bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenocortical hormone secretory response to chronic NH4Cl-induced metabolic acidosis
Authors: Schambelan M. , Sebastian A. , Katuna B. A. , Arteaga E.
Published: December 2017

We examined the effect of chronic metabolic acidosis on adrenocortical hormone production by administering NH4Cl for 5 days to four normal subjects. Plasma aldosterone concentration, aldosterone secretion, and urinary excretion of aldosterone-18-glucuronide increased significantly, whereas there were no significant changes in the plasma concentrations of cortisol, corticosterone, or deoxycorticosterone, or in the urinary excretion of 17-hydroxycorticoids. By day 2, plasma renin activity (PRA) and concentration (PRC) were not significantly different from control, and the slope of the regression line relating plasma aldosterone concentration to PRA was significantly greater than the slope in the control period, i.e., the sensitivity of aldosterone secretion to renin stimulation was increased. By day 5, however, PRA and PRC were increased above control. Plasma potassium concentration did not change significantly. Thus chronic NH4Cl-induced acidosis induces a sustained stimulation of aldosterone secretion in the absence of a change in adrenocorticotropin-dependent adrenocortical hormone secretion. Factors other than an increase in renin secretion and plasma potassium concentration may be involved in at least the early phase of aldosterone stimulation, suggesting that plasma hydrogen ion concentration might be a separate regulator of aldosterone secretion.
Hippocampal and renal type I receptors are differentially regulated
Authors: Stephenson G. , Funder J.
Published: December 2017

Previously, we have shown that renal mineralocorticoid receptors and hippocampal "corticosterone-perferring" sites have identical intrinsic steroid specificity in vitro. Others have shown that the aldosterone binding species in kidney and hippocampus have identical trypsin fragmentation patterns on isoelectric focusing. To further explore possible areas of identity, we determined levels of type I receptors in hippocampus, renal outer medulla cortex, and renal inner medulla papilla from 22 min to 16 days after adrenalectomy. Available type I sites in kidney fractions increased postadrenalectomy to plateau levels in 22 (inner medulla papilla) or 90 min (outer medulla cortex). In contrast, available hippocampal receptors attained maximal levels 24-48 h postadrenalectomy. Animals, 24-h adrenalectomized, showed no differences in steroid uptake or washout between kidney and hippocampus, determined by in vitro tracer binding 22 or 90 min after intravenous aldosterone or corticosterone. We interpret the marked difference in receptor levels between kidney and hippocampus postadrenalectomy as evidence for tissue-specific differences in the control of receptor levels by endogenous steroids.
Thresholds for physiological effects of plasma catecholamines in fetal sheep
Authors: Padbury J. F. , Ludlow J. K. , Ervin M. G. , Jacobs H. C. , Humme J. A.
Published: December 2017

To clarify the physiological role for the marked increases in circulating norepinephrine (NE) and epinephrine (E) that occur at birth, we performed graded infusions of NE and E in preterm (131 days) and full-term (142 days) fetal sheep. A variety of hemodynamic, metabolic, and endocrine responses to stepwise increases in plasma catecholamine levels were analyzed by computer-based graphical analysis of the dose-response curves. We determined the "threshold" value or minimum plasma concentration necessary to produce discernible effects. We observed increases in systolic blood pressure, diastolic blood pressure, and dP/dt beginning at plasma concentrations of 500-800 pg/ml of NE or E. In contrast, increases in plasma free fatty acid and glucose levels were observed at E concentrations as low as 50-100 pg/ml. Full-term animals had generally lower thresholds and higher peak responses than preterm animals. Because these thresholds for infused NE and E are well within the range of plasma catecholamine values seen at birth, these results underscore the importance of circulating catecholamines in the events of neonatal adaptation.
Effect of insulin on osmoregulation of vasopressin
Authors: Vokes T. P. , Aycinena P. R. , Robertson G. L.
Published: December 2017

Patients with uncontrolled insulin-dependent diabetes mellitus have elevations in plasma vasopressin that cannot be completely accounted for by recognized stimuli. To determine whether insulin deficiency per se increases plasma vasopressin, we investigated the effect of acute insulin depletion on the osmoregulation of plasma vasopressin in insulin-dependent diabetics. When intravenous insulin infusion was stopped, plasma vasopressin, osmolality, and glucose increased over the ensuing 5 h, whereas plasma sodium decreased, and blood volume and pressure did not change. This increase in vasopressin was not due to a loss of osmoregulation, because changes in plasma osmolality and sodium, induced by infusion of hypertonic saline or water loading, induced appropriate vasopressin responses under insulin deplete as well as replete conditions. However, when plasma osmolality and glucose were raised by infusion of hypertonic dextrose, plasma vasopressin increased significantly in diabetic patients under insulin-deplete but not under insulin-replete conditions and actually decreased in healthy controls. These results indicate that acute insulin depletion increases vasopressin secretion by sensitizing the osmoreceptor to stimulation by hyperglycemia. This change in osmoreceptor specificity may be explained by postulating that glucose transport by osmoreceptor neurons as insulin dependent.
Heat production during contraction in skeletal muscle of hypothyroid mice
Authors: Leijendekker W. J. , van Hardeveld C. , Elzinga G.
Published: December 2017

The effect of hypothyroidism on tension-independent and -dependent heat produced during a twitch and a tetanic contraction of extensor digitorum longus (EDL) and soleus muscle of mice was examined. The amount of heat produced during a twitch and the rate of heat development during a tetanus of EDL and soleus were measured at and above optimal length. The effect of hypothyroidism on force production was less than 30%. Straight lines were used to fit the relation between heat production and force. Hypothyroidism significantly decreases tension-independent heat during contraction of EDL and soleus muscle. Because the tension-independent heat is considered to be related to the Ca2+ cycling, these findings suggest that ATP splitting due to the Ca2+ cycling is reduced in hypothyroid mice. This conclusion was strengthened by the observation that the oxalate-supported Ca2+-uptake activity and Ca2+-loading capacity of muscle homogenates from hypothyroid mice were reduced, respectively, to 51 and to 65% in soleus and to 63 and 73% in EDL muscle as compared with euthyroid mice. The tension-dependent rate of heat development during a tetanus was also decreased in soleus muscle of hypothyroid mice. This suggests a lower rate of ATP hydrolysis related to cross-bridge cycling in this muscle due to the hypothyroid state.
Regional amino acid transport into brain during diabetes: effect of plasma amino acids
Authors: Mans A. M. , DeJoseph M. R. , Davis D. W. , Hawkins R. A.
Published: December 2017

Transport of phenylalanine and lysine into the brain was measured in 4-wk streptozotocin-diabetic rats to assess the effect on the neutral and basic amino acid transport systems at the blood-brain barrier. Amino acid concentrations in plasma and brain were also measured. Regional permeability-times-surface area (PS) products and influx were determined using a continuous infusion method and quantitative autoradiography. The PS of phenylalanine was decreased by an average of 40% throughout the entire brain. Influx was depressed by 35%. The PS of lysine was increased by an average of 44%, but the influx was decreased by 27%. Several plasma neutral amino acids (branched chain) were increased, whereas all basic amino acids were decreased. Brain tryptophan, phenylalanine, tyrosine, methionine, and lysine contents were markedly decreased. The transport changes were almost entirely accounted for by the alterations in the concentrations of the plasma amino acids that compete for the neutral and basic amino acid carriers. The reduced influx could be responsible for the low brain content of some essential amino acids, with possibly deleterious consequences for brain function.
Minimizing perioperative hypoxemia does not affect postpneumonectomy lung growth
Authors: Karl H. W. , Wolpert E. B. , Rannels D. E.
Published: December 2017

The effects of preventing the acute hypoxemia common during lung resection on postpneumonectomy lung growth were investigated. Rats that had undergone translaryngeal tracheal intubation and were supported with intermittent positive-pressure ventilation during pneumonectomy (IPPV) were compared with those allowed to breathe room air spontaneously via the natural airway (SV). A pulse oximeter was used to document intraoperative and postoperative oxygen saturation (SaO2). Almost all SV animals became acutely hypoxemic during thoracotomy [SaO2 less than 50% for 2.5 +/- 0.5 min (8/9), less than 30% for 1.7 +/- 0.4 (8/9)], whereas IPPV animals largely maintained oxygenation [SaO2 less than 50% for 0.3 +/- 0.2 min (8/13), less than 30% for 0.05 +/- 0.05 min (1/13)]. Direct measurements of oxygen saturation correlated well with the pulse oximeter (slope of regression line = 0.90, correlation 0.91), and arterial blood gases showed the SV group to be hypercapneic and acidotic as well as hypoxemic during lung removal. These abnormalities resolved soon after chest closure. Intubated animals had mild postextubation hypoxemia that normalized within 3 h of surgery. Two weeks postoperative, there were no differences in lung mass or content of water, RNA, DNA, and protein between the two groups.
Heart rate control in diabetic rabbits: blunted response to isoproterenol
Authors: Zola B. E. , Miller B. , Stiles G. L. , Rao P. S. , Sonnenblick E. H. , Fein F. S.
Published: December 2017

To study the effects of chronic diabetes on heart rate and adrenergic responsiveness we compared unanesthetized diabetic rabbits, 10-13 mo after alloxan monohydrate injection, to age-matched controls. There were no significant differences found between groups for body or heart weight. Both resting and intrinsic heart rate (the latter obtained after atropine sulfate and propranolol HCl) were similar. In addition, serum and left ventricular epinephrine and norepinephrine concentrations as well as left ventricular beta-receptor density and affinity were unchanged in diabetic animals. Heart rate responses to isoproterenol were blunted in diabetics at the three highest doses. Base-line mean blood pressure was modestly lower in diabetic rabbits, and parallel declines in pressure for both groups were observed in response to isoproterenol. The diminished heart rate response to isoproterenol in diabetic rabbits may be due to diminished myocardial sensitivity to catecholamines, possibly combined with altered baroreceptor reflexes. These experiments may provide an explanation for the blunted heart rate response to exercise described in human diabetics.
Acute effects of phorbol esters on receptor-mediated IP3, cAMP, and progesterone levels in rat granulosa cells
Authors: Davis J. S. , Weakland L. L. , Coffey R. G. , West L. A.
Published: December 2017

Luteinizing hormone (LH) stimulates the formation of adenosine 3',5'-cyclic monophosphate (cAMP) and inositol trisphosphate (IP3) in rat granulosa cells. This report describes the effects of protein kinase C activators on second messenger generation in isolated rat granulosa cells. The protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) completely inhibited LH-stimulated inositol phosphate accumulation. The inhibitory effects of TPA were rapid (5-15 min) and concentration dependent with 50 nM TPA producing maximally inhibitory effects. However 30-min incubations with 10-100 nM TPA had no effect on LH-stimulated cAMP or progesterone levels. The inhibitory effect of TPA could not be overcome by high concentrations of LH. TPA also inhibited gonadotropin-releasing hormone-stimulated phospholipase C activity, although to a much lesser extent. Increased inositol phosphate degradation and reduced inositol phospholipid synthesis were unlikely explanations for the effects of TPA. The results indicate that phorbol esters modulate the inositol phospholipid-phospholipase C transmembrane signaling system in rat granulosa cells. The results suggest that phorbol esters may alter the coupling of the hormone receptor complex to phospholipase C.
Characteristics of secondary hyperparathyroidism in vitamin D-deficient dogs
Authors: Hendy G. N. , Stotland M. A. , Grunbaum D. , Fraher L. J. , Loveridge N. , Goltzman D.
Published: December 2017

Characteristics of secondary hyperparathyroidism were evaluated in dogs with mild vitamin D deficiency. The animals were normocalcemic with reduced concentrations of 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] and elevations in parathyroid hormone (PTH) concentrations, parathyroid mass, and prepro PTH mRNA levels. Dynamic testing revealed a sigmoidal relationship between plasma calcium and PTH, although PTH concentrations were increased relative to values in vitamin D-sufficient dogs. Infusions of chelator elicited lower plasma calcium levels and greater augmentations in biologically active PTH in vitamin D-deficient than in D-sufficient animals. Induced hypercalcemia lowered both immunoreactive and bioactive hormone to stable but detectable levels. The results demonstrate the decreased capacity of vitamin D-deficient animals to defend against acute hypocalcemia, despite the presence of abundant PTH, and indicate that increased circulating PTH levels in early vitamin D deficiency is due predominantly to an augmentation in the quantity of releasable hormone. The latter appears secondary to an increase in parathyroid mass and synthetic activity regulated by 1,25(OH)2D3 per se.
Demonstration of a role for growth hormone in glucose counterregulation
Authors: De Feo P. , Perriello G. , Torlone E. , Ventura M. M. , Santeusanio F. , Brunetti P. , Gerich J. E. , Bolli G. B.
Published: December 2017

To test the hypothesis that growth hormone secretion plays a counterregulatory role in prolonged hypoglycemia in humans, four studies were performed in nine normal subjects. Insulin (15 mU.M-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 2 microU/ml), and plasma glucose decreased from 88 +/- 2 to 53 +/- 1 mg/dl for 12 h. In study 1, plasma glucose, glucose fluxes (D-[3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored. In study 2 (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretions (except for catecholamines) were prevented by somatostatin (0.5 mg/h iv) and metyrapone (0.5 g/4 h po), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of growth hormone increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma growth hormone at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of a growth hormone response caused a decrease in hepatic glucose production and an increase in glucose utilization that resulted in an approximately 25% greater hypoglycemia despite compensatory increases in plasma catecholamines. Plasma free fatty acid, 3-beta-hydroxybutyrate, and glycerol concentrations were reduced approximately 50%. It is concluded that growth hormone normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.
Contributions of gluconeogenesis and glycogenolysis during glucose counterregulation in normal humans
Authors: Lecavalier L. , Bolli G. , Cryer P. , Gerich J.
Published: December 2017

To estimate the relative contributions of gluconeogenesis and glycogenolysis to the increase in hepatic glucose output (HGO) during glucose counterregulation under conditions simulating clinical insulin hypoglycemia, we induced moderate hypoglycemia (approximately 55 mg/dl) with a continuous infusion of insulin that resulted in physiological hyperinsulinemia (approximately 20 microU/ml) in eight normal volunteers and estimated gluconeogenesis by two methods: an isotopic approach in which appearance of plasma glucose derived from lactate was determined and another approach in which we infused alcohol along with insulin to block gluconeogenesis and used the exogenous glucose required to prevent greater hypoglycemia as an index of gluconeogenesis. Both methods gave similar results. Initially glycogenolysis accounted for approximately 85% of HGO; however, once hypoglycemia became established, the contribution of gluconeogenesis increased progressively to 77 +/- 10 (isotopic method) and 94 +/- 10% (alcohol method) of overall HGO. We conclude that in normal humans during moderate protracted hypoglycemia induced by physiological hyperinsulinemia, gluconeogenesis is the predominant factor responsible for the counterregulatory increase in HGO and that increased gluconeogenesis rather than increased glycogenolysis is the primary mechanism preventing development of greater hypoglycemia.
Adrenergic control of renin during dietary sodium deprivation in conscious dogs
Authors: Hisa H. , Chen Y. H. , Radke K. J. , Izzo J. L. , Sladek C. D. , Blair M. L.
Published: December 2017

These experiments evaluated the contribution of alpha- and beta-adrenergic stimulation to plasma renin activity (PRA) during early and long-term dietary sodium restriction, compared with normal sodium intake. Uninephrectomized conscious dogs with catheters in the aorta, vena cava, and remaining renal artery were studied during normal sodium diet (approximately 70 meq/day), after 2-3 days of low-sodium diet (5-7 meq/day), and after greater than or equal to 2 wk of low-sodium diet. Direct renal arterial (ira) infusion of phenoxybenzamine plus propranolol decreased PRA by similar proportions (39-48%) during all three states of dietary sodium intake. The PRA achieved after adrenergic blockade remained higher (P less than 0.05) during early and long-term sodium restriction than during normal sodium intake. The effect on PRA of ira infusion of propranolol alone was not different from that of phenoxybenzamine plus propranolol during normal or low-sodium diet, and the magnitude of decrease in PRA during low-sodium diet was the same whether propranolol (1 microgram.kg-1.min-1) was infused ira or intravenously. In summary, beta-adrenergic stimulation accounts for similar proportions of PRA during early and long-term dietary sodium restriction and during normal sodium intake. Renal alpha-adrenoceptors appear to play little or no role in control of PRA under these conditions.
Epinephrine mediates facultative carbohydrate-induced thermogenesis in human skeletal muscle
Authors: Astrup A. , Simonsen L. , Bulow J. , Madsen J. , Christensen N. J.
Published: December 2017

The thermic effect of carbohydrate has a component mediated by the sympathoadrenal system but of unknown anatomical localization. We have studied the contribution of skeletal muscle to the thermic effect of a carbohydrate-rich natural meal (115 g of carbohydrate, approximately 80% of energy) by means of the forearm technique on two occasions, with and without intravenous beta-blockade with propranolol. The meal-induced thermogenesis was reduced from 9.6 to 7.1% by beta-blockade (P less than 0.04), the major difference was found 90 to 240 min after the meal. The postprandial increments in plasma glucose and lactate did not change by beta-blockade, but there was a trend toward a decreased insulin response (P = 0.06). The carbohydrate-induced increase in forearm oxygen consumption was reduced by 23% after beta-blockade (P less than 0.05), the entire difference being present 90-180 min postprandially and coinciding with the peak in arterial epinephrine. The present study provides evidence of a facultative thermogenic component in skeletal muscle, mediated by epinephrine via beta 2-adrenoreceptors. However, it also points to a nonmuscle component mediated through beta 1-adrenoceptors by norepinephrine released from the sympathetic nervous system. Consequently, the sympathoadrenal system seems to play a physiological role in the daily energy balance.
Effects of pulsatile delivery of insulin and glucagon in humans
Authors: Paolisso G. , Scheen A. J. , Albert A. , Lefebvre P. J.
Published: December 2017

The purpose of the present study was to investigate the respective effects of continuous intravenous delivery of both insulin and glucagon compared with those of pulsatile insulin (and continuous glucagon), pulsatile glucagon (and continuous insulin) and both hormones administered in a pulsatile manner (but out of phase) on various parameters of glucose turnover. The study was performed on six healthy male volunteers submitted to a 325-min glucose-controlled glucose intravenous infusion using the Biostator. The endogenous secretion of pancreatic hormones was inhibited by somatostatin (2 micrograms/min). Four combinations of continuous and pulsatile infusions of insulin and glucagon were performed on different days and in random order. The amounts of hormone infused were identical in all instances and were 0.2 mU.kg-1.min-1 (continuous insulin), 67 ng/min (continuous glucagon), 1.3 mU.kg-1.min-1 and 435 ng/min with a switching on-off length of 2-11 min (for intermittent insulin and glucagon delivery, respectively). In the case of pulsatile administration of both hormones, the pulses of insulin and glucagon were given out of phase with a 6-min interval. Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classic methodology using a D-[3-3H]glucose infusion allowed to study glucose turnover. When compared with pulsatile insulin and continuous glucagon, pulsatile glucagon and continuous insulin were characterized by a significantly higher endogenous (hepatic) glucose production. When both insulin and glucagon were delivered in a pulsatile manner, the effect of pulsatile glucagon was predominant, maintaining a high endogenous glucose production. Under no circumstance was an effect on glucose utilization or clearance detected. This study demonstrates that pulsatile delivery of insulin or glucagon in humans has greater effects in modulating endogenous glucose production than continuous infusion. Furthermore, when both insulin and glucagon are delivered intermittently and out of phase, the stimulatory effect of glucagon on endogenous glucose production prevails over the inhibitory effect of insulin.
Effects of obesity on insulin sensitivity and responsiveness in sheep
Authors: Bergman E. N. , Reulein S. S. , Corlett R. E.
Published: December 2017

To assess the mechanisms of insulin resistance in the ruminant, severe and adult-onset obesity was produced in Dorset ewes by overfeeding a high-energy ration over a 1- to 2-yr period. Body weights increased to 100 kg compared with 50 kg in lean control sheep; significant hyperinsulinemia (40 +/- 4 vs 10 +/- 1 microU/ml) also developed as did a moderate hyperglycemia (62 +/- 2 vs. 52 +/- 1 mg/100 ml). Tissue sensitivity and responsiveness to insulin were then determined in both obese and lean sheep by the euglycemic glucose-clamp technique. Insulin was infused at eight different rates from 0.2 to 50 mU.kg-1.min-1 and [6-3H]-glucose was infused for measurement of glucose kinetics. The mean dose-response curves for glucose utilization and clearance rates were displaced to the right in obese compared with lean sheep. As a result, the half-maximally effective insulin concentrations usually were elevated two- to fourfold, indicating decreased insulin sensitivity in obese sheep, and this is consistent with decreased insulin receptors in peripheral tissues. On the basis of fat-free body weight, the maximal glucose responses, however, were not significantly different between obese and lean sheep, indicating that postreceptor defects do not exist in muscle tissue. Furthermore, lean ruminants are more resistant to insulin than are humans, but this resistance seems only because of the sheep's decreased responsiveness to insulin and thus only because of postreceptor insulin effects in peripheral tissues.
Inhibitory effect of endothelin on renin release in vitro
Authors: Takagi M. , Tsukada H. , Matsuoka H. , Yagi S.
Published: December 2017

We previously reported that endothelin inhibits renin release in a dynamic superfusion system of collagenase-dispersed rat renal cortical cells. In the present report we investigated cellular mechanisms by which endothelin inhibits renin release from juxtaglomerular (JG) cells. In a superfusion system of dispersed rat renal cortical cells, 10(-10) M endothelin inhibited renin release stimulated by 5 x 10(-8) M isoproterenol or 5 x 10(-5) M 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8, a putative intracellular Ca antagonist). Endothelin showed a slight but significant inhibitory effect on renin release stimulated by isoproterenol or TMB-8 even in the absence of extracellular Ca. Endothelin also inhibited renin release in the presence of 10(-4) M nicardipine. In a superfusion system of renal cortical slices, both 10(-8) M endothelin and a high concentration (60 mM) of K inhibited renin release, and 10(-6) M nicardipine attenuated the inhibition of renin release by high K but did not affect the inhibition by endothelin. These results suggest that endothelin inhibits renin release from JG cells not only by the promotion of Ca influx into the cells through dihydropyridine-insensitive Ca channels but also by other mechanism(s) independent of extracellular Ca.
Glucose kinetics in gluconeogenesis-inhibited rats during rest and exercise
Authors: Turcotte L. P. , Rovner A. S. , Roark R. R. , Brooks G. A.
Published: December 2017

To evaluate the role played by gluconeogenesis in blood glucose homeostasis, female Sprague-Dawley rats were injected with mercaptopicolinic acid (MPA), a gluconeogenic inhibitor. Glucose kinetics were assessed by primed, continuous infusion of [U-14C]- and [6(-3)H]glucose via an indwelling jugular catheter at rest and during submaximal exercise at 13.4 m/min on level grade. Blood samples were taken from carotid catheters and analyzed for glucose and lactate concentrations and specific activities. Tissue glycogen samples were obtained from rats after exercise as well as from unexercised animals. When compared with the sham-injected animals, MPA-treated animals had 22% lower (5.92 +/- 0.36 vs. 7.62 +/- 0.21 mM) and 44% higher (1.90 +/- 0.11 vs. 1.32 +/- 0.09 mM) resting arterial glucose and lactate concentrations, respectively. Resting glucose appearance (Ra) rates were 20% lower in the MPA-treated animals (57.2 +/- 7.5 mumol.kg-1.min-1) than in the sham-injected animals (71.1 +/- 12.1 mumol.kg-1.min-1). During exercise, Ra increased to 174.7 +/- 32.8 mumol.kg-1.min-1 in sham-injected animals. In the MPA-treated animals, there was a 35% increase during the first 15 min of exercise, followed by a decrease to the resting values. MPA-treated animals had no measurable glucose recycling at rest or during exercise. Exercise decreased blood glucose concentration (35%) and increased blood lactate concentration (160%) in the MPA-treated animals. Exercising sham-injected animals had increased blood glucose (9.8%) but no change in blood lactate concentration. Moderate depletions in liver and skeletal muscle glycogen contents were observed after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Placental-fetal glucose exchange and placental glucose consumption in pregnant sheep
Authors: DiGiacomo J. E. , Hay W. W.
Published: December 2017

To determine the separate effects of changes in fetal glucose and insulin concentrations on uteroplacental glucose transfer (UPGT) and consumption (UPGC) we studied 24 late-gestation pregnant sheep during fetal insulin infusions alone and with simultaneous glucose clamp. Insulin infusion alone increased fetal glucose utilization rate (GUR) by 45% (P less than 0.001), decreasing fetal glucose concentration by 40% (P less than 0.01) and thereby increasing fetal glucose clearance (Clglu) by 150% (P less than 0.001). Maternal-fetal glucose gradient also increased, resulting in a 40% increase (P less than 0.02) in UPGT [measured as umbilical glucose uptake (UGU)] and a 30% decrease (P less than 0.05) in UPGC. Addition of a fetal glucose clamp returned fetal glucose concentration to base line and restored UPGC and UGU to control values with a further 2.25-fold increase in fetal GUR. Clglu did not change, as the increase in GUR was proportional to the increase in fetal glucose concentration. Similarly, in animals receiving an insulin infusion plus glucose clamp throughout, maternal glucose concentration, fetal glucose concentration, UPGC, and UGU did not change, whereas GUR and Clglu increased approximately 1.9-fold. These changes were noted at constant maternal glucose concentration and uterine glucose uptake. Thus variation in fetal glucose concentration rather than fetal insulin concentration directly regulates uteroplacental glucose transfer and consumption, whereas both fetal insulin and glucose affect, in separate ways, fetal glucose utilization and clearance.
Parameter estimation: local identifiability of parameters
Authors: Jacquez J. A. , Perry T.
Published: December 2017

For biological systems one often cannot set up experiments to measure all of the state variables. If only a subset of the state variables can be measured, it is possible that some of the system parameters cannot influence the measured state variables or that they do so in combinations that do not define the parameters' effects separately. Such parameters are unidentifiable and are in theory unestimable. Given a model of the system, linear or nonlinear, and initial estimates of the values of all parameters, we exhibit a simple theory and describe a program for checking the local identifiability of the parameters at the initial estimates for given experiments on the model. The program, IDENT, is available from the authors.
Estimation of glucose kinetics in fetal-maternal studies: potential errors, solutions, and limitations
Authors: Menon R. K. , Bloch C. A. , Sperling M. A.
Published: December 2017

We investigated whether errors occur in the estimation of ovine maternal-fetal glucose (Glc) kinetics using the isotope dilution technique when the Glc pool is rapidly expanded by exogenous (protocol A) or endogenous (protocol C) Glc entry and sought possible solutions (protocol B). In protocol A (n = 8), after attaining steady-state Glc specific activity (SA) by [U-14C]glucose (period 1), infusion of Glc (period 2) predictably decreased Glc SA, whereas. [U-14C]glucose concentration unexpectedly rose from 7,208 +/- 367 (means +/- SE) in period 1 to 8,558 +/- 308 disintegrations/min (dpm) per ml in period 2 (P less than 0.01). Fetal endogenous Glc production (EGP) was negligible during period 1 (0.44 +/- 1.0), but yielded a physiologically impossible "negative" value of -2.1 +/- 0.72 mg.kg-1.min-1 during period 2. When the fall in Glc SA during Glc infusion was prevented by addition of [U-14C]glucose admixed with the exogenous Glc (protocol B; n = 7), EGP was no longer "negative." In protocol C (n = 6), sequential infusions of four increasing doses of epinephrine serially decreased SA, whereas tracer Glc increased from 7,483 +/- 608 to 11,525 +/- 992 dpm/ml plasma (P less than 0.05), imposing an obligatory underestimation of EGP. Thus a tracer "mixing" problem leads to erroneous estimations of fetal Glc utilization and Glc production via the three-compartment model in sheep when the Glc pool is expanded exogenously or endogenously. These errors can be minimized by maintaining the Glc SA relatively constant.
Hormonal, metabolic, and cardiovascular responses to static exercise in humans: influence of epidural anesthesia
Authors: Kjaer M. , Secher N. H. , Bach F. W. , Galbo H. , Reeves D. R. , Mitchell J. H.
Published: December 2017

To determine the role of reflex neural mechanisms for hormonal, metabolic, heart rate (HR), and blood pressure (MABP) changes during static exercise, seven health young males performed 10-min periods of two-legged static knee extension both during control and during epidural anesthesia. Comparisons were made at identical absolute (29 Nm) and relative [15% maximal voluntary contraction (MVC)] force. Afferent nerve blockade was verified by hypesthesia below T10-T12 and attenuated postexercise ischemic pressor response. Leg strength was reduced to 67 +/- 5% of control. At same relative force, increases in MABP and HR occurred more rapidly without than with epidural anesthesia (P less than 0.05). This difference was diminished during identical absolute force. Changes in plasma concentrations of catecholamines followed the pattern of HR and MABP responses, with differences between epidural and control experiments being most pronounced early in the work period. Plasma beta-endorphin was elevated only after control exercise. No response at 15% MVC was found for growth hormone, adrenocorticotropic hormone, insulin, glucagon, cortisol, glycerol, free fatty acids, or glucose (P greater than 0.05). In conclusion, during static exercise with large muscle groups and moderate relative force, modest changes in plasma hormones and metabolites take place. Furthermore, afferent nervous feedback from contracting muscles is important in regulation of blood pressure, heart rate, and catecholamine responses during static exercise in humans.
Weight reduction increases adipose but decreases cardiac LPL in reduced-obese Zucker rats
Authors: Bessesen D. H. , Robertson A. D. , Eckel R. H.
Published: December 2017

Lipoprotein lipase (LPL) activity and mRNA levels were measured in cardiac muscle and adipose tissue from lean, obese, and weight-stable reduced-obese Zucker rats, both fasted and 2 h after feeding. Fasting epididymal fat LPL activity was substantially higher in obese rats relative to lean rats [6.9 vs. 0.2 nmol free fatty acid (FFA).10(6) cells-1.min-1; P = 0.0001], and was higher still in reduced-obese rats (15.7 nmol FFA.10(6) cells-1.min-1; P = 0.002). Adipose tissue LPL increased with feeding in all three groups. In marked contrast, fasting cardiac muscle LPL was lower in obese rats relative to lean (28.8 vs. 38.5 nmol FFA.g-1.min-1; P = 0.0064) and was lower still in reduced-obese rats (14.5 nmol FFA.g-1.min-1; P = 0.0001). LPL mRNA levels increased in adipose tissue along with enzyme activity; however, the magnitude of the changes were relatively small, suggesting that the primary regulatory steps are posttranslational. Weight reduction studies were also carried out in Sprague-Dawley rats with similar results. These studies show that sustained weight reduction results in coordinate changes in tissue-specific LPL, favoring delivery of lipoprotein triglyceride fatty acids to adipose tissue relative to cardiac muscle and the restoration of energy stores.
Correlation between mRNA levels for bone cell proteins and bone formation in long bones of maturing rats
Authors: Turner R. T. , Spelsberg T. C.
Published: December 2017

This report describes the relationship between bone formation and mRNA levels for selected bone proteins. Dynamic bone histomorphometry was used to measure bone formation in tibial periosteum of male rats from weanling (3 wk) to 52 wk old. Northern blot analysis of freshly isolated periosteal cells from the long bones was used to determine steady-state mRNA levels for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAP), the bone matrix proteins osteocalcin (BGP), and prepro-alpha-2 (I) chain of type 1 precollagen (collagen), the osteoblast marker enzyme alkaline phosphatase (AP), and the osteoblast-derived signaling factor (growth factor) transforming growth factor-beta (TGF-beta). Radial growth at the tibial diaphysis achieved a maximum value in 8-wk-old rats and decreased progressively with age thereafter. This age-related decrease in the radial growth rate was initially due to reduced osteoblast activity; however, in older rats (greater than 17 wk old) reduced osteoblast number contributed to the decrease in bone formation. There was a strong correlation between the steady-state mRNA level for collagen and the periosteal bone formation rate. In contrast, the mRNA levels for the other bone proteins were more weakly correlated (TGF-beta and AP) or not correlated (BGP). These results suggest that the decreased bone matrix synthesis by periosteal cells in long bones of maturing rats is due to decreased expression of genes for bone matrix proteins.
Increased activities of mitochondrial enzymes in white adipose tissue in trained rats
Authors: Stallknecht B. , Vinten J. , Ploug T. , Galbo H.
Published: December 2017

During earlier fat cell studies we noticed that homogenates of white fat cells became more brown with training, a fact that might reflect an increased content of mitochondria. This raised the question whether training (as is the case in muscle) increases the oxidative capacity in fat cells. Groups of 8-12 rats were swim trained for 10 wk or served as either sedentary, sham swim-trained, or cold-stressed controls. White adipose tissue was removed, and the activities of the respiratory chain enzyme cytochrome-c oxidase (CCO) and of the enzyme malate dehydrogenase (MDH), which participates in the tricarboxylic acid cycle as well as in the mitochondrial malate-aspartate and acetyl-group shuttles, were determined. The CCO and MDH activities expressed per milligram protein were increased in male rats 4.4- and 2.8-fold, respectively, in the swim-trained compared with the sham swim-trained rats (P less than 0.05). In female rats the CCO activity expressed per milligram protein was increased 4.5-fold in the trained compared with the sedentary control rats (P less than 0.01). Neither cold stress nor sham swim training increased CCO or MDH activities in white adipose tissue (P greater than 0.05). In conclusion, in rats, intensive endurance training induces an increase in mitochondrial enzyme activities in white adipose tissue as is seen in skeletal muscle.
Elevated skeletal muscle glucose transporter levels in exercise-trained middle-aged men
Authors: Houmard J. A. , Egan P. C. , Neufer P. D. , Friedman J. E. , Wheeler W. S. , Israel R. G. , Dohm G. L.
Published: December 2017

Exercise training has been proposed to improve whole body insulin sensitivity through a postreceptor adaptation in skeletal muscle. This study examined if levels of the insulin-responsive muscle glucose transporter protein (GLUT-4) were associated with improved insulin sensitivity in trained vs. sedentary middle-aged individuals. Muscle GLUT-4 levels and oral glucose tolerance test (OGTT) responses were obtained in age-matched trained and sedentary men (n = 11). Plasma insulin levels during the OGTT were significantly lower (P less than 0.01) in the trained men, whereas no differences were seen in plasma glucose responses. GLUT-4 protein content was approximately twofold higher in the trained men (2.41 +/- 0.17 vs. 1.36 +/- 0.11 micrograms standard, P less than 0.001). OGTT responses and GLUT-4 levels were not altered 15-18 h after a standard exercise bout in six representative sedentary subjects. These data suggest that GLUT-4 levels are increased in conjunction with insulin sensitivity in chronically exercise-trained middle-aged men. This finding suggests a possible mechanism for the improved insulin sensitivity observed with exercise training in humans.
Efficiency of compensation for absence of fall in insulin during exercise
Authors: Wasserman D. H. , Lacy D. B. , Colburn C. A. , Bracy D. , Cherrington A. D.
Published: December 2017

To assess compensation for the absence of the exercise-induced fall in insulin, dogs underwent 150 min of treadmill exercise with insulin infused intraportally with (IC + Glc; n = 7) or without (IC; n = 6) glucose clamped. Glucose production (Ra), gluconeogenic conversion (Conv), and intrahepatic gluconeogenic efficiency (Eff) were assessed with tracers ([3H]glucose, [14C]alanine) and arteriovenous differences. Glucose fell by 6 +/- 4 and 11 +/- 2 mg/dl at 30 min of exercise and by 8 +/- 2 and 36 +/- 5 mg/dl at 150 min in IC + Glc and IC. Glucagon rose by 16 +/- 8 and 55 +/- 17 pg/ml by 30 min of exercise and by 18 +/- 6 and 93 +/- 22 pg/ml by 150 min in IC + Glc and IC. Norepinephrine was unaffected by the glycemic decrement in IC, whereas epinephrine was greater for the last 60 min of exercise. Ra rose by an average of 0.9 +/- 0.3 and 3.7 +/- 0.2 mg.kg-1.min-1 in IC + Glc and IC. Conv rose by 91 +/- 39 and 325 +/- 75% in IC + Glc and IC at 150 min of exercise, and Eff rose by 87 +/- 57 and 358 +/- 99%. The compensatory Ra exceeded the maximum possible gluconeogenic rate, indicating that glycogenolysis was also stimulated. In summary, in the absence of the exercise-induced fall in insulin 1) glycemia falls approximately fourfold faster; 2) minimal glycemic decrements elicit a large and rapid increase in Ra; 3) this compensation involves a glycogenolytic and gluconeogenic response; 4) the accelerated gluconeogenic rate is due, in large part, to stimulation of Eff; and 5) the compensatory Ra is likely mediated, in part, by glucagon. Hence, although the fall in insulin is essential for normal glucoregulation during exercise, a highly sensitive counterregulatory response prevents severe hypoglycemia. The remarkable sensitivity of the liver to small changes in glycemia implies that the normal coupling of the exercise-induced increase in Ra to glucose utilization may be signaled by small, nearly imperceptible changes in glucose.
Insulin resistance and blood pressure in Dahl rats and in one-kidney, one-clip hypertensive rats
Authors: Kotchen T. A. , Zhang H. Y. , Covelli M. , Blehschmidt N.
Published: December 2017

In normal rats, sucrose feeding results in insulin resistance and an elevation of arterial pressure. The purpose of this study was twofold: 1) to evaluate the effect of sucrose feeding on blood pressure in a genetic model and in an acquired model of hypertension and 2) to determine whether these models of hypertension are associated with insulin resistance. In Dahl salt-resistant (Dahl-R) rats on both a 0.45 and a 3% NaCl intake, systolic blood pressures were higher (P less than 0.01) in sucrose-drinking than in water-drinking animals. In contrast, blood pressure was not affected by dietary sucrose in Dahl salt-sensitive (Dahl-S) rats. Blood pressure was also not affected by sucrose in the one-kidney, one-clip (1K,1C) hypertensive rat. In response to an oral glucose load, serum glucose was similar in Dahl-R and Dahl-S rats, although serum insulin was higher (P less than 0.05) in Dahl-S rats, suggesting that Dahl-S rats are insulin resistant. In contrast, glucose and insulin responses were similar in hypertensive 1K,1C animals and normotensive controls. In conclusion, sucrose feeding increased blood pressure in Dahl-R but not in Dahl-S or 1K,1C hypertensive rats. Additionally, Dahl-S rats, but not hypertensive 1K,1C rats, are insulin resistant.
Ethnic differences in sympathetic nervous system-mediated energy expenditure
Authors: Saad M. F. , Alger S. A. , Zurlo F. , Young J. B. , Bogardus C. , Ravussin E.
Published: December 2017

The impact of sympathetic nervous system (SNS) activity on energy expenditure (EE) was evaluated in nondiabetic Caucasian and Pima Indian men while on a weight-maintenance diet using two approaches as follows. 1) The relationship between 24-h EE, measured in a respiratory chamber, and 24-h urinary norepinephrine was studied in 36 Caucasians [32 +/- 8 (SD) yr, 95 +/- 41 kg, 22 +/- 13% fat] and 33 Pimas (29 +/- 6 yr, 103 +/- 28 kg, 30 +/- 9% fat). There was no difference between the two groups in 24-h EE (2,422 vs. 2,523 kcal/24 h) and in urinary norepinephrine (28 vs. 31 micrograms/24 h), even after adjusting for body size and composition. Twenty-four-hour EE correlated significantly with 24-h urinary norepinephrine in Caucasians (r = 0.78, P less than 0.001) but not in Pimas (r = 0.03), independent of fat-free mass (FFM), fat mass, and age. 2) The effect of beta-adrenoceptor blockade with propranolol (120 micrograms/kg FFM bolus and 1.2 micrograms.kg FFM-1.min-1 for 45 min) on the resting metabolic rate (RMR) was evaluated in 36 Caucasians (30 +/- 6 yr, 103 +/- 36 kg, 25 +/- 11% fat) and 32 Pimas (28 +/- 6 yr, 100 +/- 34 kg, 27 +/- 10% fat). The RMR was similar in the two groups (2,052 vs. 1,973 kcal/24 h) even after adjustment for FFM, fat mass, and age and dropped significantly after propranolol infusion in Caucasians (-3.9%, P less than 0.001) but not in Pimas (-0.8%, P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)
Downregulation of the renin-angiotensin system in streptozotocin-diabetic rats
Authors: Cassis L. A.
Published: December 2017

To determine if insulin has the ability to regulate components of the renin-angiotensin system, renin and angiotensinogen mRNA and plasma concentrations were determined in 4-wk streptozotocin (STZ)-diabetic rats. In another group of STZ-diabetic rats, replacement insulin therapy was given over the 4-wk period, and the above parameters were examined. In STZ-diabetic rats, there was a significant regression of white adipose tissue that was accompanied by an increase in the yield of RNA obtained. Changes in white adipose tissue were reversed by insulin replacement therapy in STZ-diabetic rats. There were no changes in brown adipose tissue weight or RNA yield in STZ-diabetic rats. Plasma renin activity (PRA) was significantly decreased in STZ-diabetic rats; however, plasma angiotensinogen concentration was not significantly affected by diabetes. PRA was restored to control levels in STZ-diabetic rats with insulin replacement. Kidney renin mRNA as well as liver, epididymal, and interscapular fat angiotensinogen mRNA were significantly decreased in STZ-diabetic rats. Renin and angiotensinogen mRNA were not significantly different from control in all tissues examined in STZ-diabetic rats with insulin replacement therapy. Results from this study suggest a downregulation of the renin-angiotensin system in 4-wk STZ-diabetic rats at the level of mRNA expression that is restored by replacement therapy with insulin; therefore, insulin may directly or indirectly regulate the renin-angiotensin system.
Normal plasma calcium, phosphate, and parathyroid hormone levels during 1,25(OH)2D3 infusions in rats
Authors: Fox J. , Kollenkirchen U.
Published: December 2017

The changes in plasma calcium, phosphate, and parathyroid hormone (PTH) levels that accompany 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] administration to experimental animals represent major obstacles to determining the precise role that 1,25(OH)2D3 plays in cell function in vivo. These difficulties arise because calcium, phosphate, and PTH have major cellular effects independent of 1,25(OH)2D3. To circumvent this obstacle, we have developed an animal model in which plasma 1,25(OH)2D3 levels were raised from 20 +/- 3 to 96 +/- 19, 240 +/- 49, and 459 +/- 66 pg/ml in vitamin D-deficient rats without influencing plasma ionized calcium, total calcium, phosphate, or NH2-terminal immunoreactive PTH (irPTH) levels. The elevated 1,25(OH)2D3 levels were achieved by constant subcutaneous infusion of 1,25(OH)2D3 using osmotic minipumps. Progressive reduction in the calcium and phosphorus content of the diet as the 1,25(OH)2D3 infusion rate was increased prevented concomitant changes in plasma calcium, phosphate, and irPTH levels. This experimental model, in conjunction with our previously developed normocalcemic rat model of vitamin D deficiency, provides a powerful experimental tool for the investigation of 1,25(OH)2D3 effects in vivo in the absence of concomitant changes in other parameters of calcium homeostasis.