bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF
Authors: Strijbos P. J. , Hardwick A. J. , Relton J. K. , Carey F. , Rothwell N. J.
Published: December 2017

In the present studies, the mechanisms underlying the inhibitory actions of lipocortin-1 on the pyrogenic and thermogenic properties of cytokines were investigated. Central (icv) injection of corticotropin-releasing factor (CRF, 4.7 micrograms) or the recombinant cytokines interleukin (IL)-1 alpha (50 ng), IL-1 beta (5 ng), IL-6 (20 ng), IL-8 (20 ng), or tumor necrosis factor-alpha (TNF-alpha, 1 microgram) in conscious rats produced significant increases in resting oxygen consumption (VO2, 13-26%) and colonic temperature (0.7-1.6 degrees C) within 2 h postinjection. Administration (icv) of a recombinant fragment (NH2-terminus, 1-188 amino acids) of human lipocortin-1 (1.2 micrograms) produced small increases in VO2 (< 5%) and body temperature (< 0.3 degrees C). Pretreatment (-5 min) with lipocortin-1 significantly attenuated the thermogenic and pyrogenic effects of centrally injected IL-1 beta (80% inhibition), IL-6 (60%), IL-8 (80%), or CRF (60%). However, pretreatment with lipocortin-1 failed to modify the actions of IL-1 alpha or TNF-alpha. We have previously demonstrated that the pyrogenic and thermogenic effects of IL-1 beta, IL-6, and IL-8 are dependent on the central actions of CRF, whereas IL-1 alpha and TNF-alpha act independently of CRF. Fever and thermogenesis induced by all of these cytokines (with the exception of IL-8) can also be prevented by administration of a cyclooxygenase inhibitor. The data presented here suggest that the potent antipyretic effects of lipocortin-1 may result from inhibition of the release or actions of CRF rather than modulation of eicosanoid synthesis.
Membrane receptors for aldosterone: a novel pathway for mineralocorticoid action
Authors: Wehling M. , Christ M. , Theisen K.
Published: December 2017

Rapid nongenomic in vitro effects of aldosterone on intracellular electrolytes, cell volume, and Na(+)-H+ antiport have been found in human mononuclear leukocytes (HML). Binding of 125I-labeled aldosterone to plasma membranes of HML shares important features with these functional data. This includes a very low apparent dissociation constant (Kd) of 0.1 nM for both aldosterone and the effect on the Na(+)-H(+)-antiport, a high turnover rate, and the almost exclusive binding selectivity for aldosterone. Dexamethasone, RU 26988, corticosterone, ouabain, amiloride, and 18-hydroxyprogesterone were inactive as ligands. Deoxycorticosterone acetate had an intermediate activity with an apparent Kd of 100 nM. These findings are the first to demonstrate membrane binding of aldosterone being compatible with major aspects of its nongenomic effects.
Muscle glucose uptake during and after exercise is normal in insulin-resistant rats
Authors: Kusunoki M. , Storlien L. H. , MacDessi J. , Oakes N. D. , Kennedy C. , Chisholm D. J. , Kraegen E. W.
Published: December 2017

It is not generally known whether impaired stimulation of muscle glucose metabolism in insulin-resistant states is specific to insulin stimulation. Our aim was to examine whether glucose uptake responded normally to exercise and postexercise recovery in insulin-resistant high-fat-fed (HFF) rats. Three-week HFF or Chow-fed [control (Con)] adult rats were studied 5 days after cannulation. Before, during, or immediately after (recovery) 50 min of treadmill exercise, bolus 2-deoxy-[3H]glucose and [14C]glucose were administered to estimate muscle glucose uptake (R'g) and glycogen incorporation rates. Mean exercise and recovery plasma glucose levels were similar in HFF and Con rats. In hindlimb muscles sampled, exercise and recovery R'g were similar in HFF and Con (e.g., red quadriceps exercise 104 +/- 13 vs. 113 +/- 8, recovery 45.3 +/- 3.9 vs. 47.7 +/- 4.5 mumol.100 g-1.min-1, respectively). Moreover, muscle glucose transporter (GLUT-4) content was not reduced in HFF rats. Glycogen resynthesis accounted almost entirely for R'g during recovery and was equivalent between groups. We conclude that impaired muscle glucose uptake and glycogen synthesis in HFF rats are characteristic of insulin but not of exercise or postexercise stimulation.
Ovine fetal placental lactate exchange and decarboxylation at midgestation
Authors: Carter B. S. , Moores R. R. , Battaglia F. C. , Meschia G.
Published: December 2017

In a study of the metabolic implications of the large placental-to-fetal mass ratio that characterizes early fetal development, fetal plasma lactate disposal rate and CO2 production from fetal plasma lactate by fetus and placenta were measured in six midgestation (71–80 days) pregnant sheep. A constant fetal intravenous infusion of L-[U-14C]lactate and 3H2O was given to establish fetal steady-state lactate specific activity and to measure uterine and umbilical blood flows. Fetal and placental weights were 158.6 +/- 19.7 and 441.9 +/- 32.7 g, respectively. There was a significant net lactate flux into the uterine circulation (31 +/- 4.3 mumol/min, P < 0.01) but no measurable umbilical uptake. Fetal plasma lactate disposal rate was 21.2 +/- 2.7 mumol/min, approximately one-half of which represented fetal lactate flux into the placenta (9.9 +/- 1.9 mumol/min). The oxidation rate of tracer lactate carbon to 14CO2 by placenta plus fetus was 72.6 +/- 4.7% of the infused tracer and was fairly evenly distributed between the placenta and the fetus (42.4 +/- 3.9 vs. 30.3 +/- 2.2%). The midgestation placenta metabolizes and produces fetal plasma lactate at rapid and nearly equal rates. This contrasts with the late-gestation placenta, which makes a small contribution to fetal lactate disposal and is a major net source of fetal lactate.
Effects of subbasal insulin infusion on resting and exercise-induced glucose turnover in depancreatized dogs
Authors: Shi Z. Q. , Giacca A. , Yamatani K. , Fisher S. J. , Lickley H. L. , Vranic M.
Published: December 2017

beta-Adrenergic blockade suppressed lipolysis and normalized the exercise-induced increments in glucose uptake (GlcU) and metabolic clearance rate (MCR) in alloxan-diabetic dogs with residual insulin, but not in insulin-deprived depancreatized dogs even when combined with methylpalmoxirate (MP), which suppresses fatty acid oxidation. The effects of a minimal amount of insulin (as in the alloxan-diabetic dog), were studied in depancreatized, 24-h insulin-deprived dogs during rest and treadmill exercise (6 km/h, 10% slope) using a 1/4 basal insulin infusion (50 microU.kg-1.min-1, insulin, n = 6) alone, or with MP (20 mg.kg-1.day orally, 2.5 days, MP+insulin, n = 6). At rest, insulin decreased circulating fatty acids (31%) and Glc (13%) and increased GlcU and MCR (86 and 72%). Glc production was unaffected. MP plus insulin markedly suppressed hepatic fatty acid oxidation, decreased Glc (44%) and Glc production (50%), and markedly increased MCR (128%). The exercise-induced increments in MCR were markedly improved only by MP plus insulin but were still lower than in the propranolol-treated alloxan-diabetic dogs. Plasma Glc inversely correlated with the exercise-induced increase in MCR (r = -0.86). We conclude that 1) acute infusion of subbasal insulin improved GlcU in depancreatized dogs at rest but not during exercise; 2) inhibition of fatty acid oxidation combined with subbasal insulin improved the exercise-induced increase in MCR; and 3) the difference in GlcU and MCR between the MP plus insulin-treated depancreatized dogs and the beta-blockade-treated alloxan-diabetic dogs suggests a difference between acute and chronic effects of insulin.
Calcium current regulation of depolarization-evoked calcium transients in beta-cells (HIT-T15)
Authors: Dukes I. D. , Cleemann L.
Published: December 2017

Glucose-induced insulin secretion by beta-cells is linked to phasic increases in intracellular Ca2+ concentration ([Ca2+]i) arising from membrane depolarization. We examined the source of this Ca2+in cultured beta-cells using rapid dual-wavelength spectroscopy of fura-2 under voltage-clamp conditions. Depolarization of the beta-cell initiated a sustained rise in [Ca2+]i that was dependent on the activation of L-type Ca2+current that exhibited very slow inactivation. Neither release of internally stored Ca2+nor Na(+)-Ca2+exchange contributed significantly to this calcium rise, as evidenced by the suppressive effect of rapid application of Cd2+and the lack of effect of elevations of intracellular Na+concentration. Restoration of control Ca2+levels was primarily dependent on Ca2+channel closure, but both a voltage-dependent and voltage-independent Ca2+efflux system also contributed. Both the fluorescence-based and charge-based estimates of the rise in [Ca2+]i were in broad agreement, indicating that Ca current activation was the primary source of the Ca2+transient. The results suggest that nutrient-induced changes in beta-cell membrane potential tightly regulate [Ca2+]i, and thereby insulin release, primarily via alterations in the conductive state of slowly inactivating Ca2+channels.
LPS inhibits PI-phospholipase C but not PC-phospholipase D or phosphorylase activation by vasopressin and norepinephrine
Authors: Pittner R. A. , Spitzer J. A.
Published: December 2017

Rats were infused with endotoxin (50 micrograms/100 g body wt) for 3 h, and the parenchymal cells of the liver were maintained in primary culture for 1-3 h. The effects of vasopressin, norepinephrine, and glucagon on the activation of phosphatidylinositol (PI)-phospholipase C, phosphatidylcholine (PC)-phospholipase D, and glycogen phosphorylase a were investigated. Activation of PI-phospholipase C was markedly reduced, particularly with norepinephrine. This confirms that one of the early metabolic impairments seen in acute endotoxin treatment is inhibition of PI-phospholipase C activity. However, the ability of vasopressin, norepinephrine, and glucagon to stimulate glycogen phosphorylase a and PC-phospholipase D was not affected by this endotoxin treatment. We conclude that activation of phosphorylase a by vasopressin and norepinephrine is not entirely dependent on the activation of PI-phospholipase C and inositol trisphosphate formation.
Impact of conceptus mass on glucose disposal rate in pregnant women
Authors: Marconi A. M. , Davoli E. , Cetin I. , Lanfranchi A. , Zerbe G. , Fanelli R. , Fennessey P. V. , Pardi G. , Battaglia F. C.
Published: December 2017

The impact of an increasing fetal and placental mass on maternal glucose disposal rate (GDR) was studied in 17 pregnant women. Eleven pregnancies were singleton pregnancies, five were twin and one was a triplet pregnancy. Both the maternal fasting glucose concentration [Glc] and the total fetal and placental weight (W) were significantly correlated with an increased maternal GDR. Glucose concentration and conceptus weight were interdependent. The multiple linear regression of glucose disposal rate on glucose concentration and total weight is given by GDR = -1.573 + 0.176W + 0.932[Glc] +/- 0.24, r2 = 0.52, P < 0.01. These data are utilized to estimate the glucose utilization rate of the human conceptus at a fasting glucose concentration of 3.9 mM with a range of 10-15 mg.kg-1.min-1. Maternal GDR increases with increasing glucose concentration at a rate similar to that reported for newborn infants, consistent with a high glucose utilization by the uterus.
Role of cytosolic calcium in regulation of cytoskeletal gene expression by insulin
Authors: Weinstock R. S. , Saville C. M. , Messina J. L.
Published: December 2017

Insulin and calcium ionophores rapidly stimulated transcription of the cytoskeletal beta- and gamma-actin genes in serum-deprived rat H4-II-E hepatoma cells. The calcium ionophore A23187 (1 microM) stimulated transcription of the beta-actin gene by 7.3-, 5.4-, and 2.6-fold and the gamma-actin gene by 5.9-, 5.6-, and 2.6-fold at 15, 30, and 60 min, respectively. Ionomycin (1 microM) similarly increased beta- and gamma-actin transcription. Insulin stimulated beta-actin transcription 11.4-fold and gamma-actin 8.4-fold at 30 min. alpha-Tubulin transcription was induced by both insulin and calcium ionophores but to a lesser degree. The effects of A23187 or ionomycin together with insulin for 30 min were no greater than those of insulin alone. Insulin alone, however, did not significantly increase measurable intracellular calcium concentrations in fura-2-loaded cells. When cytosolic calcium was chelated using quin2 acetoxymethyl ester, the ability of A23187 to increase beta- and gamma-actin transcription was completely abolished, whereas insulin's ability to stimulate actin transcription was only partially inhibited. This suggests that the regulation of gene transcription by insulin may include calcium-dependent pathways but strongly implies that calcium-independent pathways are also utilized.
Effects of muscle activity and fiber composition on glucose transport and GLUT-4
Authors: Megeney L. A. , Neufer P. D. , Dohm G. L. , Tan M. H. , Blewett C. A. , Elder G. C. , Bonen A.
Published: December 2017

We examined glucose uptake and GLUT-4 in rat muscles [soleus (Sol), plantaris (PL), extensor digitorum longus (EDL), tibialis anterior, and the red and white gastrocnemius (WG)]. In the normally innervated perfused rat hindlimb muscles the proportion of oxidative fibers was highly correlated with the muscle's insulin-stimulated 3-O-methyl-D-glucose (3-MG) uptake (R2 = 0.78) and GLUT-4 content (r = 0.94). Insulin-stimulated 3-MG uptake and GLUT-4 were also highly correlated (R2 = 0.996). In 3-day denervated muscles, insulin-stimulated 3-MG uptake was reduced in all six muscles (-41 to -14.6%, P < 0.05), and GLUT-4 content was also reduced (-87.5 to -34.9%), except in the WG and EDL (P > 0.05). A very high correlation was observed between the decrements in GLUT-4 (%) and the decrements in 3-MG uptake (%; r = 0.99). The relatively greater loss in muscle activity (%) due to denervation in the Sol compared with the PL coincided with the reductions (%) in GLUT-4 and 3-MG uptake. These studies demonstrate that glucose uptake and GLUT-4 are regulated by insulin-independent means, namely the oxidative capacity of the muscle and the normal activity level of the muscle.
Hepatic glucose production during the labeled IVGTT: estimation by deconvolution with a new minimal model
Authors: Caumo A. , Cobelli C.
Published: December 2017

A method for the estimation of hepatic glucose production during a labeled intravenous glucose tolerance test (IVGTT) is proposed. Stable-label IVGTT data in normal subjects have been considered. The method is based on deconvolution and uses a new two-compartment minimal model of glucose kinetics to describe the time-varying impulse response of the glucose system. A new model of glucose kinetics was needed because the available single-compartment minimal model, specifically developed to interpret labeled IVGTT data, provided a nonphysiological pattern of hepatic glucose production. The new minimal model has two novel features: glucose kinetics are described by a two-compartment structure, and insulin exerts its action on the irreversible loss of the slowly exchanging glucose pool. The deconvolution scheme used to reconstruct hepatic glucose production is described in detail both in terms of computational aspects and reliability. Confidence limits of the reconstructed hepatic glucose production in each individual are derived by taking into account both the measurement error of the data and the uncertainty associated with the description of the impulse response. Physiological plausibility of the time course of hepatic glucose production provided by this new method is discussed. The ability of the new model to reconstruct hepatic glucose production considerably enriches the kinetic portrait of glucose metabolism that can be obtained from the minimal-model analysis of labeled IVGTT data.
Increased expression of glucose transporter GLUT-4 in brown adipose tissue of fasted rats after cold exposure
Authors: Shimizu Y. , Nikami H. , Tsukazaki K. , Machado U. F. , Yano H. , Seino Y. , Saito M.
Published: December 2017

Cold exposure has been shown to increase glucose uptake specifically in brown adipose tissue (BAT), the major site for sympathetically controlled metabolic heat production. In this study, the relationship between glucose uptake and glucose transporters (GLUT) was examined in rats exposed to cold for various periods. To minimize the stimulatory effect of circulating insulin, all animals were starved for 20-24 h before the measurements. Acute (4 h) cold exposure had no effect on protein and mRNA levels of GLUT-4, the predominant isoform of GLUT in BAT, despite a significant increase in cellular glucose uptake. Prolonged (1-10 days) cold exposure produced a parallel increase in GLUT-4 expression and glucose uptake in BAT. In contrast, cold exposure had no noticeable effect on GLUT-1, another isoform of GLUT in BAT, and on GLUT-4 in other insulin-sensitive tissues such as white adipose tissue and muscles. The increased glucose uptake and GLUT-4 expression were completely abolished after surgical sympathetic denervation. These findings suggest that cold exposure increases glucose uptake in BAT by at least two distinct mechanisms, both of which are dependent on sympathetic nerve: 1) an increase in the amount of GLUT-4 due to the stimulation of its de novo synthesis, and 2) an increase without stimulation of GLUT synthesis, probably due to the change in the transport activity of GLUT-4 and/or its translocation from an intracellular pool to the plasma membrane.
Protein turnover in the human fetus studied at term using stable isotope tracer amino acids
Authors: Chien P. F. , Smith K. , Watt P. W. , Scrimgeour C. M. , Taylor D. J. , Rennie M. J.
Published: December 2017

Before elective cesarean delivery (4 h), we infused L-[1-13C]leucine and L-[15N]phenylalanine into the maternal circulation and measured enrichment and concentration of amino acids and carbon dioxide in cord blood of six normal human fetuses at delivery. There were net fetal uptakes of leucine (2.22 +/- 0.29 mumol.kg-1.min-1) and phenylalanine (0.80 +/- 0.11 mumol.kg-1.min-1) with net outputs of CO2 (6.11 +/- 1.12 ml.kg-1.min-1) and the transamination product of leucine, alpha-ketoisocaproate (1.04 +/- 0.32 mumol.kg-1.min-1). Fetal amino acid oxidation accounted for a substantial proportion of the flux from the mother (leucine, 0.36 +/- 0.09 mumol.kg-1.min-1 and phenylalanine, 0.18 +/- 0.04 mumol.kg-1.min-1). Fetal whole body accretion of leucine carbon (0.82 +/- 0.21 mumol.kg-1.min-1) was 69% of the umbilical uptake, and that of phenylalanine (0.62 +/- 0.08 mumol.kg-1.min-1) was 78%. Fetal whole body protein synthesis was approximately 13 g.kg-1.day-1, i.e., much faster than in adults but similar to that in the newborn. Net protein accretion was 2-4 g.kg-1.day-1. The placental supply of leucine and phenylalanine exceeds the fetal demand for protein synthesis by only a small amount, suggesting that the safety margin of placental transfer may be small for these amino acids. The results suggest that the method could be applied safely to studies of fetal growth retardation.
A compartmental model of acute stimulation of aldosterone secretion in vivo by potassium and ANG II
Authors: Gogerly R. L. , Coghlan J. P. , Morgenroth P. , McDougall J. G.
Published: December 2017

Conscious sheep with an adrenal autotransplant were used to study the relationship between acute change in K+ concentration and acute change in aldosterone secretion rate (ASR). The kinetics of K+ within the adrenal circulation were shown to be consistent with distribution within a single compartment. In contrast, change in ASR during and after KCl infusion was consistent with a two-compartment model, where ASR was a sigmoidal function of concentration of K+ (or other unidentified agent) in the second, or "effect," compartment. Prior work on the relationship between acute change in angiotensin II (ANG II) concentration and acute change in ASR was extended by investigating the interaction of K+ and ANG II in the control of ASR. The results of this study indicate that acute change in ANG II concentration may cause an inhibition of the usual response of the adrenal to acute change in K+ concentration.
Endothelin-1: a new autocrine/paracrine factor in rat testis
Authors: Fantoni G. , Morris P. L. , Forti G. , Vannelli G. B. , Orlando C. , Barni T. , Sestini R. , Danza G. , Maggi M.
Published: December 2017

Cultured Sertoli cells of 20-day-old rats were found to produce and release endothelin-1-like immunoreactivity (ET-1-LI) under follicle-stimulating hormone control. The elution profile of ET-1-LI from extracts of spent Sertoli cell culture medium corresponds to that of synthetic ET-1, suggesting a testicular production of authentic ET-1. In contrast, the conditioned medium from rat Leydig cells did not contain ET-1-LI. Immunohistochemical studies confirmed that, in 20-day-old rats, the positive staining was confined to some Sertoli cells, whereas interstitial cells were negative. In the adult rat testis the positivity was not limited to the tubular compartment (Sertoli cells) but was also present in the interstitium. A high concentration (13 pmol/mg protein) of high-affinity (dissociation constant = 0.6 nM) 125I-labeled ET-1 binding sites was present in Leydig cells. These sites bind ET-1 and ET-2 with 1,000-fold higher affinity than ET-3, suggesting that they correspond to the subtype ETA of the ET receptors. Specific 125I-ET-1 binding sites are present also in Sertoli cells but are 50-fold less concentrated than in Leydig cells. Our results suggest an autocrine/paracrine role for ET-1 in rat testis.
Amylin-insulin relationships in insulin resistance with and without diabetic hyperglycemia
Authors: Pieber T. R. , Stein D. T. , Ogawa A. , Alam T. , Ohneda M. , McCorkle K. , Chen L. , McGarry J. D. , Unger R. H.
Published: December 2017

To determine if increased secretion of amylin can be implicated in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) in vitro and in vivo, we studied its relationships to insulin in insulin-resistant rats with and without NIDDM. In obesity-associated and dexamethasone-induced insulin resistance without diabetes, basal and stimulated secretion of amylin and insulin by isolated pancreata were proportionately elevated, leaving the amylin-to-insulin ratio (A/I) unchanged. By contrast, whenever diabetes occurred in dexamethasone-treated rats or in spontaneously diabetic obese insulin-resistant ZDF-drt male rats, a doubling of A/I was invariably observed due to an increase in amylin without a proportional increase in insulin secretion. Correction of dexamethasone-induced hyperglycemia with the glucocorticord receptor antagonist RU-486 was accompanied by a decline in A/I. Longitudinal in vivo studies demonstrated in both spontaneous and dexamethasone-induced models of NIDDM an increase in plasma A/I at the onset of hyperglycemia. In dexamethasone-induced diabetes, the increased A/I was associated with a high proamylin mRNA relative to proinsulin mRNA. We conclude that amylin and insulin expression and secretion rise in concert in compensated insulin-resistant states, but when hyperglycemia is present the increase in amylin exceeds that of insulin. Although a role of an increased A/I in the pathogenesis of NIDDM has not been established directly, these studies indicate that such a role could be possible.
Differential glucocorticoid effects on catecholamine responses to stress
Authors: Komesaroff P. A. , Funder J. W.
Published: December 2017

There have been relatively few studies of the relationships between glucocorticoid and catecholamine responses to stress. We have therefore determined plasma levels of adrenocorticotropic hormone (ACTH), cortisol (F), norepinephrine (NE), and epinephrine (Epi) in four intact sheep treated with cortisol, dexamethasone (DM), or saline (S) and subjected to both audiovisual (barking dog) and insulin-induced hypoglycemic stress. In control sheep, exposure to both stressors resulted in acute rises in ACTH, F, Epi, and NE, with the rises after insulin being greater than those after dog stress. Pretreatment with DM blocked the ACTH and F responses to stress. Both DM and F markedly attenuated the Epi response to hypoglycemia, whereas the rises in NE after each stress and those of Epi after dog stress were unaffected by steroid treatment. In a second experiment with six sheep treated with S or DM only and subjected to the same stressors in reverse order, the same results were obtained, excluding a confounding effect of prior stress. We conclude that 1) the poststress release of NE, presumably primarily from extra-adrenal sources, is largely steroid independent; 2) the mechanism of release of Epi from the adrenal medulla in response to audiovisual stress is different from that after hypoglycemia; and 3) this may reflect different inputs from central glucocorticoid receptors to splanchnic outflow in the two situations.
Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake
Authors: Baron A. D. , Steinberg H. , Brechtel G. , Johnson A.
Published: December 2017

Insulin-mediated glucose uptake (IMGU) occurs principally in skeletal muscle. To directly examine whether skeletal muscle perfusion (F) can directly and independently modulate IMGU, we combined the hyperinsulinemic euglycemic clamp and leg balance techniques [leg glucose uptake (LGU) = arteriovenous glucose difference (delta AVG) x F]. Young (< 40 yr) healthy lean subjects were studied during euglycemic hyperinsulinemia of approximately 23 microU/ml (group I, n = 8) and approximately 950 microU/ml (group II, n = 6). Femoral delta AVG and leg F were measured, and LGU was calculated at baseline after approximately 200 min of steady-state hyperinsulinemia alone and during a superimposed intrafemoral artery infusion of methacholine hydrochloride designed to increase leg F two- to threefold. In groups I and II, insulin raised the delta AVG approximately 4- and 14-fold, respectively (P < 0.0001). Leg F was unchanged during the low-dose insulin infusion (group I) but increased 112 +/- 35% in group II (P < 0.001). During methacholine infusion the delta AVG narrowed 35.9 +/- 6.8% (P < 0.01) and 20.5 +/- 4.8% (P < 0.05) in groups I and II, respectively. Leg F rose 224 +/- 30% (P < 0.01) and 79 +/- 13% (P < 0.05) above the flow rate achieved with insulin alone. Thus, during methacholine flow modulation, LGU increased 116 +/- 36% (P < 0.01) and 47 +/- 11% (P < 0.05) in groups I and II, respectively. In conclusion, skeletal muscle perfusion during hyperinsulinemia can act as an independent determinant of IMGU.
Anabolic effect of IGF-I coinfused with total parenteral nutrition in dexamethasone-treated rats
Authors: Yang H. , Grahn M. , Schalch D. S. , Ney D. M.
Published: December 2017

We determined the anabolic effects of recombinant human insulin-like growth factor I (rhIGF-I, 800 micrograms/day) coinfused with total parenteral nutrition (TPN) in male Sprague-Dawley rats (230-250 g), with and without dexamethasone (Dex, 70 micrograms/day)-induced catabolism for 6 days. Dex without IGF-I increased serum insulin concentrations 300% and glucose concentrations 20%; IGF-I plus Dex significantly reduced serum insulin and glucose concentrations to TPN control levels. Animals given Dex without IGF-I lost 30 +/- 3 g; IGF-I plus Dex reduced the weight loss to 9 +/- 3 g, P < 0.001. IGF-I without Dex resulted in a weight gain of 14 +/- 2 g compared with a gain of 4 +/- 1 g in TPN controls, P < 0.01. Determination of nitrogen balance and body composition confirmed that changes in body weight were due to corresponding changes in nitrogen excretion and total body protein content. IGF-I significantly reduced TPN-induced intestinal atrophy, resulting in a 30% increase in weight of the small intestine plus colon compared with TPN without IGF-I. These results indicate that coinfusion of rhIGF-I with TPN counteracts Dex-induced insulin resistance and has a significant net anabolic effect when given with or without Dex in rats.
Effects of puberty and diabetes on metabolism of insulin-sensitive fuels
Authors: Caprio S. , Cline G. , Boulware S. , Permanente C. , Shulman G. I. , Sherwin R. S. , Tamborlane W. V.
Published: December 2017

Insulin's ability to stimulate glucose metabolism is reduced during normal puberty; these changes are exaggerated in adolescents with insulin-dependent diabetes mellitus (IDDM). Because the effects of puberty and IDDM on the other actions of insulin have not been established, we studied leucine kinetics (using [1-13C]leucine) and fat metabolism during euglycemic hyperinsulinemia (20 mU.m2.min-1) for 3 h in eight healthy and nine IDDM (HbA1 14 +/- 2%) adolescents and six healthy young adult controls. IDDM subjects received overnight low-dose insulin infusion to normalize fasting glucose. Basal and steady-state insulin values (approximately 240 pM) during the study were similar in all three groups. Insulin-stimulated glucose metabolism was reduced by 40% in healthy adolescents vs. adults (P < 0.05) and by an additional 40% in poorly controlled IDDM (P < 0.05 vs, normal adolescents). Although basal glucose and lipid oxidation rates (measured by indirect calorimetry) were similar in all three groups, when insulin was infused, glucose oxidation increased and lipid oxidation decreased only in the two nondiabetic groups. Similarly, insulin significantly reduced plasma free fatty acid levels only in the nondiabetics. Basal leucine flux (an index of protein degradation) was similar in healthy controls but was markedly increased in IDDM adolescents. Despite similar increments in plasma insulin during the clamp, leucine flux remained higher in IDDM adolescents than in healthy controls. Basal leucine oxidation rates were also increased in IDDM subjects compared with nondiabetic groups and declined to a lesser extent during insulin infusion. We conclude that insulin resistance of puberty is selective for glucose metabolism, sparing amino acid/protein metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Sensitivity of exercise-induced increase in hepatic glucose production to glucose supply and demand
Authors: Berger C. M. , Sharis P. J. , Bracy D. P. , Lacy D. B. , Wasserman D. H.
Published: December 2017

It was hypothesized that the exercise-induced changes in glucoregulatory hormones and glucose production (Ra) occur as a result of a small deficit in glucose availability. To test this, 18-h fasted dogs performed 150 min of treadmill exercise with either the liver as the sole source of glucose (controls, n = 5) or with glucose infused from 0 to 50 min (period 1) and from 100 to 150 min (period 3) at rates designed to track the glucose utilization (Rd) response (ExoGlc, n = 5). The liver alone supplied glucose from 50 to 100 min (period 2). Isotopic and arteriovenous methods were used to assess Ra, Rd, and gluconeogenesis (GNG). Variable [3H]glucose infusion and frequent sampling were used to facilitate Ra measurements. Arterial glucose declined by -3.1 +/- 1.4, -4.3 +/- 2.9, and -6.4 +/- 3.7 mg/dl in periods 1-3 in controls (changes are mean values during each of the 50-min periods; P < 0.05). In ExoGlc, arterial glucose did not deviate from basal in periods 1 (+0.1 +/- 1.8 mg/dl) and 3 (+1.5 +/- 4.5 mg/dl) but fell from basal (P < 0.05) by the same amount as controls in period 2 (-5.7 +/- 2.1 mg/dl). Matching the Rd response with exogenous glucose led to increases in arterial and portal vein plasma insulin levels (P < 0.05) but did not affect glucagon, norepinephrine, epinephrine, and cortisol levels. Ra was elevated by 3.1 +/- 0.5, 4.0 +/- 1.1, and 4.7 +/- 1.1 mg.kg-1.min-1 in periods 1-3 in controls (P < 0.05). In ExoGlc, Ra rose by 0.0 +/- 0.4, 4.1 +/- 1.4 (P < 0.05), and 0.4 +/- 0.7 mg.kg-1.min-1, respectively, in periods 1-3. The rise in Ra was reduced in periods 1 and 3 of ExoGlc compared with controls (P < 0.02). GNG rose to approximately 250% basal in controls and did not respond with any significant difference in ExoGlc. In summary, the exercise-induced increases in counterregulatory hormones and GNG are present even when a deficit in glucose supply is eliminated by an exogenous glucose infusion. In contrast, the fall in insulin and the rise in hepatic glycogenolysis are greatly attenuated. The regulatory components affected by exogenous glucose predominate at the liver as deviations in plasma glucose of approximately 4% correspond to approximately 60% changes in Ra.(ABSTRACT TRUNCATED AT 400 WORDS)
Effects of glucose-to-lipid ratio and type of lipid on substrate oxidation rate in patients
Authors: Delafosse B. , Viale J. P. , Tissot S. , Normand S. , Pachiaudi C. , Goudable J. , Bouffard Y. , Annat G. , Bertrand O.
Published: December 2017

This study is an investigation into the effects of different carbohydrate-to-lipid ratios on CO2 production in postoperative patients and the determination of the substrate oxidation rates induced by long-chain triglycerides (LCT) or a mixture of long- and medium-chain triglycerides (MCT/LCT) at various carbohydrate-to-lipid ratios. Two groups of eight patients randomly received either LCT or MCT/LCT emulsions. Total caloric intake was set at the measured energy expenditure provided at three different glucose-to-lipid ratios (70:30, 50:50, 30:70). We used long-term indirect calorimetry with a mass spectrometer system and measurement of natural enrichment in 13C of expired CO2 and plasma glucose. The carbon dioxide production and minute ventilation were not different among the different glucose-to-lipid ratios, whatever the type of lipid. Increasing the lipid supply up to 70% of nonprotein caloric intake led to an only minor increase in lipid oxidation rate and thus to a net fat deposit. We conclude that large amounts of lipid (LCT or MCT/LCT) were not of interest in such patients.
Hepatic denervation does not significantly change the response of the liver to glucagon in conscious dogs
Authors: Wada M. , Connolly C. C. , Tarumi C. , Neal D. W. , Cherrington A. D.
Published: December 2017

In view of the increasing frequency of liver transplantation, and the importance of glucagon in the minute-to-minute regulation of glucose production, we assessed the effect of hepatic denervation on the liver's response to a physiological rise in glucagon in 18-h fasted dogs. Before study (2 wk), the dogs underwent liver denervation (DN; n = 6) or sham operation (SH; n = 5). Endogenous insulin and glucagon secretion were inhibited using somatostatin, and the two hormones were replaced intraportally in basal amounts. After the control period the glucagon infusion rate was tripled for 3 h. Glucagon increased from 41 +/- 8 to 128 +/- 8 and 54 +/- 4 to 129 +/- 9 pg/ml in SH and DN, respectively (P < 0.05), causing tracer-determined glucose production to increase from 2.5 +/- 0.1 to 4.9 +/- 0.5 and 2.3 +/- 0.1 to 5.8 +/- 0.8 mg.kg-1.min-1 by 15 min, respectively (P < 0.05). Glucose clearance fell slightly during glucagon infusion in DN, causing a somewhat greater increase in the plasma glucose level (to 175 +/- 15 vs. 207 +/- 20 mg/dl). The changes in gluconeogenic efficiency increased 65-90% in both groups (P < 0.05). In conclusion, denervation of the liver failed to significantly alter the metabolic response of that organ to a half-maximally effective increment in the plasma glucagon level.
Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men
Authors: Coggan A. R. , Swanson S. C. , Mendenhall L. A. , Habash D. L. , Kien C. L.
Published: December 2017

In humans, endurance training markedly reduces the rate of hepatic glucose production during exercise. To determine whether this is due to a reduction in glycogenolysis, in gluconeogenesis, or in both processes, six men were studied at rest and during 2 h of cycle ergometer exercise at 60% pretraining peak O2 consumption (VO2peak), both before and after completion of a strenuous endurance training program (cycling at 75-100% VO2peak for 45-90 min/day, 6 days/wk for 12 wk). The overall rate of glucose appearance (Ra) was determined using a primed continuous infusion of [6,6-2H]glucose, whereas the rate of gluconeogenesis (Rgng) was estimated from the incorporation of 13C into glucose (via pyruvate carboxylase) from simultaneously infused [13C]bicarbonate. Training did not affect glucose kinetics at rest but reduced the average Ra during exercise by 42% [from 36.8 +/- 3.8 to 21.5 +/- 3.6 (SE) mumol.min-1.kg-1; P < 0.001]. This decrease appeared to be mostly due to a reduction in hepatic glycogenolysis. However, the estimated Rgng during exercise also decreased significantly (P < 0.001) with training, falling from 7.5 +/- 1.6 mumol.min-1.kg-1 (23 +/- 3% of total Ra) before training to 3.1 +/- 0.6 mumol.min-1.kg-1 (14 +/- 3% of total Ra) after training. These training-induced adaptations in hepatic glucose metabolism were associated with an attenuated hormonal response to exercise (i.e., higher insulin and lower glucagon, norepinephrine, and epinephrine concentrations) as well as a reduced availability of gluconeogenic precursors (i.e., lower lactate and glycerol concentrations). We conclude that endurance training reduces both hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men.
Growth hormone reduces glucose transport but not GLUT-1 or GLUT-4 in adult and old rats
Authors: Cartee G. D. , Bohn E. E.
Published: December 2017

The primary purpose of this study was to investigate the influence of administration of recombinant-derived human growth hormone (rhGH) to adult male rats of several ages (9, 20, and 31 mo) on skeletal muscle glucose transport. Rats were injected with rhGH (0.7 mg/kg) or vehicle twice daily for 10 days. The rhGH treatment led to a doubling of circulating insulin-like growth factor I levels at each age. Skeletal muscle glucose transport activity was evaluated in isolated epitrochlearis muscle with use of 3-O-methylglucose at three insulin concentrations (0, 100, and 20,000 microU/ml). The results indicate that, after 10 days of rhGH administration, 1) an approximately 20-30% reduction in basal glucose transport activity was evident in muscles from every age group, 2) the ability of a submaximally effective insulin concentration (100 microU/ml) to increase glucose transport activity above basal values was not significantly reduced in any age group, 3) maximal insulin-stimulated glucose transport activity (with 20,000 microU/ml) was significantly reduced (approximately 40%) by rhGH treatment only in the oldest rats, and 4) the alterations in glucose transport activity occurred despite no change in skeletal muscle GLUT-1 or GLUT-4 protein levels.
Bradykinin-stimulated calcium influx in cultured bovine aortic endothelial cells
Authors: Schilling W. P. , Ritchie A. K. , Navarro L. T. , Eskin S. G.
Published: December 2017

Bradykinin (BK)-stimulated release of endothelium-derived relaxing factor has been linked to a rise in cytosolic Ca2+ concentration and a change of K+ permeability of the endothelial cell. In the present study, measurement of BK-induced changes in fura-2 fluorescence and 86Rb+ efflux were used to monitor changes in cytosolic Ca2+ and K+ permeability in cultured bovine aortic endothelial cells. In the presence of normal extracellular Ca2+, BK induced a fourfold increase in cytosolic Ca2+, which peaked at 20 s and declined within 1 min to a value that was 50% of the peak level. Subsequently, cytosolic Ca2+ decreased and approached basal levels within 8 min. In the absence of Ca2+, BK produced a 1.5- to 2-fold increase in cytosolic Ca2+ that peaked within 20 s and declined to basal levels within 2 min. Addition of Ca2+ to the Ca-free reaction buffer 3-5 min after addition of BK resulted in a two-to threefold increase in cytosolic Ca2+ that declined slowly back to basal levels. Thus Ca2+ influx can occur in response to BK at a time when there is minimal elevation of cytosolic Ca2+ above the resting level. Under all conditions tested, 86Rb+ efflux paralleled changes in the cytosolic Ca2+, suggesting that efflux occurred through Ca2+-activated K+ channels. Isosmotic substitution of Na+ with N-methyl-D-glucamine did not affect the BK-stimulated changes in cytosolic Ca2+ or 86Rb+ efflux, suggesting that Na+-Ca2+ exchange plays little role in the BK response. These results suggest that BK stimulates Ca2+ influx via a BK receptor-operated channel or a channel activated by some internal messenger other than Ca2+.
Changes in coronary pressure-flow relation after transition from blood to Tyrode perfusion
Authors: Van Dijk L. C. , Krams R. , Sipkema P. , Westerhof N.
Published: December 2017

In six isolated, diastolic-arrested, maximally vasodilated cat hearts, we studied changes in coronary pressure-flow relations (zero-flow pressure intercept, resistance) during the first 25 min, after a change of perfusate, from blood to Tyrode. The apparent intercept (zero-flow) pressure changed from 2.0 +/- 0.94 (+/- SD) kPa during blood perfusion to 2.5 +/- 0.55, 2.6 +/- 0.68, 2.5 +/- 0.94, and 2.7 +/- 1.34 kPa during Tyrode perfusion for 2:15, 5:30, 10:30, and 25:00 min, respectively. Intercept pressures during Tyrode perfusion were significantly different from the intercept pressure during blood perfusion, except for the one measured after 25 min of Tyrode perfusion (P less than 0.05). Resistance (defined as the ratio of perfusion pressure and flow at 10 kPa perfusion pressure) steadily rose to approximately 170% of the value during blood perfusion. The observation that the apparent intercept pressure is maintained, when a particle-free (Newtonian) isotonic perfusate is used, may indicate that this intercept is not a result of blood rheology alone. The increase rather than decrease in resistance suggests an effect of edema, which increases interstitial volume at the expense of intravascular volume.
Baroreflex modulation of heart rate and initiation of atrial activation in dogs
Authors: Schuessler R. B. , Canavan T. E. , Boineau J. P. , Cox J. L.
Published: December 2017

In open-chest dogs, blood pressure was regulated by titrating doses of phenylephrine and nitroprusside to determine its effect on heart rate and pacemaker location. Changes in blood pressure correlated with changes in heart rate (r = 0.86). Activation time mapping demonstrated multicentric atrial activation, with a site of origin-rate relationship. The fastest pacemakers were located in the most cranial regions and slowest in the most caudal areas. In this chloralose-morphine anesthetized model, autonomic blockade with atropine and propranolol suggests that acute baroreflex-induced changes in heart rate were mediated exclusively by either increased sympathetic or parasympathetic tone and were not associated with inhibition of the opposite system. Division of right and left thoracic cardiac nerves indicated the left sympathetics participated in the baroreflex in 50% of the animals and the left parasympathetics in 90% of the animals. Both the right sympathetics and parasympathetics were active in the baroreflex in all animals. The data demonstrate that physiological heart rate response is regulated through an extensive system of right atrial pacemakers modulated by both left and right efferent cardiac nerves.
Amiloride enhances postischemic ventricular recovery: possible role of Na+-H+ exchange
Authors: Karmazyn M.
Published: December 2017

Amiloride (40 micrograms/ml) was studied in the isolated rat heart subjected to low-flow ischemia followed by reperfusion. Reperfusion after 30 min of ischemia produced recoveries of force, rate of force development (+dF/dt), and rate of relaxation (-dF/dt) of 42, 82, and 71%, respectively, in control hearts. Amiloride did not enhance the maximum degree of recovery, although, when present during ischemia, it markedly shortened the time required for peak recovery. Reperfusion after 60 min of ischemia resulted in 18, 43, and 34% recovery of force, +dF/dt, and -dF/dt, respectively. Amiloride significantly enhanced recovery to a maximum of 39, 88, and 78% for force, +dF/dt, and -dF/dt, respectively. The improved contractile recovery was accompanied with substantial reductions in the release of creatine kinase (CK) and 6-ketoprostaglandin F1 alpha. Coronary perfusion pressure and resting tension were generally unaffected by amiloride, although there was a moderate tendency to attenuate these parameters after reperfusion. The salutary effects of amiloride were dependent on the drug's presence during ischemia with maximum protection when it was administered during both ischemia and reperfusion and no benefit when added at the time of reperfusion. Because of amiloride's well-documented property in inhibiting Na+-H+ exchange, it is possible that this process plays an important role in modulating the cardiac response to reperfusion.
NE turnover in genetically hypertensive rats of Lyon strain. II. Peripheral organs
Authors: Sautel M. , Sacquet J. , Vincent M. , Sassard J.
Published: December 2017

The peripheral sympathetic nervous system (SNS) is a major determinant of blood pressure and is likely to be involved in the pathophysiology of hypertension. Because SNS activity varies among organs, we measured the in vivo turnover (TO) of norepinephrine (NE) in seven organs of 5- and 22-wk-old genetically hypertensive (LH), normotensive (LN), and low blood pressure (LL) rats of the Lyon strains. The TO of NE was found normal in the superior cervical ganglia and decreased in the heart of 5-wk-old LH rats compared with both LL and LN controls. This suggests that sympathetic cardiac innervation may not be involved in the development of hypertension. On the contrary, an increased TO of NE in the kidney cortex and an elevated TO of dopamine associated with an increased epinephrine content in the adrenal medulla were observed in 5-wk-old LH rats, which could participate in the development of hypertension in the Lyon model.
[14C]butanol distribution: a new method for measurement of spinal cord blood flow
Authors: Sakamoto T. , Shimazaki S. , Monafo W. W.
Published: December 2017

[14C]butanol distribution was used to quantitate regional blood flow (SCBF) in the spinal cord (levels T3-5, T7-9, L1-2, L3-S) and in the sciatic nerves (NBF) of control pentobarbital sodium-anesthetized rats (group A), after 1 h of hemorrhagic hypotension (group B), after 15 min of stimulation of one sciatic nerve (group C-1), and after stimulation of one sciatic nerve plus hemorrhage, which maintained mean arterial pressure (MAP) at control (130 mmHg). Group A SCBF ranged from 52.3 +/- 3.5 (L3-S) to 67.4 +/- 2.7 (L1-2) ml.min-1.100 g-1. NBF was 8.0 +/- 0.9 ml.min-1.100 g-1. Group B SCBF was unchanged. NBF fell to 4.0 +/- 0.4 ml.min-1.100 g-1. Group C-1 SCBF was markedly elevated (range 122 +/- 23.1 to 150.1 +/- 18.7 ml.min-1.100 g-1). NBF was 33.5 +/- 4.1 ml.min-1.100 g-1 (stimulated side) and 14.7 +/- 1.4 ml.min-1.100 g-1 (nonstimulated). MAP was elevated (163 +/- 6 mmHg). In group C-2 (MAP was 130 +/- 4 mmHg), SCBF was still elevated at T3-5, L3-S, and marginally elevated at L1-2. NBF was 22.6 +/- 4.7 ml.min-1.100 g-1 (stimulated) but unchanged contralaterally. [14C]butanol distribution provides a sensitive reproducible measure of SCBF and NBF. Autoregulation of SCBF (but not of NBF) occurred in the range 60-160 mmHg MAP. Spinal cord stimulation via the sciatic nerve increased SCBF two- to threefold, but when hypertension was avoided by blood withdrawal, a modest (38%) increase in SCBF still occurred.
Antibodies against ADP-ATP carrier enhance Ca2+ current in isolated cardiac myocytes
Authors: Morad M. , Davies N. W. , Ulrich G. , Schultheiss H. P.
Published: December 2017

Antibodies previously described to inhibit specifically nucleotide transport (ADP-ATP carrier) of the inner mitochondrial membrane were found to bind specifically to the sarcolemma of the enzymatically isolated rat ventricular myocytes. In this communication, we report for the first time that a component of these antibodies enhanced the Ca2+ current in isolated cardiac myocytes and potentiated twitch tension in ventricular strips. Prolonged exposure of rat myocytes to large concentrations of antibodies caused spontaneous contractions, progressive cell deterioration, and death. Our results thus show that a component of antibodies against ADP-ATP carrier cross-reacts with cardiac sarcolemmal proteins enhancing the Ca2+ channel.