bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolism of dipeptides and their constituent amino acids by liver, gut, kidney, and muscle
Authors: Lochs H. , Williams P. E. , Morse E. L. , Abumrad N. N. , Adibi S. A.
Published: December 2017

Oligopeptides may enter the bloodstream from endogenous and exogenous sources. Using an organ-balance technique in conscious dogs, we investigated the role of individual organs in removal of two model oligopeptides (glycylleucine and glycylglycine) from plasma under steady-state conditions. Despite an identical infusion rate, arterial concentration of glycylglycine was twofold greater than that of glycylleucine. This appeared to be a result of greater fractional extraction of glycylleucine than glycylglycine by organs. Although all of the organs examined participated in removal of dipeptides from plasma, their roles varied. Liver, kidney, muscle, and gut accounted for the disappearance of 25, 24, 12, and 10% of the infused amount of glycylleucine, respectively. With glycylglycine as the substrate, disappearance across kidney accounted for 37% of the infused amount, whereas muscle, liver, and gut accounted for 18, 15, and 11%, respectively. Finally, we investigated glycine and leucine balances across organs with infusion of these amino acids in free and dipeptide forms. Glycine and leucine balances were uniquely more positive across muscle during the infusion of glycylleucine than the corresponding amino acid mixture. The possible mechanisms included release of products of glycylleucine hydrolysis by all organs except muscle. We conclude that molecular structure influences the organ extraction of dipeptides; if extraction, particularly by the liver, is not sufficiently rapid, kidney assumes a greater role than other organs in dipeptide removal from plasma.
Pituitary and peripheral hormone responses to T3 administration during Antarctic residence
Authors: Reed H. L. , Ferreiro J. A. , Mohamed Shakir K. M. , Burman K. D. , O'Brian J. T.
Published: December 2017

Very little is known regarding hormonal adaptation in human subjects who are exposed to the extremes of temperature and light that are found in polar latitudes. We have previously reported a 50% elevation in the serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), a fall in serum total triiodothyronine (T3) and free T3 (fT3), and no change in serum total thyroxine (T4) or free T4 (fT4) after 42 wk of Antarctic cold exposure. To differentiate between central and peripheral mechanisms that may lead to these changes, we report the effect of sequentially increasing oral doses of T3 (Cytomel) on serum T3 and fT3 levels and on the resultant attenuation of the TSH response to TRH in nine men before, during, and after 42 wk residence in Antarctica. Serum T3 values basally and following the administration of 25, 50, and 75 micrograms/day of T3 were lower after 42 wk of cold exposure (151 +/- 4, 160 +/- 8, 189 +/- 10, and 222 +/- 14 ng/dl, respectively, compared with control values of 160 +/- 7, 178 +/- 7, 202 +/- 9, and 251 +/- 19 ng/dl, respectively, P less than 0.05). Likewise, the fT3 values measured after these three increasing T3 doses were also lower after 42 wk of cold exposure. The pituitary response to TRH was attenuated by each T3 regimen (48 +/- 6, 68 +/- 4, and 77 +/- 4% decreases in the control period), and this suppression was not different after 20 and 42 wk of Antarctic residence.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal sympathetic efferent nerve and catecholamine secretion excitation caused by capsaicin in rats
Authors: Watanabe T. , Kawada T. , Kurosawa M. , Sato A. , Iwai K.
Published: December 2017

Capsaicin enhances adrenal medullary catecholamine secretion. The participation of the central nervous system on this enhancement by capsaicin was investigated in alpha-chloralose-urethan- or halothane-anesthetized rats. Intravenous administration of capsaicin caused a rapid and marked increase in adrenal sympathetic nerve activity. The nerve activity began to show an increase with the administration of capsaicin at a dosage of 20 micrograms/kg and significantly increased with a dosage of 200 micrograms/kg, i.e., capsaicin was found to cause a dose-dependent increase in adrenal nerve activity. Cholinergic blocking with hexamethonium bromide and atropine sulfate (1 and 5 mg/kg iv, respectively) attenuated the adrenal epinephrine secretion caused by capsaicin. The direct action of capsaicin on adrenal catecholamine secretion was examined using a retrograde perfusion system of left adrenal gland. Up to 8.2 X 10(-5) M capsaicin did not enhance catecholamine secretion from the adrenal gland. These results suggest that the enhancement of physiological catecholamine secretion by capsaicin is mainly through activation of the central nervous system.
Three-compartmental analysis of effects of D-propranolol on thyroid hormone kinetics
Authors: van der Heijden J. T. , Krenning E. P. , van Toor H. , Hennemann G. , Docter R.
Published: December 2017

Tracer thyroxine (T4), 3.3',5-triiodothyronine (T3), and 3,3',5'-triiodothyronine (rT3) kinetic studies were performed in normal T4 substituted subjects before and during oral D-propranolol treatment to determine whether changes in thyroid hormone metabolism in a propranolol-induced low-T3 syndrome result from inhibition of 5'-deiodination or inhibition of transport of iodothyronines into tissues. Data were analyzed according to a three-compartmental model of distribution and metabolism. T4 plasma appearance rate decreased by 16% (P less than 0.01), reflecting a decreased intestinal absorption of orally administered T4 during propranolol. Serum T4 and free T4 levels increased significantly by 14%, whereas T4 metabolic clearance rate (MCR) was lowered by 26% (P less than 0.001). No changes were observed in size of the three T4 compartments or in fractional and mass transfer rates of T4 from plasma to the rapidly (REP) and slowly (SEP) equilibrating pools. Serum T3, free T3, T3 plasma pool, T3 mass transfer rate to REP and SEP, and the T3 pool masses were all significantly decreased during propranolol to a similar extent as the T3 plasma production rate (PR). T3 MCR decreased by 14% (P less than 0.05). Serum total and free rT3 increased, whereas the rT3 MCR was substantially lowered during propranolol (P less than 0.001). The rT3 plasma pool, rT3 REP and SEP, and the mass transfer rates to REP and SEP increased, whereas no alterations were observed in rT3 PR and fractional transfer rates of rT3 to REP and SEP.(ABSTRACT TRUNCATED AT 250 WORDS)
Binding proteins for growth hormone and prolactin in rabbit kidney cytosol
Authors: Herington A. C. , Stevenson J. L. , Ymer S. I.
Published: December 2017

Two soluble, receptor-like binding proteins with apparent somatotrophic [growth hormone (GH)] and lactogenic [prolactin (PRL)] specificities, respectively, and that are present in rabbit kidney cytosol have now been examined in more detail using specific GH receptor and PRL receptor monoclonal antibodies (MAb). Gel chromatography of 125I-labeled human GH (125I-hGH) kidney cytosol complexes in the absence of these MAbs revealed two specifically bound regions of radioactivity at molecular weights (MW) of approximately 120,000 and approximately 60,000, which are similar in size to complexes formed by the native GH receptor of rabbit liver cytosol and the PRL receptor of mammary gland. Co-incubation with GH-receptor MAb inhibited 125I-hGH binding only to the higher MW (120,000) species, whereas the PRL-receptor MAb inhibited only the lower MW (60,000) species, thus establishing definitively the hormonal specificities of the two binding proteins. The presence of both GH- and PRL-specific binding subunits in cytosol was confirmed using covalent cross-linking techniques. No GH binding protein was detected in kidney membranes. The presence of naturally soluble, receptor-like binding proteins for GH and PRL in kidney cytosol preparations raises the possibility of their playing a role in the intracellular regulation of kidney function and/or metabolism.
Quantitative study in vivo of methionine cycle in humans using [methyl-2H3]- and [1-13C]methionine
Authors: Storch K. J. , Wagner D. A. , Burke J. F. , Young V. R.
Published: December 2017

Kinetic aspects of body methionine (MET) metabolism were examined in healthy young men during the fed and postabsorptive (PA) states. Rates of MET incorporation (S) into and release (B) from body proteins; transmethylation (TM); and remethylation (RM) and transsulfuration (TS) of homocysteine (HCY) were estimated with the aid of a 5-h constant intravenous infusion of [methyl-2H3]- and [1-13C]methionine. The isotopic data (plasma methionine labeling and 13C enrichment of expired air) were submitted to a stochastic model of amino acid metabolism. During the fed state, the subjects (n = 4) received, at 20-min intervals, small isonitrogenous isocaloric meals containing a complete L-amino acid mixture supplying MET at a rate equivalent to 198 mumol.kg body wt-1.day-1. The PA subjects (n = 4) received the isotope after a 10-h overnight fast. For the PA group, the components of MET metabolism were as follows: S, 20 +/- 0.5; B, 24 +/- 0.5; TM, 5.8 +/- 0.6; RM, 1.8 +/- 0.4; and TS, 4.0 +/- 0.4 (+/-SE) mumol.kg-1.h-1. During the fed state the values were S, 26 +/- 2.5; B, 18 +/- 2; TM, 14 +/- 1.3; RM, 5.7 +/- 0.9; and TS 8.3 +/- 0.6 mumol.kg-1.h-1. The meal-induced changes in B, TM, RM, and TS were significant (P less than 0.05). Comparison of the partitioning of MET between S and TM (these two pathways of MET disposal constitute the "methionine locus") in the PA and in the fed states indicates that the MET locus is of regulatory importance in MET homeostasis. A twofold increase in the partitioning of MET to TM was observed in the fed state. The increase in HCY recycling, relative to TS (these two pathways of HCY disposal constitute the "HCY locus"), in the fed state did not reach statistical significance when compared with the PA state. Total daily TM are estimated to be 238 +/- 22 mumol/kg. This is similar to the estimate generated by the methyl balance model of Mudd and Poole (Metabolism 24: 721, 1975) which approximated 241 mumol/kg.
Effect of vasopressin on atrial natriuretic peptide release and renal function in dogs
Authors: Inoue M. , Kimura T. , Ota K. , Iitake K. , Shoji M. , Sato K. , Ota M. , Yoshinaga K.
Published: December 2017

To assess the effect of arginine vasopressin (AVP) and 1-deamino-8-D-AVP (DDAVP) on atrial natriuretic peptide (ANP) release, renal water and electrolyte excretion, and cardiovascular function, AVP and DDAVP were administered at a dose of 10 ng.kg-1.min-1 iv for 30 min into anesthetized dogs receiving saline infusion at a rate of 1 ml.kg-1.min-1 (n = 12). In the control study, saline was infused alone (n = 6). AVP potentiated the plasma ANP response to an increase in plasma volume produced by saline infusion, increased mean arterial blood pressure (MAP), and exaggerated the natriuresis and kaliuresis. DDAVP did not potentiate the increase in plasma ANP but enhanced the natriuresis without any rise in MAP. Saline alone increased plasma ANP as well as sodium and potassium excretion with no changes in MAP. Inulin and p-aminohippuric acid clearances did not change during these studies. The results suggest that in hydrated dogs, AVP may increase ANP release and arterial blood pressure via the vasopressor activity of AVP and potentiate the natriuresis and kaliuresis, but the increased ANP may play little role in the natriuresis.
Effect of prior immobilization on muscular glucose clearance in resting and running rats
Authors: Vissing J. , Ohkuwa T. , Ploug T. , Galbo H.
Published: December 2017

In vitro studies have shown that prior disuse impairs the glucose clearance of red skeletal muscle because of a developed insensitivity to insulin. We studied whether an impaired glucose clearance is present in vivo in 42-h immobilized muscles of resting rats and, furthermore, whether the exercise-induced increase in glucose clearance of red muscles is affected by prior immobilization. The 2-[3H]deoxy-D-glucose (2DG) bolus injection method was used to determine glucose clearance of individual muscles. At rest, glucose clearance was markedly impaired in rats with previously immobilized red muscles compared with nonimmobilized control rats (red gastrocnemius 0.46 +/- 0.02 vs. 0.99 +/- 0.08 and soleus 1.10 +/- 0.30 vs. 3.97 +/- 0.54 ml.min-1.100 g-1, P less than 0.005). During running (18 m/min), glucose clearance did not differ between muscles in previously immobilized and control rats. Insulin levels were always similar in the two groups and decreased during exercise. Intracellular nonphosphorylated 2DG was present in tissues with high glucose clearances. In conclusions, 42 h of immobilization markedly impairs glucose clearance of resting red muscle fibers in vivo. Apparently, physical inactivity in particular affects steps involved in insulin-mediated action that are not part of contraction-induced glucose uptake and metabolism. Presence of intracellular 2DG shows that separate determination of phosphorylated 2DG is necessary for accurate estimates of glucose metabolism and that accumulation of phosphorylated 2DG does not accurately reflect glucose transport.
Furosemide reduces insulin release by inhibition of Cl- and Ca2+ fluxes in beta-cells
Authors: Sandstrom P. E. , Sehlin J.
Published: December 2017

The effect of furosemide on insulin release, glucose oxidation, 36Cl- fluxes, and 45Ca2+ uptake was studied in isolated, beta-cell-rich pancreatic islets from ob/ob mice. Low concentrations of furosemide (0.01-0.1 mM) reduced the glucose-induced insulin release, whereas high doses (1-10 mM) increased basal and glucose-induced release. Furosemide at concentrations that reduced glucose-induced insulin release (0.01-0.1 mM) did not affect the islet production of 14CO2 from D-[U-14C]glucose. The influx rate and equilibrium content of 36Cl- were reduced by furosemide, whereas the basal and glucose-stimulated 36Cl- efflux rates were unaffected. The glucose-induced (10 mM) uptake of 45Ca2+ was inhibited by furosemide. It is suggested that the diabetogenic action of furosemide may be due, at least in part, to direct inhibition of insulin release from the pancreatic beta-cells. This may be caused primarily by inhibition of an inwardly directed Cl- pump, leading to a reduced transmembrane electrochemical gradient for chloride in the beta-cells. This reduced gradient in combination with unaltered Cl- permeability may lead to decreased total outward Cl- transport, a factor associated with stimulated calcium uptake and insulin release.
Involvement of sympathetic nervous system and brown fat in endotoxin-induced fever in rats
Authors: Jepson M. M. , Millward D. J. , Rothwell N. J. , Stock M. J.
Published: December 2017

The object of this study was to assess the role of brown adipose tissue (BAT) and the sympathetic nervous system in the rise in heat production associated with endotoxin-induced fever. Oxygen consumption (VO2) was found to be significantly increased (28%) over a 4-h period after two doses of endotoxin (Escherichia coli lipopolysaccharide, 0.3 mg/100 g body wt) given 24 h apart. Injection of a mixed beta-adrenoceptor antagonist (propranolol) reduced VO2 by 14% in endotoxin-treated rats, whereas the selective beta 1- (atenolol) or beta 2- (ICI 118551) antagonists suppressed VO2 by 10%. These drugs did not affect VO2 in control animals. BAT thermogenic activity assessed from measurements of in vitro mitochondrial guanosine 5'-diphosphate (GDP) binding was elevated by 54% in interscapular BAT and by 171% in other BAT depots. Surgical denervation of one lobe of the interscapular depot prevented these responses. Endotoxin failed to stimulate GDP binding in rats fed protein-deficient diets. This may have been because BAT thermogenic activity was already elevated in control rats fed these diets or because endotoxin caused a marked suppression of food intake in the protein-deficient animals. The results indicate that sympathetic activation of BAT is involved in the thermogenic responses to endotoxin and that these can be modified by dietary manipulation.
Mechanisms limiting glycogen storage in muscle during prolonged insulin stimulation
Authors: Richter E. A. , Hansen S. A. , Hansen B. F.
Published: December 2017

The extent to which muscle glycogen concentrations can be increased during exposure to maximal insulin concentrations and abundant glucose was investigated in the isolated perfused rat hindquarter preparation. Perfusion for 7 h in the presence of 20,000 microU/ml insulin and 11-13 mM glucose increased muscle glycogen concentrations to maximal values 2, 3, and 3.5 times above normal fed levels in fast-twitch white, slow-twitch red, and fast-twitch red fibers, respectively. Glucose uptake decreased (mean +/- SE) from 34.9 +/- 1.2 mumol.g-1.h-1 at 0 h to 7.5 +/- 0.7 after 7 h of perfusion. During the perfusion muscle glycogen synthase activity decreased and free intracellular glucose and glucose 6-phosphate increased indicating that glucose disposal was impaired. However, glucose transport as measured by the uptake of 3-O-[14C]methyl-D-glucose was also markedly decreased after 5 and 7 h of perfusion compared with initial values. Total muscle water concentration decreased during glycogen loading of the muscles. Mechanisms limiting glycogen storage under maximal insulin stimulation include impaired insulin-stimulated membrane transport of glucose as well as impaired intracellular glucose disposal.
Adrenergic blockade prevents endotoxin-induced increases in glucose metabolism
Authors: Hargrove D. M. , Bagby G. J. , Lang C. H. , Spitzer J. J.
Published: December 2017

Combined alpha- and beta-adrenergic blockade was used to investigate the role of catecholamines in endotoxin-induced elevations in glucose kinetics. Glucose kinetics were measured before and for 4 h after the injection of endotoxin [100 micrograms/100 g body wt iv, 30% lethal dose (LD30) at 24 h]. Adrenergic blockade was achieved by the bolus injection of phentolamine and propranolol followed by their continuous infusion. Endotoxin-treated rats exhibited a transient hyperglycemia and sustained (greater than 4 h) increase in plasma lactate concentration, as well as elevated rates of glucose appearance (Ra, 83%), disappearance (Rd, 58%), recycling (160%), and metabolic clearance (23%). Adrenergic blockade prevented endotoxin-induced increases in plasma glucose concentration, Ra, Rd, and recycling but not glucose clearance. The increase in plasma lactate concentration was blunted by 35%. After 2 h, endotoxic animals infused with adrenergic antagonists developed hypoglycemia, which may have resulted from an increased plasma insulin concentration. The attenuation of elevated glucose turnover by adrenergic blockade in the endotoxin-treated animals was not due to a reduction in plasma glucagon level or differences in plasma insulin concentration. Administration of the alpha- or beta-adrenergic antagonists separately blunted but did not prevent endotoxin-induced changes in glucose kinetics, and therefore the efficacy of the adrenergic blockade could not be assigned to a single receptor class. These results indicate that catecholamines are important contributory factors to many of the early alterations in carbohydrate metabolism observed during endotoxemia.
Maternal dehydration-rehydration: fetal plasma and urinary responses
Authors: Ross M. G. , Sherman D. J. , Ervin M. G. , Castro R. , Humme J.
Published: December 2017

Pregnant women may be exposed to exercise, thermal, or gastrointestinal (hyperemesis) water loss, all of which commonly induce a greater than 10 mosmol increase in plasma osmolality. Although fetal osmolality is dependent on maternal osmolality, the impact of maternal dehydration and subsequent maternal rehydration on the fetus has not been explored. Five pregnant ewes with singleton fetuses (136 +/- 1 day) were water deprived for 36 h resulting in a significant increase in plasma osmolality (298 +/- 3.4 to 313 +/- 5.0 mosmol). In response to maternal dehydration, fetal plasma osmolality (297.0 +/- 4.1 to 309.3 +/- 4.1 mosmol), arginine vasopressin (AVP) levels (1.5 +/- 0.2 to 7.9 +/- 1.0 pg/ml), hematocrit (35.1 to 38.6%), and urine osmolality (161.3 +/- 10.7 to 348.9 +/- 21.9 mosmol) significantly increased. Subsequently, ewes were rehydrated over 4 h with intravenously infused 0.45% saline (20 ml.kg-1.h-1). In response to maternal rehydration, maternal and fetal plasma osmolality decreased to basal values (298.9 +/- 3.2 and 300.1 +/- 3.8 mosmol, respectively) and fetal glomerular filtration rate (1.72 +/- 0.30 to 3.08 +/- 0.66 ml/min) and urine volume significantly increased (0.33 +/- 0.02 to 0.71 +/- 0.13 ml/min). However, fetal hematocrit (37.4%), plasma AVP (3.1 +/- 0.9 pg/ml), and urine osmolality (255.4 +/- 28.8 mosmol) did not return to basal levels during the observation period. These results demonstrate fetal hyperosmolality, blood volume contraction, AVP secretion, and altered urine production in response to maternal dehydration. Despite maternal rehydration and normalization of maternal and fetal plasma osmolality, fetal endocrine and fluid responses are prolonged.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of isotope infusion and sampling sites on glucose kinetics during a euglycemic clamp
Authors: Jahoor F. , Klein S. , Miyoshi H. , Wolfe R. R.
Published: December 2017

The importance of the location of isotope infusion and blood sampling on calculating glucose kinetics was studied in five mongrel dogs in the basal state and when glucose turnover was increased during a hyperinsulinemic euglycemic clamp. [U-14C]glucose was infused into the pulmonary artery, unlabeled glucose was infused into a femoral vein to maintain euglycemia, and blood was sampled from the right atrium (AV mode) and the femoral artery (VA mode). In the basal state there was no difference between the AV or VA mode in plateau specific activity; hence, the calculated rate of appearance of glucose was the same with either mode. During the euglycemic clamp procedure, plateau specific activity of the AV mode was significantly lower than that of the VA mode (P less than 0.05). The rate of appearance of glucose calculated from the VA mode was almost identical to the rate of infusion of unlabeled glucose (13.0 +/- 1.4 vs. 12.6 +/- 1.4 mg.kg-1.min-1, respectively), but the rate of appearance of glucose calculated from the AV mode was 12% greater. This study demonstrates that the calculation of glucose kinetics is sensitive to differences in sampling site when the turnover rate is high relative to the mass flow rate (cardiac output times substrate concentration).
Interaction of carnitine with insulin-stimulated glucose metabolism in humans
Authors: Ferrannini E. , Buzzigoli G. , Bevilacqua S. , Boni C. , Del Chiaro D. , Oleggini M. , Brandi L. , Maccari F.
Published: December 2017

To characterize the interactions of carnitine with glucose metabolism, we administered L-carnitine as a primed (3 mmol) constant (17 mumol/min) intravenous infusion to healthy young volunteers during short-term (2 h) euglycemic hyperinsulinemia. In comparison with a control (saline) infusion, exogenous carnitine administration resulted in a stable, fourfold increase in basal serum carnitine levels (160 +/- 14 vs. 36 +/- 2 microM, P less than 0.001). At similar steady-state plasma insulin levels (75 microU/ml), carnitine infusion was associated with a 17 +/- 3% stimulation of whole body glucose utilization (6.56 +/- 0.60 vs. 5.57 +/- 0.44 mg.min-1.kg-1, P less than 0.001). This effect was more pronounced in the subjects with higher rates of glucose disposal (r = 0.65, P less than 0.05). Net rates of insulin-induced glucose oxidation (measured by continuous, computerized indirect calorimetry) were similar with or without carnitine (1.67 +/- 0.23 vs. 1.65 +/- 0.10 mg.min-1.kg-1, respectively). As a consequence, the carnitine-induced enhancement of total glucose metabolism was quantitatively accounted for by a 50% increase in nonoxidative glucose disposal (2.89 +/- 0.81 vs. 1.92 +/- 0.51 mg.min-1.kg-1, P less than 0.05). The inhibitory effect of insulin on net lipid oxidation was not altered by carnitine (-0.67 +/- 0.09 vs. -0.62 +/- 0.06 mg.min-1.kg-1). Circulating levels of free fatty acids (FFA), glycerol, and beta-hydroxybutyrate fell in parallel during insulin infusion in the test and control study, and blood lactate concentrations rose by similar amounts (approximately 0.35 mM).(ABSTRACT TRUNCATED AT 250 WORDS)
Interleukin 1 is a potent stimulator of islet insulin secretion and phosphoinositide hydrolysis
Authors: Zawalich W. S. , Zawalich K. C.
Published: December 2017

The insulin stimulatory effect of 7 mM glucose on isolated perifused rat islets is dramatically potentiated by the monokine interleukin 1 (IL-1). At levels (10(-10) -10(-8) M) noted in vivo during sepsis, it reversibly amplifies peak second phase insulin release to the hexose. At 2.75 mM glucose, however, IL-1 has no effect on insulin secretion. IL-1 also potentiates glyceraldehyde (2 mM)- and alpha-ketoisocaproate (5 mM)-induced insulin secretion. In islets whose phosphoinositides were prelabeled with myo-[2-3H]inositol, 2.0-5.0 nM IL-1 increases the efflux of [3H]inositol from subsequently perifused islets, the parallel accumulation of labeled inositol phosphates, and insulin secretion in the simultaneous presence of 7 mM glucose but not 2.75 mM glucose. In support of these in vitro observations, the in vivo infusion of IL-1 (40 micrograms/kg body wt) elevated circulating plasma insulin levels two-to fourfold. These results establish IL-1 as a potent, readily reversible, glucose-dependent modulator of stimulated insulin secretion and further suggest that its positive impact on insulin release is mediated, at least in part, by phosphoinositide-derived second messenger molecules. IL-1-induced insulin secretion may participate in the multiple metabolic and immunologic adaptations occurring during sepsis.
Effects of hypercortisolemia and diabetes on skeletal muscle insulin receptor function in vitro and in vivo
Authors: Block N. E. , Buse M. G.
Published: December 2017

Activation of skeletal muscle insulin receptor tyrosine kinase in vitro and in vivo was studied in two rat models of insulin resistance: insulinopenic diabetes and hypercortisolemia. In control rats, intravenous insulin administration resulted in dose-dependent in vivo activation of the muscle insulin receptor kinase towards histone H2b. Half-maximal and maximal activation were observed 5 min after injecting 0.1 and 0.5 U insulin/100 g, respectively. Diabetes (7 days) induced with streptozotocin did not affect insulin binding affinity of solubilized muscle receptors but depressed receptor kinase activation in vivo by 52 or 40% after intravenous insulin administration (0.1 or 2 U/100 g, respectively). Cortisone treatment (5 days) resulting in weight loss, hyperglycemia, and hyperinsulinemia did not affect the number, insulin binding affinity, or kinase activity of solubilized receptors activated with insulin in vitro or in vivo. It is concluded that impaired insulin receptor tyrosine kinase activation was demonstrated in vivo in rats with insulinopenic diabetes and that glucocorticoid-induced insulin resistance probably reflects postreceptor defect(s) in muscle.
Effects of thyroid status on atrial natriuretic peptide release from isolated rat atria
Authors: Wong N. L. , Huang D. , Guo N. S. , Wong E. F. , Hu D. C.
Published: December 2017

The effect of thyroid hormone on circulating levels of atrial natriuretic peptide (ANP) was studied in experimental hyperthyroid and hypothyroid rats. Plasma ANP was 102 +/- 5 pg/ml in euthyroid rats, 82 +/- 4 pg/ml in hypothyroid rats, and 138 +/- 11 pg/ml in hyperthyroid rats. We have also measured immunoreactive ANP in the atria of euthyroid, hypothyroid, and hyperthyroid rats. ANP content and concentration in the atria were lower (546 +/- 32 pg/mg tissue) in hyperthyroid rats than in hypothyroid rats (802 +/- 74 pg/mg tissue). Right atrium from euthyroid, hypothyroid, and hyperthyroid rats was superfused with a modified Langendorff preparation. Spontaneous release of ANP was significantly higher from the hyperthyroid rats (20 +/- 2 pg.min-1.mg-1) than from the hypothyroid rats (5.6 +/- 0.5 pg.min-1.mg-1). ANP release from the euthyroid rats was 9.3 +/- 1.2 pg.min-1.mg-1. These results indicate hyperthyroidism causes an increase in ANP secretion and a decreased release occurs during hypothyroidism.
Pyrogenic and thermogenic effects of interleukin 1 beta in the rat
Authors: Dascombe M. J. , Rothwell N. J. , Sagay B. O. , Stock M. J.
Published: December 2017

Single injections of recombinant human interleukin 1 beta (IL-1 beta) caused large (up to 2 degrees C) and sustained (3 h) increases in body temperature in conscious rats. Intracerebroventricular injections (10-100 ng) were much more effective and elicited greater responses than intravenous injections (0.1-1 microgram). IL-1 beta increased resting oxygen consumption by 25-49% in a dose-dependent manner. The activity of the thermogenic proton conductance pathway in brown adipose tissue (BAT) mitochondria was assessed from purine nucleotide (GDP) binding and was elevated by 40 and 86% 1 h after intravenous (1 microgram) or intracerebroventricular (100 ng) injection of IL-1 beta, respectively. Regional tissue blood flow was determined in anesthetized rats from the distribution of radiolabeled microspheres. Blood flow to liver (hepatic arterial), testes, skin, and white adipose tissue was unaffected by IL-1 beta injection. Blood flow to brain and kidney was increased (142 and 50%) but reduced (58%) to skeletal muscle after intravenous but not intracerebroventricular injection of interleukin. In contrast, blood flow to BAT was markedly elevated after intravenous (288%) or intracerebroventricular (382%) injection of IL-1 beta. Severing the sympathetic nerves supplying the interscapular BAT depot prevented the increase in blood flow. These data indicate that the potent pyrogenic effects of IL-1 beta in the rat are due largely to a central action. Fever is associated with increases in metabolic rate and BAT activity, and these results provide support for the involvement of brown fat in thermogenesis associated with fever.
Exercise and insulin stimulate skeletal muscle glucose transport through different mechanisms
Authors: Sternlicht E. , Barnard R. J. , Grimditch G. K.
Published: December 2017

This study was designed to examine the effects of acute exercise, insulin stimulation, and their combination on the kinetics of glucose transport in rat skeletal muscle. Sarcolemmal (SL) membranes were isolated from control (C), acute exercise (E), insulin-stimulated (I), and combined (E + I) rats. Michaelis-Menten kinetics indicated that the Vmax for glucose transport was increased after each perturbation compared with C but were not different from each other (E, 4,334 +/- 377; I, 4,424 +/- 668; E + I, 4,338 +/- 602; and C, 1,366 +/- 124 pmol.mg protein-1.s-1). The apparent Km was unchanged. Scatchard plots of cytochalasin B binding sites indicated that both I and E + I increased the number of binding sites compared both E and C (9.4 +/- 0.5 and 7.8 +/- 0.5 vs. 5.1 +/- 0.2 and 5.5 +/- 0.3 pmol/mg protein) without altering the dissociation constant. The increase in Vmax was greater than the increase in cytochalasin B binding sites indicating that both I and E + I caused an increase in the turnover rate of transport molecules as well as an increase in the total number of transport molecules. Because there was no change in the Km for glucose transport and no increase in cytochalasin B binding sites after exercise, the increase in Vmax was due solely to an increased turnover rate of existing transport molecules.
Effect of physical training on the insulin resistance of aging
Authors: Tonino R. P.
Published: December 2017

Part of the insulin resistance associated with aging may be attributable to a loss of physical fitness. It was hypothesized that an increase in level of physical training would result in an increase in peripheral insulin action. Eleven healthy 60- to 80-yr-old subjects with normal oral glucose tolerance were studied by a euglycemic two-step hyperinsulinemic clamp before and after 12 wk of physical training. Weight and body composition were held constant, and the clamp was separated by 7 days from the last bout of exercise. There was a positive correlation before training between maximum O2 uptake (Vo2 max) and total body glucose disposal rate (M) at the 40 mU.m-2.min-1 insulin infusion (r = 0.69, P less than 0.02). After training Vo2 max increased 6.7%, M increased 13.4% during the 40 mU.m-2.min-1 and 11.0% during the 200 mU.m-2.min-1 insulin infusion. These results show that peripheral insulin resistance in older persons can be decreased by increasing the level of physical training, independent of changes in weight or body composition. Therefore a part of the insulin resistance of aging is reversible, and level of physical training should be considered in its measurement.
Local and systemic estradiol-17 beta: effects on uterine and systemic vasodilation
Authors: Magness R. R. , Rosenfeld C. R.
Published: December 2017

Systemic estradiol-17 beta (E2 beta) administration increases uterine blood flow (UBF), cardiac output (CO), heart rate (HR), and plasma renin activity (PRA). We sought to determine if the E2 beta-induced systemic responses were dependent on the observed uterine responses. Nonpregnant, ovariectomized ewes (n = 5) received 3 micrograms E2 beta into both uterine arteries followed 120 min later by systemic E2 beta, 1 microgram/kg. At 120 min after local E2 beta, UBF increased from 26 +/- 5 to 161 +/- 21 ml/min (P less than 0.05); uterine vascular resistance (UVR) decreased 83 +/- 2.5% (P less than 0.05); and systemic parameters were unchanged. At 120 min after systemic E2 beta, UBF remained elevated and CO had increased gradually from 4.4 +/- 0.2 to 5.5 +/- 0.32 l/min (26 +/- 3.4%, P less than 0.05), reflecting a 37 +/- 3.9% (P less than 0.05) increase in HR; mean arterial pressure (MAP) remained unchanged. The increased CO was associated with a 20 +/- 3.1% (P less than 0.05) fall in systemic vascular resistance (SVR), with % delta SVR less than % delta UVR (P less than 0.05). Base-line PRA and angiotensin II, 1.31 +/- 0.2 ng.ml-1.h-1 and 10.3 +/- 2.1 pg/ml, respectively, were unchanged by local E2 beta; systemic E2 beta caused increases to 3.56 +/- 0.51 ng.ml-1.h-1 (P less than 0.05) and 34.1 +/- 11.3 pg/ml (P less than 0.05), respectively. E2 beta-induced uterine hyperemia occurs independent of its systemic effects and is not responsible for systemic cardiovascular alterations, and the relative uterine vascular responses exceed systemic responses.(ABSTRACT TRUNCATED AT 250 WORDS)
Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys
Authors: Bodkin N. L. , Metzger B. L. , Hansen B. C.
Published: December 2017

The purpose of this study was to identify the relationship between basal hepatic glucose production (HGP) and peripheral insulin sensitivity as assessed by the hyperinsulinemic euglycemic clamp prior to and during the development of non-insulin-dependent (type 2) diabetes mellitus in rhesus monkeys. Twenty-six male monkeys (Macaca mulatta), including normal animals and monkeys in various phases of the development of spontaneous obesity-associated type 2 diabetes were studied. Fasting plasma glucose (FPG) and insulin (FIRI), basal HGP using a [3H]glucose infusion, and peripheral insulin sensitivity (as determined by the euglycemic clamp technique) were examined. The earliest change that could be detected was a significant reduction in peripheral insulin sensitivity accompanied by increased FIRI. These changes preceded a significant deterioration of glucose tolerance. Basal HGP changed in parallel with FPG (r = 0.90, P less than 0.001), becoming significantly elevated only when FPG rose to levels diagnostic of diabetes (greater than 140 mg/dl). Thus basal HGP and fasting glucose levels showed no significant changes early in the development of type 2 diabetes. We conclude that the early serial decreases in insulin sensitivity and progressive increases in FIRI, with or without decreased glucose tolerance, are prognostic of the future development of diabetes in obese monkeys, a longitudinal process that is also likely to be observed in most if not all obese humans progressing to diabetes.
Role of antiglucocorticoid RU 486 on dexamethasone-induced hypertension in rats
Authors: Kalimi M.
Published: December 2017

This study was conducted to investigate whether hypertension induced by long-term in vivo administration of dexamethasone in rats could be prevented by the newly synthesized potent antiglucocorticoid drug RU 486. Subcutaneous implantation of 5 mg of dexamethasone pellets in Sprague-Dawley rats resulted in a rapid increase in the blood pressure that remained elevated during the 3 wk of experimental observation. RU 486 (50 mg) administered alone surprisingly showed slight elevation of blood pressure over untreated control animals. However, the blood pressure leveled off to control levels over the next 2 wk. Interestingly, a 50-mg RU 486 pellet implanted along with 5 mg of dexamethasone effectively prevented the dexamethasone-induced increase in blood pressure. RU 486 administered together with dexamethasone prevented dexamethasone-induced diuresis and urinary Na+ excretion. However, RU 486 was unable to reverse the weight loss or involution of thymus observed by long-term treatment with dexamethasone alone. No abnormalities were found in either kidneys or hearts in any of the treated groups under microscopic examination. These results suggest that RU 486 successfully prevented the hypertension produced by the long-term administration of dexamethasone in male Sprague-Dawley rats.
Time dependence of the interaction between lipid and glucose in humans
Authors: Bonadonna R. C. , Zych K. , Boni C. , Ferrannini E. , DeFronzo R. A.
Published: December 2017

The time-dependent effect of Intralipid infusion on glucose metabolism was examined in seven healthy young subjects who participated in the following three experimental protocols: study I, a 4-h euglycemic insulin clamp (0-240 min) with [3-3H]glucose and indirect calorimetry; study II, a 4-h insulin clamp with Intralipid infusion started at time 0; and study III, a 4-h insulin clamp with Intralipid infusion started at 120 min. When Intralipid infusion was begun at the start of the insulin clamp, the increase in insulin-mediated glucose oxidation was completely inhibited, and the rise in nonoxidative glucose disposal was diminished by 22%. When Intralipid infusion was begun 120 min after the start of the insulin clamp, no inhibitory effect on either glucose oxidation or nonoxidative glucose disposal was observed. The change in lipid oxidation was closely and inversely correlated with the change in glucose oxidation (r = -0.826, P less than 0.001) during studies I-III; no correlation between the change in lipid oxidation and nonoxidative glucose disposal was observed. These results indicate that, in healthy subjects, the metabolic competition between lipid and glucose is very time dependent. Furthermore, mitochondrial oxidative processes are more sensitive and are affected earlier than the cytosolic metabolic pathways, i.e., nonoxidative glucose disposal.
Amplitude modulation of a burstlike mode of cortisol secretion subserves the circadian glucocorticoid rhythm
Authors: Veldhuis J. D. , Iranmanesh A. , Lizarralde G. , Johnson M. L.
Published: December 2017

We have examined the mechanism subserving the in vivo circadian rhythm of cortisol in men. To this end, blood samples were withdrawn at 10-min intervals for 24 h in each of six men to yield well-defined profiles of episodic cortisol release. A novel multiple-parameter deconvolution model was applied to discriminate the number, amplitudes, and durations of all statistically significant underlying cortisol secretory bursts from the plasma hormone concentrations and simultaneously estimate the endogenous half-life of cortisol disappearance in each subject. These experiments disclosed randomly occurring cortisol secretory bursts at a mean frequency of 19 +/- 0.82 events per day (interpulse interval 77 +/- 4.0 min). Secretory bursts exhibited a mean half-duration (duration at half-maximal amplitude) of only 16 +/- 0.61 min indicating that 95% of daily cortisol secretion occurred in 8.2 h. Cortisol secretory burst frequency varied 2.2-fold over 24 h, whereas cortisol secretory burst amplitude varied 6.6-fold. We conclude that the nyctohemeral pattern of cortisol variation in vivo can be accounted for by an amplitude-modulated, random burstlike mode of cortisol secretion without the need to postulate a tonic mode of cortisol release.
Biophysical modeling of sensitivity and positive accuracy of detecting episodic endocrine signals
Authors: Urban R. J. , Johnson M. L. , Veldhuis J. D.
Published: December 2017

To investigate the nature of false-negative and false-positive errors in endocrine signal detection, we used a multiparameter convolution procedure to create random hormone secretory bursts. We observed that 1) data containing high signal frequency, amplitude, and/or duration can be analyzed at less stringent peak-detection thresholds; 2) for any given secretory burst amplitude, increasing the peak-detection threshold enhances positive accuracy but decreases sensitivity; 3) increased sampling frequency improves sensitivity but requires more stringent peak-detection thresholds; and 4) increasing noise diminishes both sensitivity and positive accuracy. We conclude that secretory properties, peak-detector thresholds, investigator-specified sampling intensity, and experimental variance all significantly influence false-positive and false-negative errors associated with the enumeration of episodic endocrine pulse signals. The present observations should offer objective principles to aid in the rational design and analysis of neuroendocrine studies of pulsatile physiological phenomena.
Stretch-related changes in lung cAMP after partial pneumonectomy
Authors: Russo L. A. , Rannels S. R. , Laslow K. S. , Rannels D. E.
Published: December 2017

In rats, left pneumonectomy (PNX) initiates rapid compensatory hyperplastic growth of the right lung. Previous work indicated that increased polyamine uptake associated with post-PNX distortion or “stretch” of the remaining tissue and altered adenosine 3',5'-cyclic monophosphate (cAMP) metabolism may play a role in the early phase of the growth response. Evidence was sought to link these observations with the goal of understanding control of compensatory growth. At day 1 or 3 after left PNX in vivo, increased right lung cAMP was associated with activation of the cAMP-dependent protein kinase (PKa). Total PKa activity was unaffected, but the PKa activity ratio (-cAMP/+cAMP) doubled, providing evidence for PNX-associated activation of the kinase in vivo. Neither cAMP nor PKa was altered in sham-operated control lungs. To determine whether increased distension of the right lung after PNX might initiate these changes, lungs of unoperated animals were perfused 40 min in vitro, either without ventilation or with a distending constant positive airway pressure (CPAP) of 20 cmH2O. CPAP rapidly increased uptake of the polyamine spermidine (SPD; 1.5 microM), tissue cAMP, and the PKa activity ratio, in a manner similar to that observed after PNX. Both tissue cAMP and the kinase activity ratio increased with 1 microM forskolin (FSK), as expected, but SPD uptake was unaffected by FSK. FSK did not diminish the CPAP-associated elevations of SPD uptake (P less than 0.01) or cAMP (P less than 0.05), but the kinase was not further activated by CPAP with FSK present.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma norepinephrine in humans: limitations in assessment of whole body norepinephrine kinetics and plasma clearance
Authors: Henriksen J. H. , Christensen N. J.
Published: December 2017

To investigate catecholamine residence in plasma, constant intravenous infusions of increasing duration (20, 40, and 80 min) of [3H]norepinephrine [( 3H]NE), [3H]isoproterenol [( 3H]IP) IP) and a reference substance: 131I-labeled hippurate were performed in six normal volunteers. In contrast to [3H]IP and 131I-hippurate, whole body clearance from plasma of [3H]NE, as obtained from infusion rate divided by plasma concentration of tracer [1.74 +/- 0.64 (SD) 1/min] was significantly higher than the value obtained by total tracer infusion divided by total plasma area of tracer (1.27 +/- 0.51, P less than 0.01). Mean residence time in plasma (theta) after stopping the infusion of [3H]NE increased along an almost straight line with progressive infusion time, theta of 131I-hippurate increased less, and constant values were recorded after 40 min infusion of [3H]IP. Our results suggest the presence of a very large (cellular) pool from which a reversible transport of [3H]NE back into plasma takes place. The plasma clearance of tracer NE, as determined from infusion rate and plasma concentration of tracer, includes transport to and accumulation in this large store. Thus the "final metabolic clearance," reflecting irreversible removal of NE, is smaller than previously estimated due to recycling through the plasma space. Attention has been drawn to limitations of [3H]NE kinetics.
A1-adenosine receptor-mediated inhibition of adipocyte adenylate cyclase and lipolysis in Zucker rats
Authors: Vannucci S. J. , Klim C. M. , Martin L. F. , LaNoue K. F.
Published: December 2017

Hormone-stimulated lipolysis is reduced in genetically obese rodents and may contribute to the increased adiposity characteristic of the obese state. Endogenously released adenosine, acting via the A1 receptor coupled to the inhibitory guanosine 5'-triphosphate binding protein, Gi, provides a tonic inhibition of lipolysis in rat adipocytes. Removal of this inhibition by the addition of adenosine deaminase frequently results in maximal lipolytic activity. Adipocytes isolated from lean Zucker (Fa/?) rats responded normally to adenosine deaminase, where lipolysis in adipocytes from obese Zucker (fa/fa) rats remained approximately 50% inhibited. Adipocyte adenylate cyclase was equally responsive to activation by forskolin, but lipolytic hormones were significantly less effective in stimulating adenosine 3',5'-cyclic monophosphate (cAMP) production in the obese adipocytes. These cells also exhibited an increased sensitivity to inhibition by the adenosine agonist, N6-(L-2-phenylisopropyl)-adenosine, either in combination with forskolin or beta-adrenergic hormone stimulation. Treatment of isolated adipocytes with pertussis toxin, which uncouples receptor-mediated Gi function, had little effect in cells from lean rats but increased isoproterenol stimulated cAMP production of cells from obese rats to levels observed in the lean cells. In addition, the adenosine A1 antagonist, 8-phenyltheophylline, increased cAMP and lipolytic activity in the obese adipocytes while having little significant effect in the lean adipocytes. These results suggest that hormonal control of lipolysis is altered in the obese Zucker rat because of an alteration in A1-adenosine receptor-mediated inhibition of adenylate cyclase.