Glucose, fatty acid, and urea kinetics in patients with severe pancreatitis. The response to substrate infusion and total parenteral nutrition.

Rates of glucose turnover and oxidation in normal volunteers (N = 16) and in severely ill patients with pancreatitis (N = 9) were isotopically determined. Glucose turnover was determined using primed constant infusions of either 6-3H-glucose or 6-d2-glucose, and glucose oxidation with either U-14C-glucose or U-13C-glucose after appropriate priming of the bicarbonate pool. Urea kinetics were determined using primed constant infusions of either (15N2)-urea or U-14C-urea, whereas free fatty acid (FFA) kinetics were determined by the constant infusion of 1,2-13C palmitate. Basal rates of glucose production and plasma glucose clearance were significantly higher in the patients than in the volunteers. During glucose infusion (4 mg/kg/min) endogenous glucose production was virtually totally suppressed in the volunteers (94 +/- 4%). There was significantly less suppression in the patients, however (44 +/- 1%). In addition, the percentage of available glucose oxidized (i.e., percentage of uptake oxidized) was significantly less in the patients than in the volunteers. The basal rate of urea production was significantly higher in the patients; however, in both patients and volunteers, glucose infusion resulted in a significant decrease. The rate of FFA turnover was similar in the patients and volunteers, and the patients and volunteers were equally sensitive to the suppressive effects of glucose infusion. When the patients were studied during total parenteral nutrition (TPN), there was no further suppression of endogenous glucose turnover than that seen during 2 hours of glucose infusion, and the mean rate of urea turnover measured during TPN (7.0 +/- 1.9 mumol/kg/min) was also not significantly different than the value determined during glucose infusion (8.9 +/- 1.8 mumol/kg/min). It was concluded from these studies that patients with pancreatitis are metabolically similar to septic patients, have an impairment in their ability to oxidize infused glucose when compared with normal volunteers, have an elevated rate of net protein catabolism, and have FFA kinetics similar to those seen in normal humans.     

Whole body protein kinetics in severely septic patients. The response to glucose infusion and total parenteral nutrition.

Rates of whole body protein synthesis and catabolism in normal volunteers and in a group of severely septic patients were isotopically determined. In addition, the effect in the patients of either glucose infusion or total parenteral nutrition (TPN) on protein dynamics was assessed. The basal rate of net protein catabolism (NPC) was significantly higher in the septic patients than in the volunteers (p less than 0.05). The values obtained in the volunteers and patients were 1.44 +/- 0.18 and 2.20 +/- 0.10 g/kg/day, respectively. This increase in NPC was primarily due to a major increase in whole body catabolism that was partially counteracted by a modest increase in protein synthesis. When the patients were infused with glucose (4 mg/kg/min), NPC decreased significantly (p less than 0.001) to 1.96 +/- 0.08 g/kg/day, and during TPN the value was significantly lower again (p less than 0.04) (0.63 +/- 0.28 g/kg/day). In each instance the conservation of host tissue was due to an increase in protein synthesis: the accelerated rate of whole body protein catabolism continued irrespective of the nutritional status. The following conclusions were reached from these data: severely ill septic patients have an accelerated rate of NPC compared with normal volunteers, and this is primarily due to a large increase in whole body protein catabolism; TPN is an effective means of conserving host tissue in severely septic patients via the promotion of whole body protein synthesis; despite the beneficial effect of TPN in these patients, whole body protein catabolism continues unabated, and as a result, protein losses still occur at approximately one fourth the rate seen in the absence of TPN; and there is no obvious advantage in terms of protein-sparing when protein is provided in amounts exceeding 1.5 g/kg/day.     

Energy and protein metabolism in sarcoma patients.

We have performed a series of isotopic infusions both in normal volunteers (N = 16) and in sarcoma patients (N = 7). Using the primed-constant infusion of stable or radioisotopes we have determined the rates of glucose turnover, glucose oxidation, glucose recycling, and net protein catabolism (NPC). In addition, we have measured VO2 and VCO2. The values for VCO2 and VO2 were higher in the patients than in the volunteers (mean VO2 values in volunteers and patients: 107 +/- 13 and 158 +/- 13 mumol/kg/min, respectively). The basal rate of glucose appearance in the sarcoma patients was twice the value seen in the volunteers (28.3 +/- 3.5 vs. 13.9 +/- 0.3 mumol/kg/min). Glucose infusion in the volunteers resulted in virtually total suppression of endogenous glucose production, while in the patients glucose infusion induced only a 30% suppression of endogenous glucose production (p less than 0.01). The rate of glucose clearance in the patients was approximately twice the value seen in the volunteers [5.4 +/- 1.0 vs. 2.7 +/- 0.1 mL/kg/min (p less than 0.01)]. The per cent of glucose uptake oxidized in the patients was significantly less than in the volunteers [22% vs. 36% (p less than 0.05)], and the per cent of glucose uptake that was recycled was significantly higher in the patients [55% vs. 10% (p less than 0.01)]. In addition, the basal rate of net protein loss was increased twofold in the patients [3.2 +/- 0.5 vs. 1.4 +/- 0.4 g (protein)/kg/d (p less than 0.01)], and in contrast to the situation in the volunteers there was no suppression in the rate of net protein loss when the patients were infused with glucose. The basal insulin concentration and the insulin response to glucose infusion in the patients were similar to that of the volunteers, but the plasma cortisol level was similar in volunteers and in the patients (p less than 0.05). We conclude from these studies the following: (1) Sarcoma patients have significantly elevated rates of glucose production and glucose clearance, but they have an impaired capacity to directly oxidize either endogenous or infused glucose, coupled with an increased rate of glucose recycling. (2) Sarcoma patients have an elevated metabolic rate and are catabolic. In addition, in contrast with normal volunteers, glucose infusion does not result in a suppression of protein loss.     

Metabolic intervention in surgical patients. An assessment of the effect of somatostatin, ranitidine, naloxone, diclophenac, dipyridamole, or salbutamol infusion on energy and protein kinetics in surgical patients using stable and radioisotopes.

We have assessed the effect of a variety of forms of metabolic intervention on both energy and protein metabolism in 44 severely ill surgical patients. The patients were studied either in the basal state or while receiving total parenteral nutrition (TPN), and the metabolic effects were assessed using the primed-constant infusion of a combination of stable isotopes and radioisotopes. Somatostatin infusion, either in the basal state or in the TPN, did not change glucose kinetics, but there was a significant decrease in the rate of net protein catabolism (NPC). In the basal studies the rate of NPC decreased from 3.4 +/- 0.7 g/kg/d to 2.9 +/- 0.7 g/kg/d (p less than 0.002), while in the TPN patients the corresponding values were 1.48 +/- 0.61 g/kg/d and 1.10 +/- 0.50 g/kg/d, respectively (p less than 0.005). Histamine type 2 blockade with ranitidine did not significantly alter glucose kinetics, but in both the TPN patients and in the basal state ranitidine was associated with a significant decrease in the rate of NPC. In the basal state rate of NPC was 2.44 +/- 0.53 g/kg/d and during ranitidine infusion the value was 2.08 +/- 0.42 g/kg/d (p less than 0.04). Naloxone infusion did not alter glucose kinetics, but there was a significant decrease in the rate of NPC from a basal value of 2.6 +/- 0.6 g/kg/d to 2.3 +/- 0.5 g/kg/d (p less than 0.04). The infusion of the prostaglandin antagonists diclofenac or dipyridamole resulted in increases in the plasma insulin level, and as a result glucose turnover decreased in both groups. In the diclofenac group the rate of glucose turnover decreased from 14.4 +/- 1.7 mumol/kg/min to 12.6 +/- 1.3 mumol/kg/min (p less than 0.02). Neither prostaglandin antagonist resulted in any significant change in the rate of NPC. Beta-adrenergic stimulation with salbutamol resulted in a significant increase in glucose turnover from 12.1 +/- 1.1 mumol/kg/min to 13.4 +/- 0.9 mumol/kg/min (p less than 0.02), and the rates of appearance (Ra) of both alanine and free fatty acids (FFAs) also increased. Alanine Ra increased from 11.7 +/- 2.5 mumol/kg/min to 12.8 +/- 3.0 mumol/kg/min, and the corresponding values for FFA turnover were 7.6 +/- 1.1 mumol/kg/min and 10.3 +/- 2.1 mumol/kg/min (p less than 0.03), respectively. Salbutamol infusion did not result in any significant change in the rate of NPC.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fatty acid and glycerol kinetics in septic patients and in patients with gastrointestinal cancer. The response to glucose infusion and parenteral feeding.

The rates of glycerol and free fatty acid (FFA) kinetics in normal volunteers (VOL), non-weight-losing (NWL) gastrointestinal cancer patients, weight-losing (WL) gastrointestinal cancer patients, and in severely septic patients, using constant infusions of d-glycerol and 1-13C palmitic acid; were determined. Rates of FFA oxidation have also been quantitated. Measurements were made in the basal state, during glucose infusion (4 mg/kg/min), and during total parenteral nutrition (TPN). Rates of glycerol and FFA appearance (Ra) in volunteers and NWL cancer patients were similar, and in both groups there was a significant suppression after glucose infusion. The basal Ra values for glycerol and FFA were 2.4 +/- 0.2 and 6.5 +/- 0.8 mumol/kg/min, respectively, in the volunteers, and in the NWL cancer patients the corresponding values were 2.7 +/- 0.4 and 7.1 +/- 1.1 mumol/kg/min (not significantly different). Compared with the volunteers, the rates of glycerol and FFA turnover were significantly elevated in both septic patients and WL cancer patients. The values for glycerol and FFA Ra were 6.3 +/- 1.1 and 13.1 +/- 3.0 mumol/kg/min, respectively, in the septic patients. The corresponding values were 4.1 +/- 0.4 and 11.7 +/- 1.6 mumol/kg/min in the WL cancer patients. In contrast to the response seen in the volunteers and NWL cancer patients, glucose infusion did not suppress lipolysis in either the septic or WL cancer patients. In all groups studied, glucose infusion resulted in an increase in FFA recycling. Despite the fact that the WL cancer patients had an increased FFA availability, they were significantly less able to oxidize either endogenous FFA or infused lipid when compared with NWL cancer patients (the basal % of FFA uptake oxidized in WL cancer patients was 10 +/- 2% vs. 18 +/- 3% in NWL cancer patients). In contrast, the septic patients had an enhanced capacity to oxidize either endogenous FFA or infused lipid (the basal % of FFA uptake oxidized was 40 +/- 8%, and during TPN this increased in 65 +/- 10%). From these studies the following was concluded: in terms of lipid kinetics, NWL cancer patients are not significantly different from volunteers; WL cancer patients and septic patients have elevated rates of lipolysis, and in contrast to what was seen in NWL cancer patients and in volunteers, glucose infusion in WL cancer patients and in septic patients does not result in a significant inhibition of lipolysis; and WL cancer patients have an impaired capacity to oxidize either endogenous FFA or infused lipid.(ABSTRACT TRUNCATED AT 400 WORDS)     

The mechanism of the reduction of protein catabolism following trauma and during sepsis using xylitol

Total parenteral nutrition (TPN) after trauma and sepsis has two major goals. One is the reduction of enhanced protein catabolism; the second is the avoidance of enhancement of whole-body glucose turnover. Glucose and xylitol differ in their quantitative utilization rate after trauma and sepsis. Maximal glucose utilization is reduced during such states, while the utilization of xylitol is more than doubled. In order to investigate whether these differences are associated with beneficial effects with regard to whole-body glucose turnover rate of gluconeogenesis and protein sparing, we conducted two studies using animal models and two clinical studies. METHODS. For the determination of glucose and protein turnover, radioactive and stable isotope techniques were applied. In an animal model a primed constant infusion of 3-H-6-glucose, 14-C-1-alanine and 13-C-3-alanine and 14-C-U-acetate was used to determine total glucose appearance, gluconeogenesis from 3-C-precursors and alanine flux. In the human studies hepatic glucose production was determined by using a primed constant infusion of 6.6-D-2-glucose and urea synthesis rate was determined by a primed constant infusion of 2-N-15-urea. RESULTS. In the first rat model we were able to show that hypocaloric xylitol compared to glucose significantly reduced whole-body glucose turnover from 1741 +/- 232 mumol/h during glucose infusion to 449 +/- 49 mumol/h during xylitol infusion and gluconeogenesis from C-3 carbons form 382 +/- 24 mumol/h during glucose infusion to 155 +/- 39 mumol/h during xylitol infusion after a burn trauma. In a second septic rat model the exchange of glucose calories by xylitol in a proportion of 1:1 was associated with a significantly ameliorated N-balance from +144 +/- 90 mgN/kg body weight per day during glucose infusion to +699 +/- 80 mgN/kg body weight per day during glucose-xylitol infusion and a reduced 3-methyl-histidine excretion from 7.14 +/- 0.61 mumol/kg body wt. per day during glucose infusion to 4.10 +/- 0.56 mumol/kg per day during glucose-xylitol infusion, respectively. In two studies with surgical intensive care patients we were able to confirm the nitrogen-sparing properties of xylitol infusion, together with amino acids during hypocaloric feeding or during TPN with a glucose/xylitol mixture in a proportion of 1:1. From a basal urea production rate of 9.2 +/- 1.6 mumol/kg min. xylitol led to a significant reduction with 6.4 +/- 1.5 mumol/kg per min. Hepatic glucose production was significantly reduced during xylitol infusion from basal 4.8 +/- 0.6 mg/kg per min to 3.1 +/- 0.7 mg/kg per min, respectively. Equicaloric glucose in a dosage of 3 g/kg per day had no effect. During TPN glucose/xylitol, in a proportion of 1:1 at a total dosage of 0.24 g/kg per h, significantly reduced whole-body glucose turnover, endogenous glucose production and lactate concentrations compared to an isocaloric glucose infusion. DISCUSSION. In animal as well as in human studies hypocaloric xylitol as well as a glucose-xylitol mixture were more efficient in preserving body protein than glucose alone. Whole-body glucose turnover was significantly reduced during hypocaloric xylitol or glucose-xylitol infusion compared to isocaloric glucose infusion. During the acute phase after trauma we therefore recommend a carbohydrate supplementation of 3 g/kg body wt. per day using xylitol. During long-term TPN, a glucose-xylitol mixture in a proportion of 1:1 in a dosage of 3 g/kg body wt. per day each is recommended as energy source, together with amino acids and, if necessary, lipids.     

Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion and total parenteral nutrition

We have isotopically determined rates of whole-body protein synthesis and catabolism in a group of normal volunteers and in two groups of cancer patients: 20 patients with advanced weight-loss (AWL) upper gastrointestinal cancer and 7 patients with early non-weight-loss (ENWL) lower gastrointestinal cancer. In both patients and volunteers we determined protein kinetics in the basal state and during glucose infusion at 4 mg/kg/min. In addition, in the AWL patients the effect of total parenteral nutrition (TPN) on protein dynamics was also assessed. The rate of net protein breakdown was determined with the primed constant infusion of either 15N-urea or 14C-urea, the rate of whole-body protein catabolism was measured with the primed constant infusion of 15N-lysine, and the rate of whole-body protein synthesis was deduced from the above two values. The basal rates of net protein catabolism, whole-body protein catabolism, and whole-body protein synthesis were similar in the volunteers and ENWL cancer patients. The basal values for net protein catabolism in the volunteers and ENWL patients were 1.46 +/- 0.18 and 1.34 +/- 0.08 gm/kg/min, respectively. In both volunteers and ENWL patients glucose infusion resulted in a significant decrease in net protein catabolism. In the ENWL patients this decrease was due to a significant decrease in whole-body protein catabolism (p less than 0.05); the rate of whole-body protein synthesis did not change significantly. In the AWL cancer patients the rate of net protein catabolism was significantly higher than in either the volunteer or ENWL group (p less than 0.05), and glucose infusion did not result in a decrease in net protein catabolism. However, when the AWL group was studied during TPN there was a significant decrease in net protein catabolism from 2.24 +/- 0.30 to 0.17 +/- 0.09 gm/kg/day (p less than 0.01). This decrease was due to the combined effect of a significant decrease in whole-body protein catabolism coupled with an increase in whole-body protein synthesis. From these studies we conclude the following: (1) ENWL cancer patients and normal volunteers have similar protein dynamics, and in both groups glucose infusion resulted in a significant decrease in protein loss. (2) AWL cancer patients have an elevated rate of net protein catabolism, and this is not sensitive to glucose infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of major thermal injury and carbohydrate-free intake on serum triglycerides, insulin, and 3-methylhistidine excretion.

The severely burned patient responds differently to starvation ketosis in the early stage of injury as compared to the normal individual. A similar response has been observed in the patient after skeletal trauma and sepsis. In order to determine the extent of muscle protein contribution and the mechanism(s) involved, 11 burn patients with 35% to 80% BSA burn were resuscitated using carbohydrate-free solutions for 3 days followed by unrestricted intake. Blood was drawn daily and 24-hour urinary nitrogens were determined. Controls consisted of 10 preoperative elective surgical patients and two normal volunteers. The burned patients lost a mean +/- SEM of 17.1 +/- 1.72 g nitrogen per day on the third day. The mean +/- SEM ketone body response on the third day for burned patients was 385 +/- 77 mumol/l compared to 727 +/- 81 mumol/l for control patients. The mean +/- SEM 3-methylhistidine loss for burned patients on the third day was 9.83 +/- 0.82 mumol/kg compared to 3.6 mol/kg for control patients. Insulin levels on the third day of fast were three times the normal group. This insulin increase may be the modulating factor that suppresses excessive fat mobilization. This metabolic response causes a lower plasma ketone level, which may then necessitate the need for continued protein catabolism for glucose production for certain tissues. The protein contribution to the hypercatabolic response as assessed by increased urinary nitrogen losses is in part supported by an increased muscle protein breakdown as indicated by increased 3-methylhistidine excretion.     

Metabolic intervention in surgical patients: the effect of alpha- or beta-blockade on glucose and protein metabolism in surgical patients receiving total parenteral nutrition

We performed a series of isotopic studies on the role of alpha- or beta-adrenergic activity in the regulation of glucose and protein metabolism in a group of surgical patients receiving total parenteral nutrition. We quantitated rates of glucose turnover and net protein breakdown by the primed constant infusion of 3H-glucose and 14C-urea, respectively. Basal measurements were first performed, and then the effect of either alpha- or beta-adrenergic blockade was assessed by means of the constant infusion of either phentolamine or propranolol. In addition, we assessed the effect of beta-stimulation by infusing the beta-agonist, salbutamol. The institution of alpha-adrenergic blockade did not significantly alter either the plasma glucose level or the rate of glucose production. However, the rate of net protein catabolism decreased significantly after alpha-adrenergic blockade. Before alpha-blockade the value for NPC was 0.88 +/- 0.27 gm/kg/day, and after alpha-blockade the corresponding value was 0.73 +/- 0.24 gm/kg/day (p less than 0.01). beta-Adrenergic blockade resulted in a decrease in the rate of glucose appearance from 38.2 +/- 6.1 mumol/kg/min to 35.1 +/- 5.7 mumol/kg/min, and the plasma glucose clearance increased from 5.0 +/- 0.8 ml/kg/min to 5.4 +/- 0.8 ml/kg/min. As a result of these changes the plasma glucose concentration decreased significantly (p less than 0.01) from 7.4 +/- 0.3 mumol/ml to 6.5 +/- 0.5 mumol/ml. beta-Adrenergic blockade did not significantly decrease the rate of net protein catabolism. beta-Stimulation with salbutamol resulted in a significant increase (p less than 0.05) in the rate of glucose production from 31.3 +/- 4.2 mumol/kg/min to 38.0 +/- 6.5 mumol/kg/min, and as a result the plasma glucose level increased significantly from 6.7 +/- 0.6 mumol/ml to 7.4 +/- 0.6 mumol/ml (p less than 0.04). We conclude from these studies that the role of the adrenergic nervous system in the promotion of endogenous glucose turnover in surgical patients receiving total parenteral nutrition is primarily a beta-adrenergic effect, whereas the promotion of protein catabolism is mainly an alpha-adrenergic effect.     

Whole-body protein breakdown and 3-methylhistidine excretion during brief fasting, starvation, and intravenous repletion in man.

Simultaneous whole-body protein breakdown (using 15N-glycine) and urinary 3-methylhistidine (3MH) excretion rates were determined in six hospitalized normal volunteers after 10 days of starvation and a subsequent 10-day period of total parental nutrition (TPN). These data were contrasted to whole-body protein breakdown and urinary 3MH excretion in ten depleted (14.8% body weight loss) patients with benign intraabdominal disease studied in the basal (48 hours without nutrient intake) and intravenously refed states. The rates of whole-body protein breakdown were significantly reduced from basal (brief fasting or starvation) conditions in both normal volunteers (p less than 0.01) and depleted patients (p less than 0.01) during TPN. The rate of protein catabolism normalized for creatinine excretion in patients was higher than that observed in normal subjects during both basal (p less than 0.05) and intravenous feeding conditions. Daily urinary 3MH excretion was reduced during intravenous feeding in both starved normal volunteer (235 +/- 13 mumol/d to 197 +/- 9 mumol/d p less than 0.05) and in depleted patients (209 +/- 31 mumol/d to 140 +/- 35 mumol/d), and an apparent linear relationship between protein breakdown and urinary 3MH, normalized for creatinine excretion, was obtained in both volunteer and patient (r = 0.85) populations during fasting-refeeding. However, separate regression analysis of the protein breakdown and 3MH responses of both volunteer and patient groups under conditions of fasting, starvation, and refeeding revealed significant differences between volunteer and patient populations during intravenous refeeding (p less than 0.01). Further analysis of 3MH excretion in relationship to nitrogen balance during refeeding suggests a complex relationship between urinary 3MH excretion and whole-body protein metabolism that may be partly related to the degree of antecedent malnutrition.     

Glucose and urea kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion, parenteral feeding, and surgical resection

We isotopically determined rates of glucose turnover, urea turnover, and glucose oxidation in normal volunteers (n = 16), patients with early gastrointestinal (EGI) cancer (n = 6), and patients with advanced gastrointestinal (AGI) cancer (n = 10). Studies were performed in the basal state, during glucose infusion (4 mg/kg/min), and during total parenteral feeding (patients with AGI cancer only). Patients with early stages of the disease were also studied 2 to 3 months after resection of the cancer. Basal rates of glucose turnover were similar in volunteers and in patients with EGI cancer (13.9 +/- 0.3 mumol/kg/min and 13.3 +/- 0.2 mumol/kg/min, respectively) but were significantly higher in patients with AGI cancer (17.6 +/- 1.4 mumol/kg/min). Glucose infusion resulted in significantly less suppression of endogenous production in both patient groups than that seen in the volunteers (76% +/- 6% for EGI group, 69% +/- 7% for AGI group, and 94% +/- 4% for volunteers). The rate of glucose oxidation increased progressively in proportion to the tumor bulk. In the volunteers the percent of VCO2 from glucose oxidation was 23.9% +/- 0.7%, and in EGI and AGI groups the values were 32.8% +/- 2.0% and 43.0% +/- 3.0%, respectively. After curative resection of the cancer, glucose utilization decreased significantly (p less than 0.05). The rate of urea turnover was significantly higher in the AGI group (8.4 +/- 1.0 mumol/kg/min) in comparison with the volunteer group value of 5.9 +/- 0.6 mumol/kg/min (p less than 0.03). Glucose infusion resulted in a significant suppression of urea turnover in the volunteers (p less than 0.02), but in the AGI group glucose infusion did not induce a statistically significant decrease. We conclude from these studies that the presence of even a small, potentially curable gastrointestinal cancer is associated with a loss of the normal host-regulatory mechanisms designed to conserve body resources; this effect is more marked as the tumor bulk increases; increasing tumor bulk effects a progressive increase in glucose utilization and in protein breakdown.     

Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury.

OBJECTIVE: The effect of insulin-like growth factor-1 (IGF-1) on energy expenditure and protein and glucose metabolism in a group of patients with thermal injury was determined. SUMMARY BACKGROUND DATA: Accelerated protein catabolism is a constant feature of the hypermetabolic response to thermal injury. Insulin-like growth factor-1 has been reported to minimize protein catabolism and normalize energy expenditure in animal models of thermal injury. METHODS: To determine the efficacy of IGF-1 in human burn patients, resting energy expenditure (metabolic cart), whole body protein kinetics (N15 Lysine), and glucose disposal (glucose tolerance test) were assessed in eight burn patients before and after a 3-day infusion of IGF-1 (20 micrograms/kg/hr). All patients were fluid-resuscitated uneventfully and were without obvious infection at the time of study. Enteral nutrition was administered at a constant rate before and during the IGF-1 infusion. RESULTS: Resting energy expenditure was not altered by IGF-1 (40.3 +/- 2.2 vs. 39.1 +/- 2.3 kcal/kg/day). However, glucose uptake was promoted, and protein oxidation decreased significantly (0.118 +/- 0.029 vs. 0.087 +/- 0.021 g/kg/d, p < 0.05) by IGF-1. In addition, insulin secretion, in response to a glucose challenge, was blunted. CONCLUSIONS: Insulin-like growth factor-1 therapy has a beneficial effect in preserving lean body mass during severe stress conditions by minimizing the flux of amino acids toward oxidation.     

Glucose Disposal in Morbidly Obese Patients in the Early Post-operative Period

Background: In surgical patients, operative stress causes protein catabolism, muscle mass loss, and impaired glucose tolerance. We investigated fuel metabolism and glucose and protein turnover in 15 obese subjects who underwent biliopancreatic diversion (BPD) by using stable labelled isotopes. Methods: 6 males and 9 females (age 45.11±8.9 years, BMI of 48.85±4.43 kg/m²) who underwent BPD were studied, and the APACHE II score was calculated. Patients were studied 3 times (before BPD, 1st and 3rd postoperative day). Glycemia was stable - maintained by continuously infusing Rapid Insulin. Each day of the study, the patients received a primed, constant infusion [¹⁵N₂]of urea, and, 180 min after, a [6.6-²H] glucose infusion started and continued for 3 hours. Indirect calorimetry was performed during the study, under TPN (30 kcal/kg). Results: The APACHE score was lower on the 3rd postoperative day than on the 1st postoperative day (7.4±2.7 vs 6.3±2.6, p<0.05). The npRQ was different throughout the post-operative period (0.82±0.03 vs 0.9±0.06, p< 0.05), while urinary nitrogen excretion, energy expenditure and glycemia did not change. The insulin amount infused was lower during the 3rd post-operative day (44.25±12.3 vs 64.12±11 UI on the 1st one, p<0.05). Insulinemia was lower during the 3rd than during the 1st postoperative day (66.4±9.49 vs 117.44±8.49 μU/ml, p<0.05). Non-essential fatty acid levels were higher on the 3rd post-operative day than on the 1st one (0.98±0.6 vs 0.45 ±0.34 mmol/L, p<0.01). No differences were observed in glucose and urea turn-over. Conclusion: The metabolic pattern of morbidly obese patients operated by BPD was similar to that of other critically ill patients previously studied in the literature. Furthermore, the increased glucose oxidation rate observed on the 3rd post-operative day was coupled with an improved clinical condition.     

Determinations of glucose turnover and oxidation in normal volunteers and septic patients using stable and radio-isotopes: the response to glucose infusion and total parenteral feeding

Rates of glucose turnover and oxidation were isotopically determined in normal volunteers (n = 16) and in severely septic patients (n = 10). Glucose turnover was determined using primed constant infusions of either 6-3H- or 6,6-d-glucose and glucose oxidation with either U-14C-glucose or U-13C-glucose after appropriate priming of the bicarbonate pool. Basal rates of glucose turnover, oxidation, and plasma clearance were significantly higher in the septic patients than in the volunteers. During glucose infusion (4 mg/kg.min) endogenous glucose production was virtually abolished in the volunteers (94 +/- 4% suppression). There was significantly less suppression in the septic patients (39 +/- 7%); (P less than 0.01). In addition, the percentage of available glucose oxidized (i.e. the percentage of glucose uptake oxidized) was significantly less in the septic patients. When the patients were studied during total parenteral nutrition (at a similar rate of glucose infusion) there was no further suppression of endogenous glucose production compared with that seen during 2 h of glucose infusion. However, the percentage of available glucose oxidized increased significantly. From these studies it is concluded that septic patients continue to have ongoing consumption of host tissue despite receiving either glucose infusion or total parenteral nutrition, and septic patients are less able to oxidize glucose than normal volunteers when infused for only 2 h. However, adaptation occurs with the longer infusion time used in total parenteral nutrition (TPN).     

Glucose, fat, and protein kinetics in patients with primary and secondary hyperparathyroidism

We performed a series of isotopic studies in 16 normal volunteers, four patients with secondary hyperparathyroidism (SHPT), and in nine patients with primary hyperparathyroidism (PHPT). Using the primed constant infusion of stable and radioisotopes, we have determined glucose, glycerol, free fatty acids, and urea kinetics, as well as glucose oxidation. Measurements were performed both in the basal state and during glucose infusion (4 mg/kg body weight/min). Compared with normal volunteers, PHPT patients are intolerant of glucose because of a limited suppression of endogenous glucose turnover during glucose infusion (34% versus 96% suppression). In addition, the plasma cortisol level increased in the PHPT patients during glucose infusion. Glucose oxidation and fat kinetics in both PHPT patients and volunteers were similar, but the rate of net protein loss was significantly greater in the PHPT patients than in the volunteers (2.1 +/- 0.5 versus 1.4 +/- 0.2 gm/kg/day). Rates of VO2 in the PHPT patients and volunteers were similar, but the value in the SHPT patients was higher (120 +/- 9 versus 142 +/- 20 mumol/kg/min for PHPT and SHPT patients, respectively). The SHPT patients had significantly increased rates of glucose turnover, glucose clearance, and glycerol turnover, compared with the other two groups, as well as an increased reliance on glucose for energy. We conclude from these studies that (1) SHPT patients are catabolic and have increased rates of glucose and fat turnover; (2) PHPT patients have limited suppression of endogenous glucose turnover after glucose infusion compared with volunteers and higher rates of net protein loss; (3) fat metabolism and glucose utilization are unimpaired in PHPT patients; and (4) these alterations in metabolism and hormonal response to glucose infusion suggest that some of the symptoms seen in these patients may have a metabolic-hormonal basis.     

Glucose turnover, oxidation, and indices of recycling in severely traumatized patients

Hyperglycemia is often seen in trauma patients and its etiology is not clearly understood. We have determined parameters of glucose metabolism by using simultaneous primed-constant intravenous infusion of both [6-3H] glucose and [U-14C] glucose in ten severely traumatized hypermetabolic subjects during the early "flow phase" of injury and in six post-absorptive normal volunteers. The mean rate of glucose production (determined by means of [6-3H] glucose) was 3.96 +/- 0.40 mg/kg/min in trauma patients, which was significantly (p = 0.025) higher than the value of 2.75 +/- 0.13 observed in normal volunteers. Glucose turnover rates determined with [U-14C] glucose as tracer were lower in all subjects. The difference between the turnover rates determined by the two tracers represents an index of recycling of glucose through three-carbon fragments. This recycling index was similar in both groups of subjects in amount (0.24 +/- 0.07 vs. 0.26 +/- 0.08 mg glucose/kg/min) but different when expressed as percentage of total glucose turnover (5.6 +/- 1.4% vs. 9.8 +/- 1.7%; p = 0.05). The absolute rates of glucose clearance, oxidation, and recycling were similar in stressed trauma patients and unstressed controls although the rate of production was increased by 44% due to injury. Post-trauma hyperglycemia was mainly due to an increased hepatic output of glucose and not due to a decreased ability of the tissue to extract glucose from the plasma. Hyperglycemia may be the driving force in the metabolic effects of injury.     

Low-dose glucose infusion in patients who have undergone surgery. Possible cause of a muscular energy deficit

To evaluate the effect of the glucose-induced insulin release on peripheral substrate metabolism, we studied muscle metabolism in seven patients after elective surgery and in four healthy volunteers combining the forearm and the euglycemic glucose clamp technique (insulin infusion, 0.2 mU/kg per minute). Arterial and deep venous concentrations of substrates and hormones were determined in the basal period and during steady state of the infusion period. After 90 minutes of insulin infusion, the whole-body glucose infusion rate was significantly lower in patients who had elective surgery, although plasma insulin concentrations were comparable. In both groups this was related to a reduced supply of free fatty acids and ketones in muscle. In controls the resulting lack of substrates in muscle appeared to be compensated by an enhanced uptake of glucose, not seen in the patients who had elective surgery. Surprisingly, as indicated by the significantly reduced lactate production (-0.15 +/- 0.05 vs -0.62 +/- 0.32 mumol/100 g per minute basal), in this group the glucose taken up was oxidized aerobically to a greater extent. However, the total resulting energy gain was small. Thus, a peripheral energy deficit might arise favoring increased oxidation of amino acids. To avoid this undesired side effect, only those substrates should be administered that minimize pancreatic insulin release.     

Alterations in glucose metabolism associated with liver cirrhosis persist in the clinically stable long-term course after liver transplantation.

With increasing long-term survival rates after orthotopic liver transplantation (OLT), metabolic alterations complicating the clinical course, such as diabetes mellitus (DM), become increasingly important. Liver cirrhosis is associated with severe alterations in glucose metabolism. However, it is currently unclear whether these changes are reversed by successful OLT. We therefore characterized glucose metabolism in patients with liver cirrhosis and normal fasting glucose levels before OLT (cir), in the clinically stable long-term course after OLT (OLT), and control subjects (con) using oral glucose tolerance tests (cir = 100, OLT = 62, con = 32), euglycemic-hyperinsulinemic clamps (cir = 10, OLT = 27, con = 14), and positron emission tomography (PET) scan analysis with 18F-fluorodeoxyglucose (FDG) as a tracer (cir = 7, OLT = 7, con = 5). Fasting insulin and C-peptide levels were significantly elevated in patients with liver cirrhosis compared with both control subjects (P <.001) and patients after OLT (P <.001). After OLT, insulin was normalized, whereas C-peptide remained elevated (P < 0.01). In the patients with liver cirrhosis, 27% had a normal glucose tolerance, 38% had an impaired glucose tolerance (IGT), and 35% were diabetic. After OLT, 34% had a normal glucose tolerance, 29% an IGT, and 37% were diabetic. Comparison of the same patients before and after OLT demonstrated that IGT or diabetes before OLT was the major risk factor for these conditions after OLT, which was independent of either immunosuppression (cyclosporine vs FK506) or low-dose prednisolone. Total glucose uptake was reduced in patients with liver cirrhosis to less than half the values in control subjects (21.2 +/- 2.8 vs 43.7 +/- 2.4 micromol/kg/minute, respectively, P <.001), whereas patients after OLT showed intermediate values (35.7 +/- 1.4 micromol/kg/minute, P < 0.05 vs con, P < 0.01 vs cir). This difference was caused by a reduction in nonoxidative glucose metabolism in patients with liver cirrhosis compared with control subjects (7.4 +/- 1.9 vs 28.7 +/- 1.8 micromol/kg/minute, respectively, P <.01) and patients after OLT (20.1 +/- 1.4 micromol/kg/minute, P < 0.05 vs con and OLT). In the PET study, skeletal muscle glucose uptake was significantly reduced in patients with liver cirrhosis compared with control subjects (3.5 +/- 0.4 vs 11.8 +/- 2.5 micromol/100g/minute, respectively, P <.05). After OLT, muscle glucose uptake improved compared with patients with liver cirrhosis (5.9 +/- 1.0 micromol/100g/minute, P <.05) but remained significantly lower than in control subjects (P <.05). In conclusion, these results demonstrate that preexisting IGT or diabetes are the major risk factors for IGT and diabetes after OLT. This finding was independent of the immunosuppressive medication. The peripheral insulin resistance in cirrhosis is characterized by a decrease in nonoxidative glucose disposal that is improved, but not normalized, after OLT.     

Amino acid uptake in isolated, perfused liver: effect of trauma and sepsis

To examine alterations in amino acid metabolism after trauma and sepsis, male Sprague-Dawley rats underwent no operation (control, CON), celiotomy (trauma, TRA), or cecal ligation and puncture (sepsis, CLP). After 16 hr, plasma amino acid concentrations were determined. A second group of similarly prepared animals underwent isolated liver perfusion, and net amino acid uptake or release was determined over 30 min. Sepsis significantly decreased total amino acid concentration in portal plasma (CON, 3486 +/- 156 nmole/ml; TRA, 3407 +/- 150 nmole/ml; CLP, 2738 +/- 148 nmole/ml). Glutamine concentrations were uniformly lower in portal plasma than in arterial plasma in all states. There were depressed concentrations of the branched chain amino acids (BCAA) in portal plasma after trauma but not sepsis. In the isolated liver perfusion model, a marked increase in amino acid uptake was induced by sepsis (CON, 39.9 +/- 7.9 mumol/g liver protein; TRA, 49.5 +/- 17.3 mumol/g liver protein; CLP, 124 +/- 11 mumol/g liver protein). In addition, there was significantly greater uptake of threonine, asparagine, proline, methionine, tyrosine, and arginine. Although the BCAA isoleucine and valine were taken up to a greater extent in sepsis, the overall BCAA uptake was not significantly greater in sepsis than in control (CON 6.92 +/- 2.15 mumol/g liver protein vs CLP 15.8 +/- 1.9 mumol/g liver protein). The greatest increase in uptake following sepsis was among the gluconeogenic precursor amino acids alanine, glycine, threonine, and serine (CON, 27.0 +/- 4.2 mumol/g liver protein, TRA, 38.8 +/- 8.9 mumol/g liver protein; CLP, 62.8 +/- 6.0 mumol/g liver protein).(ABSTRACT TRUNCATED AT 250 WORDS)     

Whole body protein turnover, synthesis and breakdown in patients receiving total parenteral nutrition (TPN) before and after recovery from surgical stress

This study was conducted to clarify the mechanisms underlying the loss of body nitrogen after trauma. Six patients who underwent abdominal surgery and six for control were studied. The measurement of whole body protein turnover was made on the third and tenth postoperative day during TPN with constant infusion of [15N] glycine according to Picou and Taylor-Roberts. The measurement was also made on six control patients during TPN in non-stressed state. The rates of whole body protein turnover (Q), synthesis (S) and breakdown (B) were calculated from the plateau 15N enrichment of urinary total N, which was analyzed with a mass spectrometer. The values were compared with control and the changes in the individual patients were examined by a paired t-test. Immediately after operation, Q and B were significantly elevated (p less than 0.05 and p less than 0.02, respectively), and reduced with the improvement of N-balance after recovery from stress by 0.95 +/- 0.21 and 0.61 +/- 0.13 g X protein/kg X day, respectively. The changes in Q and B were statistically significant (p less than 0.005 and p less than 0.005, respectively). Whereas, no tendency of alteration in S was found throughout the study. It is concluded that protein turnover rate increases in surgical stress, and that the increased protein catabolism rather than the alteration in synthesis could account for the postoperative nitrogen losses.