Somatostatin suppresses secretin and pancreatic exocrine secretion.

Somatostatin, a hypothalamic peptide, suppresses hydrochloric acid-stimulated release of secretin, pancreatic flow rate, and bicarbonate and protein secretion in fasted, conscious dogs. It also reduces nonstimulated pancreatic exocrine secretion but does not affect basal secretin concentrations. Suppression of HCl-stimulated secretin release is complete, whereas pancreatic flow rate and bicarbonate and protein secretions are only partially inhibited. The action of somatostatin is rapid in onset and quickly reversible.

Human forearm metabolism during progressive starvation.

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 beta-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 beta-hydroxybutyrate consumption after an overnight fast was low. At 3 days of fasting with increased arterial concentrations of acetoactate and beta-hydroxybutyrate, consumption of these substrates rose dramatically. At 24 days of fasting, despite further elevation of arterial levels of acetoacetate and beta-hydroxybutyrate, the utilization of acetoacetate did not increase further and if anything decreased, while five out of eight subjects released beta-hydroxybutyrate across the forearm. Acetoacetate was preferentially extracted over beta-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.

Metabolic effects of exogenous glucocorticoids in fasted man.

The influence of administering excessive amounts of glucocorticoids on circulating substrates and hormones and on urinary excretion of nitrogenous compounds and ketone bodies was examined in man after prolonged starvation. After 35 days of total caloric deprivation the administration of high physiologic doses of glucocorticoids increased circulating glucose and insulin levels without intensifying total urinary nitrogen excretion. The increased blood glucose seemed to be due to diminished peripheral uptake rather than augmented gluconeogenesis. A small, transient increase in circulating plasma amino acids was observed. However, the secondary rise in serum insulin seemed to block the proteolytic effect(s) of glucocorticoids, preventing them from mobilizing body protein stores during starvation. There was no change in circulating free fatty acids or glycerol. Thus, it appeared that the potential catabolic action of excessive glucocorticoids was offset by the anabolic effect of insulin, and a new state of homeostasis was established.An additional effect of glucocorticoid administration was a marked diminution of renal excretion of ketone bodies.

Effects of glucagon on plasma amino acids.

The effects of glucagon deficiency and excess on plasma concentrations of 21 amino acids were studied in six normal human subjects for 8 h. During glucagon deficiency, produced by intravenous infusion of somatostatin (0.5 mg/h) and insulin (5 mU/kg per h), amino acid concentration (sum of 21 amino acids) rose from 2,607 +/- 76 to 2,922 +/- 133 microM after 4 h (P less than 0.025). The largest increases occurred in lysine (+26%), glycine (+24%), alanine (+23%), and arginine (+23%) concentrations. During glucagon excess produced by intravenous infusion of somatostatin (0.5 mg/h), insulin (5 mU/kg per h), and glucagon (60 ng/kg per h), amino acid concentration decreased from 2,774 +/- 166 to 2,388 +/- 102 microM at 8 h (P less than 0.01). The largest decreases occurred in citrulline (-37%), proline (-32%), ornithine (-30%), tyrosine (-23%), glycine (-20%), threonine (-21%), and alanine (18%) concentrations. Urinary urea nitrogen and total nitrogen excretions were lower during glucagon deficiency than during glucagon excess (3.1 +/- 0.2 vs. 6.3 +/- 2.3 g/8 h, P less than 0.05 and 4.8 +/- 1.0 vs 7.0 +/- 2.6 g/8 h, respectively, P less than 0.05). Biostator-controlled euglycemic glucagon deficiency was produced in four normal subjects for 4 h to eliminate possible effects of changes in glucose concentration on amino acids. Amino acid concentration (sum of 18 amino acids) increases occurred in arginine (+42%), alanine (+28%), glutamine (+25%), and glycine (+16%) concentrations. The data show that small changes (-66 pg/ml and +50 pg/ml) in basal glucagon concentrations cause plasma amino acid concentrations to change in opposite directions. The finding that urinary excretion of nitrogen and urea nitrogen was greater during glucagon excess than during glucagon deficiency suggested alterations in the rate of gluconeogenesis from amino acids as one mechanism by which glucagon controls blood amino acid levels.

Amino acid metabolism during prolonged starvation.

Plasma concentration, splanchnic and renal exchange, and urinary excretion of 20 amino acids were studied in obese subjects during prolonged (5-6 wk) starvation. Splanchnic amino acid uptake was also investigated in postabsorptive and briefly (36-48 hr) fasted subjects.A transient increase in plasma valine, leucine, isoleucine, methionine, and alpha-aminobutyrate was noted during the 1st wk of starvation. A delayed, progressive increase in glycine, threonine, and serine occurred after the 1st 5 days. 13 of the amino acids ultimately decreased in starvation, but the magnitude of this diminution was greatest for alanine which decreased most rapidly during the 1st week of fasting. In all subjects alanine was extracted by the splanchnic circulation to a greater extent than all other amino acids combined. Brief fasting resulted in an increased arterio-hepatic venous difference for alanine due to increased fractional extraction. After 5-6 wk of starvation, a marked falloff in splanchnic alanine uptake was attributable to the decreased arterial concentration. Prolonged fasting resulted in increased glycine utilization by the kidney and in net renal uptake of alanine. It is concluded that the marked decrease in plasma alanine is due to augmented and preferential splanchnic utilization of this amino acid in early starvation resulting in substrate depletion. Maintenance of the hypoalaninemia ultimately serves to diminish splanchnic uptake of this key glycogenic amino acid and is thus an important component of the regulatory mechanism whereby hepatic gluconeogenesis is diminished and protein catabolism is minimized in prolonged fasting. The altered renal extraction of glycine and alanine is not due to increased urinary excretion but may be secondary to the increased rate of renal gluconeogenesis observed in prolonged starvation.

Liver and kidney metabolism during prolonged starvation.

This study quantifies the concentrations of circulating insulin, growth hormone, glucose, free fatty acids, glycerol, beta-hydroxybutyrate, acetoacetate, and alpha amino nitrogen in 11 obese subjects during prolonged starvation. The sites and estimated rates of gluconeogenesis and ketogenesis after 5-6 wk of fasting were investigated in five of the subjects. Blood glucose and insulin concentrations fell acutely during the 1st 3 days of fasting, and alpha amino nitrogen after 17 days. The concentration of free fatty acids, beta-hydroxybutyrate, and acetoacetate did not reach a plateau until after 17 days. Estimated glucose production at 5-6 wk of starvation is reduced to approximately 86 g/24 hr. Of this amount the liver contributes about one-half and the kidney the remainder. Approximately all of the lactate, pyruvate, glycerol, and amino acid carbons which are removed by liver and kidney are converted into glucose, as evidenced by substrate balances across these organs.

Effects of intraduodenal administration of HCl and glucose on circulating immunoreactive secretin and insulin concentrations.

A new radioimmunoassay for secretin was used to investigate (a) serum secretin responses to intraduodenally infused HCl and glucose, (b) the metabolic half-life and the volume of distribution of exogenous secretin and (c) the effect of endogenously released secretin on insulin secretion in 25 anesthetized dogs. Portal and femoral venous blood samples were taken simultaneously before, during, and after intraduodenal infusion of HCl (21 meq/30 min) and glucose (131 ml/30 min). Control experiments were performed with intraduodenal infusion of saline. Mean portal venous immunoreactive secretin concentration of six dogs rose from 313 muU/ml before to 1,060 muU/ml 10 min after initiation of the intestinal acidification (P < 0.005). Femoral venous immunoreactive secretin concentration rose from 220 muU/ml before to 567 muU/ml 15 min after intestinal acidification (P < 0.01). Secretin concentrations remained elevated during the remainder of the infusion. In the same six dogs mean portal venous immunoreactive insulin concentration rose from 38 muU/ml before to 62 muU/ml at the end of the infusion (P < 0.05). Peripheral immunoreactive insulin, glucose, and free fatty acid concentrations, however, did not change significantly. Pancreatic exocrine function was studied in four dogs. The rise in secretin concentration was followed promptly by a highly significant increase in exocrine pancreatic flow rate and bicarbonate secretion, indicating biological activity of the circulating immunoreactive secretin. The effect of intraduodenal infusion of glucose on immunoreactive secretin concentration was studied in 12 dogs. Glucose in concentrations ranging from 2.5% to 10% had no detectable influence on portal or peripheral secretin concentration. Infusion of 50% glucose caused a slight decline in secretin concentration. The metabolic clearance rate, half-life of disappearance, and volume of distribution of exogenous secretin was studied in three dogs by the constant infusion technic. The metabolic clearance rate was 730+/-34 ml/min, volume of distribution was 17.4+/-0.8% of body weight, and the half-life of disappearance was 2.8+/-0.1 min. It could be calculated that 1.38 U/kg-h(-1) of endogenous secretin was released into the peripheral circulation during the steady state period of the HCl infusion experiments. The data indicated that immunoreactive secretin was released rapidly after intestinal acidification, continued to be secreted throughout the duration of HCl infusion, and was promptly distributed in the extracellular compartment. Furthermore, they suggested that endogenously released secretin could stimulate insulin secretion. The HCl-mediated insulinogenic effect of immunoreactive secretin, however, was too weak to influence peripheral immunoreactive insulin, glucose, and free fatty acid concentrations. The failure of intraduodenal glucose to stimulate secretin release suggests that secretin is not the insulin-stimulatory factor released from the gastrointestinal tract in response to glucose.

Hepatic ketogenesis and gluconeogenesis in humans.

Splanchnic arterio-hepatic venous differences for a variety of substrates associated with carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in five patients after 3 days of starvation. Despite the relative predominance of circulating beta-hydroxybutyrate, the splanchnic productions of both beta-hydroxybutyrate and acetoacetate were approximately equal, totaling 115 g/24 h. This rate of hepatic ketogenesis was as great as that noted previously after 5-6 wk of starvation. Since the degree of hyperketonemia was about threefold greater after 5-6 wk of starvation, it seems likely that the rate of ketone-body removal by peripheral tissues is as important in the development of the increased ketone-body concentrations observed after prolonged starvation as increased hepatic ketone-body production rate. Splanchnic glucose release in this study was 123 g/24 h, which was less than that noted previously after an overnight fast, but was considerably more than that noted during prolonged starvation. Hepatic gluconeogenesis was estimated to be 99 g/24 h, calculated as the sum of lactate, pyruvate, glycerol, and amino acid uptake. This was greater than that observed either after an overnight fast or after prolonged starvation. In addition, a direct relationship between the processes of hepatic ketogenesis and gluconeogenesis was observed.

Nitrogen sparing induced by a mixture of essential amino acids given chiefly as their keto-analogues during prolonged starvation in obese subjects.

11 normal obese subjects were fasted for 33 days. In five, who served as controls, urine urea nitrogen excretion remained constant for 2 wk thereafter. The other six were given seven daily infusions containing 6-8 mmol each of the alpha-keto-analogues of valine, leucine, isoleucine, phenylalanine, and methionine (as sodium salts) plus 3-4 mmol each of the remaining essential amino acids (lysine, threonine, tryptophan, and histidine). Rapid amination of the infused ketoacids occurred, as indicated by significant increases in plasma concentrations of valine, leucine, isoleucine, alloisoleucine, phenylalanine, and methionine. Glutamine, glycine, serine, glutamate, and taurine fell significantly. Blood glucose, ketone bodies, plasma free fatty acids, and serum immunoreactive insulin concentrations were unaltered. Urine urea nitrogen fell from 1.46 to 0.89 g/day on the last day of infusions; 5 days later it was still lower (0.63 g/day) and in two subjects studied for 9 and 17 days postinfusion it remained below preinfusion control values. Urine ammonia, creatinine, and uric acid were unaltered. Nitrogen balance became less negative during and after infusions. The results indicate that this mixture of essential amino acids and their keto-analogues facilitates nitrogen sparing during prolonged starvation, in part by conversion of the ketoacids to amino acids and in part by altering mechanisms of nitrogen conservation. The latter effect persists after the ketoacids are metabolized.

Glucagon deficiency and hyperaminoacidemia after total pancreatectomy.

The first goal of this study was to investigate whether totally pancreatectomized patients are glucagon deficient and if so, to what degree. Immunoreactive glucagon (IRG) concentrations in peripheral plasma of nine pancreatectomized patients were not significantly different from those of 10 normal controls as measured by two antisera (30-K and RCS-5) both detecting the COOH-terminal portion of the molecule and one (RCS-5) postulated to be specific for pancreatic glucagon. Plasma from six of nine pancreatectomized patients were fractionated over Sephadex G-50 and IRG was measured with both antisera in the column eluates. Using 30-K, 80.8 +/- 9% of the IRG eluted within the void volume. This material was rechromatographed on Sephadex G-200 and found to have an apparent mol wt of approximately 200,000. Only 18.3 +/- 9% eluted in the IRG3500 region. IRG3500 was significantly reduced in pancreatectomized patients as compared to normal controls (49 +/- 9 vs. 18 +/- 9 pg/ml, P less than 0.05). Using RCS-5, all IRG (corresponding to 20 +/- 6 pg/ml of plasma) eluted in the IRG3500 region. The second goal of this study was to investigate the effects of chronic glucagon deficiency on plasma amino acids. In the nine pancreatectomized patients studied, postabsorptive plasma concentrations of serine, alanine, arginine, glycine, threonine, citrulline, alpha-aminobutyrate, and tryosine were significantly elevated compared to values obtained from 20 normal controls. Physiological glucagon increments produced in two pancreatectomized patients by infusion of glucagon (6.25 and 8.0 microgram/h, respectively) resulted in normalization of the hyperaminoacidemia within 22 h. We conclude (a) that pancreatectomized patients are partially glucagon deficient because of diminished basal as well as diminished stimulated glucagon secretion; (b) that fasting concentrations of certain glucogenic amino acids are elevated in pancreatectomized patients probably as result of reduce; hepatic gluconeogenesis; and (c) that the RCS-5 antiserum is not "pancreatic glucagon" specific.

Brain metabolism during fasting.

Catheterization of cerebral vessels in three obese patients undergoing 5-6 wk of starvation demonstrated that beta-hydroxybutyrate and acetoacetate replaced glucose as the predominant fuel for brain metabolism. A strikingly low respiratory quotient was also observed, suggesting a carboxylation mechanism as a means of disposing of some of the carbon of the consumed substrates.

Ketone-body production and oxidation in fasting obese humans.

Rates of plasma acetoacetate and total ketone-body production and oxidation to CO2 were determined by an isotope tracer technique in eight obese subjects undergoing progressive starvation. After a brief fast and under conditions of mild ketonemia and minimal ketonuria, rates of acetoacetate and total ketone-body production and oxidation were directly related to the increasing plasma concentration. After a longer fast and with severer ketonemia, acetoacetate and total ketone-body production and oxidation rates were higher but became constant and unrelated to the plasma concentrations. The maximum rates of total ketone-body production and oxidation were about 150 g/24 h and 129 g/24 h, respectively. Although an increased ketone-body production was the primary factor responsible for the hyperketonemia, an imbalance between production and removal of the ketone bodies cannot be excluded. Such an imbalance could account, at least in part, for the developing hyperketonemia and for the lack of relationship between production rates and plasma concentrations.

Rapid intravenous sodium acetoacetate infusion in man. Metabolic and kinetic responses.

The metabolic and kinetic responses to rapidly intravenously administered sodium acetoacetate (1.0 mmol/kg body wt) was studied after an overnight fast in 12 male and female adults weighing between 88 and 215% of average body weight. Blood was obtained before, during, and after the infusion for determination of circulating concentrations of immunoreactive insulin, glucose, acetoacetate, beta-hydroxybutyrate and free fatty acids. In three obese subjects the studies were repeated after 3 and 24 days of total starvation. After the overnight fast acetoacetate rose rapidly reaching a peak concentration at the end of the infusion; beta-hydroxybutyrate concentrations also increased rapidly and exceeded those of acetoacetate 10 min postinfusion. Total ketone body concentration at the end of the infusion period was comparable to that found after prolonged starvation. After the initial mixing period, acetoacetate, beta-hydroxybutyrate and total ketone bodies rapidly declined in a parallel manner. There were no obvious differences between the subjects with regard to their blood concentrations of ketone bodies. The mean plasma free fatty acid concentration decreased significantly during the 20th to 90th min postinfusion period; for example the control concentration of 0.61 mmol/liter fell to 0.43 mmol/liter at 60 min. In the three obese subjects studied repeatedly, fasting plasma free fatty acids decreased with acetoacetate infusion from 0.92 to 0.46 mmol/liter after the 3 day fast and from 1.49 to 0.71 mmol/liter after the 24 day fast. Acetoacetate infusion caused no changes in blood glucose concentration after an overnight fast. However, in the three obese subjects restudied after 3- and 24-day fasts blood glucose decreased, respectively, from 3.49 to 3.22 mmol/liter and from 4.07 to 3.49 mmol/liter. The mean serum insulin concentration in all subjects significantly increased from 21 to 46 muU/ml at the completion of the infusion and rapidly declined. In the three obese subjects restudied after 3- and 24-day fasts an approximate two-fold increase of serum insulin was observed after each acetoacetate infusion. The mean fractional utilization rate of exogenously derived ketone bodies for all 12 subjects after an overnight fast was 2.9% min(-1). In the three obese subjects studied after an overnight, 3 and 24 day fast the mean fractional utilization rates were 2.1%, 1.5%, and 0.6% min(-1), respectively. Ketone body volumes of distribution in the overnight fasted subjected varied from about 18% to 31% of body wt, suggesting that ketone bodies are not homogenously distributed in the body water. In the three obese subjects restudied after 3- and 24-day fasts volumes of distribution remained approximately constant. When total ketone body concentrations in the blood were below 2.0 mmol/liter, there was a linear relationship between ketone body utilization rates and ketone body concentrations; no correlation was found when blood concentrations were higher.

The effect of carbohydrates on ammonium and ketoacid excretion during starvation.

The metabolic effects of oral ingestion of minute quantities of carbohydrate during prolonged starvation were studied in nine obese subjects. Measurements were made during a control period of total starvation, during the ingestion of 7.5 g carbohydrate daily, and finally during the ingestion of 15.0 g carbohydrate daily. Daily ketoacid excretion fell after carbohydrate ingestion and was significantly correlated (r = 0.62, P < 0.01) with the amount of carbohydrate administered. Despite this fall in ketoacids, the concentration of blood ketoacids, plasma free fatty acids, and serum insulin remained constant throughout the study. Urinary ammonium excretion, closely correlated with ketoacid output (r = 0.95, P < 0.001), also fell significantly after carbohydrate ingestion. No significant changes were present in extracellular or urinary pH. Urea nitrogen excretion did not change when urinary ammonium output fell. These results indicate that: the excretion of ketoacids and ammonium in starving man is exquisitely sensitive to minute amounts of ingested carbohydrate; the change in ketonuria appears to be due to increased renal ketoacid reabsorption after carbohydrate ingestion; and the nitrogen-sparing effect of reducing renal ammonium output in starvation can be dissociated from nitrogen sparing occurring because of changes in urine urea excretion.

Hepatic and renal metabolism before and after portasystemic shunts in patients with cirrhosis.

Hepatic cirrhosis with portal hypertension and gastroesophageal hemorrhage is a disease complex that continues to be treated by surgical portasystemic shunts. Whether or not a reduction or diversion of portal blood flow to the liver adversely affects the ability of the liver to maintain fuel homeostasis via gluconeogenesis, glycogenolysis, and ketogenesis is unknown. 11 patients with biopsy-proven severe hepatic cirrhosis were studied before and after distal splenorenal or mesocaval shunts. Hepatic, portal, and renal blood flow rates and glucose, lactate, pyruvate, glycerol, amino acids, ketone bodies, free fatty acids, and triglyceride arteriovenous concentration differences were determined to calculate net precursor-product exchange rates across the liver, gut, and kidney. The study showed that hepatic contribution of glucose and ketone bodies and the caloric equivalents of these fuels delivered to the blood was not adversely affected by either a distal splenorenal or mesocaval shunt. In addition to these general observations, isolated findings emerged. Mesocaval shunts reversed portal venous blood and functionally converted this venous avenue into hepatic venous blood. The ability of the kidney to make a substantial net contribution of ketone bodies to the blood was also observed.

Plasma acetone metabolism in the fasting human.

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 mumol/m(2) per min) and concentration (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 congruent with60% of the production rate in 3-d fasted subjects and about 25% of the production rate in 21-d fasted subjects. About 1-2% of the total CO(2) production was derived from plasma acetone oxidation and was not related to the plasma concentration or production rate. Radioactivity from [(14)C]acetone was not detected in plasma free fatty acids, acetoacetate, beta-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 production 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.

Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes.

Sera and their IgG from 10/104 diabetic patients (five with insulin-dependent and five with noninsulin-dependent diabetes, NIDDM), contained antibodies that bound 125I-labeled purified human insulin receptors. 9 of these 10 sera failed to inhibit insulin binding (to rat hepatocytes and human placental membranes), did not stimulate glucose oxidation (by isolated rat adipocytes), and did not bind human placental IGF-1 receptors. Only one serum (and its IgG) modestly inhibited insulin binding and stimulated glucose oxidation. We conclude (a) that sera from 9/104 diabetics (five insulin-dependent and four noninsulin-dependent) contained a newly identified species of IgG antiinsulin receptor autoantibodies (AIRA), which bound to the insulin receptor at a locus different from the insulin binding site and did not inhibit insulin binding; and (b) that only 1/104 diabetic sera contained low-titer "conventional" antiinsulin receptor autoantibodies that bound to the insulin receptor at or near the insulin binding site, inhibited insulin binding and caused a clinical condition, which was difficult to distinguish from typical NIDDM.

Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance.

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 H2O. 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 (GRa) by 30% and the basal rate of glucose disappearance (GRd) 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.

Nature and quantity of fuels consumed in patients with alcoholic cirrhosis.

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 [14C]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 health 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 [14C]palmitate, which showed that in overnight fasted patients with alcoholic cirrhosis, 63 +/- 4% of their total CO2 production was derived from oxidation of 287 +/- 28 mumol free fatty acids (FFA)/min per 1.73 m2. In contrast, normal overnight fasted humans derived 34 +/- 6% of their total CO2 production from the oxidation of 147 +/- 25 mumol FFA/min per 1.73 m2. On the other hand, values obtained from the normal volunteers fasted 36-72 h were similar to the overnight fasted cirrhotic patients. These results show that after an overnight fast the caloric requirements of patients with alcoholic cirrhosis are normal, but the nature of fuels oxidized are similar to normal humans undergoing 2-3 d of total starvation. Thus, patients with alcoholic cirrhosis develop the catabolic state of starvation more rapidly than do normal humans. This disturbed but compensated pattern for maintaining fuel homeostasis may be partly responsible for the cachexia observed in some patients with alcoholic cirrhosis. This study also showed remarkably good agreement between the results obtained with indirect calorimetry and those obtained with 14C tracer analyses.

Thermic effect of food in lean and obese men.

A systemic reappraisal of the thermic effect of food was done in lean and obese males randomly fed mixed meals containing 0, 8, 16, 24, and 32 kcal/kg fat-free mass. Densitometric analysis was used to measure body composition. Preprandial and postprandial energy expenditures were measured by indirect calorimetry. The data show that the thermic effect of food was linearly correlated with caloric intake, and that the magnitude and duration of augmented postprandial thermogenesis increased linearly with caloric consumption. Postprandial energy expenditures over resting metabolic requirements were indistinguishable when comparing lean and obese men for a given caloric intake. Individuals, however, had distinct and consistent thermic responses to progressively greater caloric challenges. These unique thermic profiles to food ingestion were also independent of leanness or obesity. We conclude that the thermic effect of food increases linearly with caloric intake, and is independent of leanness and obesity.