Endogenous Rate Of Appearance Research Articles

Insulin resistance of protein anabolism accompanies that of glucose metabolism in lean, glucose-tolerant offspring of persons with type 2 diabetes

ObjectiveTo test whether protein anabolic resistance is an early defect in type 2 diabetes (T2D).Research design and methodsSeven lean, normoglycemic T2D offspring (T2D-O) and eight matched participants without family history...

Enteral Glutamine Administration in Critically Ill Nonseptic Patients Does Not Trigger Arginine Synthesis.

Glutamine supplementation in specific groups of critically ill patients results in favourable clinical outcome. Enhancement of citrulline and arginine synthesis by glutamine could serve as a potential mechanism. However, while receiving optimal enteral nutrition, uptake and enteral metabolism of glutamine in critically ill patients remain unknown. Therefore we investigated the effect of a therapeutically relevant dose of L-glutamine on synthesis of L-citrulline and subsequent L-arginine in this group. Ten versus ten critically ill patients receiving full enteral nutrition, or isocaloric isonitrogenous enteral nutrition including 0.5 g/kg L-alanyl-L-glutamine, were studied using stable isotopes. A cross-over design using intravenous and enteral tracers enabled splanchnic extraction (SE) calculations. Endogenous rate of appearance and SE of glutamine citrulline and arginine was not different (SE controls versus alanyl-glutamine: glutamine 48 and 48%, citrulline 33 versus 45%, and arginine 45 versus 42%). Turnover from glutamine to citrulline and arginine was not higher in glutamine-administered patients. In critically ill nonseptic patients receiving adequate nutrition and a relevant dose of glutamine there was no extra citrulline or arginine synthesis and glutamine SE was not increased. This suggests that for arginine synthesis enhancement there is no need for an additional dose of glutamine when this population is adequately fed. This trial is registered with NTR2285.

Effect of 10% dietary protein intake on whole body protein kinetics in type 2 diabetic adults

Insulin resistance of protein metabolism occurs in obesity and type 2 diabetes (T2D). Hyperaminoacidemia during a simulated fed steady-state clamp compensates for this resistance. We tested whether decreasing protein intake affects the response to insulin with or without added amino acids, and if this response differs by sex. Protein intake was reduced from usual (15%) to 10% of an isoenergetic diet energy for 11 days, in T2D obese men (n = 8) and women (n = 10). Whole-body leucine kinetics (1-(13)C-leucine, surrogate for protein) were determined postabsorptive and during a hyperinsulinemic (∼600 pmol/L), hyperglycemic (8 mmol/L), isoaminoacidemic, followed by hyperaminoacidemic clamp and compared to those of T2D men on a 17% protein diet. Initial negative nitrogen balance approached equilibrium by day 10 but remained lower than with the 17% protein diet. During the hyperinsulinemic, isoaminoacidemic clamp, total leucine flux was less, with both lower endogenous rates of appearance (catabolism) and nonoxidative rates of disposal (synthesis), resulting in net balance at zero. With hyperaminoacidemia, net balance increased to 0.39 ± 0.09 μmol/kgLBM⋅min in men, significantly less than in men on 17% protein (0.98 ± 0.09, p < 0.01). There were no sex differences in clamp responses with 10% protein. After 11 days of 10% protein diet, there was a slight improvement in insulin sensitivity, but a blunted anabolic response to hyperaminoacidemia. Longer-term consequences of lesser anabolic efficiency at reduced protein intakes require study and may contribute to increased risk of sarcopenia in persons with T2D with aging.

Enhanced anabolic response to milk protein sip feeding in elderly subjects with COPD is associated with a reduced splanchnic extraction of multiple amino acids

We previously observed in elderly subjects with Chronic Obstructive Pulmonary Disease (COPD) an enhanced anabolic response to milk protein sip feeding, associated with reduced splanchnic extraction (SPE) of phenylalanine. Milk proteins are known for their high Branched-chain Amino Acids (BCAA) content, but no information is present about splanchnic extraction and metabolism of the individual BCAA in COPD. To investigate whether BCAA metabolism and SPE of the individual BCAA are altered in COPD during milk protein sip feeding. In elderly subjects with COPD and in healthy age-matched elderly SPE, endogenous rate of appearance (Raendo) of the leucine (LEU), isoleucine (ILE) and valine (VAL) were measured before and during sip feeding of a Whey protein meal. To study the effect of aging, the healthy elderly were compared to a group of healthy young subjects. Stable isotopes of l-[(2)H(3)]-LEU, l-[1-(13)C]-ILE and l-[1-(13)C]-VAL were given on two separate test days orally or intravenously. Simultaneously, l-[ring-(2)H(5)]-phenylalanine (PHE) and l-[ring-(2)H(2)]-tyrosine (TYR) were given to determine the whole body protein breakdown (WbPB), synthesis (WbPS) and NetPS. SPE of all BCAA, TYR, and PHE (p < 0.01) were lower in the COPD group, and the increase in netPS during feeding was higher in the COPD group (P < 0.01) due to higher values for PS (P < 0.001). Raendo of all BCAA, PHE and TYR were higher in the COPD than the healthy elderly group (P < 0.05) before and during feeding (P < 0.001). Sip feeding resulted in a reduction of Raendo of PHE, ILE and VAL (P < 0.05). Postabsorptive Raendo was not different for any of the measured amino acids between the healthy elderly and young group, while sip feeding resulted in a reduction of Raendo of PHE. Only SPE of TYR was higher in the elderly (P < 0.05) and the increase in netPS during sip feeding was independent of aging. The enhanced anabolic response to milk protein sip feeding in normal-weight COPD patients is associated with a reduced splanchnic extraction of multiple amino acids including all branched-chain amino acids. Registration ClinicalTrials.gov = NCT01418469.

High-carbohydrate/low-protein–induced hyperinsulinemia does not improve protein balance in children after cardiac surgery

ObjectiveIn pediatric cardiac surgery, fluid-restricted low-protein (LoProt) diets account for cumulative protein deficits with increased morbidity. In this setting, we aimed to inhibit proteolysis by a high-carbohydrate (HiCarb)-intake–induced hyperinsulinemia and improve protein balance. MethodsThe effect of a HiCarb/LoProt (glucose 10 mg · kg−1 · min−1/protein 0.7 g · kg−1 · d−1) versus a normal-carbohydrate (NormCarb)/LoProt (glucose 7.5 mg · kg−1 · min−1/protein 0.3 g · kg−1 · d−1) enteral diet on whole-body protein breakdown and balance was compared in a prospective, randomized, single-blinded trial in 24 children after cardiac surgery. On the second postoperative day, plasma insulin and amino acid concentrations, protein breakdown (endogenous rate of appearance of valine), protein synthesis (non-oxidative disposal of valine), protein balance, and the rate of appearance of urea were measured by using an isotopic infusion of [1-13C]valine and [15N2]urea. ResultsThe HiCarb/LoProt diet led to a serum insulin concentration that was three times higher than the NormCarb/LoProt diet (596 pmol/L, 80–1833, and 198 pmol/L, 76–1292, respectively, P = 0.02), without differences in plasma glucose concentrations. There were no differences in plasma amino acid concentrations, non-oxidative disposal of valine, and endogenous rate of appearance of valine between the groups, with a negative valine balance in the two groups (−0.65 μmol · kg−1 · min−1, −1.91 to 0.01, and −0.58 μmol · kg−1 · min−1, −2.32 to −0.07, respectively, P = 0.71). The serum cortisol concentration in the HiCarb/LoProt group was lower compared with the NormCarb/LoProt group (204 nmol/L, 50–544, and 532 nmol/L, 108–930, respectively, P = 0.02). ConclusionIn children with fluid restriction after cardiac surgery, a HiCarb/LoProt diet compared with a NormCarb/LoProt diet stimulates insulin secretion but does not inhibit proteolysis further and therefore cannot be advocated for this purpose.

Preoperative Glucose and Protein Metabolism: The Influence of Diabetes Mellitus Type 2 in Patients With Colorectal Tumors

Hypermetabolism, abnormal plasma amino acid profiles, increased gluconeogenesis, and changes in liver and muscle protein turnover are well-described undesirable effects in patients with cancer and diabetes mellitus type 2 (DM2) The aim of the present study was to analyze the specific impact and interaction of these 2 disease patterns on patients’ preoperative glucose and protein metabolism. Eight nondiabetic and 8 diabetic patients devoid of cachexia underwent a stable isotope infusion study on the day before surgery for colorectal cancer or adenoma with high-grade dysplasia. Protein and glucose kinetics were assessed in a fasted state by L-[1-13C]leucine and [6,62H2]glucose. In diabetic patients, glucose metabolism was found to be elevated as the plasma glucose level increased (P = 0.013) and endogenous rate of appearance of glucose tended to be higher compared to nondiabetic patients (P = 0.083). Protein metabolism was not affected by the metabolic state of the 2 groups. Resting energy expenditure was higher in diabetic patients (P = 0.028). Under postabsorptive conditions, noncachectic patients with DM2 suffering from colorectal tumors showed an elevated turnover in glucose metabolism whereas the nondiabetic counterparts failed to demonstrate any metabolic changes due solely to malignancy.

Protein Balance in Nondiabetic Versus Diabetic Patients Undergoing Colon Surgery

Surgical injury provokes a stress response that is thought to be pronounced in patients with diabetes mellitus type 2 (DM2) leading to intensified catabolism. The aim of this study was to compare the effects of perioperative epidural analgesia (EDA) versus patient controlled analgesia (PCA) and amino acid infusion on postoperative metabolism in patients with and without DM2. For this study, 12 nondiabetic patients and 12 diabetic patients undergoing colorectal surgery were randomly assigned to 4 groups (n = 6 per group) receiving either EDA (nondiabetic EDA and diabetic EDA [DEDA group]) or PCA with morphine (nondiabetic PCA and diabetic PCA) for perioperative pain control. Protein and glucose kinetics were measured on the second postoperative day using L-[1-13C]leucine and [6,6-2H2]glucose infusion during a fasted state and a 3-hr fed state with amino acid infusion. The transition from the fasted to fed state suppressed endogenous rate of appearance (Ra) of glucose (P G 0.001) with a distinct effect for the DEDA group (P G 0.001). The Ra of leucine and the endogenous rate of appearance of leucine tended to be lower in the DEDA group(P = 0.056 and P = 0.07). Leucine oxidation was more suppressed in the DEDA group (P = 0.02) and when receiving amino acids(P = 0.001). Diabetic patients achieved a higher protein balance than nondiabetic patients (P = 0.032) and when receiving EDA instead of PCA (P = 0.012) or infusion of amino acids (P = 0.014). A short-term infusion of amino acids reduced protein breakdown, increased protein synthesis, and rendered protein balance positive. This anabolic effect was pronounced in diabetic patients with EDA compared with nondiabetic patients or PCA, respectively, and prevented an undesirable hyperglycemia.

Epidural Analgesia Enhances the Postoperative Anabolic Effect of Amino Acids in Diabetes Mellitus Type 2 Patients Undergoing Colon Surgery

It has been suggested that diabetes mellitus type 2 amplifies the endocrine-metabolic stress response to surgery, and patients become more catabolic during the postoperative period. The aim of this study, conducted in patients with diabetes mellitus type 2 scheduled to undergo elective colorectal surgery, was to determine whether the anabolic effects of intravenous amino acids are more pronounced when receiving perioperative epidural analgesia compared with patient-controlled analgesia with intravenous morphine. Twelve patients were randomly assigned to receive either epidural analgesia or patient-controlled analgesia with intravenous morphine for perioperative pain control. Protein and glucose kinetics were measured before surgery and on the second postoperative day using L-[1-C]leucine and [6,6H2]glucose infusion during a fasted and a fed (amino acid infusion) state. Preoperative parameters for glucose and protein kinetics were comparable in the fasted state for both groups. Postoperative amino acid infusion increased glucose concentration slightly (P = 0.124) and suppressed the endogenous rate of appearance of glucose (P < 0.0001) and glucose clearance (P < 0.0001) regardless of analgesia technique. The rate of appearance of leucine (P = 0.002), leucine oxidation (P < 0.0001), and protein synthesis (P = 0.026) increased, whereas net protein breakdown was decreased (P = 0.002), leading to a positive protein balance (P < 0.0001) in both groups. The increase in protein balance was greater in the epidural group compared with the patient-controlled analgesia group (P = 0.027). Diabetic patients receiving an amino acid infusion after surgery achieved a positive protein balance without hyperglycemia. This anabolic effect was greater in patients receiving epidural analgesia compared with patient-controlled analgesia with intravenous morphine.

Acute Effects of Enteral Nutrition on Protein Turnover in Adolescents with Crohn Disease

Adults with inactive Crohn disease have been shown to have normal rates of protein turnover when compared with healthy adults. It is not known whether this is true for adolescents with inactive Crohn disease, when rate of protein synthesis must be greater than that of breakdown for normal development. The objective of this study was to determine whether enteral nutrition acutely suppresses proteolysis and increases protein synthesis in adolescents with inactive Crohn disease. Six adolescents (five males/one female; mean age, 15.8 +/- 1.9 y; range, 13.2-17.6 y; mean bone age, 14.6 +/- 1.8 y; range, 12.5-17 y) participated. Leucine (Leu) and phenylalanine (Phe) kinetics were measured using stable isotopes under fasted and fed conditions during a single study visit. In response to enteral nutrition, the endogenous rates of appearance (Ra) of Leu and Phe (reflecting proteolysis) decreased significantly by 40%. The percentages of splanchnic uptake of Leu and Phe were 35 +/- 10% and 13 +/- 12%, respectively. Under fed conditions, utilization of Phe for protein synthesis increased significantly. We conclude that in clinically stable adolescents with Crohn disease, enteral nutrition promotes anabolism by suppressing proteolysis and increasing protein synthesis. Rates of suppression of proteolysis were similar to those reported previously in normal children.

Intraoperative Infusion of Amino Acids Induces Anabolism Independent of the Type of Anesthesia

The infusion of dextrose in patients receiving epidural and light general anesthesia or general anesthesia alone failed to achieve a positive protein balance. We sought to verify the hypothesis that nutritional supplementation with i.v. amino acids induced a greater protein balance in patients receiving epidural blockade compared with those receiving general anesthesia. Sixteen patients were randomly assigned to receive either general anesthesia with desflurane (control group) or general anesthesia combined with epidural analgesia (EDA group). A primed constant infusion of stable isotope tracers L-[1-(13)C]leucine and [6,6-(2)H2]glucose was started after a 32-h fast before surgery, (3 h of fasted state), and continued for 3 h during surgery during which amino acids were infused i.v. (fed state). Compared with the fasted state, the endogenous rate of appearance of leucine decreased to a similar extent in both groups, and protein synthesis increased, with no difference between the two groups. Leucine oxidation did not change in either group. After amino acids infusion, endogenous glucose production remained unchanged and glucose clearance decreased in both groups. Blood glucose, plasma cortisol, serum insulin, and glucagon concentrations increased to the same extent in both groups. Epidural anesthesia provided no additional benefit beyond the anabolism obtained with amino acids.

Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans

Insulin increases plasma nonesterified fatty acid (NEFA) clearance in humans, but whether this is independent of change in plasma NEFA appearance is currently unknown. Nine nondiabetic men (age: 28+/-3 yr, body mass index: 27.2+/-1.7 kg/m2) underwent euglycemic clamps to maintain low (LINS) vs. high (HINS) physiological insulin levels for 6 h. An intravenous infusion of heparin+Intralipid (HI) was performed during 4 of the 6 h of the clamps (in the last 4 h at LINS and in the first 4 h at HINS), whereas saline infusion (SAL) was administered in the remaining 2 h to modulate plasma NEFA levels independently of plasma insulin levels. Four experimental conditions were obtained in each individual: LINS with saline (LINS/SAL) and with HI infusion (LINS/HI) and HINS with saline (HINS/SAL) and with HI infusion (HINS/HI). Plasma palmitate appearance during HINS/SAL was lower than during the three other experimental conditions (P<0.05). In contrast, plasma linoleate appearance, as expected, was increased by HI independently of insulin level (P<0.02). Plasma palmitate clearance during HINS/SAL was higher than LINS/SAL and LINS/HI (P<0.008), and this increase was blunted during HINS/HI. We observed a linear decrease in plasma palmitate clearance with increasing plasma NEFA appearance independent of insulin levels. Plasma NEFA levels increased exponentially with increase in plasma NEFA appearance. We conclude that insulin stimulates plasma NEFA clearance by reducing the endogenous appearance rate of NEFA. The relationship between plasma NEFA level and appearance rate is nonlinear.

Altered interorgan response to feeding in patients with chronic obstructive pulmonary disease

Previously, we reported increased values for whole-body protein turnover in patients with chronic obstructive pulmonary disease (COPD) in the postabsorptive state. The objective was to investigate whether intake of a carbohydrate-protein meal influences whole-body protein turnover differently in COPD patients and control subjects. Eight normal-weight patients with moderate COPD and 8 healthy control subjects were examined in the postabsorptive state and after 2 h of repeatedly ingesting a maltodextrin casein-based protein meal (0.02 g x kg body wt(-1) x 20 min(-1)). Combined simultaneous, continuous, intravenous infusion of L-[ring-2H5]-phenylalanine and L-[ring-2H2]-tyrosine tracer and oral repeated ingestion of 1-13C-phenylalanine were performed to measure whole-body protein synthesis (WbPS) and first-pass splanchnic extraction of phenylalanine. Endogenous rate of appearance of phenylalanine as the measure of whole-body protein breakdown (WbPB) and netWbPS was calculated as WbPS--WbPB. Arterialized venous blood was sampled for amino acid enrichment and concentration analyses. Feeding induced an increase in WbPS and a reduction in WbPB. The reduction in WbPB was larger in the COPD group than in the control group (P < 0.05) and was related to the lower splanchnic extraction of phenylalanine in the patients. Consequently, netWbPS increased more after feeding in the COPD group than in the control group (P < 0.05). Feeding induces more protein anabolism in normal-weight patients with moderate COPD than in healthy control subjects. This is probably because these COPD patients are characterized by an adaptive interorgan response to feeding to prevent or delay weight loss at this disease stage.

Altered interorgan response to feeding in patients with chronic obstructive pulmonary disease

Background: Previously, we reported increased values for whole-body protein turnover in patients with chronic obstructive pulmonary disease (COPD) in the postabsorptive state. Objective: The objective was to investigate whether intake of a carbohydrate-protein meal influences whole-body protein turnover differently in COPD patients and control subjects. Design: Eight normal-weight patients with moderate COPD and 8 healthy control subjects were examined in the postabsorptive state and after 2 h of repeatedly ingesting a maltodextrin casein-based protein meal (0.02 g · kg body wt−1 · 20 min−1). Combined simultaneous, continuous, intravenous infusion of l-[ring-2H5]-phenylalanine and l-[ring-2H2]-tyrosine tracer and oral repeated ingestion of 1-13C-phenylalanine were performed to measure whole-body protein synthesis (WbPS) and first-pass splanchnic extraction of phenylalanine. Endogenous rate of appearance of phenylalanine as the measure of whole-body protein breakdown (WbPB) and netWbPS was calculated as WbPS − WbPB. Arterialized venous blood was sampled for amino acid enrichment and concentration analyses. Results: Feeding induced an increase in WbPS and a reduction in WbPB. The reduction in WbPB was larger in the COPD group than in the control group (P < 0.05) and was related to the lower splanchnic extraction of phenylalanine in the patients. Consequently, netWbPS increased more after feeding in the COPD group than in the control group (P < 0.05). Conclusion: Feeding induces more protein anabolism in normal-weight patients with moderate COPD than in healthy control subjects. This is probably because these COPD patients are characterized by an adaptive interorgan response to feeding to prevent or delay weight loss at this disease stage.

Whole-body protein anabolic response is resistant to the action of insulin in obese women

Background: Obesity is associated with insulin resistance of glucose and lipid metabolism. Objective: We sought to determine the effects of obesity on the insulin sensitivity of protein metabolism. Design: Whole-body [13C]leucine and [3H]glucose kinetics were measured in 9 lean and 10 obese women in the postabsorptive state and during a hyperinsulinemic, euglycemic, isoaminoacidemic clamp. Results: In the postabsorptive state, the leucine endogenous rate of appearance (catabolism), normalized for fat-free mass, was 11% greater and the nonoxidative rate of disappearance (synthesis) was 8% greater in the obese than in the lean women, but net balance was 29% more negative (P < 0.05). Clamp amino acid and glucose infusion rates were significantly lower in the obese women than in the lean women (0.65 ± 0.02 compared with 0.85 ± 0.04 and 5.7 ± 0.3 compared with 9.1 ± 0.5 mg · kg fat-free mass−1 · min−1, respectively; P < 0.0001 for both), and their rates correlated positively (r = 0.635, P = 0.005). During hyperinsulinemia, synthesis was stimulated less and net leucine balance was much lower in the obese women than in the lean women (−0.08 ± 0.06 and 0.30 ± 0.03 μmol · kg fat-free mass−1 · min−1, respectively; P < 0.0001). The percentage change in net leucine balance correlated negatively with all adiposity indexes. Plasma free fatty acids were less suppressed and the respiratory quotient was lower in the obese women than in the lean women. Conclusion: Obese women show a blunted protein anabolic response to hyperinsulinemia that is consistent with resistance to the action of insulin on protein concurrent with that on glucose and lipid metabolism.

Whole-body protein anabolic response is resistant to the action of insulin in obese women

Obesity is associated with insulin resistance of glucose and lipid metabolism. We sought to determine the effects of obesity on the insulin sensitivity of protein metabolism. Whole-body [(13)C]leucine and [(3)H]glucose kinetics were measured in 9 lean and 10 obese women in the postabsorptive state and during a hyperinsulinemic, euglycemic, isoaminoacidemic clamp. In the postabsorptive state, the leucine endogenous rate of appearance (catabolism), normalized for fat-free mass, was 11% greater and the nonoxidative rate of disappearance (synthesis) was 8% greater in the obese than in the lean women, but net balance was 29% more negative (P < 0.05). Clamp amino acid and glucose infusion rates were significantly lower in the obese women than in the lean women (0.65 +/- 0.02 compared with 0.85 +/- 0.04 and 5.7 +/- 0.3 compared with 9.1 +/- 0.5 mg x kg fat-free mass(-1) x min(-1), respectively; P < 0.0001 for both), and their rates correlated positively (r = 0.635, P = 0.005). During hyperinsulinemia, synthesis was stimulated less and net leucine balance was much lower in the obese women than in the lean women (-0.08 +/- 0.06 and 0.30 +/- 0.03 mumol x kg fat-free mass(-1) x min(-1), respectively; P < 0.0001). The percentage change in net leucine balance correlated negatively with all adiposity indexes. Plasma free fatty acids were less suppressed and the respiratory quotient was lower in the obese women than in the lean women. Obese women show a blunted protein anabolic response to hyperinsulinemia that is consistent with resistance to the action of insulin on protein concurrent with that on glucose and lipid metabolism.

Amino acids do not suppress proteolysis in premature neonates.

To determine whether increased amino acid availability can reduce proteolysis in premature neonates and to assess the capacity of infants born prematurely to acutely increase the irreversible catabolism of the essential amino acids leucine (via oxidation) and phenylalanine (via hydroxylation to form tyrosine), leucine and phenylalanine kinetics were measured under basal conditions and in response to a graded infusion of intravenous amino acids (1.2 and 2.4 g. kg(-1). day(-1)) in clinically stable premature (approximately 32 wk gestation) infants in the 1st wk of life. In contrast to the dose-dependent suppression of proteolysis seen in healthy full-term neonates, the endogenous rates of appearance of leucine and phenylalanine (reflecting proteolysis) were unchanged in response to amino acids (297 +/- 21, 283 +/- 19, and 284 +/- 31 micromol. kg(-1). h(-1) for leucine and 92 +/- 6, 92 +/- 4, and 84 +/- 7 micromol. kg(-1). h(-1) for phenylalanine). Similar to full-term neonates, leucine oxidation (40 +/- 5, 65 +/- 6, and 99 +/- 7 micromol. kg(-1). h(-1)) and phenylalanine hydroxylation (12 +/- 1, 16 +/- 1, and 20 +/- 2 micromol. kg(-1). h(-1)) increased in a stepwise fashion in response to graded amino acids. This capacity to increase phenylalanine hydroxylation may be crucial to meet tyrosine needs when exogenous supply is limited. Finally, to determine whether amino acids stimulate glucose production in premature neonates, glucose rate of appearance was measured during each study period. In response to amino acid infusion, rates of endogenous glucose production were unchanged (and near zero).

Response of glutamine metabolism to glutamine-supplemented parenteral nutrition

Increasing evidence suggests that glutamine is important for the function of many organ systems and supports the use of glutamine-enriched total parenteral nutrition (TPN) during severe illness. However, the effect of prolonged glutamine supplementation on glutamine kinetics has not been studied. We investigated the effect of 8-10 d of TPN enriched with glutamine dipeptides on glutamine kinetics. Twenty-three preoperative patients were randomly allocated to receive either TPN enriched with glutamine dipeptides (60 micromol glutamine*kg body wt(-1)*h(-1)) or isonitrogenous, isoenergetic, glutamine-free TPN. A primed, continuous, 6-h intravenous infusion of L-[5-(15)N]glutamine and L-[1-(13)C]leucine was given before (baseline) and 8-10 d after the TPN solutions were administered. Baseline measurements were performed after a 40-h administration of a standard solution of glucose and amino acids (no glutamine). Glutamine-enriched TPN increased the total appearance rate of glutamine (P: < 0.05) but did not inhibit or increase the endogenous appearance rate. The standard TPN solution also increased the glutamine appearance rate (P: < 0.05), but the change was much smaller than in the glutamine-supplemented group (P: < 0.01). The plasma glutamine concentration did not rise significantly during either treatment, suggesting increased tissue glutamine utilization, especially in the glutamine-supplemented group. In view of the enhanced glutamine requirements in response to trauma and disease by tissues such as those of the gut, the immune system, and the liver, increased glutamine availability during glutamine-enriched TPN may be beneficial preoperatively in patients with gastrointestinal disease.

Response of Leucine Metabolism to Hyperinsulinemia in Hypothyroid Patients before and after Thyroxine Replacement1

We have investigated the effect of hypothyroidism and insulin on protein metabolism in humans. Six hypothyroid patients were studied in a postabsorptive state before and after 5 months of regular treatment for hypothyroidism (153 +/- 17 microg/day of L-T4). The effect of insulin was assessed under hyperinsulinemic euglycemic and eukalemic conditions. Insulin was infused for 140 min at 0.0063 +/- 0.0002 nmol/kg x min. An amino acid infusion was used to blunt insulin-induced hypoaminoacidemia. Whole body protein turnover was measured using L-[1-13C] leucine. When compared to L-T4-induced subclinical thyrotoxic state, hypothyroidism induced a significant decrease (P < 0.05) in leucine endogenous appearance rate (a reflection of proteolysis; 0.89 +/- 0.09 vs. 1.33 +/- 0.05 micromol/kg x min), oxidation (0.19 +/- 0.02 vs. 0.25 +/- 0.03 micromol/kg x min), and nonoxidative disposal (a reflection of protein synthesis; 0.87 +/- 0.11 vs. 1.30 +/- 0.05 micromol/ kg x min). Insulin lowered proteolysis during both the subclinical thyrotoxic and hypothyroid states. Hypothyroidism impaired the antiproteolytic effects of insulin. Thyroid hormones are, therefore, essential for the normal antiproteolytic action of insulin.

The Effect of Increased Nonprotein Energy on Protein Kinetics during Parenteral Nutrition in ELBW Infants • 1564

Adequate amino acid availability is crucial in achieving positive protein balance in parenterally fed ELBW infants; maximal accretion of protein may additionally depend on a critical level of energy intake. We hypothesized that additional nonprotein energy intake would promote protein accretion in these infants. To assess this, we measured the endogenous rates of appearance (Endog Ra) of the essential amino acids leucine (LEU) and phenylalanine (PHE) (each reflecting proteolysis), utilization of PHE for protein synthesis (PS), PHE hydroxylation (OH) (reflecting irreversible loss of PHE), and the rate of urea production in seven clinically stable, ventilated ELBW infants in the first few days of life (27±0.8 wks gestation, 1006±81 gms birth wt, 980±70 gms study wt, 2±0.3 days of age) during a graded increase in nonprotein substrate (70 and 90 kcal/kg/d). Protein intake was held constant at 3.5 gm/kg/d (Aminosyn PF) and a balanced ratio of caloric intake from glucose and lipid was maintained throughout the 5.5 hour study. Kinetics are shown below in mean±SE in μmol/kg/h; *p≤0.05.

AMINO ACIDS DO NOT SUPPRESS PROTEOLYSIS IN PRETERM NEONATES. • 1413

We have recently demonstrated dose dependent suppression of proteolysis with graded amino acid (aa) infusion in healthy term neonates (Am J Physiol, 1997). Rates of proteolysis are higher in preterm individuals, perhaps related to a greater need for aa supply for tissue remodeling and rapid growth. We hypothesized that preterm neonates would be resistant to suppression of proteolysis in response to aa infusion. To assess this, we measured the endogenous rates of appearance (Ra) of the essential aa's leucine (LEU) and phenylalanine (PHE) (reflecting proteolysis), LEU oxidation (LEU OX) and phenylalanine hydroxylation (PHE OH) (reflecting irreversible losses), and utilization of LEU and PHE for protein synthesis (PS) in 7 clinically stable preterm infants (32±0.5 wks gestation, 1.5±0.1 kg birth wt, 1.4±0.1 kg study wt, 6±1 days of age) during a basal glucose infusion (6mg/kg/min) and in response to a graded infusion of aa's (Aminosyn PF-1.2 & 2.5gm/kg/day).