Glucose Flux in Relation to Energy Expenditure in Malnourished Patients with and Without Cancer During Periods of Fasting and Feeding1

[CANCER RESEARCH 44, 1718-1724, April 1984]

Glucose Flux in Relation to Energy Expenditure in Malnourished Patients with and without Cancer during Periods of Fasting and Feeding1

Elisabeth EdÃ©n,Staffar) EdstrÃ¶m,Klas BennegÃ¡rd, Tore ScherstÃ©n,and Kent Lundholm2

Surgical Metabolic Research Laboratory, Department of Surgery I [T. S., K. L], Anaesthasiology l-ll [E. E., K. B.] and Otolaryngology [S. Â£.],Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden

ABSTRACT fuel economy in progressive neoplasia (12). Our recent evidence suggests that elevated lactate turnover in cancer patients may Glucose dynamics, energy metabolism, and nitrogen balance be counteracted by depressed recycling of carbon in the glucose- were studied in eight malnourished cancer patients and seven alanine cycle (2), supported by the findings that a decreased malnourished patients without cancer. Glucose flux was mea alanine release occurred in combination with a diminished glu sured by single injection of [6-3H]glucose and [U-14C]glucose. cose uptake across the leg in cancer patients after an overnight Energy expenditure was measured by indirect calorimetry. Each fast (2), and that intrahepatic cycling of glucose carbon was patient was studied after an overnight fast and during constant decreased in sarcoma-bearing mice (21). Thus, the evidence gastric infusion of a formula diet. points to the possibility that net recycling of glucose in cancer Cancer patients had elevated glucose flux when fasting, cor cachexia may not influence the overall fuel economy, even if the responding to 42% of their spontaneous daily intake of glucose. Cori cycle activity is highly elevated (16). Instead, it is rather the At least one-half of the elevated flux in cancer patients compared sum of whole-body gluconeogenesis and glycogenolysis, mea with controls was due to increased recycling of glucose carbon sured as glucose turnover, that may be of quantitative impor after an overnight fast. Feeding doubled the total glucose flux in tance in weight loss. Net recycling probably represents a minor both cancer and control patients. The recycling was unchanged part of the total flux of glucose through the plasma pool in cancer in the cancer group and disappeared in the controls during patients, provided that hepatic glycogen is available (32). feeding. The increased glucose flux in cancer patients was We have calculated that elevated glucose turnover may im concomitant with normal resting energy expenditure during pe pose an energy cost of up to 40% of increased energy expend riods of both fasting and feeding. Glucose flux in relation to iture in metastatic cancer (22). Although the elevation in energy energy expenditure was doubled in cancer patients compared to expenditure is low in cancer patients3 (250 to 300 kcal/day; Refs. controls, and the glucose flux in fed cancer patients was similar 7,24, and 34), the cumulative effect may be one important factor to the rate of glucose infusion, which shows that the endogenous behind the negative energy balance. This is most obvious in production of glucose was not inhibited. Cancer and control those patients with a very low caloric intake. It was reported patients reached a comparable positive energy and nitrogen recently that some human soft tissue sarcoma have a very high balance, allowing for their overall caloric intake. glucose uptake (130 mg/min/tumor) (26). This amount of glucose Our results show that cancer patients seem to have a char contains more than 700 kcal/day, assuming normal and complete acteristically increased glucose demand, which contributes to oxidation of glucose. However, if this glucose is metabolized their weight loss when fasting. The energy drain by this elevated only to lactate, then a significant energy wastage is imposted on glucose flux can explain, as a maximum estimate, a loss of about the host, considering that lactate production in the tumor tissue 0.9 kg of body fat per 30-day period. would extract only 5 to 10% of the energy content of the glucose molecule. INTRODUCTION This study evaluates the role of elevated overall flux of glucose as a metabolic pathway of energy drain on cancer patients. As the glucose use and the metabolic rate are normally low ered in the phase of caloric deprivation, findings of elevated MATERIALS AND METHODS glucose flux have been taken to suggest an increased demand for glucose in weight-losing cancer patients (17, 22, 35, 37). Patients. Malnourished cancer patients were compared with malnour Consistent evidence suggests that an increased lactate turnover ished patients without cancer. The clinical details and the nutritional state contributes significantly to the increase in whole-body flux of of the patients are given in Table 1. The patients were selected on the glucose in metastatic cancer (16, 18). Neosynthesis of glucose clinical grounds that all patients were in the need of nutritional support from lactate is an energy-requiring metabolic process. The pos and that they were chosen to be comparable with the patients in our recent studies with respect to tumor stage and degree of malnutrition sible role of a wasteful metabolic pathway through recycling of (2,3,22). AnthropomÃ©trie and biochemical assessments and the patients' glucose carbon may therefore contribute significantly to overall history of weight loss were used to judge the degree of malnutrition (5). All patients had normal body temperature, and none of them was 1This work was supported by grants from the Swedish Cancer Society (Project suffering from acute illness. None was severely anemic. Both cancer and 93), the Swedish Medical Research Council (Project 536), the Assar Gabrielsson Foundation, the Serena EhrenstrÃ¶m Foundation, and the Gothenburg Medical control patients had an increased erythrocyte sedimentation rate, and 7 Society. 2 To whom requests for reprints should be addressed, at Department of Surgery 3 L. Ljndmark, K. BennegÃ¡rd, E. EdÃ©n,L. Ekman, T. ScherstÃ©n,G. Svaninger, I. Sahlgrenska Hospital, S-413 45 Gothenberg, Sweden. and K. Lundholm. Resting energy expenditure in malnourished patients with and Received March 23, 1983; accepted January 4, 1984. without cancer, submitted for publication.

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Table 1 Nutritional status of weight-losing cancer and noncancerous patients Wt-losing cancer patients Controls BAge A* (n = 8) (n = 7)A63 (yr)Height Â±173 (cm)Wt Â±10 toss(kg)Wt(kg)1IIWt Â±62.2

Â±65.6 Â±0.78 wt)1IITotalindex (actual/ideal Â±0.82 Â±2740 (mmol)1IITricepsbody potassium Â±2948 Â±7.3 (mm)1IIArmskinfold Â±8.2 Â±23.4 (cm)1IIHemoglobincircumference Â±25.3 Â±132 c88210.030.0622220.10.1321111 (g/liter)1IISerumconcentration "71 Â±119 Â±37 (g/liter)1IISerumalbumin "2 Â±36 "0.03 Â±0.25 (g/liter)1IIErythrocyteprealbumin "0.0312110.20.111427/87/8Wt-tosing Â±0.31 Â±49 (mm/hr)1IIRectalsedimentation rate Â±50 5437.237.21817102106++Â±Â±Â±Â±Â±Â±Â±Â±Â±Â±+Â±Â±Â±Â±+Â±+Â±Â±Â±Â±Â±Â±Â±5"112.63.30.050.051152151.51.21.31.07 Â±37.0 (Â°C)1IIRespiratorytemperature Â±37.0 Â±24 (breaths/min)1IIMeanfrequency Â±20 Â±105 (beats/mm)1IIAbnormaldaily heart rate Â±104 Â±2/72/75418.99.40.070.083583621.61.52.72.6 tests1II551741050.454.70.680.7320502481727.321.723.311611329290.140.1349cliver function

A, comparison before/after nutrition; B, comparison between the groups; I, before nutrition; II, after nutrition. 6 Mean Â±S.E. Â°p< 0.05. "p< 0.025. "p<0.01. of 8 cancer patients had abnormal liver function test results. However, the study. The diagnoses were: (a) one testicular carcinoma; (o) one none of them had elevated levels of plasma bilirubin, and transaminases gastric carcinoma; (c) 2 hepatic carcinomas; (d) 2 head and neck were lower than 2 /ikat/liter (normal value, <0.7 /Â¿kat/liter)and alkaline carcinomomas; (e) one esophageal carcinoma; and (f) one colon carci phosphatases <10 jtkat/liter (normal value, <5 /tkat/liter). The hepatic noma. influence was qualitatative rather than quantitative. All patients were Group 2: Malnourished Patients without Cancer. The group con subjected to isotopie scintigrams and computerized tomography of the sisted of 7 malnourished patients without cancer (one with chronic liver. The heart rate was high in both cancer and control patients. All malnutrition due to gastric resection 4 years earlier, one with chronic patients had normal blood pressure. None of the patients had received pancreatitis, one with senile depression due to generalized arterioscle any diuretics which could influence total body potassium. The metabolic rosis, one with previous bile fistula without extrarenai losses, and 2 with response of whole-body and peripheral tissues to the enterai nutrition in senile depression). All of these patients were manifestly malnourished 7 of the 8 cancer patients and Â¡n5 of the malnourished noncancer but without any other signs of disease when studied. They had lost patients has been reported in detail eslewhere (3). about 14% of their normal body weight. This study was approved by the Ethical Committee of the Faculty of Investigative Protocol. For all patients who entered this study, total Medicine of the University of Gothenburg. body potassium, nutritional assessment, food intake, energy expendi Group 1: Cachetic Cancer Patients. This group consisted of 8 weight- ture, and glucose turnover were measured during 3 days (Days 1 to 3) losing cancer patients with generalized disease (Stages III and IV) and a before nasograstric tube feeding was started. Spontaneous food intake history of weight loss corresponding to about 15% of their normal body and whole-body energy expenditure were recorded 24 hr a day, and weight. They were admitted to our ward for diagnostic and therapeutic urine was collected over these 3 days when all patients ate the ordinary evaluation. None was totally bedridden, but all had clinical signs of hospital diet of their own choice. Glucose turnover was measured on the malnutrition and cachexia. The diagnosis was confirmed by angiography, morning of the fourth day after an overnight fast with the patients at rest computerized tomography, and histolÃ³gica! evaluation of tumor biopsies. in bed. Immediately afterwards, a nasogastric tube was inserted, and a None of the patients had received any treatment for their disease before liquid formula diet was continuously administered 24 hr a day with a

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1984 American Association for Cancer Research. E. Eden et al. pump. The formula diet, (Clinifeed, 142 kcal/g nitrogen; Roussel Uclaf, on nasogastric tube feeding. The food intake records were made by the Romaineville, France) (Table 2) was given at a rate of 30 to 40 kcal/kg/ patients in collaboration with ourselves and the staff on the ward. day (approximately 1900 kcal and 70 g protein/day) for 14 days (during Conventional food tables were used to calculate energy and protein Days 5 to 19). All patients were allowed to eat what they wanted in intake from the food intake records. excess of the infused formula diet. The patients' spontaneous food The caloric intake consisted of 48% carbohydrate, 34% fat, and 18% intake and whole-body energy expenditure were then again recorded, protein in both cancer and control patients before and during enterai and urine was collected daily over 3 days (Days 17 to 19) on enterai nutrition. nutrition. Total body potassium was also measured, and nutritional Energy Expenditure. Energy expenditure was calculated from contin assessment was repeated on Day 19. Glucose turnover was measured uous heart rate recordings made over 72 hr and from the individual with the patient at rest in bed on the morning of Day 19. During the final relationship between oxygen consumption and heart rate in each subject 14 hr before measurements of glucose turnover, no additional p.o. intake as described previously (33, 34). This method was used, since it does was allowed in excess of the formula diet, which was infused at a rate not disturb the patient or influence his level of daily activity. The calibration of 35 kcal/kg/24 hr. This procedure was used so that the influence of lines were based on simultaneous measurements of oxygen consumption substrate on quantitative measurements of glucose metabolism would and heart rate during lying, sitting, and walking. The oxygen content of be comparable among patients. the expired air was analyzed in a paramagnetic oxygen analyzer (O:M- Nutritional Status. Nutritional assessment included physical and bio 11 ; Beckman) and the energy expenditure was calculated according to chemical (albumin and prealbumin) measurement of body weight, height, the method of De Weir (10). The resting metabolic rate was calculated triceps skinfold, and upper midarm circumference (5). Body potassium from heart rates during sleep at night, and the calibration was done was measured in a whole-body counter. Body weight index (actual to before the patients got out of bed in the morning. The conditions for ideal weight) was calculated from standard tables for ideal weight of measurements were exactly the same before and during nutrition. Sep people living in the area of Sweden from which the patients were selected arate calibration lines for each patient were performed on both occasions (1). There is no reason to believe that the ideal weight of the 2 groups in all patients. Details of this method have been reported, and the should have been different before the patients became ill. The absolute advantages and shortcomings of the method have been discussed decrease in body weight was similar for cancer patients and controls, elsewhere (11,13). and they did not differ significantly with respect to anthropomÃ©trie tests, Nitrogen Balance and Urinary Analyses. Urine was collected daily but hemoglobin, serum albumin, and prealbumin were lower in the cancer over 3 days for the approximation of nitrogen balance before enterai group, which may indicate a more severe protein depletion. In spite of nutrition and during the last 3 days on enterai nutrition. The daily urinary this, we have considered them to be comparable with respect to the nitrogen excretion was determined as described previously (2, 34). The degree of malnutrition. extrarenai nitrogen loss was, for the sake of simplicity, estimated to be Dietary and Energy Intake. All patients ate a balanced hospital diet 2 g/day in each patient (9). Nitrogen balance was calculated as the of their own choosing but of similar overall fat, protein, and carbohydrate difference between nitrogen intake and nitrogen loss. The nitrogen composition, for several days before the metabolic studies were per content in consumed proteins was assumed to be 16%. Urea and formed. Food intake was recorded in all patients for 3 days before enterai creatinine in urine were measured with kits from Boehringer-Mannheim, nutrition started and then again during the last 3 days (Days 17 to 19) West Germany. Adrenaline and noradrenaline were measured at the Department of Clinical Chemistry and described elsewhere (31). Table 2 Glucose Turnover. The methods of measurement and calculation of contentsClinifeedClinifeed glucose flux (turnover and recycling of radioactive glucose) have been described in detail elsewhere (22, 27). The full contribution of recycling solution)Protein,(400/375 ml of of glucose intermediates to gluconeogenesis cannot be derived exactly caseinLipidsCarbohydratessoya proteins, lactalbumin, and g13.4 from measurements of radioactive recycling only. Radioactive recycling g55.0g200mg229mg242mg487mg49mg1.5probably underestimates the total chemical cycle of glucose degradation (oligopolysaccharides)MineralsCalciumPhosphorusSodiumPotassiumMagnesiumIronCopperZincManganeseChlorideIodineVitaminsRatinaiDEThiaminRiboflavinBeNiacinFolacinB,2Pantothenicand the return to glucose for the reasons discussed by others (15, 19, 32). Therefore, recycling of glucose carbons in this study represents radioactive recycling. The radial artery of the patients was cannulated at 3 hr before measurement of glucose turnover. All blood samples were drawn from this artery. The blood glucose and insulin concentration were determined just before, during, and at the end of the investigation to ensure that the patients were in steady-state condition during turnover mg0.2 measurements. [6-3H]Glucose (30 ^Ci) and [U-14C]glucose (20 Â¿Â¿Ci)were mg3 mg0.1 mixed in 0.9% NaCI solution (saline) and injected into the cubital vein as mg250 a single dose. Arterial blood samples were drawn after 30, 45, 60, and mgTrace0.3 120 min for determination of the specific radioactivity of [14C]glucose and [3H]glucose. We purified the glucose fraction more extensively than is generally done. This was done since a considerable amount of radioac mg2.5 tivity appears in glycerol, which comigrates with glucose. Therefore, we ^g11 mg0.5 separated glycerol from glucose by means of an additional Chromato mg0.6 graphie step (22). This demanded a total amount of blood of 170 ml mg0.7mg3.3 drawn from each patient. Therefore, only 4 samples were routinely drawn for measurement of the specific radioactivity of glucose in order to mg150 â€žg4.9 minimize the blood loss. Separate experiments had shown reliable esti iig1.7mg50 mates of the radioactivity decay curve of glucose at these time points. acidBiotinCmOsmol/literEnergy Glucose and lÃ¡clate were measured with the aid of kits from Boehringer- ng27 Mannheim, West Germany, and insulin with a kit (Phadebas) from Phar mg370400 macia, Uppsala, Sweden. The isolation of glucose and counting of radioactivity for determination of the specific radioactivity of blood glu contentNonprotein kcal142:1 cose were performed as described previously (22). cal/g nitrogenAmount15.0 Other Clinical Tests. Body temperature was measured in the rectum.

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The respiratory rate was measured over 1 min immediately before nutrition doubled the glucose flux through the plasma pool in measurement of glucose turnover. The heart rate was measured as the both cancer and control patients (Table 3). mean daily heart rate by means of a portable electrocardiogram recorder. Recycling of radioactive glucose carbon in the cancer patients Hemoglobin concentration, erythrocyte sedimentation rate, serum albu was increased significantly compared to the control subjects min, prealbumin, and liver function (serum bilirubin, alkaline phospha- during both the fasting and enterai feeding periods. The absolute tases, aspartate aminotransferase, and alanine aminotransferase) were rate of recycling was, however, virtually unchanged during feed measured according to routine procedures at the Department of Clinical ing in the cancer subjects. The low level of glucose carbon Chemistry of our hospital. Statistics. Nonparametric tests were applied for the statistical com recycling exhibited by the control subjects during the fasting putations, since normal distributions cannot be assumed in small groups period was reduced to zero when these individuals were studied of malnourished patients. Measurements before and after enterai nutri while receiving enterai nutrition (Table 2). tion were tested by means of Wilcoxon's test for paired observations Resting and total energy expenditure did not differ significantly (30). The Mann-Whitney U test was used for comparisons between the between the groups before or during enterai nutrition. Control groups (30). patients had a significantly elevated resting energy expenditure during enterai nutrition. Both the cancer and the control groups changed from a negative to a positive energy (Table 3) and RESULTS nitrogen balance (Table 4) on enterai nutrition. The magnitude of these changes may have been lower in cancer patients, account Blood glucose concentration rose 25 to 30%, and lÃ¡clate ing for differences in overall food intake between the groups, but concentration rose approximately 40% in both cancer and control the difference in balance did not reach statistical significance subjects during enterai nutrition. Insulin levels rose significantly (Table 3). in both subject groups but were significantly lower in the cancer The difference in glucose metabolism between cancer and subjects compared to controls (Table 3). control patients was not accompanied by any differences in Cancer patients had elevated glucose flux during both fasting urinary excretion of adrenaline, noradrenaline, urea, or creatinine and feeding periods when expressed in relation to body weight. during the fasting or feeding period (Table 4). The daily urinary When glucose flux was expressed in relation to energy expend excretion of creatinine did not increase during the 2-week course iture, this difference between the groups disappeared during the of enterai nutrition. In contrast, the urea excretion increased fasting period, while a statistically significant difference between similarly in cancer and control patients in response to enterai the groups was still found during the feeding period (during the nutrition. Noradrenaline excretion increased only in the cancer fasting period, glucose turnover is equal to glucose use). Enterai group during enterai nutrition (25).

Table 3 Whole-bodyglucose dynamics and energy expenditure in weight-losing cancer patients and controls

cancer patients controls A* (n = 8)B4.92 (n =7)4.86 Blood(mmol/liter)IIILÃ¡clate glucose Â±0.2066.22 Â±0.196.58 Â±0.411.12Â± Â±0.190.87 (mmol/liter)IIIInsulin 0.161.56 Â±0.191.41 Â±0.357 Â±0.1911 (milliunlt/liter)IIIGlucose "28 Â± 1 Â±247 Â±1024.54 Â±1617.95 (mmol/kg/day)IIIRecyclingturnover "49.82Â± 1.84 Â±3.9531.98Â± Â±4.633.33 4.570.68 (mmol/kg/day)IIITotalof glucose '3.86 Â± 0.73 Â±0.300 Â±1.4432.3 Â±038.0 (kcal/kg/day)IIIRestingenergy expenditure Â±2.335.0 Â±9.344.3 Â±2.124.9 Â±6.225.3 (kcal/kg/day)IIICaloricenergy expenditure Â±1.824.6 Â±8.230.8 Â±2.424.0 Â±5.530.0 (kcal/kg/day)IIIEnergyintake Â±2.943.0 Â±13.163.0 Â±4.9-8.4 Â±20.5-7.8 (kcal/kg/day)IIIGlucosebalance Â±3.48.0 Â±4.618.5 Â±4.31.03+ Â±16.50.95 (mmol/kcal)IIIWt-tosingturnover/resting energy expenditure 0.10c Â±0.331.10 2.30 Â± 0.34 cWt-tosing Â± 0.17Aceccdde " A, comparison before/after nutrition; B, comparison between the groups; I, fasting period; II, feeding period. " Mean Â±S.E. cp<0.01. "p < 0.05. "p< 0.025.

APRIL 1984 1721

Tabte4 Urinary excretion and nitrogen balance in weight-losing cancer patients and controls Wt-tosing Wt-losing cancer patients controls AAdrenaline A* (n = 8) B (n = 7)

(nmol/24 hr) Â±11.8"45.5 1IINoradrenaline Â±5.0442.8 9.1290.3Â± 8.9303.3Â± (nmol/24 hr) 1IIUrea 45.7351.3Â± 64.9271.8Â± Â±54.8234.4 Â±97.7230.8 (mmol/24 hr) 1IICreatinine, 22.9405.1Â± 25.5470.8Â± Â±35.77.35 Â±68.77.98 hr)1IINitrogen(mmol/24 Â±2.407.70 Â±1.297.95 Â±1.020.003 Â±1.020.062 balance (g N/kg/24 hr) 0.038c Â± Â±0.0610.211 1II49.3 0.119 Â± 0.08645.3 Â± 0.053 c * A, comparison before/after feeding period; B, comparison between groups; I, fasting period; II, feeding period. 6 Mean Â±S.E. cp<0.05. tÃp<0.01. "p< 0.025.

DISCUSSION by up to 50% as reported by Hetenyi (15). It is not possible to assess what this means in terms of energy expenditure under Glucose dynamics in cancer patients have been studied in these circumstances, but it can be calculated that the range of several previous investigations. Most studies have demonstrated energy loss may be 2.4 to 4.7 kcal/kg/day, since 1 g of glucose an elevation in glucose turnover, although this has not been a generates 4 kcal with complete oxidation. The lower estimate in completely consistent finding (28, 37). On the other hand, in this respect was of similar magnitude to the S.E. of the mean creased activity of the Cori cycle has been a consistent finding for measurements of resting energy expenditure in the cancer (16-18). Previous studies have generally used well-nourished group (8%). Substantial changes in radioactive glucose recycling normals (22, 28, 37) and well-nourished cancer patients as can obviously be demonstrated within the range of variation for controls (16-18). Therefore, it has been difficult to judge whether energy expenditure measurements. The increased glucose flux elevated glucose flux in cancer disease is a reflection of energy during the fasting period corresponded to 65 g of glucose, which drain by the neoplasm or is merely a consequence of the mal was 42% of the daily sugar intake in the cancer group. This nutrition per se. Therefore, in this study, we have compared amount of glucose corresponds to a potential loss of 521 mg cancer patients to malnourished noncancerous patients with body lipids/kg/day in cancer patients when an incomplete oxi similar degrees of negative energy balance, resting energy ex dation of glucose (glycolysis in the tumor or elsewhere) is to be penditure, and weight loss. However, differences in food intake, substituted for by complete oxidation of lipids. In agreement with body composition, and degree of malnutrition may exist between this, we have recently found a significantly lower respiratory our study and control groups. In spite of such possible differ quotient in both sarcoma-bearing mice (20) and cancer patients.3 ences, a 2-week course of nutritional support brought the cancer This alteration in tumor-host metabolism would lead to a loss of and control patients into comparable positive energy and nitro 0.8 to 0.9 kg body fat/month. Thus, elevated glucose turnover gen balance. Because of this, we have considered the cancer may account for a considerable proportion (260 kcal/day) of the and the control groups to be comparable. signficantly elevated energy expenditure (250 to 300 kcal/day) Glucose Flux during the Fasting Period. This study ad in cancer patients (7, 24, 34).3 We have recently calculated that dressed the question of whether elevated glucose flux has increased amino acid flux (protein turnover) may also be a significance to the overall fuel economy in progressive neoplasia. contributing factor.4 The cancer patients did not have a measurable elevated energy A further question is whether an increased gluconeogenesis expenditure. In spite of this, they had elevated glucose turnover in itself may be a factor of quantitative importance in relation to of the same magnitude as recently reported for patients with oat weight loss. The answer is probably yes, but the total glucone cell lung carcinoma, a tumor group known to be associated with ogenesis cannot exceed the glucose turnover. Turnover of glu hypermetabolism (14). Therefore, it is obvious that increased cose through the plasma compartment during the fasting period glucose flux can occur in cancer patients with unchanged resting probably reflects the sum of gluconeogenesis and glycogeno- energy expenditure, suggesting that flux through nonoxidative lysis. In these experiments, it is equal to the rate of glucose use. pathways is of significance, or that glucose competes with other It is not possible to distinguish between gluconeogenesis and substrates for oxidation. Actually, 51% of the elevated glucose glycogenolysis by the present method, but the elevation of the turnover in the cancer patients during the fasting period was 2 together shows that the glucose demand is significantly in explained by net recycling of radioactive glucose carbon. How creased in cancer patients. This may well be explained by ever, the true chemical recycling of glucose carbons may explain the difference (6.59 mmol/kg/day) in postabsorptive glucose 4E. EdÃ©n,L.Ekman, K. BennegÃ¢rd,L.Undmark, and K. Lundholm. Whole body turnover between cancer and controls, since the rate of glucose tyrosine flux in relation to energy expenditure in weight-losing cancer patients, synthesis from lÃ¡clate may be underestimated from tracer data submitted for publication.

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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1984 American Association for Cancer Research. Glucose Turnover in Patients with Cancer glucose consumption in the tumor, but other explanations may Recycling of Radioactive Glucose Carbons. In our recent also exist. study, we did not find any significantly increased net recycling of Glucose Flux during the Feeding Period. The nutritional labeled glucose carbon, but we reported a quantitatively greater protocol in this study brought all patients into positive energy recycling in both the cancer and the control patients compared and nitrogen balance. Therefore, we can say that the prerequisite to the results in this study (22). In the previous study, we labeled for weight gain was fulfilled, even though differences in the time the glucose pool with [U-14C]glycerol, which means that the course for restitution of body composition may have occurred glucose decay curve was a composite of an appearance-disap between the groups. Unfortunately, nutrition by the enterai route pearance curve. Therefore, we can now draw conclusions based does not allow for differences in the rate of absorption of calories on 2 different methods, reflecting different degrees of whole- or, more specifically, glucose. The rate of infusion of the formula body recycling. Net radioactive recycling in cancer patients, is diet corresponded to 188 mg glucose/kg/hr in cancer patients, probably not greater than found with the present method which which corresponded to the elevation of glucose flux in these is, from a theoretical point of view, the most appropriate for patients during the feeding period (190 mg/kg/hr). This indicates measuring the net recycling of labeled glucose carbon. The that glucose was absorbed at the rate at which it was infused recycling in our cancer patients did not increase further in re and also shows that the endogenous production of glucose was sponse to feeding, which agrees with a recent report (8). In not inhibited during enterai nutrition in our cancer patients. This contrast, feeding almost doubled the total flux of glucose through is in contrast with the results in a recent study (8). The expla the plasma pool in both cancer and control patients. This shows nation to our results may be the combination of lower insulin that recycling of glucose probably does not contribute more to levels (Table 3) and insulin resistance in cancer patients (23). It energy wastage during the feeding period than it does during has been suggested that insufficient inhibition of endogenous the fasting period. Elevated recycling of radioactive glucose glucose production might play a role in weight loss in progressive carbons seems to be a characteristic metabolic feature of a neoplasia. The control patients received glucose at a rate cor tumor-bearing host, during both fasting and feeding periods. responding to 205 mg/kg/hr, but the mean glucose flux in the In conclusion, this study confirms that elevated flux of glucose group only increased by 104 mg/kg/hr. Malabsorption may have carbon is a characteristic feature in cancer patients, even com been one reason for this, but visual inspection of the measure pared to severely malnourished patients without cancer. The ments of nitrogen excretion before and during enterai nutrition study does not provide enough evidence to suggest that altered in these patients did not confirm this. Therefore, a more likely glucose metabolism in these 8 malnourished cancer patients explanation is that the endogenous production of hepatic glucose would be characteristic of all cancer types and stages. However, was suppressed in the controls. It seems that endogenous it clearly supports that elevated glucose flux can account for a glucose release was suppressed and that glucose released into considerable proportion of the altered fuel economy in cancer the circulation originated from the gut. This accounts for the cachexia. The energy demand, due to increased flux, corre absence of recirculation of 14C-atoms into plasma glucose in the sponded to 41% of the daily glucose intake of the cancer controls (Table 3). patients. In terms of potential weight loss, this may explain the The uncertainties of complete absorption of enterai diets in loss of 0.8 to 0.9 kg body fat/30-day period. However, this this kind of investigation make quantitative comparisons between negative consequence of an elevated glucose demand in cancer glucose flux in our cancer and control patients during feeding patients may, to some extent, have been counteracted by a periods less precise. However, in connection with simultaneous normal replenishment of energy stores during feeding. The ex measurements of energy expenditure and recycling of glucose planation for this may be that our cancer patients may have a carbon, it may be possible to make some quantitative compari lower dietary-induced thermogenesis, which is consistent with sons. Flux of glucose per resting oxygen uptake increased 2- findings in fasting-refeeding experiments (4, 6, 29). fold in cancer patients during enterai nutrition, concomitant with an unchanged radioactive recycling. This probably means that a REFERENCES considerable amount of the intestinally absorbed glucose in the 1. 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Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1984 American Association for Cancer Research. Glucose Flux in Relation to Energy Expenditure in Malnourished Patients with and without Cancer during Periods of Fasting and Feeding

Elisabeth Edén, Staffan Edström, Klas Bennegård, et al.

Cancer Res 1984;44:1718-1724.

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