Plasma glucose turnover and oxidation during hemodialysis: nutritional effect of dialysis fluid.

Mass transfer of glucose from dialysis fluid into patients is a source of energy and a form of nutrition during hemodialysis. The effect of glucose mass transfer on endogenous glucose metabolism and the overall nutritional importance of glucose transfer is not known. Rates of plasma glucose turnover and oxidation were determined by radioisotope-dilution techniques in patients with chronic renal failure (CRF) in the basal state, during hemodialysis, and during the infusion of glucose at a rate similar to the mass transfer rate (Mt: 6.6 +/- 0.7 mumol.min-1.kg-1). Rates of plasma glucose turnover (11.8 +/- 0.8 mumol.min-1.kg-1) and oxidation (4.0 +/- 0.4 mumol.min-1.kg-1) and contribution of glucose oxidation to the metabolic rate were similar to those of control subjects both in the basal state and during glucose infusion. During hemodialysis with acetate and glucose, the plasma glucose turnover rate was similar to that in the basal state, but the energy from glucose oxidation was less (P < or = 0.02) even though energy expenditure was increased by 21%. Immediate oxidation of plasma glucose and acetate accounted for 65% of the patients' energy expenditure. Energy (1172 kJ) from acetate Mt and glucose Mt surpassed the patients' energy requirements, offsetting the utilization of endogenous fuels, a sparing effect equivalent to 31 g fat or 70 g carbohydrate. Rates of plasma glucose turnover and oxidation during bicarbonate-glucose and glucose-free acetate hemodialysis were similar to that during acetate-glucose hemodialysis. However, without glucose or acetate in the bath fluid, a deficit as much as 669 kJ must be met by the oxidation of endogenous fuels. Addition of organic nutrients that supply energy to dialysis fluids may over time be a beneficial supplemental treatment for the malnutrition and body wasting commonly observed in CRF.

Increased osmolal gap in alcoholic acidosis.

We studied a patient with alcoholic acidosis and an increased osmolal gap. Ethyl alcohol and other compounds that are known to increase serum osmolality in alcoholics were not detected. However, the levels of glycerol, acetone, and the acetone metabolites acetol and 1,2-propanediol were increased in the serum of this patient. On admission and 3 and 7 hours after admission, the combined serum osmolality of glycerol, acetone, acetol, and 1,2-propanediol accounted for 48%, 92%, and 62% of the increase in the osmolal gap above the highest normal level of 10 mOsm/kg H2O. The disappearance of the osmolal gap correlated with the correction of the acidosis and the concomitant reduction in serum glycerol and acetone levels. Elevations of endogenous glycerol, acetone, and acetone metabolite levels should now be added as causes for an increased osmolal gap in the alcoholic patient. Ingestion of toxic alcohols can no longer be assumed to be the only cause for an increased osmolal gap in alcoholic patients.

Acetone and acetol inhibition of insulin-stimulated glucose oxidation in adipose tissue and isolated adipocytes.

The response of peripheral tissues to insulin is reduced in fasting and diabetes mellitus. The experiments described herein were designed to determine whether insulin-stimulated glucose oxidation is affected by the free-fatty acid-derived plasma metabolites acetone, acetol, and propylene glycol (1,2-propanediol [1,2-PD]), concentrations of which are elevated in both starvation and diabetic ketosis. In epididymal adipose tissue from fed and 48-h--fasted rats given 3% acetone drinking water for 7 days, insulin-stimulated glucose oxidation was reduced by approximately 30-40%. After ingestion of 2% acetol for 7 days, basal and insulin-stimulated glucose oxidation was lowered approximately 30%, whereas the consumption of 1,2-PD had no influence on either basal or insulin-stimulated glucose oxidation. Similar effects on glucose oxidation were observed in isolated adipocytes from fed rats after ingestion of 3% acetone and 2% acetol for 7 days. The reduction in insulin-stimulated glucose oxidation in adipose tissue in vitro required the consumption of 3% acetone water for greater than 3 days. In 48-h--fasted rats that ingested 3% acetone for 5 days, insulin-stimulated glucose oxidation remained depressed 4 days after withdrawal of acetone from the drinking water. These studies imply that at least part of the insulin resistance indigenous to fasting and diabetic ketosis may be attributed to the metabolic influence of acetone and/or acetol in body fluids.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Acetone metabolism in humans during diabetic ketoacidosis.

Plasma acetone turnover rates were measured with the primed continuous infusion of 2-[14C]acetone in patients with moderate to severe diabetic ketoacidosis. Plasma acetone turnover rates ranged from 1.52 to 15.9 mumol X kg-1 X min-1 (108-1038 mumol X 1.73 m-2 X min-1) and were directly related to the plasma acetone concentrations that ranged from 0.47 to 7.61 mM. The average acetone turnover rate was 6.45 mumol X kg-1 X min-1 (533 mumol X 1.73 m-2 X min-1), a value twice that obtained in a similar group of diabetic ketoacidotic patients via the single-injection technique of 2-[14C]acetone administration. Degradation of urine glucose revealed that 14C from administered 2-[14C )acetone was principally located in carbons 1, 2, 5, and 6 of the glucose molecule in five of six patients. This distribution is similar to that expected from 2-[14C]pyruvate, suggesting that acetone was converted to glucose through pyruvate. In one patient, label was located predominantly in glucose carbons 3 and 4, indicating that acetone metabolism may be different in some patients. Acetol (1-hydroxyacetone) and 1,2-propanediol (PPD), two possible metabolites of acetone, were detected in plasma of the patients. The concentrations of Acetol ranged from 0 to 0.48 mM and of PPD ranged from 0 to 0.53 mM. The concentrations of each metabolite were directly related to the plasma acetone concentrations. During the continuous infusion of 2-[14C]acetone, the specific activities of plasma glucose and PPD rose continuously but did not reach constant values. Estimates of the minimal percent plasma glucose and PPD derived from plasma acetone averaged 2.1 and 74%, respectively.

Glucose metabolism in cachectic patients with colorectal cancer.

We have studied a defined group of 12 weight-losing patients with metastatic colorectal cancer to evaluate the occurrence of and possible relationship between those determinants of carbohydrate metabolism which have been reported to occur commonly in cancer cachexia. The rates of endogenous glucose production and recycling via lactate (Cori cycle) were measured following an infusion of 50 to 100 microCi of [1-14C]glucose. Compared to an age-related group of control subjects without cancer, significantly elevated rates of glucose production [136.4 +/- 9.0 (S.E.) versus 101.0 +/- 4.6 mg/kg/hr; p less than 0.01] and recycling (43.0 +/- 7.2 versus 15.4 mg/kg/hr; p less than 0.01) were observed. Values for glucose production and recycling ranged from normal to markedly elevated. Glucose tolerance was then determined following a p.o. glucose load of 40 g/sq m in 10 of the 12 patients. Compared to control subjects, all showed a significantly delayed clearance of glucose (p less than 0.01) and a blunted insulin-secretory responsiveness (p less than 0.025). Increased glucose production and recycling was only observed in the presence of carbohydrate intolerance, but the latter occurred in a manner which seemed independent of the rate of glucose turnover. In order to obtain an estimate of hepatic glycogen reserves, glucagon, 15 ng/kg/min, was infused over 40 min in seven subjects. A significantly blunted glycemic response was observed in the cancer patients compared to controls (delta 25.0 +/- 6.9 versus 57.8 +/- 8.5 mg/dl; p less than 0.025). Neither the rate of glucose production nor the glycemic response to glucagon appeared to correlate with the immediate antecedent caloric intake. An apparent relationship was observed, however, between increased glucose production and recycling and a lack of response to infused glucagon, probably reflecting decreased glycogen stores in the face of an increased glucose requirement by the patient. We have shown that diverse abnormalities of carbohydrate metabolism commonly occur in cancer cachexia and that significant metabolic heterogeneity may be expected, despite a uniform diagnosis. These results should prove useful in the interpretation and development of clinical studies on cancer cachexia.

Acetate and energy metabolism during hemodialysis.

The oxidation of acetate infused in acetate infused in large quantities during acetate dialysis should provide considerable energy for the hemodialysis patient. Previous attempts to measure acetate oxidation rate and thus energy yield by measuring bicarbonate generation rate are flawed because bicarbonate generation occurs by equimolar proton consumption when acetate is activated to acetyl Co-A but before acetyl Co-A has entered the Krebs cycle. Besides the Krebs cycle, acetyl Co-A could enter many other nonoxidative pathways. By using the primed continuous infusion radioisotope (1-14C acetate) dilution technique of Steele, in conjunction with indirect calorimetry, we obtained direct measurements of acetate turnover and immediate oxidation rates and energy yield in 7 stable hemodialysis patients. Commercial dialysate contained glucose (12.4 mmoles/liter), acetate (38 mmoles/liter), plus routine electrolytes. Acetate turnover was 57.2 +/- 2.9 mumoles/min X kg. Of the acetate entering the body, 31.6 +/- 3.8 mumoles/min X kg were immediately oxidized to carbon dioxide and water, which accounted for 54.4 +/- 5.2% of the turnover rate. The amount that entered the blood was 869 mmoles, and 472 mmoles (54.4%) were oxidized; 138 mmoles (15.8%) made up the steady-state pool, and 258 mmoles were directed into nonoxidative pathways (29.7%). During dialysis, 40.3 +/- 4.8% of the carbon dioxide output or metabolic rate was accounted for by acetate oxidation. Thus, acetate emerged as the major contributor to energy production, supplying up to 65% of the total caloric needs during dialysis. The RQ calculated from the lung carbon dioxide excretion was 0.74 +/- 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Contribution of dialysate acetate to energy metabolism: metabolic implications.

During hemodialysis large amounts of acetate enter the bloodstream. Generally, it is assumed that this exogenous acetate load is oxidized immediately to carbon dioxide and water; however, the rate of plasma acetate oxidation and the effect of acetate oxidation on energy metabolism during hemodialysis has not been determined previously. The rates of plasma acetate turnover and oxidation were determined during hemodialysis in seven chronic renal failure patients by the primed continuous infusion of [1-14C] acetate. The plasma acetate turnover rate (57.2 +/- 2.9 mumoles/min X kg) agreed closely with the mass transfer rate of dialysate acetate into the bloodstream (55.3 +/- 3.2 mumoles/min X kg). Of the acetate entering the bloodstream, 54.5 +/- 5.2% or 31.6 +/- 3.77 mumoles/min X kg was oxidized immediately accounting for 40.3 +/- 4.8% of the patient's caloric expenditure. Although the oxidation of acetate during dialysis supplied a major portion of the patient's caloric need, a significant quantity of acetate was eliminated by pathways other than direct oxidation. An average overall respiratory quotient (RQ) of 1.0 +/- 0.02 indicated that fat oxidation was spared to maintain energy homeostasis during hemodialysis. The calculated non-protein RQ exceeded unity suggesting that net fat synthesis actually occurred.

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.

Plasma free fatty acid turnover and oxidation during fat-free and intralipid TPN.

Plasma free fatty acid (FFA) turnover and oxidation were determined by the primed continuous infusion of albumin bound (1-14C) palmitic acid in 2 patients after an overnight fast and during fat-free total parenteral nutrition (TPN), in 1 during fat-free TPN, and in another in whom one-third of calories were administered by the continuous infusion of Intralipid via a central venous catheter in conjunction with a standard glucose-amino acid solution. During TPN, plasma FFA concentrations in 2 patients were reduced from 0.7 to 0.11 and 0.08 mM, respectively, and their plasma FFA turnover during TPN was only 26% (3.86 and 2.68 mu mol/min/kg) of that prior TPN. In these subjects prior to TPN, 33 and 47% of the plasma FFA turnover was immediately oxidized, accounting for 58% of the CO2 output; however, during TPN only 16% of the plasma FFA turnover was oxidized, accounting for 10% of the caloric expenditure. The plasma FFA kinetics in the third patient were similar to those described for the first two. In contrast, the plasma FFA concentration of the fourth patient during Intralipid TPN was 0.4 mM. His plasma FFA production was 11.3 mu mol/min/kg, of which 18.4% was immediately oxidized, contributing 28% to the total CO2 output. These studies indicated that during fat-free TPN plasma FFA turnover is reduced and plasma FFA oxidation is a minor contributor to energy homeostasis; however, when one-third of the calories are supplied by fat emulsion, plasma FFA turnover is appreciable and the oxidation of plasma FFA is an important source of energy.

Plasma acetate turnover and oxidation.

Plasma acetate turnover and oxidation were determined in 11 healthy subjects by the constant infusion of a trace amount of [1-14C]acetate for 6 h. The subjects ages ranged from 22 to 57 yr. There was a positive correlation (P less than 0.001) between plasma acetate concentration and turnover rate, and a negative correlation (P less than 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 less than 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 mumol/min . kg, P less than 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 less than 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. Uptake or output of acetate by various tissues was measured by arterial-venous plasma acetate concentration differences. In seven of eight subjects undergoing elective surgery, the arterial-portal venous concentration difference was negative, which indicated that the gastrointestinal tract can contribute to plasma acetate production. Uptake of plasma acetate by both the leg and liver appeared to be dictated by the arterial acetate concentration. Net production of acetate by both the leg and liver was most often observed at arterial plasma acetate concentrations less than 0.08 mM.

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.