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.

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.

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.

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.

Hepatic, gut, and renal substrate flux rates in patients with hepatic cirrhosis.

The roles of liver, kidney, and gut in maintaining fuel homeostasis were studied in 28 patients with severe hepatic cirrhosis, 25 of whom had alcohol-induced cirrhosis. Hepatic, portal, and renal blood flow rates were measured and combined with substrate concentration differences across liver, gut, and kidney to calculate the net flux of free fatty acids, ketone bodies, triglycerides, and glucose with selected glucose precursors, including glycerol, lactate, pyruvate, and amino acids. Data from the catheterization studies were related to hepatic histology, glycogen content, and activities of gluconeogenic enzymes and compared with data obtained from control patients. The effects of food deprivation on net flux of fuels across the liver, gut, and kidney were assessed after overnight and after 3d of fasting. Activities of gluconeogenic enzymes were normal, but hepatic glycogen content was diminished in cirrhotic livers, probably as a consequence of extensive hepatic fibrosis. Extrahepatic splanchnic tissues (gut) had only a small influence on total splanchnic flux rates of carbohydrates, lipids and, amino acids. In cirrhotic patients, there was no mean renal glucose contribution to the bloodstream after an overnight or after a 3-d fast. After an overnight fast hepatic glucose production in patients with cirrhosis was diminished as a result of low-rate glycogenolysis. Hepatic gluconeogenesis and ketogenesis were increased. This pattern of hepatic metabolism mimics that seen in "normal" patients after more advanced stages of starvation. After 3 d of starvation, patients with hepatic cirrhosis have hepatic gluconeogenic and ketogenic profiles comparable to those of normal patients undergoing starvation of similar duration. Nevertheless, the total number of caloric equivalents derived from ketone bodies plus glucose corrected for recycled lactate and pyruvate added to the bloodstream by the cirrhotic livers that could be terminally oxidized by peripheral tissues was less than the contributions made by the normal livers, both after and overnight and after a 3-d fast.

Acetone metabolism during diabetic ketoacidosis.

The presence and the importance of acetone and its metabolism in diabetic ketoacidosis has largely been ignored. Therefore, we studied acetone metabolism in nine diabetic patients in moderate to severe ketoacidosis. The concentration of acetone in plasma, urine, and breath, and the rates of acetone production and elimination in breath and urine were determined and the rates of vivo metabolism were calculated. Plasma acetone concentrations (1.55-8.91 mM) were directly related and were generally greater than acetoacetate concentrations (1.16-6.08 mM). The rates of acetone production ranged from 68 to 581 mumol/min/1.73 m2, indicating the heterogeneous nature of the patients studied. The average acetone production rate was 265 mumol/min/1.73 m2 and accounted for about 52% of the estimated acetoacetate production rate. Urinary excretion of acetone remained constant and accounted for about 7% of the acetone production rate in all patients. There was a positive linear relationship between the percentage of the acetone production rate accounted for by excretion in breath and the plasma acetone concentration. At low plasma acetone concentrations, approximately 20%, and at high plasma acetone concentrations, approximately 80% of the production rate was accounted for by breath acetone. In contrast, there was a negative linear relationship between the percentage of acetone production rate undergoing in vivo metabolism and plasma acetone concentration. At low plasma acetone concentrations, approximately 75%, and at high concentrations, approximately 20% of acetone production rate was accounted for by in vivo metabolism. Radioactivity from 2-[14C]-acetone was variably present in plasma acetone, glucose, lipids and proteins. No radioactivity was found in plasma acetoacetate, beta-hydroxy butyrate or free fatty acids or other anionic compounds. Exchange rates of acetone into other metabolites could not be estimated because of non-steady-state precursor product relationships in these patients.

Resting metabolic rate and body composition of achondroplastic dwarfs.

Indirect calorimetry was used to measure resting metabolic rates (RMR), and densitometry and anthropometry were used to measure body fat and fat-free masses of 32 adults with very short stature. Twenty-seven of them were achondroplastic dwarfs. Their results were compared to those obtained from 103 lean and obese adults with normal heights. All 32 dwarfs had distinctly greater RMR per kg fat-free mass by densitometry than adults with average stature. However, there was a wide variation in the RMR among dwarfs, which was independent of leanness or obesity. In spite of increased RMR, obesity among dysplastic adult dwarfs was twice as prevalent as among average-height adults. Increased abdominal:hip ratios were prevalent among dwarfs, but these ratios do not reflect body fat. Body mass indices were worthless, and skinfold thicknesses and other anthropometric measurements were of very limited value in predicting the body fat of dwarfs. Although our new and specific equations for estimating RMR and body composition give reasonable values, we recommend that the caloric requirements and body compositional variables be measured if nutritional therapy is needed to induce weight loss or gain in Little People.

Oxidative and nonoxidative macronutrient disposal in lean and obese men after mixed meals.

Oxidative and nonoxidative macronutrient disposal rates were measured in lean and obese males randomly fed mixed meals containing 0, 33, 67, 100, and 134 kJ/kg fat-free mass (0, 8, 16, 24, and 32 kcal/kg). Body composition, preprandial and postprandial energy expenditure, and macronutrient concentrations in the extracellular space were measured. Relationships among carbohydrate, fat, and protein disposal rates; body weight; and body composition were examined. Oxidative and nonoxidative disposals of macronutrients were not different between the lean and obese groups. Glucose was preferentially oxidized and fat was preferentially stored after nutrient ingestion. Macronutrient storage increased linearly with caloric intake. Oxidative and nonoxidative macronutrient disposals were completed within 8 h after ingesting the meals. Serum insulin concentrations rose to 3000-6000 pmol/L in two obese men after their two largest meals. Eight hours after nutrient ingestion, concentrations of macronutrient substrates, metabolic products, and insulin were indistinguishable from preprandial values.

Protein, fat, and carbohydrate requirements during starvation: anaplerosis and cataplerosis.

The purpose of this work was to clarify the essentiality of glucose production from amino acids in obese subjects undergoing prolonged starvation and to provide an explanation for death after the depletion of lean body mass when some body fat is still available to meet body energy requirements. Five obese subjects fasted for 21 d. Nitrogen balance studies were combined with measurements of blood metabolite and hormone concentrations, indirect calorimetry, determination of body-composition changes, and catheterization techniques. Phenylacetate was administered from day 19 to day 21 to remove glutamine from the body and to assess this perturbation on energy requirements, ammoniagenesis, ureagenesis, gluconeogenesis, and ketogenesis. The obese subjects lost body fat and fat-free mass in parallel and resting metabolic energy requirements per mass remained constant during starvation. Urinary nitrogen excretion reflected continuous demands for amino acid oxidation. Phenylacetate administration decreased blood glutamine concentrations, increased plasma epinephrine concentrations, and increased urinary nitrogen loss through phenylacetylglutamine excretion; urinary excretion rates of urea, ammonium, urate, creatinine, and ketone bodies remained unchanged. The essentiality of amino acid oxidation was therefore shown. Late in prolonged starvation, aminogenic oxidation amounted to 7% and fat provided the remaining energy requirements. Hepatic and renal gluconeogenesis were not curtailed. Blood glutamate served as a vehicle for carbon and nitrogen transport; the contribution of glycerol to gluconeogenesis equaled that of all amino acids combined. The minimal quantities of amino acid (0.27 +/- 0.08 and 0.52 +/- 0.10 g) and fat (1.53 +/- 0.21 and 2.98 +/- 0.15 g) oxidized per kg body wt or fat-free mass/d, respectively, were determined. Included within amino acid and fat oxidation were the minimal amounts of precursors needed for synthesizing the essential quantity of glucose (0.34 +/- 0.14 and 0.66 +/- 0.20 g) oxidized per kg body wt or fat-free mass, respectively.

A reappraisal of caloric requirements in healthy women.

The caloric expenditure of 44 healthy, lean and obese women, 8 of whom were trained athletes, was measured by indirect calorimetry. Body composition was determined. Ages ranged from 18-65 yr and body weights from 43-143 kg. Stepwise, multiple-regression analysis was used to determine whether one or several variables best predicted the resting metabolic rate (RMR) of the women. The RMR and the thermic effect of food (TEF) were measured before and after the women consumed a mixed breakfast meal. The results showed that the currently available tables and regression equations overestimate the RMR of healthy women by 7-14%. Body weight was highly related to the RMR, and stepwise inclusions of various variables did not improve predictions of RMR. The slopes of the regression lines for nonathletes and athletes were significantly different. Regression equations for predicting RMR of women were developed: Nonathletes RMR = 795 + 7.18 kg WT; Athletes RMR = 50.4 + 21.1 kg WT. The range of RMR per kilogram body weight was wide for nonathletic, but narrow for athletic women. The metabolism of some lean and obese, nonathletic women was highly efficient, predisposing these women for developing and maintaining body fat. The TEFs were indistinguishable between nonathletic and athletic women, and formed a continuum from the lightest to the heaviest woman.

A reappraisal of the caloric requirements of men.

The resting metabolic rates (RMR) of 60 lean and obese men, aged 18-82 y and weighing 60-171 kg, were measured and body compositions were determined. Body compositional variables reflecting active protoplasmic tissue were all highly interrelated. Body weight alone gave prediction values for RMR that were comparable to those of other variables of active protoplasmic tissue mass. Regional distribution of fat had no influence on the RMR and the influence of age on RMR was trivial. The classic prediction equations and tables overestimate RMR of men. The 95%-confidence limits for both lean and obese men were broad. This conclusively demonstrates that metabolic efficiency is not necessarily or exclusively related to obesity. New regression equations for predicting the RMR based on weight and fat-free mass were developed: RMR = 879 + 10.2 WT kg and RMR = 290 + 22.3 FFMD kg, where FFMD is fat-free mass from densitometry measurements.

Mebendazole and insulin secretion from isolated rat islets.

In a preliminary communication we reported that mebendazole, a vermicide, decreased plasma glucose and free fatty acid concentrations and increased plasma C peptide concentrations in both type II diabetic patients. Therefore, we suggested that mebendazole was an insulin secretagogue. However, these were uncontrolled studies, and improved metabolic control in these patients due to spontaneous remission rather than drug-induced insulin secretion was a possibility. To investigate the direct effect of mebendazole on insulin secretion we used intact islets isolated from normal rat pancreata. Mebendazole in concentrations as low as 10 to 20 mumol/L caused a twofold to threefold increase in acute-phase insulin release from isolated perifused rat islets. This heightened insulin release occurred in the presence of glucose-stimulated insulin secretion.

Substrate, hormone, and temperature responses in males and females to a common breakfast.

To evaluate the response to a mixed meal we studied oral temperature, metabolite, and hormonal responses to a common American breakfast containing 11 kcal/kg body weight (carbohydrate 43%, fat 42%, and protein 15%) in 12 normal volunteers (6 males and 6 females). There was a significant rise in oral temperature during the postcibal period. This change in oral temperature did not depend upon food consumption in males but was meal-dependent in females. Food ingestion caused increases in the peripheral circulating concentrations of glucose, lactate, pyruvate, and amino acids and reciprocal decreases in the concentrations of free fatty acids, glycerol, and urea nitrogen. Acetoacetate and beta-hydroxybutyrate decreased during the postcibal period but the changes were not statistically significant. Although peripheral venous serum insulin and plasma glucagon concentrations were indistinguishable between the sexes, males had higher concentrations of plasma triglycerides, plasma amino acids, and serum urea nitrogen. Peripheral venous plasma somatostatin and secretin remained unchanged, but pancreatic polypeptide hormone showed a large biphasic response to the meal. After breakfast the blood glucose concentration tended to be greater in males than in females and this difference was significant at 60 and 120 min postcibal. Furthermore, every female had a 120 min postcibal glucose concentration that was lower than her basal fasting glucose concentration. This suggests that postcibal glucose concentrations should be related to gender in making the diagnosis of carbohydrate intolerance or reactive hypoglycemia.

Improvement of metabolic control in diabetic patients during mebendazole administration: preliminary studies.

After the observation of decreasing insulin resistance in a diabetic patient during treatment with mebendazole for nematosis, we investigated the effect of mebendazole on metabolic control in six Type 1 (insulin-dependent) and six Type 2 (non-insulin-dependent) diabetic patients, eight of whom were chronically resistant to conventional treatment. Before and after mebendazole treatment for 1 month, plasma glucose and serum C-peptide concentrations were determined both fasting and 4 h after a mixed breakfast. Improvements in fasting blood glucose concentrations occurred in Type 1 (12.83 +/- 1.11 versus 6.56 +/- 0.56 mmol/l; p less than 0.05) and Type 2 (10.22 +/- 0.56 versus 7.56 +/- 0.67 mmol/l; p less than 0.05) diabetic patients and were associated with increases in post-cibal C-peptide responses in Type 1 and Type 2 diabetic patients. Following discontinuation of mebendazole, metabolic control deteriorated in five out of the six Type 1 diabetic patients and in all the Type 2 diabetic patients. We conclude that mebendazole increases insulin secretion, and decreases plasma glucose concentration in Type 1 and Type 2 diabetic patients. However, these beneficial effects may be transient.