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Biomedical subjects

T T Aoki

Publications and source records attributed to T T Aoki.

At least 37 records · Page 2Linked to original sources
PubMed1986

Insulin stimulates branched chain amino acid uptake and diminishes nitrogen flux from skeletal muscle of injured patients.

Resistance to insulin-mediated glucose disposal occurs in uninjured skeletal muscle of trauma patients but the effect of insulin on the accelerated proteolysis of trauma is unknown. We examined the influence of insulin on forearm amino acid and substrate exchange in five normals and four trauma patients using the hyperinsulinemic glucose clamp technique. Forearm substrate and amino acid flux (Q, nM/100 ml tissue/min), the product of blood flow and arterial deep venous concentration difference, was calculated before and during insulin infusion. Total nitrogen release (NQ, nM/100 ml tissue/min) was calculated as the algebraic sum of all nitrogen groups contained in the amino acids released. Among normal subjects, total nitrogen release from the forearm did not change (581 +/- 197 nM/100 ml tissue/min to 1167 +/- 455) during insulin infusion nor did total branched chain amino acid flux (0 +/- 30 nM/100 ml/min to 106 +/- 36). Under conditions of hyperinsulinemia, neither glutamine nor alanine changed in control subjects. In trauma patients, total nitrogen release (3843 +/- 1383 nM/100 ml/min) was inhibited during insulin administration (819 +/- 314, P less than 0.05). Total branched chain amino acid flux went from a net release of 460 +/- 134 nM/100 ml/min to a net uptake of 10 +/- 82 (P less than 0.05). In patients, statistically significant (P less than 0.05) differences were seen in individual amino acids as well. Forearm nitrogen flux was directly related to total branched chain amino acid flux in patients (r2 = 0.89). Additional studies in normals (n = 4) at higher insulin infusion rates confirmed that these effects were unique to injured subjects and not an effect of the insulin dose. Insulin attenuates the accelerated release of skeletal muscle amino acid in trauma patients. This effect may be mediated in part by facilitated branched chain amino acid uptake. The manipulation of both insulin and branched chain amino acid concentrations may provide a method to reduce post-traumatic protein catabolism.

Adult↗
PubMed1986

Plasma level of 13,14-dihydro-15-keto-PGE2 in patients with diabetic ketoacidosis and in normal fasting subjects.

Plasma levels of 13,14-dihydro-15-keto-PGE2, a stable derivative of PGE2, are elevated in rats with diabetic ketoacidosis (DKA) and decrease in response to insulin therapy. In patients with insulin-dependent diabetes mellitus type I (IDDM) the plasma levels of this derivative also rise in response to insulin withdrawal and then fall in response to insulin replacement. We wished to determine whether the level of this substance is elevated acutely when patients present with DKA and to determine whether the levels fall during treatment. We also wished to identify the origin of the circulating 13,14-dihydro-15-keto-PGE2 in patients with DKA and in normal fasting subjects. We measured the plasma level of 13,14-dihydro-15-keto-PGE2 in five patients with DKA and in six normal subjects during a 24-h fast. In the patients with DKA before treatment, the plasma 13,14-dihydro-15-keto-PGE2 level was threefold above normal. During therapy, the 13,14-dihydro-15-keto-PGE2 level fell toward normal. There was a significant direct correlation between the plasma free fatty acid (FFA) level and the plasma 13,14-dihydro-15-keto-PGE2 level before and during treatment. In addition, the inverse correlation between the plasma free-insulin level and the plasma 13,14-dihydro-15-keto-PGE2 level approached significance (P = .06). In contrast, in the normal fasting subjects the plasma FFA level rose to values comparable to those observed in the patients with DKA, but there was no significant increase in the plasma 13,14-dihydro-15-keto-PGE2 level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1985

Fuel utilization following injury: relationship to hormonal environment.

To investigate the relationship between fuel metabolism, insulin resistance, and hormonal environment, insulin clamp studies and indirect calorimetry were performed in nine normal volunteers after they had received a continuous infusion of the three "stress" hormones, cortisol, glucagon, and epinephrine, for 3 days. Studies after a 3-day infusion of saline served as control. Diets were constant and matched on both occasions. Hormonal infusion achieved hormone concentrations similar to those seen following mild to moderate injury. In this altered environment, insulin failed to suppress endogenous glucose production and resulted in reduced glucose disposal. The glucose that was taken up was oxidized, not stored. Furthermore, insulin failed to suppress fat oxidation. The altered hormonal environment achieved by triple hormonal infusion, simulated many of the features of post-traumatic fuel metabolism.

Basal Metabolism↗
PubMed1985

Role of muscle in CO2 production after oral glucose administration in man.

A significant increase in CO2 production, reflecting carbohydrate oxidation and/or fat synthesis, is observed in normal subjects after the ingestion of glucose. The anatomic site(s) of this CO2 production has not yet been localized, although liver and muscle are logical considerations. To assess the contribution of skeletal muscle to this process, we measured whole-body and forearm CO2 flux in normal, postabsorptive subjects after the ingestion of 100 g of glucose and calculated their total muscle CO2 production. In the basal state, muscle accounted for 19% of total CO2 production, and, after glucose administration, muscle CO2 production did not change significantly. Thus, muscle is not the principal site of the observed increase in CO2 production.

Adult↗
PubMed1984

Post-traumatic insulin resistance in uninjured forearm tissue.

Insulin resistance is a hallmark of post-traumatic metabolism. The mechanism and site of this resistance, however, have not been elucidated. To further define the site of this abnormality, glucose uptake across the uninjured forearm was measured in conjunction with hyperinsulinemic glucose clamp studies in 21 normals and 5 patients with multiple trauma. Under these conditions, glucose infused approximates whole body glucose disposal (M, milligrams/kilogram/min). Forearm glucose flux (Q, milligrams/100 ml tissue/min) is the product of blood flow and arterial-deep venous glucose difference (A-DV). In the basal, unperturbed state forearm glucose uptake (Q) was significantly lower in the patients (0.01 +/- 0.04 mg/100 ml/min) than in the normals (0.06 +/- 0.02) and not significantly different from zero. Basal serum insulin in patients (17 +/- 3 microU/ml) was significantly greater than controls (11 +/- 1). During steady-state conditions of euglycemia and hyperinsulinemia, forearm glucose uptake in the patients (0.36 +/- 0.18 mg/100 ml/min was not significantly different from the basal value. At comparable serum insulin levels in controls, forearm glucose uptake was approximately three times that of the injured patients. This is the first in vivo confirmation of the hypothesis that post-traumatic insulin resistance occurs in uninjured forearm tissue, primarily skeletal muscle. Diminished forearm glucose uptake is present in the resting basal state and cannot be overcome by increasing insulin concentrations.

Adult↗
PubMed1984

Metabolic, endocrine, and reproductive changes of a woman channel swimmer.

We report the coordinated metabolic, hormonal, and reproductive data of a female channel swimmer during the pre-swim training period, immediately post-swim, and in the post-swim untrained state. Urine and blood samples collected at these times were assayed for diurnal urinary catecholamines, urinary C-peptide and 3-methylhistidine, total blood ketone bodies, glycerol, the reproductive hormones, adrenal androgens, and thyroid hormones. Subcutaneous fat was measured by ultrasonography. All of the metabolic and hormonal data post-swim except cortisol reflected the severe physiological stress. Urinary catecholamines returned to near-normal levels by 12 hours post-swim. The metabolic changes were associated with reproductive changes, including a shortened luteal phase, absence of ovulation, and increased LH secretion relative to FSH. The swimmer maintained high levels of body fat; she did not become amenorrheic. Metabolic and reproductive hormone levels returned to normal by 2 months post-swim.

Adipose Tissue↗
PubMed1984

Combined hormonal infusion simulates the metabolic response to injury.

To investigate the role of hormones as mediators of the metabolic response to injury, nine normal male volunteers received a continuous 74-hour infusion of the three 'stress' hormones: cortisol, glucagon, and epinephrine. As a control, each subject received a saline infusion during another 4-day period. Diets were constant and matched on both occasions. Hormonal infusion achieved hormone concentrations similar to those seen following mild-moderate injury. With this alteration in the endocrine environment significant hypermetabolism, negative nitrogen and potassium balances, glucose intolerance, hyperinsulinemia, insulin resistance, sodium retention, and peripheral leukocytosis were observed. Additional studies with single hormone infusions indicated that these responses resulted from both additive and synergistic interactions of the hormones. Triple hormone infusion simulated many of the metabolic responses observed following mild-moderate injury and other catabolic illnesses.

Blood Flow Velocity↗
PubMed1983

The relationship between glutamate deamination and gluconeogenesis in kidney.

The effect of 3-mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase [GTP:oxaloacetate carboxy-lyase (transphosphorylating), EC 4.1.1.32], was tested on NH3 formation via the purine nucleotide cycle and glutamate dehydrogenase (EC 1.4.1.2). NH3 excretion in rats increased 70-fold after 48 h of NH4Cl feeding, from 12.2 +/- 4.5 to 862 +/- 190 mumol/mg of creatinine. At 4 h after a single intraperitoneal injection of 3-mercaptopicolinate into NH4Cl-fed rats, NH3 excretion was inhibited by 93%. Kidneys of NH4Cl-fed plus 3-mercaptopicolinate-treated rats, compared with those of NH4Cl-fed rats, showed a 3.5-fold increase in the content of IMP, 5-fold increase in adenylosuccinate, 4-fold increase in aspartate, and a 30% increase in AMP. 3-Mercaptopicolinate completely inhibited NH3 and glucose formation from glutamate in tubules from acidotic rats and NH3 formation from aspartate in kidney perfusion experiments. When transamination in tubules was prevented by 2-amino-4-methoxy-trans-but-3-enoic acid, formation of glucose, but not of NH3, from glutamate was inhibited. 3-Mercaptopicolinate completely inhibited NH3 formation from aspartate in the presence of the aminotransferase inhibitor in kidney tubules. The data show that NH3 can be formed via glutamate dehydrogenase and the purine nucleotide cycle at significant and approximately equal rates. 3-Mercaptopicolinate has no direct effect on NH3 formation via glutamate dehydrogenase, but inhibits that via the purine nucleotide cycle. We conclude that gluconeogenesis is not regulatory for NH3 formation in kidney.

Aminobutyrates↗
PubMed1983

Early events in the initiation of ammonia formation in kidney.

Experiments were designed to examine the early events in the initiation of glutamate deamination in kidney. Perfused kidneys from methionine sulfoximine-treated rats formed ammonia from [15N]glutamate via the purine nucleotide cycle. The turnover of the 6-amino group of adenine nucleotides to yield ammonia occurred at the rate of 0.30 mumol/g of kidney/min. This rate is 3-4 times larger than in liver and is in agreement with published rates of the purine nucleotide cycle in kidney. The addition of 0.1 mM fluorocitrate to glutamate perfusions stimulated ammonia formation 3 1/2-fold. The turnover of the 6-amino group of adenine nucleotides increased during the first 5 min after adding fluorocitrate to form ammonia predominately from tissue glutamate and aspartate. This turnover correlates with a 3 1/2-fold increase in kidney tissue IMP levels. As the ATP/ADP ratio fell the purine nucleotide cycle was inhibited and glutamate dehydrogenase was stimulated to form ammonia stoichiometric with glutamate taken up from the perfusate. Ammonia formation via glutamate dehydrogenase occurred at a rate of 1.0 mumol/g of kidney/min. Fluorocitrate completely blocked ammonia formation from aspartate in perfusions. The perfused kidney formed ammonia from aspartate via the purine nucleotide cycle at a rate of 1.0 mumol/g of kidney/min. The results indicate a discrete role for aspartate in renal metabolism. Ammonia formation via the purine nucleotide cycle can occur at significant rates and equal to the rate of ammonia formation from glutamate via glutamate dehydrogenase.

Amino Acids↗
PubMed1983

Effects of exogenous glucagon on pancreatic and biliary ductal and sphincteric pressures in man demonstrated by endoscopic manometry and correlation with plasma glucagon.

An endoscopic manometric technique was used to investigate the effects of glucagon on pancreatic duct, common bile duct, pancreatic duct sphincter, and bile duct sphincter pressures in 20 healthy volunteers. Glucagon was given by intravenous infusion at rates of 0.016, 0.0625, 0.25, 1.0, 4.0, and 16.0 micrograms/kg/hr and also as an intravenous bolus of 1 mg. Plasma glucagon was measured by radioimmunoassay. Glucagon significantly reduced peak bile duct sphincter pressure from 49.1 +/- 3.7 mm Hg (mean +/- SD) to 37.8 +/- 2.9 mm Hg (P less than 0.01) at a rate of 0.016 microgram/kg/hr, reaching a maximum effect at rates of 0.25 microgram/kg/hr and above. Reduction in pancreatic duct sphincter, pancreatic duct, and bile duct pressures; slowing of sphincter wave frequency; and shortening of wave duration occurred at infusion rates of 1.0 microgram/kg/hr or greater when plasma concentrations were supraphysiological. We conclude that glucagon has a physiological action on the bile duct sphincter but that all other effects on this area are pharmacological.

Adolescent↗
PubMed1983

Peripheral tissue metabolism in cancer-bearing man.

Whole-body tracer studies have documented abnormal glucose and amino acid kinetics in cancer-bearing man. Whether these abnormalities are related to systemic or local tumor effects is questioned. Forearm metabolism was examined in six patients with localized squamous cell carcinoma of the distal esophagus and six healthy normal male volunteers. Substrate arterio-venous differences and blood flow across forearm tissues were determined and substrate flux calculated. The mean forearm blood flow (ml min-1 100 ml forearm-1) was not significantly different between cancer patients (3.67 +/- 0.12) and normal subjects (2.80 +/- 0.40). The uptake of glucose (mumol min-1 100 ml forearm-1) was significantly higher in cancer patients (1.99 +/- 0.45) compared to control subjects without weight loss (0.47 +/- 0.18). Lactic acid release (mumol min-1 100 ml forearm-1) was significantly higher in cancer patients (-1.15 +/- 0.35) compared to control subjects (-0.26 +/- 0.14). There was no significant difference in the flux of individual amino acids between the groups, although the mean total nitrogen released from forearms of cancer-bearing patients was greater than that from normal controls. The arterial serum insulin level was significantly lower and the arterial plasma glucagon level significantly higher in cancer patients compared to control subjects. These data cannot be explained by weight loss alone and suggest a peripheral defect in metabolism in this group of cancer-bearing patients.

Adult↗
PubMed1983

Evidence for restoration of hepatic glucose processing in type I diabetes mellitus.

The role of muscle in the processing of dietary carbohydrate in nine type I diabetic patients was assessed using combined forearm-indirect calorimetry-glucose meal (100 g) studies performed before and after 72 h of artificial beta-cell directed insulin therapy. On conventional insulin therapy, initially elevated arterial glucose concentrations rose markedly, free insulin increased slightly, and the respiratory quotient (R.Q.) did not change during the study. The forearm glucose extraction rate increased significantly over basal at 60 min. After 72 h of artificial beta-cell therapy and while still on the instrument, arterial glucose increased moderately, and free insulin levels increased markedly. The R.Q. increased significantly at 60 and 120 min. The forearm glucose extraction rate increased significantly over basal at 30 and 60 min. Importantly, forearm glucose extraction rates did not differ during the two studies at each of the measured time points. These observations demonstrate that conventional insulin therapy is effective in facilitating glucose entry into muscle. In addition, they suggest that the marked improvement in glucose processing exhibited by type I diabetic patients after 72 h of artificial beta-cell therapy is primarily attributable to the liver. Finally, the data strongly imply that the primary clinical objective of insulin therapy in type I diabetes mellitus should be reactivation of the hepatic component of the glucose disposal system.

Adult↗
PubMed1983

Epinephrine acutely mediates skeletal muscle insulin resistance.

Alterations in carbohydrate metabolism and insulin resistance are major features of the metabolic response to injury. The mediators of these changes are not defined. In this study we investigated the influence of epinephrine on insulin-mediated glucose uptake by peripheral tissue. Forearm blood flow and substrate exchange were determined during insulin clamp studies with and without epinephrine infusion in normal persons. During control studies insulin concentration was raised to 103 +/- 5 microU/ml. Whole body glucose disposal was 9.23 +/- 1.01 mg/kg . min. At a comparable level of hyperinsulinemia (93 +/- 4 microU/ml), epinephrine reduced glucose disposal to 4.54 +/- 0.39 mg/kg . min (P less than 0.01). Forearm glucose uptake was reduced from 0.66 +/- 0.08 to 0.18 +/- 0.13 mg/100 ml . min (P less than 0.05) despite a doubling of forearm blood flow. Epinephrine reduces whole body glucose disposal in part by reducing glucose uptake in peripheral tissue, primarily muscle. Epinephrine-induced skeletal muscle insulin resistance may play a major role in insulin-resistant states and may contribute to accelerated protein catabolism seen following injury.

Adult↗
PubMed1982

Regulation of hemoglobin AIc formation in human erythrocytes in vitro. Effects of physiologic factors other than glucose.

The formation of hemoglobin AIc was studied in intact human erythrocytes in vitro. Satisfactory methods were developed for maintaining erythrocytes under physiologic conditions for greater than 8 d with less than 10% hemolysis. Hemoglobin AIc levels were determined chromatographically on erythrocyte hemolysates after removal of reversible components by incubation for 6 h at 37 degree C. Hemoglobin AIc concentration was found to increase linearly with time during 8 d of incubation. The rate of formation of hemoglobin AIc increased linearly as glucose concentration was increased from 40 to 1,000 mg/dl. Deoxyhemoglobin was glycosylated twice as rapidly as oxyhemoglobin. The rate of hemoglobin AIc formation was further increased by elevated 2,3-diphosphoglycerate levels, an effect that was most marked with deoxyhemoglobin. We conclude that the nonenzymatic glycosylation of hemoglobin is influenced by factors other than glucose, including oxygen tension and 2,3-diphosphoglycerate levels.

2,3-Diphosphoglycerate↗
PubMed1982

Restoration of glucose homeostasis in insulin-dependent diabetic subjects. An inducible process.

To assess the change in glucose handling capability of diabetic patients regulated with an artificial beta-cell, five insulin-dependent diabetic subjects were challenged with a 100-g glucose meal while on conventional (*single or split mixed insulin injections) therapy and again after 72 h on an artificial beta-cell unit. It was determined that while receiving conventional therapy, the diabetic patient's capacity to oxidize glucose was severely impaired. In addition, glucose storage was markedly reduced. After 72 h on the artificial beta-cell unit, the diabetic patient's capacity to oxidize glucose following the ingestion of the glucose meal significantly exceeded that of the control group, and glucose storage returned to normal. Since the above study did not reveal the amount of time on the artificial beta-cell required to restore the glucose processing capability of the diabetic patients to normal, their response to a mixed test meal ingested at noon was monitored while they were on conventional insulin therapy and during four consecutive days that they were on the artificial beta-cell. This inquiry revealed a gradual increase in their capacity to oxidize carbohydrate in response to the test meal. In contrast, their ability to store carbohydrate was normalized within 24 h following initiation of artificial beta-cell therapy. These studies clearly reveal that the conventionally treated diabetic patient's capacity to both oxidize and store carbohydrate is severely impaired. Both functions can be restored to normal by the use of the artificial beta-cell for 48-72 h. Most importantly, the gradual improvement in carbohydrate oxidation with respect to the daily mixed meal challenge suggests that it is an "inducible" process which requires at least 2-3 days to accomplish. Since the ability to both oxidize and store incoming carbohydrate is essential for glucose homeostasis, these observations may have significant implications for the care of diabetic patients.

Adolescent↗
PubMed1981

Regulation of proline biosynthesis: the inhibition of pyrroline-5-carboxylate synthase activity by ornithine.

Mammalian cells have the capacity for proline biosynthesis from ornithine or glutamic acid. Using a radioisotopic assay, we have studied the regulation by ornithine of delta 1-pyrroline-5-carboxylate synthase, the enzyme that catalyzes the first step of proline biosynthesis from glutamic acid. In homogenates from Chinese hamster ovary cells, ornithine was found to be a potent inhibitor of pyrroline-5-carboxylate synthase activity(50% inhibition at 0.37 mM). The effect was reversible and did not occur with amino acids other than ornithine. Preliminary findings suggest that the inhibition does not result from altered requirements for the cofactors NADPH and ATP. Significant inhibition was observed in four different Chinese hamster cell lines. Ornithine was also shown to inhibit the conversion of 3H-glutamic acid to 3H-proline in intact human skin fibroblasts. Cells from patients with a rare ocular disease, gyrate atrophy of the choroid and retina, were used for these studies since they lack interfering ornithine aminotransferase activity. We conclude that ornithine may be a physiologic regulator of the rate of proline formation from glutamic acid. This information allows us to construct an hypothetical model for the overall regulation of proline biosynthesis and also to suggest a pathophysiologic mechanism for the disease gyrate atrophy.

Animals↗