Insulin's effect on Leucine turnover changes during early fasting in the conscious dog

To study the effects of insulin on leucine turnover during fasting, acute insulin deficiency was induced by the simultaneous infusion of somatostatin and glucagon in conscious dogs fasted 18 h (N = 10) and 48 h (N = 11). Insulin levels during the basal period (before hormone perturbation) were similar in both groups of dogs (12 +/- 3 versus 10 +/- 3 microU/ml, respectively). Glucagon levels were similar in the two groups (94 +/- 9 versus 106 +/- 19 pg/ml). Leucine levels rose from 118 +/- 9 mumol/L to 155 +/- 12 mumol/L as fasting progressed (P less than 0.005). Its rate of appearance also increased by 30% (P less than 0.005) from 3.4 +/- 0.3 to 4.3 +/- 0.4 mumol/kg/min (P less than 0.005), while its clearance remained unchanged. Acute insulin deficiency caused an increase in leucine levels in both 18-h and 48-h-fasted dogs by 55% (to 181 +/- 10 mumol/L) and 45% (to 225 +/- 20 mumol/L), respectively (P less than 0.005). However, while the rate of appearance of leucine remained unchanged in dogs fasted overnight, it rose to 5.1 +/- 0.3 mumol/kg/min (P less than 0.01) in those fasted 48 h. The metabolic clearance rate fell in both groups, although this drop was twice as great in the 18-h group (from 28 +/- 3 to 17 +/- 3 ml/kg/min, P less than 0.005) as in the 48-h group (from 28 +/- 3 to 23 +/- 2 ml/kg/min, P less than 0.005). We conclude that insulin has disparate effects on protein turnover as fasting becomes more prolonged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of glucagon in enhancing ketone body production in ketotic diabetic man

To assess the role of endogenous glucagon in regulating hepatic ketone body production in ketotic insulin-withdrawn diabetic subjects, ketone body kinetics were determined in two groups of C-peptide-negative diabetics 6 h after interruption of a s.c. insulin infusion. In group 1 (N = 5), glucagon levels were suppressed by infusion of somatostatin (SRIF), whereas in group 2 (N = 6) glucagon was replaced during SRIF by infusing glucagon at 2 ng/kg/min. Ketone body production rates as determined by primed-continuous infusion of [3-14C]acetoacetate declined from 19.5 +/- 0.8 to 16.4 +/- 0.4 mumol/kg/min (P less than 0.01) during 105 min of SRIF-induced glucagon suppression, whereas they remained unchanged (+0.2 +/- 0.4 mumol/kg/min, P less than 0.01 compared with SRIF) during glucagon replacement. Total ketone body concentrations remained unchanged during SRIF infusion but increased from 2.2 +/- 0.3 to 2.9 +/- 0.2 mmol/L (P less than 0.01) during glucagon replacement. The metabolic clearance rate of total ketone bodies declined significantly (P less than 0.01) by 27% and 21% in the two groups. Plasma free fatty acid and glycerol concentrations remained unchanged in both groups whereas plasma glucose decreased by 3.2 +/- 0.5 mmol/L during SRIF (P less than 0.01). Thus, endogenous glucagon contributed significantly to the maintenance of ketone body production rates in ketotic insulin-deficient diabetics. Since ketogenesis was altered in the absence of changes in free fatty acid levels, the results suggested that glucagon enhanced ketogenesis by an intrahepatic effect.     

Lipid metabolites and nitrogen balance after abdominal surgery in man.

The relation of lipid metabolism to nitrogen balance was studied in patients having undergone abdominal surgery and was compared with control subjects who had fasted for a similar period. The patients had lower circulating concentrations of glycerol, non-esterified fatty acids and ketone bodies. There were inverse correlations between blood alanine and ketone body concentrations in both patients (r = -0.64, P less than 0.01) and controls (r = -0.58, P less than 0.01). Nitrogen excretion by patients (12.7 mmol/kg body weight/day +/- 1.4 s.e. mean) was greater than by controls (9.2 mmol kg(-1)d(-1) +/- 0.8, P less than 0.05), but a more marked difference was noted for urinary methyl histidine excretion of 5.1 +/- 0.5 mmumol kg(-1) d(-1) by patients and only 2.5 +/- 0.3 mumol kg(-1) d(-1) by controls (P less than 0.01), a disparity indicative of more active protein turnover after surgery.     

Minor role of ketone bodies in energy metabolism by skeletal muscle tissue during the postoperative course.

To evaluate changes of peripheral ketone body (KB) metabolism after operation, muscle metabolism in postsurgical patients was studied at 3 hours (SI) and 24 hours (SII) after surgery by the forearm catheter technique. Data were compared to those of equivalent fasted controls (CI, CII). In a manner consistent with enhanced mobilization of endogenous substrate stores, arterial concentrations of free fatty acids (FFA), 3-hydroxybutyrate (3-HOB), and acetoacetate (AcAc) were markedly elevated immediately after surgery. This increase was accompanied by a rise in muscular utilization of AcAc (SI: 0.21 +/- 0.05 mumol/100 g/min; CI: 0.08 +/- 0.05, p less than 0.05) and 3-HOB (SI: 0.24 +/- 0.06 mumol/100 g/min; CI: 0.11 +/- 0.01, p less than 0.05). Surprisingly, on the first postoperative day, concentrations of AcAc and 3-HOB fell below those of fasting controls. Concomitantly, the utilization rate of AcAc by muscle (SII: 0.07 +/- 0.03 mumol/100 g/min; CII: 0.27 +/- 0.04, p less than 0.05) was significantly lower in patients than in controls. Reduction of the fractional extraction rate of AcAc (SI: 38.4 +/- 3.8%; SII: 24.0 +/- 6.1%, p less than 0.05), as well as a net production of 3-HOB by muscle (SII: -0.08 +/- 0.05 mumol/100 g/min; CII: 0.49 +/- 0.13, p less than 0.05) 24 hours after surgery indicated a reduced peripheral capacity for KB removal. Since this finding was related to a significantly higher rate of muscular glycerol production (SII: -0.13 +/- 0.03 mumol/100 g/min; CII: -0.06 +/- 0.02, p less than 0.05), one may suggest that increased intramuscular availability of FFA from triglyceride hydrolysis was responsible for the impairment of peripheral KB utilization. These results indicate that KBs contribute little to energy metabolism in skeletal muscle tissue in the late postoperative phase.     

Effect of epinephrine and somatostatin-induced insulin deficiency on ketone body kinetics and lipolysis in man

The effect of elevated plasma epinephrine concentrations (approximately equal to 800 pg/ml) on ketone body kinetics was determined in postabsorptive normal subjects using primed-continuous infusions of 3-14C-acetoacetate. Infusion of epinephrine (60 ng/kg/min) resulted in a transient increase in total ketone body production to a maximum of 2.5-fold the basal rate within 45 min (P less than 0.01 versus controls). Ketone body uptake increased with a delay, compared with production, causing a 2.8-fold increase in total ketone body concentrations (P less than 0.05 versus controls). Plasma free fatty acid (FFA) and blood glycerol concentrations increased transiently during epinephrine; their course was similar to that of ketone body production. Epinephrine administration resulted in hyperglycemia, hyperlactatemia, and a modest increase in plasma insulin and glucagon concentrations. To assess epinephrine's effect on ketone body kinetics during lack of insulin, and to avoid epinephrine-induced alterations in plasma insulin and glucagon concentrations, epinephrine was also infused combined with somatostatin (6.5 micrograms/kg/h). During somatostatin infusion, epinephrine administration resulted in an enhanced and sustained elevation of total ketone body production from 4.4 +/- 0.8 to 15.1 +/- 1.2 mumol/kg/min (P less than 0.01 versus somatostatin alone). Ketone body concentrations increased markedly from 310 +/- 63 to 1763 +/- 137 mumol/L (P less than 0.01 versus somatostatin alone); the ketonemic effect was enhanced due to a 40% decrease of the metabolic clearance rate associated with somatostatin infusion. The increase in plasma FFA and blood glycerol concentrations during somatostatin-induced insulin deficiency was transiently enhanced by epinephrine, such that they increased to 3.2- and 5.6-fold their basal values after 45 min, respectively (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of 3-hydroxybutyrate on posttraumatic metabolism in man

Of 20 patients suffering trauma, with Injury Severity Scores greater than 20, 11 patients received DL-3-hydroxybutyrate (3-OHB) at a rate of 25 mumol/kg/min for 3 hours. The remaining nine patients received sodium DL-lactate at the same rate as the control subjects. With increased arterial concentrations of ketone bodies, the femoral arteriovenous difference (arterial concentration minus venous concentration) of ketone bodies increased proportionally in the 3-OHB group (R = 0.853, p less than 0.001). Venous concentrations of nonesterified free fatty acids, alanine, glycine, and valine were decreased significantly in the 3-OHB group as compared to the control group. The concentration difference between femoral vein and artery (venous concentration minus arterial concentration) for these substrates also decreased, indicating decreased release from the extremity. A decrease in venous concentration of alanine and difference between femoral vein and artery reached 102.3 +/- 69.3 mumol/L and 32.6 +/- 22.8 mumol/L (mean +/- SD), respectively, after 3-OHB infusion. Decreased alanine release from muscle during 3-OHB infusion in traumatized patients suggests a suppressive effect of ketone body on posttraumatic protein catabolism.     

Post-heparin lipolytic activity in acute renal failure

Total post-heparin lipolytic activity (PHLA), hepatic triglyceride lipase (HTGL) and protamine inactivated lipoprotein lipase (LPL) and plasma lipoprotein pattern were investigated in 8 patients with acute renal failure (ARF). PHLA was determined at 5, 10, 15, 30, 45 and 60 minutes after heparin administration (100 U/kg b.w.). Maximal PHLA in ARF was 6.12 +/- 1.56 mumol FFA/ml/h at 10 minutes versus 14.62 +/- 4.29 at 45 min in controls (= 42%, p less than 0.001). PHLA was reduced in ARF throughout the study period (p less than 0.001). Maximal HTGL activity (3.06 +/- 0.84 mumol FFA/ml/h) was obtained at 10 min in ARF versus 8.97 +/- 3.11 after 15 min in controls (= 34%, p less than 0.001). HTGL in ARF differed from controls at all points of determination (p less than 0.001). LPL maximum was 3.12 +/- 1.93 mumol FFA/ml/h at 15 min in ARF and 7.65 +/- 3.44 at 45 min in controls (= 40%, p less than 0.001). LPL activity was different from controls at 30, 45 and 60 min (p less than 0.001) but not at 5, 10 and 15 min after heparin injection. Due to a rapid decrease of LPL activity (half maximal activity after 34 min in ARF versus 94 min in controls, p less than 0.05) activity half life of PHLA was diminished in ARF (49 min in ARF versus 112 min in controls, p less than 0.01). Thus both the activity of HTGL and LPL is impaired in ARF. Because of the different activation kinetics of the two PHLA fractions no conclusions concerning maximal enzyme activities can be drawn from single determinations as suggested in previous studies on chronic renal failure.     

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.     

Insulin increases sodium reabsorption in diluting segment in humans: evidence for indirect mediation through hypokalemia

To examine the mechanism of renal sodium (Na) and potassium (K) retention during insulin infusion, seven healthy volunteers underwent clearance studies without (time control) and with insulin infusion (40 mU bolus, followed by 1 mU/kg/min for 150 min). Maximal free water clearance and fractional lithium clearance (FELi) were used to analyze renal sodium handling. Insulin decreased Na excretion (from 189 +/- 25 to 121 +/- 19 mumol/min, P less than 0.01) and K excretion (from 64 +/- 8 to 19 +/- 1 mumol/min, P less than 0.01), but did not change in glomerular filtration rate. FELi increased from 29.8 +/- 1.9 to 32.3 +/- 1.9% (P less than 0.05), minimal urine osmolality decreased from 59 +/- 3 to 46 +/- 3 mOsm/kg (P less than 0.01), and the diluting segment reabsorption index increased from 88.0 +/- 0.9 to 93.7 +/- 0.9%, P less than 0.01). Insulin also decreased plasma K, from 3.91 +/- 0.08 to 3.28 +/- 0.08 mmol/liter, P less than 0.01. In a third clearance study KCl was infused simultaneously (3.75 mumol/kg/min) to prevent this fall in plasma K. In this study insulin had no effect on Na and K excretion and diluting segment reabsorption, but the rise in FELi remained. In a fourth clearance study NaCl (3.75 mumol/kg/min) instead of KCl was infused together with insulin. This maneuver did not prevent the Na and K retaining effect of insulin, nor any of its effects on renal sodium handling parameters. These data suggest that Na and K retention during insulin infusion are largely secondary to hypokalemia, which causes increased reabsorption in the diluting segment.     

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)     

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.     

Failure of infused beta-hydroxybutyrate to decrease proteolysis in man

Ketone bodies have been suggested to have a protein-sparing effect, since infusion of Na-beta-hydroxybutyrate in man decreases plasma alanine concentrations and urinary nitrogen (N) excretion. To test this hypothesis, six normal postabsorptive volunteers were infused with Na-beta-hydroxybutyrate for 3 h. Rates of glucose, leucine carbon, and alanine appearance and disappearance from the plasma space were traced with [3-3H]glucose, L-[6,6,6-2H3]leucine, and [2,3,3,3-2H4]alanine. Rates of leucine N appearance and disappearance and the rate of transfer of leucine N to alanine were assessed with [15N]leucine. During ketone body infusion, plasma alanine decreased (P less than 0.05), whereas plasma leucine increased (P less than 0.05). Rates of alanine appearance increased (5.3 +/- 0.3 to 7.8 +/- 0.6 mumol/kg X min), but the increase in its rate of disappearance was slightly greater, accounting for the decrease in plasma alanine concentration. Leucine N flux and the rate and percent of leucine N transferred to alanine increased, whereas leucine carbon flux was unchanged. To determine the effect of the alkalemia induced by Na-beta-hydroxybutyrate, four additional subjects were infused with NaHCO3. Alkalemia had no effect on leucine N or carbon flux or on the rate of appearance of alanine, but increased the rate of alanine disappearance, resulting in a decrease in the plasma alanine concentration. Since the rate of appearance of leucine carbon was unaltered during the infusion of Na-beta-hydroxybutyrate, it is unlikely that hyperketonemia per se decreases proteolysis in postabsorptive man.     

Regulation of ketogenesis by epinephrine and norepinephrine in the overnight-fasted, conscious dog

The effects on ketogenesis and lipolysis of a norepinephrine (0.04 microgram/kg-min), epinephrine (0.04 microgram/kg-min), or saline infusion were examined in the overnight-fasted, conscious dog. Plasma insulin and glucagon levels were maintained constant by means of a somatostatin infusion (0.8 microgram/kg-min) and intraportal replacement infusions of insulin and glucagon. In saline-infused dogs, plasma epinephrine (62 +/- 8 pg/ml), norepinephrine (92 +/- 29 pg/ml), blood glycerol (87 +/- 10 microM), and plasma nonesterified fatty acid (NEFA) (0.82 +/- 0.17 mM) levels did not change. Total blood ketone body levels tended to rise (62 +/- 10 to 83 +/- 11 microM) by 3 h as did total ketone body production (1.5 +/- 0.4 to 2.2 +/- 0.4 mumol/kg-min) over the same time interval. Norepinephrine infusion to produce plasma levels of 447 +/- 86 pg/ml caused a sustained 50% rise in glycerol levels (66 +/- 17 to 99 +/- 15 mumol/L, P less than 0.05) and 53% rise in nonesterified fatty acids (0.53 +/- 0.07 to 0.81 +/- 0.15 mumol/L, P less than 0.05). Total ketone body levels rose by 43% (51 +/- 8 to 73 +/- 10 mumol/L) and ketone body production rose by a similar proportion (1.5 +/- 0.2 to 2.2 +/- 0.3 mumol/kg-min), changes that did not differ significantly from control animals. A similar increment in plasma epinephrine levels (75 +/- 15 to 475 +/- 60 pg/ml) caused glycerol levels to rise by 82% (105 +/- 23 to 191 +/- 26 mumol/L) in 30 min, but this rise was not sustained and the level fell to 146 +/- 14 mumol/L by 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal of abnormal glucose production after pancreatic resection by pancreatic polypeptide administration in man

Pancreatic polypeptide (PP) deficiency has been associated with impaired hepatic sensitivity to insulin and pancreatogenic diabetes in chronic pancreatitis. Since pancreatic resection might also result in PP deficiency, hepatic responses to insulin infusion (0.25 mU/kg/min) were determined by the euglycemic glucose clamp technique in 10 patients who had previously undergone pancreatic resection for trauma and in eight healthy control subjects. Six resection patients (RES-PP) demonstrated deficient PP levels, with a mean increase of plasma immunoreactive PP of 20 +/- 7 pg/ml above basal rate after a test meal compared with 232 +/- 82 pg/ml in control subjects (p less than 0.01) and 353 +/- 133 pg/ml in four other patients undergoing resection with normal levels of immunoreactive PP (RES + PP) (p less than 0.03). Three identical insulin infusion studies were performed in each subject, the second of which was performed during the final 2 hours of an 8-hour infusion of bovine PP (2.0 pmol/kg/min). Whereas hepatic glucose production (HGP) in control subjects fell 74% +/- 4% from a basal rate of 2.0 +/- 0.1 mg/kg/min to a 60- to 120-minute value of 0.5 +/- 0.1 mg/kg/min during insulin infusion, HGP was suppressed only 58% +/- 5% in RES-PP subjects, from 1.9 +/- 0.1 to 0.8 +/- 0.1 mg/kg/min (p less than 0.05 vs controls). Intravenous infusion of PP corrected the hepatic resistance to insulin seen in the PP-deficient group. During PP infusion, HGP was suppressed 74% +/- 5% in RES-PP subjects, from 2.1 +/- 0.2 to 0.5 +/- 0.1 mg/kg/min (p less than 0.04 compared with initial study). PP infusion produced no significant change in glucose metabolism in control and RES + PP subjects. Overall glucose disposal rates were not altered by PP infusion in any group. These findings support a role of PP as a glucoregulatory hormone and suggest that PP deficiency may serve as a reversible pathophysiologic factor in the abnormal glucose metabolism seen after pancreatic resection.     

Glomerulotubular function in patients undergoing moderate surgical stress.

Glomerular function and renal tubular function assessed by measurements of creatinine clearance rates (CCR), lithium clearance rates (CLi, and N-acetyl-beta-D-glucosaminidase (NAG) enzymuria were measured immediately prior to and within 24 h of operation (average operative time 150 min) in 16 patients undergoing a moderate surgical stress. Although serum creatinine concentrations and CCR were similar pre- and postsurgery at 105 +/- 21 and 108 +/- 21 mumol/L and 108 +/- 67 and 110 +/- 59 mL/min/100 kg body weight (mean +/- SD), respectively, both CLi and NAG were significantly increased following the surgical insult. CLi was increased from 19.7 +/- 6.1 to 31.7 +/- 16.7 mL/min/100 kg (p less than 0.01) and NAG from 71 +/- 58 to 164 +/- 10 U/mmol urinary creatinine (p less than 0.001). In addition, the absolute distal tubular reabsorption of sodium and water increased from 18.3 +/- 5.9 and 15.8 +/- 9.7 to 30.6 +/- 16.4 and 27.6 +/- 12.2 mL/min/100 kg body weight (both p less than 0.05), respectively. These results indicate early postoperative renal tubular dysfunction following a moderate surgical stress, undetected by conventional screening.     

The inhibition of thromboxane synthesis has no influence on HgCl2-induced acute renal failure in the rat

Renal function parameters and urinary thromboxane B2-excretion were studied in the rat in HgCl2-induced acute renal failure. Studies were performed before and 3 h after the inhibition of thromboxane synthesis alone, after HgCl2 alone, or after the combination of HgCl2 and thromboxane-synthesis inhibition. Thromboxane-synthesis inhibition alone by indomethacin (5 mg/kg i.v.), imidazole (25 and 50 mumol/kg per min i.v.) and dazoxiben (5 mg/kg i.v.) had no effect on glomerular filtration rate (GFR) or para-aminohippuric acid clearance (CPAH), whereas urinary thromboxane excretion was suppressed. Only the administration of the selective blockers imidazole and dazoxiben resulted in a marked increase in urinary volume (V) and fractional sodium excretion (FENa). HgCl2 alone (2 mg/kg i.v.) caused a decrease in GFR and CPAH with -38% (P less than 0.01), and urinary thromboxane B2 excretion increased from 20.3 +/- 1.5 to 30.6 +/- 2.6 pg/min. (P less than 0.01). The administration of indomethacin, imidazole (50 mumol/kg per min) and dazoxiben prevented the increase in thromboxane B2 excretion 3 h after HgCl2 to values of 3.3 +/- 1.2, 6.9 +/- 0.6 and 13.0 +/- 1.6 pg/min respectively (P less than 0.01 versus control for all values). Despite this, the decrease in GFR and CPAH after HgCl2 could not be prevented. A decrease of GFR with -44, -54, -57 and -32% and of CPAH with -37, -49, -57 and -27% were observed for indomethacin, imidazole 25 and 50 mumol/kg per min and dazoxiben respectively. This evolution was not significantly different from what was observed with mercury alone. Selective thromboxane synthesis inhibition resulted in a decrease of serum free ionised calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effect of sodium D-3-hydroxybutyrate on amino acidemia in hemorrhagic hypotension.

The effect of sodium D-3-hydroxybutyrate (3-OHB) on the amino acidemia caused by hemorrhagic stress was studied. Rats were infused 3-OHB (3-OHB group, n = 11) at a rate of 30 mumol/min.kg or the same volume of saline (control group, n = 11) for 1 h prior to hemorrhage. Mean arterial pressure was maintained at 40 mm Hg using reserved bottle for 30 min. While ketosis was suppressed in control group, plasma ketone body concentration increased from 2,062.9 +/- 223.7 to 3,151.4 +/- 794.8 mumol/l in the 3-OHB group during hemorrhage. Although significant difference in plasma concentrations of amino acids were not shown between two groups at the onset of shock, it was shown after 30 min of shock in alanine, proline, and threonine. Particularly severity of hyperalaninemia was clear. In the control group plasma alanine concentration increased as shock proceeded (p less than 0.01), and no significant change was shown in the 3-OHB group. These results indicate that pretreatment with 3-OHB suppress the hyperalaninemia seen in hemorrhagic hypotension. Ketone body administration may inhibit the protein catabolism in stressed states, such as hemorrhagic hypotension.     

Influence of hemodilution on hepatic energy metabolism in rat

The effects and safety limits of acute hemodilution on hepatic energy status were investigated in relation to arterial blood ketone body ratio and hepatic energy charge in a hemodilution rat model. As long as the hematocrit value was maintained above 20%, ketone body ratio and energy charge level at 6 h after hemodilution remained at the same levels as those of the sham-diluted groups. However, when hematocrit value was less than 15%, the ketone body ratio markedly decreased from the control value of 0.686 +/- 0.044 to 0.278 +/- 0.048 (p less than 0.001), and energy charge decreased from the control value of 0.856 +/- 0.012 to 0.0806 +/- 0.011 (p less than 0.01). From these results, it was suggested that hemodilution exerts no influence on the energy status of the liver as long as hematocrit is maintained above 20%.     

Influence of dopamine on the liver assessed by changes in arterial ketone body ratio in brain-dead dogs

The influence of dopamine on liver metabolism in the state of brain death was assessed by measuring arterial ketone body ratio (AKBR) in dogs. Mean arterial blood pressure (MABP) was significantly decreased, from 137.4 +/- 3.7 to 64.7 +/- 2.8 mm Hg, 1 hour after completion of brain death (p less than 0.01). In the control group AKBR was maintained at the near control value of 1.07 thereafter, concomitant with a significant decrease in serum lactate levels, despite marked hypotension (p less than 0.05). Dopamine infusion at rates of 5 and 10 micrograms/kg/min sustained both AKBR and MABP at near control values. In contrast, dopamine given at doses greater than 15 micrograms/kg/min caused a significant reduction of AKBR, to less than 0.66 +/- 0.12 (p less than 0.01), although MABP was restored to near-normal levels. In addition, serum levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were significantly elevated, reflecting liver cell injury. It is suggested that the liver is primarily tolerant to hypotension in the state of brain death and that dopamine administered at a rate of 15 micrograms/kg/min or more impairs liver metabolism by reducing the redox state (free nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide) of liver mitochondria.