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Android obesity is associated with increased cortisol secretion. Direct effects of cortisol on gluconeogenesis and other parameters of insulin resistance were determined in normal subjects. Gluconeogenesis was determined using the reciprocal pool model of Haymond and Sunehag (HS method), and by the Cori cycle/lactate dilution method of Tayek and Katz (TK method). Glucose production (GP) and gluconeogenesis were measured after a 3 h baseline infusion and after a 4-8 h pituitary-pancreatic infusion of somatostatin, replacement insulin, growth hormone (GH), glucagon and a high dose of cortisol (hydrocortisone). The pituitary-pancreatic infusion maintains insulin, GH and glucagon concentrations within the fasting range, while increasing the concentration of only one hormone, cortisol. Two groups of five subjects were each given high-dose cortisol administration, and results were compared with those from a group of six 'fasting alone' subjects (no infusion) at 16 and 20 h of fasting. Fasting GP (12 h fasting) was similar in all groups, averaging 12.5+/-0.2 micromol x min(-1) x kg(-1). Gluconeogenesis, as a percentage of GP, was 35+/-2% using the HS method and 40+/-2% using the TK method. After 16 h of fasting, GP had fallen (11.5+/-0.6 micromol x min(-1) x kg(-1)) and gluconeogenesis had increased (55+/-5% and 57+/-5% of GP by the HS and TK methods respectively; P<0.05). High-dose cortisol infusion for 4 h increased serum cortisol (660+/-30 nmol/l; P<0.05), blood glucose (7.9+/-0.5 mmol/l; P<0.05) and GP (14.8+/-0.8 micromol x min(-1) x kg(-1); P<0.05). The increase in GP was due entirely to an increase in gluconeogenesis, determined by either the HS or the TK method (66+/-6% and 65+/-5% of GP respectively; P<0.05). Thus cortisol administration in humans increases GP by stimulating gluconeogenesis. Smaller increases in serum cortisol may contribute to the abnormal glucose metabolism known to occur in the metabolic syndrome.
A 59-year-old man with a 30-year history of type 2 diabetes mellitus presented with fatigue, confusion, and weight loss over a 3-month period. He was found to be hypercalcemic (11.8 mg/dL) and dehydrated, and his hypercalcemia improved with intravenous fluids. While in the hospital, he developed hyponatremia, hypoglycemia, and hypotension. He was found to have a subnormal cortisol level of 2.3 microg/dL at baseline, which increased to only 5.6 microg/dL 60 minutes after a 250-microg corticotropin intravenous stimulation test. The patient developed pneumonia and adult respiratory distress syndrome and died of an acute myocardial infarction. During the autopsy, he was found to have lymphocytic hypophysitis with a severe reduction in corticotropin-producing anterior pituitary cells. No malignancy was identified at autopsy. He is the first male patient to be described in the literature who presented with hypercalcemia caused by lymphocytic hypophysitis.
The analysis of mass isotopomers in blood glucose and lactate can be used to estimate gluconeogenesis (Gneo), glucose production (GP), and, by subtraction, nongluconeogenic glucose release by the liver. At 6 AM, 18 normal subjects received a 7-hour primed constant infusion of [U-13C6] glucose. After a 3-hour baseline period (12 hours of fasting), somatostatin, insulin, hydrocortisone, growth hormone (GH), and glucagon were infused for 4 hours. Glucagon was infused at a low-dose (n = 6) or high-dose (n = 6) concentration for 4 hours and was compared with fasting alone (n = 6). Low-dose glucagon infusion increased plasma glucagon (64 +/- 3 v 44 +/- 7 ng/L, low glucagon v baseline). GP increased above baseline (15.5 +/- 0.5 v 13.8 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11 .5 +/- 0.6 micromol/kg/min, P < .05). The elevation in GP was due to a near doubling of nongluconeogenic glucose release compared with fasting alone (8.3 +/- 0.6 v 4.7 +/- 0.5 micromol/kg/min, P < .01). High-dose glucagon infusion (125 +/- 25 ng/L) increased GP above baseline (15.8 +/- 0.6 v 13.5 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11.5 +/- 0.6 micromol/kg/min, P < .05). The increase in GP was due to an increase in Gneo (8.5 +/- 0.5 v 6.8 +/- 0.7 micromol/kg/min, P < .05) and nongluconeogenic glucose release (7.4 +/- 0.5 v 4.7 +/- 0.4 micromol/kg/min, P < .05) compared with fasting. Low-dose glucagon increases GP only by stimulation of nongluconeogenic glucose release. High-dose glucagon increases GP by an increase in both Gneo and nongluconeogenic glucose release.
We have derived equations, by employing [U-(13)C]glucose and mass isotopomer analysis, to determine the pathways of glycogen synthesis (J. Katz, W. P. Lee, P. A. Wals, and E. A. Bergner. J. Biol. Chem. 264: 12994-13004, 1989). More recently, by use of these methods we have derived equations to determine the rate of glucose recycling and of gluconeogenesis [Tayek and Katz. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E709-E717, 1996 and 272 (Endocrinol. Metab. 35): E476-E484, 1997, and Katz and Tayek. Am. J. Physiol. 275 (Endocrinol. Metab. 38): E537-E542, 1988]. The former equations have been criticized and challenged by C. Des Rosiers, B. R. Landau, and H. Brunengraber [Am. J. Physiol. 259 (Endocrinol. Metab. 22): E757-E762, 1990], and the latter recently by B. R. Landau, J. Wahren, S. F. Previs, G. K. Ekberg, D. Yang, and H. Brunengraber [Am. J. Physiol. 274 (Endocrinol. Metab. 37): E954-E961, 1998]. Landau et al. claimed that our equations were in error and "corrected" them. Their analysis, and their values for recycling and gluconeogenesis (GNG) differ markedly from ours. We show here our equations and estimates of recycling and GNG to be correct. We present here a theoretical analysis of recycling and discuss the determination of the Cori Cycle and GNG. We illustrate by numerical examples the difference in parameters of glucose metabolism calculated by the methods of Katz and Landau. J. Radziuk and W. N. P. Lee [Am. J. Physiol. 277 (Endocrinol Metab. 40): E199-E207, 1999] and J. K. Kelleher [Am. J. Physiol. 277 (Endocrinol. Metab. 40): E395-E400, 1999] present a mathematical analysis that, although differing in some respects from Landau's, supports his equation for GNG. We show in the APPENDIX that their derivation of the equation for GNG is incorrect.
Weight loss in humans is associated with elevated hypothalamic-pituitary growth hormone (GH) secretion. This study evaluates the effects of weight loss on the hypothalamic-pituitary (GH-releasing hormone [GHRH]-GH) axis in 14 normal-weight (body mass index [BMI], 25+/-1 Kg/m2) subjects, of whom half had undergone a diet-induced weight loss of 14%+/-2% (mean+/-SEM). Insulin-like growth factor-1 (IGF-1), insulin, oral glucose tolerance, leptin, and GH pulse patterns were determined in both groups after weight maintenance for 1 week. Of note, we tested the effects of recent weight loss (3 months) and not a recent dietary intake, since both groups ingested a normal calorie diet for 2 days in the Clinical Research Center (CRC) prestudy. Serum insulin (3.8+/-0.7 v 9.0+/-0.9 microU/mL, P < .01) and C-peptide (0.44+/-0.06 v 0.59+/-0.04 ng/mL, P < .05) were significantly lower in the weight loss group. Serum leptin was not different. Endogenous GH pulse height (11.9+/-4.8 v 1.3+/-0.1 microg/L, P < .05), area per GH pulse ([AUC] 57+/-28 v 6+/-1 microg/L, P < .05), and mean GH (3.91+/-0.76 v 0.85+/-0.16 microg/L, P < .01) were increased in the weight loss group. The serum insulin level was inversely associated with the mean GH concentration (r=-.678, P < .01) and GH pulse height (r=-.733, P < .01). In addition to spontaneous GH secretion, the GHRH-stimulated GH pulse height (41.8+/-18.1 v7.1+/-1.6 microg/L, P < .05) and AUC (161+/-35 v46+/-13 microg/L/min, P < .05) were also increased in the weight loss group. The insulin concentration was also inversely correlated with the GHRH-stimulated GH pulse height (r=-.718, P < .01). The leptin concentration was correlated with the BMI (r=.554, P < .05) and body fat (r=.744, P < .01), but not with GH secretion. In summary, even though these patients were on a normal calorie diet, a history of recent weight loss in young men and women of normal weight and health can be associated with a significant increase in spontaneous GH pulse height and GHRH-stimulated pulse height. Weight loss was also associated with a reduced serum insulin level. The observed increase in GH secretion may be secondary to the reduction in insulin or alterations of other factors acting at the site of the pituitary.
Six subjects were infused with [U-13C]glucose (0.03-0.05 mg . kg-1 . min-1) starting 8-9 h after a meal, and the production of glucose, the recycling of glucose (the Cori cycle), the dilution of glucose by unlabeled carbon into the hepatic lactate-pyruvate pool, and gluconeogenesis were determined in these fasted volunteers by use of mass isotopomer analysis and equations previously described [J. A. Tayek and J. Katz. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E476-E484, 1997]. A primed continuous 11-h infusion was started at 6:00 AM, and the above parameters were calculated after 3 h (for the 12-h fast) and at the end of the infusion (for the 20-h fast). Another group of five subjects was fasted for 40 h, and the above parameters were calculated as before. At 12, 20, and 40 h of fasting, respectively, blood glucose was 93 +/- 2, 83 +/- 2, and 71 +/- 2 (SE) mg/dl; glucose production was 2.3, 1.8, and 1.77 mg . kg-1 . min-1; the recycling of labeled carbon was 8, 15, and 15%, and that of glucose molecules (Cori cycle) was 18, 35, and 36%; the contribution of gluconeogenesis to glucose production was 41, 71, and 92% or 0.96, 1.29, and 1.64 mg . kg-1 . min-1; and the contribution of other sources to glucose production was 1.37, 0.53, and 0.15 mg . kg-1 . min-1. The recycling of glucose is important in prolonged fasting for the maintenance of plasma glucose concentration. We demonstrate here that gluconeogenesis can be easily measured and that it accounts for approximately 90% of glucose production after a 40-h fast.
Severe malnutrition (< 65% ideal body weight [IBW]) is associated with reduced insulin secretion, decreased receptor affinity, and glucose intolerance. To characterize the abnormality of mild malnutrition in terms of insulin action, both the insulin sensitivity index and insulin secretion were measured in 15 underweight and 15 normal-weight volunteers. Ten patients had localized squamous cell carcinomas of the head and neck, and 20 were normal controls. After a 10-hour overnight fast, all volunteers were studied using Bergman's modified intravenous (IV) glucose tolerance test (IVGTT). Body weight and diagnosis were compared using a 2 x 2 ANOVA. The acute insulin response to IV glucose was reduced in normal-weight and underweight cancer patients by approximately 40% to 50% (P < .05). Both groups of cancer patients had a significantly reduced rate of glucose disposal (1.25 +/- 0.29 and 1.27 +/- 0.23 %/min) compared with the healthy volunteers (1.82 +/- 0.21 and 1.81 +/- 0.24 %/min, respectively, P < .05). Glucose production (GP) was significantly increased in the underweight cancer patients versus the weight-matched volunteers (13.9 +/- 1.3 v 10.8 +/- 0.5 micromol/kg/min, P < .05). Normal-weight and underweight cancer patients had a 32% to 44% reduction in insulin sensitivity (P < .05). In contrast to the effects of cancer, underweight controls had twice the insulin sensitivity compared with normal-weight controls (P < .01). Since insulin secretion decreased in underweight controls, the increased insulin sensitivity may have been due to an increased insulin action and to factors associated with leanness.
Six normal subjects (NL group) and 13 cancer patients (CAI and CAII groups) were fasted overnight and infused with [U-(13)C]glucose (0.016-0.058 mg x min(-1) x kg(-1)). Plasma glucose and lactate were isolated, and mass isotopomer distributions were determined by gas chromatography-mass spectroscopy. Applying equations modified from those previously described [J. A. Tayek and J. Katz. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E709-E717, 1996], we determined glucose production (GP), recycling of glucose carbons, fraction of recycled molecules in blood glucose (Cori cycle), formation of pyruvate from unlabeled carbons, dilution of pyruvate via the tricarboxylic acid cycle and other reactions, and rate of gluconeogenesis. Glucose production was similar in all groups: 2.4 +/- 0.2 mg x min(-1) x kg (-1). The fraction of recycled carbon and of the Cori cycle were elevated in the CAI group vs. the CAII and NL groups: 15 and 33% vs. 7.8 and 19%, respectively (P = 0.01). Gluconeogenesis was 1.9 +/- 0.1, 1.0 +/- 0.1, and 0.83 +/- 0.11 mg x min(-1) x kg(-1) in the CAI, CAII, and NL groups, respectively. In the NL and CAII groups, 20% of GP is via recycling, 20% from unlabeled carbon sources (muscle glycogen, amino acids), and 60% from hepatic glycogenolysis; in the CAI group, 30% is from recycling, 50% from unlabeled carbon, and 20% from glycogen and other sources. Serum cortisol was elevated in the CAI group vs. the CAII group: 11.2 +/- 1.2 vs. 7.7 +/- 1.2 microg/dl (P < 0.05). There was a strong correlation between plasma cortisol and Cori cycle in the NL (r = 0.963) and CAI and CAII groups (r = 0.771). Serum cortisol was directly, and insulin was inversely, correlated with gluconeogenesis in the NL (r2 = 0.967) and CAI and CAII groups (r2 = 0.727). We conclude that whereas the cancer population is heterogeneous with respect to gluconeogenesis, many cancer patients derive their GP predominantly from gluconeogenesis compared with healthy controls, who derive less than one-half of their GP from gluconeogenesis.
OBJECTIVE: The present study was performed to determine the chronology of the effects of a single 50 ug subcutaneous dose of TNF on food intake, weight gain, and skeletal muscle protein metabolism in normal rats. Earlier work demonstrated that a single subcutaneous dose of 50 ug of tumor necrosis factor alpha (TNF) significantly increased skeletal muscle protein synthesis and breakdown in the tumor bearing rat [1]. Some of the earlier work demonstrated that TNF can reduce food intake, weight gain and enhance muscle catabolism. DESIGN: Twenty-five male Sprague Dawley rats were randomized assigned to treatment or saline arms of the study. Rates of in vivo incorporation of L-1-14C-leucine into skeletal muscle were measured by the flooding dose technique. Rats were studied 6 and 60 hours after TNF or saline. RESULTS: Six hours after administration of the TNF, the total skeletal muscle amino acid concentration was significantly reduced by 20%. The greatest reductions were seen in lysine, arginine, and isoleucine (39-53%) followed by serine, tyrosine, ornithine, threonine and alanine (18-32%). Despite this drop in skeletal muscle amino acid concentrations, the rate of skeletal muscle protein synthesis was similar to the controls (12.2 +/- 4.1 vs 13.8 +/- 3.7 %/day, mean +/- sd, saline vs TNF treated, respectively). Dietary intake (8.2 +/- 0.5 vs 7.3 +/- 1.1 g/day) and weight gain (7.1 +/- 1.1 vs 9.1 +/- 3.8 g/day) were not affected by TNF administration. However, there was a significant increase in skeletal muscle protein synthesis rate in the TNF treated group after 60 hours (17.8 +/- 4.0 vs 12.2 +/- 4.1 %/day) but not after 6 hours (13.8 +/- 3.7 vs 13.7 +/- 3.3 %/day) compared to saline treated rats, respectively. TNF administration after 60 hours was not associated with an elevated skeletal muscle 3-methyl-histidine concentration or a reduced nitrogen balance. CONCLUSION: These data suggest that at a 50 ug subcutaneous dose of TNF, an early (6 hours) effect is to reduce skeletal muscle of amino acids without effecting either synthesis or breakdown. A later effect (60 hours) is to normalize skeletal muscle amino acid concentration and to increase skeletal muscle protein synthesis. This suggests that TNF may acutely alter amino acid transport as one of its modes of action.
Eight normal controls and nine non-insulin-dependent diabetes mellitus diabetics were, after an overnight fast, infused for 3 h with [6-3H]- and with [U-13C]glucose with six 13C carbons at rates from 0.03 to 0.15 mg.kg-1.min-1. Plasma glucose and lactate were assayed by gas chromatography-mass spectroscopy. Several parameters of glucose metabolism were calculated from the mass isotopomer distribution. Glucose production (GP) determined with [6-3H]- and [U-13C]glucose agreed closely. GP was 1.9 +/- 0.16 (range 1.3-2.5) mg.kg-1.min-1 in controls and 2.8 +/- 0.29 (1.7-4.5) mg.kg-1.min-1 in diabetics (P < 0.05). The correlation in diabetes between plasma glucose and GP (r = 0.911, P < 0.01) was close. Recycling of carbon (8 vs 7%) dilution by unlabeled carbon (2- vs 2.3-fold), and dilution via the tricarboxylic acid cycle (1.5-fold) were similar in controls and diabetics. Gluconeogenesis was 0.90 +/- 0.08 (0.5-1.3) mg.kg-1.min-1 in controls and 1.30 +/- 0.13 (0.8-1.9) mg.kg-1.min-1 in diabetics (P < 0.05). Gluconeogenesis contributions to GP were 46.6 +/- 4.0% (26-61%) in the controls and 48.8 +/- 5.7% (32-83%) in diabetics. We show that, using [U-13C]glucose infusion of 2-5% of glucose turnover (0.03-0.10 mg.kg-1.min-1), a large number of parameters of glucose metabolism may be determined in humans.
OBJECTIVE: Approximately 70% of all cancer patients have elevations in hepatic glucose production and/or reductions in glucose utilization. To identify an explanation for insulin resistance, we measured fasting hepatic glucose production (HGP), leucine appearance (Leu Ra), leucine oxidation (LO), glucose oxidation (GO) and non-oxidative glucose utilization at baseline and after identical insulin infusion rates (2 pmol/kg/minute, 7 pmol/kg/minute, and 70 pmol/kg/minute) in eight head and neck cancer patients and eight weight-matched disease-free volunteers. METHODS: A step increase in insulin administration during a euglycemic clamp protocol was used to measure insulin effects on glucose and leucine metabolism. HGP and Leu Ra were determined by performing a primed, continuous 10-hour intravenous infusion of 6-3H glucose and 1-14C leucine. Baseline insulin, thyroid, TNF, and counter-regulatory hormonal measurements, HGP, GO and Leu Ra were obtained between hours 3 and 4. An insulin infusion was started at hour 4 and increased every 2 hours for 6 hours. Glucose appearance, Leu Ra, GO, LO and insulin concentrations were determined at the end of each 2-hour interval. RESULTS: Fasting HGP, GO, fat oxidation and Leu Ra were similar between the two groups. Insulin administration in cancer patients and normal volunteers had a similar effect on LO and Leu Ra. The insulin concentration required to stimulate half maximal glucose utilization in cancer patients was significantly increased by 58% (470 +/- 82 pM vs. 741 +/- 124 pM; p < or = 0.05). Non-oxidative glucose utilization was reduced in the cancer patients at both lower doses of insulin infusion (6.4 +/- 2.1 mumol/kg/minute vs. 0.1 +/- 1.6 mumol/kg/minute p < or = 0.05; and 23.7 +/- 1.3 mumol/kg/minute vs. 15.1 +/- 2.0 mumol/kg/minute p < 0.01). Triiodothyronine (T3) was directly correlated in the cancer patients with non-oxidative glucose utilization at the two physiological insulin concentrations (r = 0.673, p < 0.05 and r = 0.731, p < 0.01) and the supraphysiological insulin concentration (r = 0.791, p < 0.01). The insulin sensitivity index from the euglycemic clamp study was significantly reduced in the cancer patients (4.7 +/- 0.7 vs. 2.4 +/- 0.1 (dl/min)/(microU/ml); p < 0.05). CONCLUSIONS: In summary, head and neck cancer patients have an abnormal reduction in non-oxidative glucose utilization which occurs before abnormalities in HGP, GO, or Leu Ra [corrected]. One explanation for the reduced glucose utilization may be the influence of a reduced T3 concentration on non-oxidative glucose metabolism but further work is needed to confirm these preliminary observations.
Glyburide is an effective hypoglycemic agent in patients with type II diabetes even after the loss of its ability to increase insulin secretion. The exact mechanism is unknown. In an attempt to describe the direct effect of glyburide on glucose metabolism, a very low dose of glyburide (20 micrograms/kg body weight) was given orally to 12 healthy volunteers in an attempt to increase blood concentrations of the drug without causing a marked increase in insulin secretion. Fasting hepatic glucose production (HGP), carbohydrate oxidation (CO), leucine appearance, leucine oxidation, and fat oxidation were determined between hours 3 and 4 and hours 7 and 8. The changes seen in the glyburide-treated volunteers were compared with the changes seen in 5 non-treated, healthy volunteers during the same 8-hour period. Mean blood glucose decreased greater in the glyburide-treated volunteers (20 +/- 2% vs 5 +/- 2%, P < 0.01). Insulin and C-peptide concentrations after glyburide administration (hour 7 to 8) did not differ significantly from baseline (hour 3 to 4) values (insulin: 53 +/- 9 pmol/L vs 52 +/- 9 pmol/L; C-peptide: 0.34 +/- 0.06 ng/mL vs 0.39 +/- 0.07 ng/mL). This low dose of glyburide resulted in a significantly greater decrease in HGP (16 +/- 2%; P < 0.001) than seen with fasting alone (8 +/- 4%; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
To identify the metabolic effects of 5-fluorouracil and hydrazine sulfate therapy, 22 patients with colon cancer were admitted prospectively to a Clinical Research Center for serial measurement of counter-regulatory hormones, fasting hepatic glucose production (HGP), intravenous glucose tolerance test, plasma leucine appearance (LA) and leucine oxidation. Combined therapy was associated with a significant reduction in fasting glucose level (98 +/- 2 mg/dL to 94 +/- 2, P < 0.025) without a significant fall in fasting HGP (2.09 +/- 0.11 mg/kg/min versus 2.03 +/- 0.13; P > 0.05). The decreased fasting glucose value was associated with a mild but not statistically improved glucose disposal rate in response to the intravenous glucose tolerance test (1.34 +/- 0.07 %/min vs 1.47 +/- 0.11, P = 0.15). Plasma leucine appearance was significantly reduced after 2 months of therapy (63.3 +/- 3.0 mumol/kg/hr vs 57.1 +/- 3.9 mumol/kg/hr; P < 0.025), but leucine oxidation (11.5 +/- 1.1 mumol/kg/hr vs 11.2 +/- 1.1 mumol/kg/hr) was not altered. Despite the fact that plasma triiodothyronine concentrations significantly increased with therapy, it was not associated with plasma LA. Half of the patients with cancer died 14 +/- 4 months after the study, and the other half were alive 58 +/- 2 months later. Survival time can be estimated with 59% accuracy using plasma LA, HGP, carcino-embryonic antigen, and insulin concentration. Multiple regression analysis identified that plasma LA was related directly to length of survival time, and baseline HGP, carcino-embryonic antigen, and insulin concentration were related inversely to length of survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous work demonstrated that the provision of adequate or even excessive nutritional support is unable to reverse the negative nitrogen balance in many cancer patients. Our goal in a preliminary, short term study was to determine whether three daily GH injections (0.125 mg/kg.day, im) in cancer patients would increase insulin-like growth factor I concentrations and reverse the catabolic metabolic response to cancer, as indicated by reduced urinary nitrogen loss. Three days of GH therapy were associated with a significant increase in mean circulating GH (1.6 +/- 0.4 vs. 15.4 +/- 3.0 micrograms/L; P < 0.01), insulin-like growth factor I (112 +/- 15 vs. 329 +/- 54 micrograms/L; P < 0.01), insulin (57 +/- 11 vs. 184 +/- 46 pmol/L; P < 0.01), glucagon (63 +/- 11 vs. 77 +/- 11 ng/L; P < 0.05), and glucose (5.4 +/- 0.1 vs. 6.2 +/- 0.2 mmol/L; P < 0.05) concentrations. Twenty-four-hour urinary urea nitrogen (6.7 +/- 0.9 vs. 4.9 +/- 0.5 g; P < 0.05) and total nitrogen (7.8 +/- 1.2 vs. 6.0 +/- 1.2 g; P < 0.05) were significantly reduced. GH treatment in the group overall failed to alter leucine appearance (77.3 +/- 4.0 vs. 76.1 +/- 5.4 mumol/kg.h), leucine oxidation (11.8 +/- 1.5 vs. 9.6 +/- 1.0 mumol/kg.h), hepatic glucose production (13.5 +/- 0.8 vs. 14.2 +/- 0.8 mumol/kg.min), or estimated mean nitrogen balance (-0.24 +/- 0.97 vs. 0.85 +/- 0.75 g/day; t = 1.56; P = 0.10). Nitrogen balance was directly correlated with the percentage of the patient's ideal body weight (r = 0.776; P < 0.01). Seven of the 10 cancer patients were at or above 90% of ideal body weight, and they had a significant improvement in nitrogen balance (-1.46 +/- 0.99 vs. 0.60 +/- 1.03 g/day; P < 0.01). These patients also demonstrated a significant reduction in leucine oxidation (14.1 +/- 1.3 vs. 10.0 +/- 1.4 mumol/kg.h) and leucine appearance (81.2 +/- 3.8 vs. 72.9 +/- 3.3 mumol/kg.h; P < 0.05). This suggests that those most severely malnourished cancer patients may not respond anabolically to short term GH administration. We conclude that GH administration may be anabolic in cancer patients if there is not severe preexisting malnutrition.
In 1919, glucose intolerance became the earliest recognized metabolic abnormality in cancer patients. Prior to the development of severe malnutrition, colon, gastric, sarcoma, endometrial, prostate, localized head, neck, and lung cancer patients had many of the metabolic abnormalities of type II (noninsulin dependent) diabetes mellitus. These metabolic abnormalities include glucose intolerance, an increase in both hepatic glucose production (HGP) and glucose recycling, and insulin resistance. In a study of over 600 cancer patients, a diabetic pattern of glucose tolerance test was noted in over one-third of the patients. An increased rate of HGP, commonly seen in diabetics, has been noted in almost all types of cancer patients studied to date. Etiology of the increased glucose production in the cancer patient is not known, but abnormalities in the counter regulatory hormones, especially growth hormone, may contribute to the development of abnormal glucose metabolism. A second possible stimulus for the increase in HGP could be the glucose needs of the tumor. Abnormally high glucose utilization rates in small amounts of tumor tissue have recently been described. This suggests that small tumors may have large needs for glucose calories. An increase in anaerobic glycolysis in the tumor tissue can increase lactate production in the tumor-bearing human, thus supplying substrate to the liver to increase glucose production rates. In this paper, the nature of abnormal glucose metabolism in cancer patients is described.
Hepatic glucose production (HGP) and glucose carbon recycling are traditionally estimated by the combined use of hydrogen and carbon-labeled glucose tracers. A single-isotope method such as that of Reichard et al. for the determination of HGP and glucose carbon recycling requires the determination of activities in different glucose carbons by chemical degradation. Since the 13C content in the glucose carbon skeleton can be determined from mass fragmentography, the use of 13C-labeled glucose and mass fragmentography can provide a single-isotope method for the quantification of the recycled carbons. Correction for the recycling makes it possible to determine the true HGP. In this study, (1-13C1)glucose and mass fragmentography were used for the determination of HGP and glucose carbon recycling in six colon cancer patients. Molar enrichment of the molecular ion (m/z 328 cluster of glucose aldonitrile pentaacetate) was used to determine 'uncorrected' HGP, which was 1.93 +/- 0.11 mg kg-1 min-1 (mean +/- s.e.m.). The difference in molar enrichment of the molecular ion C1-C6 (m/z 328) and the ion corresponding to C1-C4 fragment (m/z 242) was used to determine the contribution of recycled label carbon. After this correction, the 'corrected' HGP was 2.04 +/- 0.12 mg kg-1 min-1, which is not significantly different from the 'true' HGP rate of 2.05 +/- 0.15 mg kg-1 min-1 determined by using (6-3H)glucose. HGP determined from the enrichment of the molecular ion C1-C6 underestimates true HGP, as expected. The corrected HGPs correlate well with those from 6-3H method (r = 0.86, y = 1.06x - 0.12; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Human tumor necrosis factor alpha (TNF) inhibits tumor growth, but its effects on tumor and skeletal muscle protein metabolism in vivo have not been adequately studied. Walker 256 carcinosarcoma growth rate was followed over an 11-day period in Sprague-Dawley rats. Tumor-bearing rats received either saline or 50 micrograms of TNF (Genentech, Inc.) s.c. on day 8 of tumor growth. This single dose of TNF reduced tumor protein growth during a 2-day posttreatment period from 27.6 +/- 4.4 to 10.5 +/- 3.7%/day (mean +/- SE; P less than 0.01). The rate of in vivo incorporation of L-[1-14C]leucine into skeletal muscle protein was significantly increased (P less than 0.05) from 5.1 +/- 0.2%/day in the saline-treated tumor-bearing rats to 7.7 +/- 1.3%/day in the TNF-treated tumor-bearing rats. The latter value was not statistically different from the 9.2 +/- 0.9%/day observed in the tumor-free control animals. TNF administration significantly increased both the total and individual acid-soluble skeletal muscle amino acid concentrations in tumor-bearing rats by an average of 86 +/- 7%, compared to values in saline-treated tumor-bearing rats. Similarly, acid-soluble skeletal muscle 3-methyl-histidine concentrations increased from 66 +/- 14 to 113 +/- 19 pmol/g protein (P less than 0.05). Tumor protein synthesis in the TNF-treated group was 50% greater than in the saline-treated group, whether expressed as %/day (72.7 +/- 9.1 versus 47.9 +/- 4.8; P less than 0.05) or was micrograms/g tumor/min (58.7 +/- 7.7 versus 40.7 +/- 4.5; P less than 0.05). In contrast, estimated tumor protein degradation rates were increased by over 200% in the TNF-treated rats, compared to the values in the saline-treated rats [62.1 +/- 10.7 versus 20.3 +/- 6.0%/day (P less than 0.01) and 50.0 +/- 8.9 versus 17.5 +/- 5.4 micrograms/g tumor/min (P less than 0.01)]. Thus, TNF appears to stimulate tumor protein degradation more than protein synthesis, explaining the overall decrease in tumor growth.