responsible for about one-third of the net lean body mass loss.

To determine the fetal response to altered maternal fuel supply, the effects of prolonged maternal fasting, begun 24-96 h before term, were examined and compared with values from normally fed term animals. Fetal weight decreased only after 48 h of maternal fasting. Prolonged maternal fasting was associated with low blood glucose, high blood ketone bodies, and decreased gluconeogenic substrate in the fetus. Plasma insulin was decreased, whereas plasma glucagon was increased in the fetus of fasted mothers. Infusion of [2-3H]glucose into the mother to constant specific activity gave a ratio of maternal to fetal glucose activity of 1.0 in fed and 1.56 in fasted mothers. Fetal liver from fasted mothers showed both increase in activity of key gluconeogenic enzymes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) and increased conversion in vitro of lactate, alanine, serine, and glycerol in glucose by liver slices. It is inferred that maternal fasting induces fetal substrate alterations and hormonal changes appropriate to premature appearance of hepatic gluconeogenesis. The priority for endogenous fuel provision in this state leads to impaired fetal growth.

The role of glucagon in the metabolic adaptation to prolonged fasting in man has been examined. Plasma immunoreactive glucagon was determined during 6-wk fasts and during infusion of exogenous glucagon using an assay which minimized nonpancreatic immunoreactivity. Plasma glucagon concentrations rose twofold to a peak on the 3rd day of fasting and then declined thereafter to a level maintained at or above postabsorptive. Insulin concentration declined to a plateau by the 3rd day. Thus a persisting altered relationship of glucagon and insulin concentrations characterized the fasted state. A synergism of low insulin and relative or absolute elevation of glucagon levels is viewed as a hormonal mechanism controlling the rate of hepatic substrate extraction for gluconeogenesis. Glucagon was infused systemically into 4-6 wk fasted subjects at three dose levels. A marked sensitivity of individual plasma free amino acids to the induced elevations of plasma glucagon within the physiologic range was demonstrated. At higher concentrations, equivalent to those present in the portal vein, stimulation of hepatic gluconeogenesis occurred, and the effects on glucose, insulin, and growth hormone levels and on ketone metabolism were induced.