bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of extracellular glucose distribution and glucose transport activity in conscious rats
Authors: Youn J. H. , Kim J. K. , Steil G. M.
Published: December 2017

The effects of insulin on extracellular glucose distribution and cellular glucose transport activity were studied by simultaneously analyzing the plasma kinetics of L-[1-14C]glucose and 3-O-[3H]methylglucose after an intravenous injection during saline or insulin infusion (euglycemic glucose clamp) in conscious rats (n = 7 for each). The time profiles of plasma L-glucose were almost superimposable in the two protocols, and compartmental analysis showed that neither distribution volumes nor distribution rate constants were affected with insulin (P > 0.05 for all), suggesting that glucose distribution within the extracellular space was not influenced with insulin. In contrast, the time profile of plasma 3-O-methylglucose (3-MG) was markedly altered with insulin; the initial decrease was much faster during insulin infusion than during saline infusion, indicating stimulation of 3-MG transport into intracellular spaces with insulin. The 3-MG data were analyzed using a comprehensive model separately describing extracellular distribution and cellular transport of 3-MG by incorporating information on extracellular distribution kinetics obtained from L-glucose data. The combined L-glucose and 3-MG kinetic analysis precisely estimated insulin's effect in vivo to stimulate glucose transport into and out of intracellular spaces. We conclude that 1) insulin does not affect extracellular glucose distribution kinetics or volumes in conscious rats and 2) insulin's effects on cellular glucose transport in vivo can be assessed by simultaneous analysis of plasma L-glucose and 3-MG kinetics.
Endocrinologic and metabolic effects of interleukin-6 in humans
Authors: Stouthard J. M. , Romijn J. A. , Van der Poll T. , Endert E. , Klein S. , Bakker P. J. , Veenhof C. H. , Sauerwein H. P.
Published: December 2017

Interleukin-6 (IL-6) is one of the major circulating cytokines in catabolic states. To investigate its endocrinologic and metabolic actions in vivo, we studied eight patients with metastatic renal cell cancer two times, once during infusion of saline (control) and once during a 4-h infusion of 150 micrograms recombinant human IL-6 (rhIL-6). Rates of appearance (Ra) of glucose and free fatty acids (FFA) in plasma were measured by using the isotope dilution method. Energy expenditure and substrate oxidation were determined by indirect calorimetry. rhIL-6 induced increases in plasma norepinephrine (+261 +/- 97%, P < 0.001), cortisol (+210 +/- 48%, P < 0.001), and glucagon (+70 +/- 18%, P < 0.001), in resting energy expenditure (+25 +/- 2%, P < 0.001 vs. control), and in plasma FFA concentration (+60 +/- 30%, P < 0.001), FFA Ra (+105 +/- 18%, P < 0.001), and fat oxidation (+38 +/- 16%, P < 0.001). Glucose Ra increased by 20 +/- 5% (P < 0.01) during rhIL-6 infusion with a concomitant increase in the metabolic clearance rate of glucose. In conclusion, our data demonstrate that rhIL-6 induces many of the endocrinologic and metabolic changes found in catabolic states and thus may mediate some of the metabolic effects previously ascribed to other cytokines.
Involvement of renin-angiotensin system in the reduced pressure natriuresis response of hyperthyroid rats
Authors: Garcia-Estan J. , Atucha N. M. , Quesada T. , Vargas F.
Published: December 2017

Previous studies have indicated that the pressure diuresis and natriuresis (PDN) response is greatly impaired in thyroxine-treated hypertensive rats. In the present study, we have examined the role of the renin angiotensin system (RAS) as a mediator of these alterations by characterizing the relationships between renal perfusion pressure and urine flow and sodium excretion in hyperthyroid rats acutely treated with a converting-enzyme inhibitor (captopril, 2 mg/kg) or an AT1 angiotensin II receptor blocker (losartan, 10 mg/kg). In the control animals, captopril did not change mean arterial pressure (MAP) or renal blood flow (RBF) but significantly decreased MAP and increased RBF and glomerular filtration rate in the hyperthyroid rats. Captopril did not change the PDN response of the control animals but improved significantly that of the hyperthyroid rats, although it was not completely normalized. Losartan also significantly improved renal hemodynamics and excretion in hyperthyroid rats. These results indicate that an increased intrarenal activity of the RAS is partly responsible for the blunted renal PDN mechanism of the hyperthyroid rats.
Mechanism of gluconeogenesis inhibition in rat hepatocytes isolated after in vivo hypoxia
Authors: Pison C. M. , Chauvin C. , Fontaine E. , Catelloni F. , Keriel C. , Paramelle B. , Leverve X. M.
Published: December 2017

Gluconeogenesis was studied in hepatocytes isolated from fasted rats submitted to 24 h of hypoxic exposure (inspired O2 fraction 0.1) or to room air. Hepatocytes from hypoxic rats compared with controls exhibited a lower gluconeogenic rate with lactate (5.1 +/- 0.3 vs. 7.2 +/- 0.3 mumol.min-1.g dry cells-1, P < 0.001) but not with dihydroxyacetone (9.1 +/- 0.3 vs. 9.4 +/- 0.4 mumol.min-1.g dry cells-1), suggesting involvement of the phosphoenolpyruvate-pyruvate cycle. Experiments with perifused hepatocytes from hypoxic and control rats showed a single relationship between phosphoenolpyruvate and glucose flux (JGlc) but two different curves when cytosolic oxalacetate was plotted against JGlc. The decreased phosphoenolpyruvate carboxykinase (PEPCK) activity in the hypoxic group (9.0 +/- 0.9 vs. 16.2 +/- 1.9 nmol.min-1.mg protein-1, P < 001) without change in the Michaelis constant further settled the involvement of this step. The significant decrease in PEPCK mRNA levels in livers from hypoxic rats led us to propose that in vivo hypoxic exposure inhibits gluconeogenesis at the PEPCK level by decreasing PEPCK gene transcription.
Insulin-stimulated glucose uptake is enhanced in sedentary and endurance-trained low insulin responders
Authors: Pigon J. , Efendic S. , Ostenson C. G. , Lam L. , Vranic M. , Giacca A.
Published: December 2017

The mechanisms by which healthy sedentary subjects with low insulin response (LIR; 5-min insulin response to glucose load within lowest quartile of healthy population) maintain a normal glucose tolerance are not clear. We studied glucose uptake and hepatic glucose production in LIR, in healthy subjects with high insulin response (HIR; two highest quartiles of insulin response) matched for weight and physical fitness, and in endurance-trained subjects (ET). For this purpose, we performed hyperinsulinemic euglycemic clamps using the “hot-GINF” method with high-pressure liquid chromatography purified [6-3H]glucose. All groups had a similar basal glucose appearance rate (Ra). During clamps, plasma insulin levels were doubled to 169 +/- 9 pmol/l, whereas Ra decreased similarly in all groups. Glucose utilization rate increased more in LIR and ET than in HIR (to 20.9 +/- 1.5 mumol.kg-1.min-1 in LIR, P < 0.001 vs. HIR; 27.4 +/- 3.6 in ET, P < 0.01 vs. HIR and LIR; and 14.3 +/- 0.6 in HIR). In conclusion, the present study demonstrates increased insulin sensitivity in LIR and ET with respect to glucose uptake but not glucose production.
Creatine kinase kinetics in diabetic cardiomyopathy
Authors: Matsumoto Y. , Kaneko M. , Kobayashi A. , Fujise Y. , Yamazaki N.
Published: December 2017

One feature of the diabetic cardiomyopathy is the appearance of contractile dysfunction as the workload increases. We hypothesized that this resulted from an impaired creatine kinase/phosphocreatine system and therefore examined the creatine kinase kinetics at both low and high workloads. Creatine kinase flux (by 31P nuclear magnetic resonance saturation transfer method), cardiac performance, and oxygen consumption were measured in control and streptozotocin-induced diabetic rat hearts. Creatine kinase flux was inhibited by iodoacetamide in control hearts to confirm the role of the creatine kinase/phosphocreatine system in cardiac performance. In diabetic hearts, 1) the contractile dysfunction became apparent only at high workloads, 2) the ATP synthesis rate was not significantly different from control hearts, 3) the creatine kinase flux was reduced by 30.8% (257.5 +/- 7.7 mumol.g wet wt-1.min-1 in control vs. 178.3 +/- 9.4 in diabetes, P < 0.001), and 4) the creatine kinase flux did not increase as the workload increased. In control hearts, 5) iodoacetamide inhibited the creatine kinase flux to the same degree as that in diabetic hearts, and 6) the contractile dysfunction was not as severe as that observed in diabetic hearts. These results suggest that the impaired creatine kinase/phosphocreatine system is, at least in part, responsible for the contractile dysfunction in the diabetic cardiomyopathy.
Blood-brain barrier permeability of glucose and ketone bodies during short-term starvation in humans
Authors: Hasselbalch S. G. , Knudsen G. M. , Jakobsen J. , Hageman L. P. , Holm S. , Paulson O. B.
Published: December 2017

The blood-brain barrier (BBB) permeability for glucose and beta-hydroxybutyrate (beta-OHB) was studied by the intravenous double-indicator method in nine healthy subjects before and after 3.5 days of starvation. In fasting, mean arterial plasma glucose decreased and arterial concentration of beta-OHB increased, whereas cerebral blood flow remained unchanged. The permeability-surface area product for BBB glucose transport from blood to brain (PS1) increased by 55 +/- 31%, whereas no significant change in the permeability from brain back to blood (PS2) was found. PS1 for beta-OHB remained constant during starvation. The expected increase in PS1 due to the lower plasma glucose concentration was calculated to be 22% using previous estimates of maximal transport velocity and Michaelis-Menten affinity constant for glucose transport. The determined increase was thus 33% higher than the expected increase and can only be partially explained by the decrease in plasma glucose. It is concluded that a modest upregulation of glucose transport across the BBB takes place after starvation. Brain transport of beta-OHB did not decrease as expected from the largely increased beta-OHB arterial level. This might be interpreted as an increase in brain transport of beta-OHB, which could be caused by induction mechanisms, but the large nonsaturable component of beta-OHB transport makes such a conclusion difficult. However, beta-OHB blood concentration and beta-OHB influx into the brain increased by > 10 times. This implies that the influx of ketone bodies into the brain is largely determined by the amount of ketones present in the blood, and any condition in which ketonemia occurs will lead to an increased ketone influx.
Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects
Authors: Marfella R. , Verrazzo G. , Acampora R. , La Marca C. , Giunta R. , Lucarelli C. , Paolisso G. , Ceriello A. , Giugliano D.
Published: December 2017

The present study aimed at evaluating whether acute elevations of plasma glucose concentrations could influence systemic hemodynamic parameters and baroreflex activity in humans. Plasma glucose concentrations were acutely raised to 15 mmol/l in 12 healthy male volunteers. During hyperglycemia, there were significant increments of systolic [from 118 +/- 9 to 138 +/- 12 (SD) mmHg, P < 0.01] and diastolic (from 71 +/- 5 to 85 +/- 6 mmHg, P < 0.001) blood pressure, as well as heart rate (from 76 +/- 7 to 85 +/- 10 beats/min, P < 0.01) and plasma catecholamine levels. Both maximal and steady-state mean arterial pressure after squatting were higher during hyperglycemia (27 +/- 8 and 16 +/- 6 mmHg, respectively) compared with levels obtained during euglycemia (18 +/- 5 and 2 +/- 0.6 mmHg, respectively, P < 0.001). The infusion of the somatostatin analogue octreotide (25 micrograms as i.v. bolus followed by a 0.5 microgram/min infusion), to avoid the possible confounding vascular actions of insulin, did not influence the hemodynamic effects of hyperglycemia except for a lesser increase of both heart rate and plasma catecholamines. Glutathione (600 mg as an iv bolus followed by a 5 mg/min infusion) completely prevented the vascular effects of hyperglycemia. This study shows that acute hyperglycemia, similar to that observed in poorly controlled diabetic patients, produces relevant systemic hemodynamic changes and also alters baroreflex activity via a glutathione-sensitive presumably free radical-mediated pathway.
Cold acclimation induces zonal heterogeneity in gluconeogenic responses to glucagon in rat liver lobule
Authors: Shiota M. , Inagami M. , Fujimoto Y. , Moriyama M. , Kimura K. , Sugano T.
Published: December 2017

The relationship between the enhanced responses of gluconeogenesis to norepinephrine (NE) and glucagon and its zonal distribution was studied in liver lobules of cold-exposed rats by examination of preparations enriched for periportal hepatocytes (PP-H) and for perivenous hepatocytes (PV-H) by the digitonin-collagenase perfusion technique. In the control group, gluconeogenesis from lactate (10 mM) plus pyruvate (1 mM) was higher in PP-H than in PV-H. NE (100 nM) and glucagon (100 nM) increased the rate of gluconeogenesis by 80 and 70%, respectively, in both PP-H and PV-H. Gluconeogenesis in PP-H was unchanged by cold exposure. The rate in PV-H increased to the rate in PP-H at 5 days after cold exposure, and then the rate returned to the control value at 20 days. The gluconeogenic response to the alpha-adrenergic action of NE in both PP-H and PV-H doubled after 5 days. The response to glucagon tripled in PP-H and was cut in half in PV-H after 20 days. Phorbol 12-myristate 13-acetate (PMA; 1 microM), A-23187 (100 nM), and dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP; 1 mM) increased the rate of gluconeogenesis by 200, 100, and 80%, respectively, in both PP-H and PV-H from the control group. The responses to PMA and A-23187 were unchanged by exposure to cold. The response to DBcAMP was doubled in PP-H and was cut in half in PV-H after 20 days of cold exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Central adiposity and its metabolic correlates in obese adolescent girls
Authors: Caprio S. , Hyman L. D. , Limb C. , McCarthy S. , Lange R. , Sherwin R. S. , Shulman G. , Tamborlane W. V.
Published: December 2017

To establish whether alterations in insulin action and secretion and their relationship to body fat distribution occur early in the course of developing obesity, we studied 14 obese adolescent girls [13.2 +/- 0.7 yr, body mass index (BMI) 32 +/- 1.4], 16 nonobese young women (24.0 +/- 0.6 yr, BMI 21.0 +/- 0.9). Insulin action was assessed by a sequential two-step (8 and 40 mU,m-2.min-1) euglycemic insulin clamp in combination with [1-13C]glucose and indirect calorimetry. Insulin secretion was determined by the hyperglycemic clamp technique (6.9 mmol/l). Magnetic resonance imaging was used to quantify visceral and subcutaneous abdominal fat depots. In obese girls, an impairment in glucose disposal was present with both insulin doses; at the higher dose, rates of glucose uptake were reduced by 30% in nonobese girls (240 +/- 30 vs. 340 +/- 19 mg.m-2.min-1, P < 0.05) and by an additional 29% (170 +/- 17 mg.m-2.min-1, P < 0.05) in obese girls. Insulin infusion failed to stimulate glucose oxidation and to suppress lipid oxidation only in obese girls. Suppression of free fatty acid levels, but not hepatic glucose production, was decreased in obese girls compared with controls. Fasting and glucose-stimulated insulin responses were greater in obese than in nonobese adolescents, who, in turn, had greater responses than lean women. In obese girls, visceral fat, but neither waist-to-hip circumference ratio nor subcutaneous fat, was highly correlated with basal insulin secretion (r = 0.89, P < 0.001), stimulated insulin secretion (r = 0.61, P < 0.05), and insulin resistance (r = -0.87, P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Bicarbonate kinetics in humans: identification and validation of a three-compartment model
Authors: Saccomani M. P. , Bonadonna R. C. , Caveggion E. , DeFronzo R. A. , Cobelli C.
Published: December 2017

A model of bicarbonate kinetics is crucial to a correct interpretation of experiments for measuring oxidation in vivo of carbon-labeled compounds. The aim of this study is to develop a compartmental model of bicarbonate kinetics in humans from tracer data by devoting particular attention to model identification and validation. The data base consisted of impulse-dose studies of 14C-labeled bicarbonate in nine normal subjects. The decay curve of specific activity of CO2 in expired air (saRCO2) was frequently sampled for 4-7 h. In addition, endogenous production of CO2, VCO2, was measured by indirect calorimetry. A model of data, i.e., an exponential model, analysis of decay curves of saRCO2 showed first that three compartments are necessary and sufficient to describe bicarbonate tracer kinetics. Compartmental models were then used as models of system. To correctly describe the input-output configuration, labeled CO2 flux in the expired air, phi RCO2 (= saRCO2.VCO2), has been used as measurement variable in tracer model identification. A mammillary three-compartment model with a respiratory and a nonrespiratory loss has been studied. Whereas there is good evidence that respiratory loss takes place in the central compartment, whether nonrespiratory loss is taking place in the central compartment or in one of the two peripheral compartments is uncertain. Thus three competing tracer models were considered. Using a model-independent analysis of data, based on the body activity variable, to calculate mean residence time in the system, we have been able to validate a specific model structure, i.e., with the two irreversible losses taking place in the central compartment. This validated tracer model was then used to quantitate bicarbonate masses in the system. Because there is uncertainty about where endogenous production enters the system, lower and upper bounds of masses of bicarbonate in the body are derived.
Responses of immunoreactive ACTH and bioactive ACTH to large hemorrhage and resuscitation in conscious dogs
Authors: Lilly M. P. , Gala G. J. , Sutherland B. E. , Gann D. S.
Published: December 2017

We studied the effect of fluid resuscitation on immunoreactive adrenocorticotropic hormone (irACTH) and bioactive ACTH (bioACTH) after hemorrhage in conscious dogs. Animals (n = 7) were bled 30% (approximately 25 ml/kg) over 3 min and 30 min later were either resuscitated [43.3 ml/kg 0.9% NaCl (1.8 times hemorrhage volume) over 10 min] or not. Blood was reinfused after 210 min. Animals had both treatments (> 4 days apart). irACTH, bioACTH, cortisol, angiotensin II, and aldosterone increased rapidly after hemorrhage. Resuscitation increased blood volume and cardiac output to resting values, but arterial hypotension persisted. bioACTH and irACTH decreased 40-90 min after hemorrhage in both groups, but each decreased more rapidly after resuscitation. The elimination half-life of bioACTH was shorter than that of irACTH, but neither was affected by resuscitation. The ratio of bioACTH to irACTH followed the same pattern with or without resuscitation. Angiotensin II and aldosterone remained increased without resuscitation but decreased promptly after resuscitation. In conclusion, 1) saline infusion at 1.8 x hemorrhage volume provides effective cardiovascular resuscitation, with resolution of hormonal responses to hemorrhage; 2) although ACTH responses resolved with or without resuscitation, resuscitation produced more rapid resolution without changing the parameters of ACTH elimination; 3) the dynamics of the resolution of the ACTH response to hemorrhage are similar whether induced by stimulus removal or feedback inhibition.
Role of prolactin and gonadal steroids in regulation of oxytocin mRNA during lactation
Authors: Ghosh R. , Sladek C. D.
Published: December 2017

The role of suckling, prolactin, and gonadal steroids in regulating hypothalamic oxytocin (OT) mRNA content during the 1st and 2nd wk of lactation was evaluated. On day 4 of lactation, OT mRNA content decreased in rats removed from their litter for 24 h compared with suckled controls. Either suckling (in the absence of prolactin release) or prolactin (in the absence of suckling) maintained OT mRNA content at this stage of lactation. In contrast, at day 11 of lactation, OT mRNA content remained unchanged in rats deprived of pups for 24 h. Ovariectomy did not compromise the ability of day 11 nonsuckled rats to maintain OT mRNA content; however, the increased water intake, plasma prolactin, plasma vasopressin (VP), plasma renin concentration, and hypothalamic VP mRNA content at day 11 compared with day 4 suggest a role for fluid balance in determining OT mRNA content during the 2nd wk of lactation. Thus, at day 4, suckling is a major determinant of OT mRNA content as a result of both direct activation of neuronal afferents to the OT neurons and stimulation of prolactin release. This is in contrast to day 11, when fluid balance may predominate in regulation of OT mRNA.
Melatonin inhibition of GnRH-induced LH release from neonatal rat gonadotroph: involvement of Ca2+ not cAMP
Authors: Vanecek J. , Klein D. C.
Published: December 2017

Melatonin inhibits gonadotropin-releasing hormone-induced release of luteinizing hormone (LH) from the neonatal rat gonadotrophs. The second messenger involved is not known, although there are several candidates, including adenosine 3',5'-cyclic monophosphate (cAMP) and intracellular free Ca2+. The present study addresses the question of which second messenger mediates melatonin inhibition of LH release. We found that the effect of melatonin was not prevented by cAMP protagonists, including 8-bromo-cAMP, dibutyryl cAMP, 3-isobutyl-1-methylxanthine, and forskolin. However, treatments that enhanced Ca2+ influx masked the effects of melatonin, and treatments that blocked Ca2+ influx mimicked the effects of melatonin. Moreover, melatonin decreased K(+)-induced LH release, which is dependent on Ca2+ influx but did not block release of LH due to thapsigargin-induced mobilization of Ca2+ from intracellular stores. These findings indicate that melatonin inhibits gonadotropin-releasing hormone-induced LH release, primarily through an action involving inhibition of Ca2+ influx, and that cAMP does not seem to be involved in this effect of melatonin.
Gastric inhibitory polypeptide release from a tumor-derived cell line
Authors: Kieffer T. J. , Huang Z. , McIntosh C. H. , Buchan A. M. , Brown J. C. , Pederson R. A.
Published: December 2017

A cell line derived from intestinal tumors of transgenic mice (STC-1) was subcloned to produce a stable line with approximately 30% immunoreactive gastric inhibitory polypeptide (irGIP)-containing cells (STC 6-14). High-performance liquid chromatography (HPLC) of STC 6-14 extracts indicated that the tumor cell-derived irGIP had the same retention time as synthetic porcine GIP-(1-42) (pGIP). Approximately 30% of the cells also contained immunoreactive somatostatin (irSS), which eluted as a single peak on HPLC, corresponding with SS-(1-14). On average, each well of extracted cells (5.0 x 10(5) cultured 4 days) contained 33.3 +/- 1.4 ng irGIP and 18.4 +/- 1.5 ng irSS. Basal release of irGIP in the presence of 5 mM glucose was 733 +/- 58 pg.ml cells-1.2h-1 (2.20 +/- 0.17% of total cell content; TCC) and doubled at 20 mM glucose (4.20 +/- 0.42% TCC). The response to glucose was augmented by addition of a SS neutralizing antibody (SOMA-10) and suppressed by 10 nM SS. Basal release of irSS in 5 mM glucose was 377 +/- 35 pg.ml cells-1.2h-1 (2.05 +/- 0.19% TCC) and was increased by glucose (> or = 15 mM) and the addition of pGIP (> or = 1 nM). The STC 6-14 cell line represents a model to study the synthesis, storage, and release of GIP and SS in a controlled environment.
Interaction of decreased arterial PO2 and exercise on carbohydrate metabolism in the dog
Authors: Zinker B. A. , Wilson R. D. , Wasserman D. H.
Published: December 2017

To determine the mechanism by which low arterial PO2 (PaO2) affects muscle carbohydrate (CHO) metabolism during exercise, dogs inhaled gas consisting of 0.21 (NO; n = 6) or 0.11 (LO; n = 6) inspired oxygen fraction (FIO2) during rest and 150 min of moderate treadmill exercise. Limb arteriovenous difference and isotopic ([3H]- and [14C]glucose) methods were used to assess muscle carbohydrate metabolism: PaO2 was reduced by approximately 50% in LO vs. NO, but limb O2 uptake was similar. Glucose disappearance was increased during rest (13 +/- 2 vs. 19 +/- 1 mumol.kg-1.min-1) and exercise (23 +/- 4 vs. 36 +/- 6 mumol.kg-1.min-1 at 150 min) in LO vs. NO, but arterial glucose was unchanged because hepatic glucose production was increased similarly. Limb glucose and pyruvate oxidation (derived from vein [14C]lactate specific activity) rates were elevated about twofold during rest and exercise in LO vs. NO. Estimated limb glycogenolysis increased at rest (21 +/- 9 vs. 96 +/- 23 mumol/min) and during exercise (70 +/- 21 vs. 184 +/- 41 mumol/min at 150 min) in LO vs. NO. The %CO2 and %lactate from glucose in LO were about twofold the values in NO in rest and exercise. The %CO2 from pyruvate was greater and free fatty acid levels were lower, suggesting reduced fat metabolism in LO. Arterial lactate and pyruvate levels were elevated during rest and the initial 30 min of exercise, even though net limb outputs were no greater. Lactate-to-pyruvate ratios and pH were similar in LO and NO during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Trophic effects of angiotensin II on neonatal rat cardiac myocytes are mediated by cardiac fibroblasts
Authors: Kim N. N. , Villarreal F. J. , Printz M. P. , Lee A. A. , Dillmann W. H.
Published: December 2017

Cultured neonatal rat cardiac fibroblasts (NF) and myocytes (NM) were used to examine the distribution of angiotensin II (ANG II) receptors and the potential role of NF in mediating the trophic response to ANG II in the heart. In NM preparations cultured for 2-5 days, specific binding to 125I-ANG II was < 10% of the specific binding in cultured NF. Binding assays, immunocytochemistry, and autoradiography in NM cultured for > 5 days identified two populations of cells, one with fibroblast-like morphology and high density of ANG II receptors and another with low binding, comparable to NM cultures at day 5 or earlier. Conditioned medium (CM) from untreated NF increased cell surface area and net [3H]leucine (Leu) incorporation 1.4-fold in NM. CM from ANG II-treated NF enhanced [3H]Leu incorporation 2.2-fold in NM. This potentiating effect of ANG II was inhibited by losartan and was absent when ANG II was added directly to NM. In addition, studies using antibodies and bioassay for transforming growth factor-beta 1 (TGF-beta 1) suggested that TGF-beta 1 does not mediate the trophic effects of ANG II on NM. We conclude that ANG II receptors are localized predominantly on NF and that ANG II can indirectly stimulate hypertrophy of NM by stimulating NF to produce a transferrable factor(s). These data suggest that cardiac fibroblasts may play a critical role in mediating the hypertrophic response to ANG II in the rat heart.
Blunting of the immediate-early gene and mitogenic response in hepatectomized type 1 diabetic animals
Authors: Chin S. , Ramirez S. , Greenbaum L. E. , Naji A. , Taub R.
Published: December 2017

Studies suggest that liver regeneration is delayed in insulin-deficient animals, but defining a role of insulin as a growth factor in hepatic regeneration has remained elusive. By examining gene expression of hepatectomized liver in type 1 diabetic BB rats, we have identified dramatic changes in the expression of primary or immediate-early growth response genes compared with normal animals. These include altered expression of insulin-regulated genes such as glucose-6-phosphatase (G-6-Pase), phosphoenolpyruvate carboxykinase (PEPCK), and beta-actin, and genes such as CL-6 and map kinase phosphatase-1 (MKP-1) that were previously unlinked to insulin action in animals. Abnormal elevation of mRNAs encoding G-6-Pase, MKP-1, and PEPCK in the time 0 diabetic liver results in decreased induction after partial hepatectomy. Other genes, such as CL-6 and beta-actin, are induced at a lower level in the hepatectomized diabetic animals. The net effect is a blunting of the immediate-early gene response after partial hepatectomy in diabetic animals. As determined by DNA synthesis assays, the regenerative capacity of insulin-deficient BB diabetic livers is reduced, and this defect is corrected at least in part by insulin therapy. These findings suggest that because of insulin deficiency, common intracellular signaling pathways that are required for both metabolism and mitogenesis are aberrant in the type 1 diabetic liver and, as a result, the regenerative response is deficient.
Transgenic animals in the study of blood pressure regulation and hypertension
Authors: Thompson M. W. , Merrill D. C. , Yang G. , Robillard J. E. , Sigmund C. D.
Published: December 2017

It is generally accepted that the etiology of essential hypertension is due to a complex interplay of genetic and environmental factors. A great deal of research effort over the past ten years has been focused on the identification of genes the variants of which predispose individuals to high blood pressure. Consequently, transgenic and knockout animals have become important research tools, providing experimental systems in which defined genetic manipulations can be introduced on uniform genetic backgrounds while minimizing environmental variation. These animal models have provided the means by which candidate genes thought to be involved in blood pressure regulation have been studied. Furthermore, these models can be used to test the significance of genes and gene variants identified via genome-wide searches as potential causes of hypertension. The purpose of this review is to provide a brief discussion of transgenic and knockout methodology and its application to study the genetic basis of hypertension.
Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis
Authors: Urban R. J. , Bodenburg Y. H. , Gilkison C. , Foxworth J. , Coggan A. R. , Wolfe R. R. , Ferrando A.
Published: December 2017

Aging men develop a significant loss of muscle strength that occurs in conjunction with a decline in serum testosterone concentrations. We investigated the effects of testosterone administration to six healthy men [67 +/- 2 (SE) yr] on skeletal muscle protein synthesis, strength, and the intramuscular insulin-like growth factor I (IGF-I) system. Elderly men with serum testosterone concentrations of 480 ng/dl or less were given testosterone injections for 4 wk to produce serum concentrations equal to those of younger men. During testosterone administration muscle strength (isokinetic dynamometer) increased in both right and left hamstring and quadricep muscles as did the fractional synthetic rate of muscle protein (stable-isotope infusion). Ribonuclease protection assays done on total RNA from muscle showed that testosterone administration increased mRNA concentrations of IGF-I and decreased mRNA concentrations of insulin-like growth factor binding protein-4. We conclude that increasing testosterone concentrations in elderly men increases skeletal muscle protein synthesis and strength. This increase may be mediated by stimulation of the intramuscular IGF-I system.
PACAP stimulates catecholamine release from adrenal medulla: a novel noncholinergic secretagogue
Authors: Watanabe T. , Shimamoto N. , Takahashi A. , Fujino M.
Published: December 2017

The secretory response of the adrenal medulla to pituitary adenylate cyclase-activating polypeptide (PACAP), a novel polypeptide with 68% structural homology to vasoactive intestinal polypeptide (VIP), was investigated in anesthetized rats by in vivo microdialysis. The injection of PACAP (1.5 nmol) caused a greater amount of increase in catecholamine concentration than carbachol (30 nmol) or VIP (30 nmol) in the dialysate for a period of 60 min. The ratios of norepinephrine to epinephrine in the dialysate after stimulation with these compounds showed no change from resting conditions. The simultaneous application of both nicotinic and muscarinic antagonists (10 mM mecamylamine and 1 mM atropine) eliminated the increase in catecholamine secretion induced by carbachol. In contrast, PACAP-induced catecholamine secretion was not inhibited by these cholinergic antagonists. These data led to the following conclusions: 1) PACAP was more potent than either carbachol or VIP in enhancing the secretion of catecholamine from the adrenal medulla, and 2) PACAP-induced catecholamine secretion was due to the direct action of PACAP on the adrenal medulla rather than an indirect action mediated by acetylcholine release. These results strongly suggest that PACAP is a noncholinergic secretagogue of the adrenal medulla in rats.
Insulin increases blood volume in human skeletal muscle: studies using [15O]CO and positron emission tomography
Authors: Raitakari M. , Knuuti M. J. , Ruotsalainen U. , Laine H. , Makea P. , Teras M. , Sipila H. , Niskanen T. , Raitakari O. T. , Iida H. , et al.
Published: December 2017

High insulin concentrations increase blood flow in the leg, but it is unknown whether this effect is associated with a change in muscle blood volume. In the present study, we used positron emission tomography combined with inhalation of [15O]carbon monoxide to quantitate the effect of insulin on skeletal muscle blood volume in humans. The reproducibility of the method was determined from two consecutive measurements performed in the basal state in five normal subjects. The coefficient of variation of the repeated measurements was 3.0 +/- 1.8%. In 14 normal subjects [age 35 +/- 3 yr, body mass index 24.9 +/- 1.3 (SE) kg/m2], skeletal muscle blood volume was determined in the femoral region in the basal state and during euglycemic hyperinsulinemia (serum insulin 3,200 +/- 190 pmol/l). The mean muscle blood volume was 3.3 +/- 0.1 ml/0.1 kg muscle in the basal state. Insulin increased muscle blood volume by 9 +/- 2% to 3.6 +/- 0.2 ml/0.1 kg muscle (P < 0.01). The rate of whole body glucose uptake was 53 +/- 6 mumol.kg-1.min-1 and correlated with muscle blood volume during insulin stimulation (r = 0.65, P < 0.02). We conclude that high insulin concentrations exert a true vasodilatory effect in human skeletal muscle.
Effects of epinephrine on regional free fatty acid and energy metabolism in men and women
Authors: Jensen M. D. , Cryer P. E. , Johnson C. M. , Murray M. J.
Published: December 2017

Upper-body and lower-body adipocytes respond differently to physiological catecholamines in vitro. It is not known whether this is true in vivo or whether gender differences exist in the regional adipose tissue responses to epinephrine. These studies were therefore conducted to examine free fatty acid (FFA) release ([3H]palmitate) from lower-body (leg), splanchnic, and upper-body adipose tissue in normal-weight adult men (n = 8) and women (n = 7). In response to intravenous epinephrine (10 ng.kg-1.min-1), palmitate release increased (P < 0.01) in both men (168 +/- 10 to 221 +/- 15 mumol/min) and women (177 +/- 12 to 234 +/- 18 mumol/min). Basal leg palmitate release was similar in women and men (16.8 +/- 2.9 and 12.4 +/- 1.3 mumol/min, P = not significant) but doubled (P < 0.01) in response to epinephrine in men and was virtually unchanged in women. Splanchnic palmitate release increased (P < 0.05) in men (n = 6) but not in women (n = 6), whereas nonsplanchnic upper-body palmitate release increased more in women than in men. Upper-body (splanchnic and nonsplanchnic) palmitate release increased (P < 0.05) in both men and women in response to epinephrine. In summary, lower-body adipose tissue FFA release increased in response to epinephrine in men but not women, whereas upper-body palmitate release increased in both groups. These findings are consistent with some in vitro findings and suggest that catecholamine action may play a role in determining gender-based differences in body fat distribution.
Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise
Authors: Winder W. W. , Hardie D. G.
Published: December 2017

Malonyl-CoA, an inhibitor of fatty acid oxidation in skeletal muscle mitochondria, decreases in rat skeletal muscle during exercise or in response to electrical stimulation. Regulation of rat skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme that synthesizes malonyl-CoA, was studied in vitro and in vivo. Avidin-Sepharose affinity-purified ACC from hindlimb skeletal muscle was phosphorylated by purified liver AMP-activated protein kinase with a concurrent decrease in ACC activity. AMP-activated protein kinase was quantitated in resuspended ammonium sulfate precipitates of the fast-twitch red (type IIa fibers) region of the quadriceps muscle. Rats running on a treadmill at 21 m/min up a 15% grade show a 2.4-fold activation of AMP-activated protein kinase concurrently with a marked decrease in ACC activity in the resuspended ammonium sulfate precipitates at all citrate concentrations ranging from 0 to 20 mM. Malonyl-CoA decreased from a resting value of 1.85 +/- 0.29 to 0.50 +/- 0.09 nmol/g in red quadriceps muscle after 30 min of treadmill running. The activation of the AMP-activated protein kinase with consequent phosphorylation and inactivation of ACC may be one of the primary events in the control of malonyl-CoA and hence fatty acid oxidation during exercise.
Improvement of glucose and lipid metabolism in diabetic rats treated with molybdate
Authors: Ozcelikay A. T. , Becker D. J. , Ongemba L. N. , Pottier A. M. , Henquin J. C. , Brichard S. M.
Published: December 2017

Molybdenum mimics certain insulin actions in vitro. We have investigated the effects of oral administration of Na2MoO4 (Mo) for 8 wk on carbohydrate and lipid metabolism in streptozotocin-diabetic rats. Mo decreased hyperglycemia and glucosuria by 75% and corrected the elevation of plasma nonesterified fatty acids. Tolerance to glucose loads was improved, and glycogen stores were replenished. These effects were not due to a rise of insulinemia. In liver, Mo restored the blunted mRNA and activity of glucokinase and pyruvate kinase and decreased to normal phosphoenolpyruvate carboxykinase values. Finally, Mo totally reversed the low expression and activity of acetyl-CoA carboxylase and fatty acid synthase in liver, but not in white adipose tissue. In conclusion, Mo exerts a marked blood glucose-lowering effect in diabetic rats by an insulin-like action. This effect results in part from a restoration of hepatic glucose metabolism and is associated with a tissue-specific correction of lipogenic enzyme gene expression, both processes being essentially mediated by reversal of impaired pretranslational regulatory mechanisms. These observations raise new therapeutic perspectives in diabetes, particularly in the insulin-resistant condition.
Forearm vasodilator mechanisms during mental stress: possible roles for epinephrine and ANP
Authors: Lindqvist M. , Kahan T. , Melcher A. , Bie P. , Hjemdahl P.
Published: December 2017

The contribution of epinephrine (Epi) to forearm vasodilator responses to mental stress was evaluated in 12 healthy men by comparing hemodynamic and plasma catecholamine responses to mental stress and to intravenous and intra-arterial infusions of epinephrine. Mental stress decreased forearm vascular resistance (FVR) by 45%, increased arterial Epi from 0.23 to 0.44 nmol/l in arterial plasma, and increased forearm norepinephrine overflow. Intra-arterial Epi infusion decreased FVR concentration dependently by up to 43%. Intravenous Epi infusion decreased diastolic arterial pressure and increased heart rate and systolic blood pressure dose dependently. FVR decreased by up to 39% at 4.60 nmol/l Epi in arterial plasma. The average Epi contribution to forearm vasodilation during mental stress was calculated to be between 9 and 30%, depending on if responses to stress were compared with intravenous or intra-arterial Epi infusion. Arterial atrial natriuretic peptide immunoreactivity increased by 23% during stress, supporting a vasodilator influence, whereas vasopressin immunoreactivity was unaffected. Thus secretion of Epi explains only part of the stress-induced forearm vasodilation. Intravenous infusion of Epi appears to activate sympathetic counterregulation.
Cocaine and exercise: temporal changes in plasma levels of catecholamines, lactate, glucose, and cocaine
Authors: Han D. H. , Kelly K. P. , Fellingham G. W. , Conlee R. K.
Published: December 2017

To determine the combined sympathoadrenal effects of cocaine and exercise in awake animals, rats were assigned to one of four treatment groups: saline-rest (SR), saline-exercise (SE), cocaine-rest (CR), and cocaine-exercise (CE). Venous blood samples from jugular catheters were obtained at -40, 0-4, 7, 10, 13, 16, 19, 26, and 36 min after intravenous injection of cocaine (5 mg/kg) or saline and the simultaneous onset of a 16-min treadmill run (26 m/min, 10% grade). CE increased plasma epinephrine (24.2 nM at 16 min), norepinephrine (28.0 nM at 10 min), and lactate (11.2 mM at 4 min) to levels 2-5 times greater than either treatment (SE and CR) alone (P<0.05) and 11-35 times higher that SR. Blood glucose values were significantly depressed in CE (-33% vs. SE) but increased in CR (+26% vs. SR). Plasma cocaine peaked < 2 min after injection in both CR and CE, and the peak was 69% higher in CE (P<0.05); however, the plasma elimination half-life (12-14 min) was not different. These results indicate that the combined effect of the two sympathoadrenal stimulants, exercise and cocaine, amplify the catecholamine responses to levels far greater than when each stimulant is used alone.
Metabolic fate of an oral long-chain triglyceride load in humans
Authors: Binnert C. , Pachiaudi C. , Beylot M. , Croset M. , Cohen R. , Riou, J. P. , Laville M.
Published: December 2017

To determine the steps involved in the metabolism of ingested triglycerides (TG), 10 healthy women were studied during 6 h after ingestion of 30 g olive oil labeled with [1,1,1-13C3] triolein. The appearance of 13C was followed in chylomicron-TG (CM-TG), nonesterified fatty acid (NEFA), very low-density lipoprotein (VLDL)-TG, and in expired gas. Indirect calorimetry was used to determine total lipid oxidation. After 90 min, labeling was higher in CM-TG than in NEFA or VLDL. At 180 min, a plateau of enrichment was obtained for CM-TG and NEFA, demonstrating the entry of exogenous lipids in the NEFA pool. After 300 min, a plateau was observed for VLDL-TG with levels of enrichment (0.38 +/- 0.04%) similar to those observed for NEFA (0.36 +/- 0.03%), suggesting a precursor-product relationship. Only 19 +/- 2% of the load was oxidized. From 300 to 360 min, 70% of total lipid oxidation was from exogenous TG. We conclude that, after ingestion of a lipid load, a cycle of fatty acids-TG occurs from CM to NEFA and from NEFA to VLDL. Furthermore, this lipid load has a sparing effect on endogenous lipid stores.
Internal dissociation of the circadian markers of the cortisol rhythm in night workers
Authors: Weibel L. , Spiegel K. , Follenius M. , Ehrhart J. , Brandenberger G.
Published: December 2017

To determine whether the circadian system of night workers is adapted to a night-active schedule, we submitted 11 night workers and 11 day-active subjects to a 10-min blood sampling procedure during their usual sleep-wake cycle, permitting a precise determination of circadian and ultradian cortisol variations. In night works, the usual shift of 8 h in the sleep period was associated with a distortion of the normal 24-h cortisol rhythm. The acrophase exhibited a shift of approximately 6.5 h, whereas the quiescent period, abruptly interrupted by a large peak, underwent a shift of only 3 h and lasted for approximately 5 h, as in day-active subjects. Slow-wave sleep and sleep onset occurred during periods of low or decreasing cortisol secretory rates, whereas awakenings were associated with an increase in cortisol secretory rates. These results revealed that the circadian system of night workers only partially adapts to night work and that adaptation processes rely on an internal dissociation of the markers of the cortisol pattern, without disturbing the processes that couple cortisol release and specific sleep stages.
Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia
Authors: Hasselbalch S. G. , Madsen P. L. , Hageman L. P. , Olsen K. S. , Justesen N. , Holm S. , Paulson O. B.
Published: December 2017

During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.
Exercise increases fat oxidation at rest unrelated to changes in energy balance or lipolysis
Authors: Calles-Escandon J. , Goran M. I. , O'Connell M. , Nair K. S. , Danforth E.
Published: December 2017

The hypothesis that exercise increases fat oxidation at rest independently of changes in energy balance, body composition, and/or lipolysis was tested in 21 volunteers. After a period of energy balance, volunteers were randomly allocated to one of four groups: control, overfed (OF), overfed and exercised (OF-EX), and exercised (EX). OF and OF-EX were overfed 50% excess of energy balance calories; OF-EX and EX spent 50% excess of energy balance calories during daily exercise sessions. Exercise increased fat oxidation at rest independently of dietary intake (OF-EX = + 22 +/- 2.4, EX = + 23 +/- 1.5 mg/min) and reduced carbohydrate oxidation (OF-EX = - 49 +/- 6.2, EX = - 46 +/- 5.4 mg/min). Volunteers in the OF group had an increase in carbohydrate oxidation (85 +/- 5.9 mg/min) and a decline in fat oxidation (- 33 +/- 1.4 mg/min). Protein oxidation did not change in any group. These changes occurred without a direct relation with changes in lipolysis and persisted even when expressed as a percentage or as an absolute equivalent of resting metabolic rate in calories. Thus exercise, independent of changes in energy intake and body composition and not related to changes in lipolysis, increases fat oxidation at rest, which may explain the beneficial effects of exercise in weight loss programs.