bluuebunny/crossref_metadata_2025 huggingface dataset:
Islet cell responses to glucose in human transplanted pancreas
Authors: Elahi D. , Clark B. A. , McAloon-Dyke M. , Wong G. , Brown R. , Shapiro M. , Minaker K. L. , Flanagan T. L. , Pruett T. , Gingerich R. , et al.
Published: December 2017

Postsurgery, pancreas transplantation results in alterations of carbohydrate metabolism. Additionally, immunosuppressive therapy impacts on glucose regulation. We evaluated the hormonal and metabolic responses of pancreas allografts, utilizing the hyperglycemic clamp technique coupled with the tritiated glucose methodology, in 11 volunteers who had received simultaneous pancreas-kidney transplantation (P-K) with systemic drainage. Their responses were compared with seven volunteers who had received only a kidney (K) graft and with seven normal control (C) volunteers. Although basal glucose and hepatic glucose output were similar in all three groups, basal insulin, C-peptide, glucagon, and pancreatic polypeptide were highest in the P-K group and lowest in normal subjects. During hyperglycemia, all groups showed a similar characteristic, initial complete suppression of hepatic glucose production, with recovery followed by a later suppression. Peripheral glucose uptake was similar in P-K and C subjects but decreased in K patients. Systemic insulin levels were fourfold higher in the pancreas transplant patients than in healthy subjects. Thus, under basal and hyperglycemic stimulation, 1) hepatic glucose homeostasis is regulated normally, even with pancreatic drainage into the systemic circulation; 2) overall glucose disposal is normal in P-K patients because of marked hyperinsulinemia; and 3) there is loss of tonic inhibition of endocrine pancreatic function secondary to pancreatic denervation.
Increased glucose transport in nonexercising muscle
Authors: Megeney L. A. , Elder G. C. , Tan M. H. , Bonen A.
Published: December 2017

Changes in blood flow and muscle glycogen in nonexercising muscle during exercise suggest that glucose transport may be increased in nonexercising muscles. Therefore, we compared 3-O-methyl-D-glucose (3-MG) transport in exercised and nonexercised perfused rat hindlimb muscles (soleus, plantaris, and red and white gastrocnemius), in the absence and presence of insulin (30 nM). Specifically, the following four treatments were used: 1) normal rest, 2) normal exercise animals (90 min running 15 m/min, 8% grade), 3) hindlimb-suspended animals at rest (90 min), and 4) hindlimb-suspended animals while exercising on the forelimbs (90 min running 15 m/min, 8% grade). In separate groups of animals, it was shown from the analyses of the electromyographic interference patterns that muscle activity was sharply reduced in hindlimb-suspended muscles both at rest and during exercise (soleus and plantaris). Glycogen decrements were also observed in nonexercising muscles during exercise (soleus, plantaris, and red gastrocnemius; P less than 0.05), although these decrements were less than in the exercised muscles (P less than 0.05). Glucose transport differed among muscles (soleus = plantaris greater than red gastrocnemius greater than white gastrocnemius), and typical increments were observed after exercise (P less than 0.05) and with insulin stimulation (P less than 0.05). An additive effect of insulin and exercise was also observed (P less than 0.05). In nonexercised muscles with no insulin in the perfusate, an increase in 3-MG transport occurred (P less than 0.05). In the presence of insulin, an increase in 3-MG transport was also observed in the nonexercised red and white gastrocnemius muscles (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypocalcemia, but not PTH or hypophosphatemia, induces a rapid increase in 1,25(OH)2D3 levels in rats
Authors: Fox J.
Published: December 2017

This study determined whether acute decreases in plasma ionized calcium (Ca2+) levels regulate plasma 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels independent of changes in parathyroid hormone (PTH) secretion and plasma phosphate levels. Chronically catheterized rats were subjected to a hypocalcemic clamp (mean decrement of Ca2+ levels 0.38 +/- 0.04 mM), a rat PTH-(1-34) infusion, and a PTH vehicle infusion for 2 h. Plasma NH2-terminal immunoreactive PTH levels were elevated 3.2- and 8.7-fold during hypocalcemia and PTH infusion, respectively. Plasma phosphate decreased by 23 +/- 4 and 42 +/- 3% during hypocalcemia and PTH infusion, respectively. In response to hypocalcemia, plasma 1,25(OH)2D3 levels increased promptly, were significantly elevated by 15 min (56 +/- 23% increase), and continued to increase until the end of the experiment at 5 h (350 +/- 30% increase). In contrast, no changes in plasma 1,25(OH)2D3 levels occurred during the PTH infusion, but levels were elevated by 5 h, i.e., 3 h after the end of the infusion (360 +/- 20% increase). No significant changes in 25(OH)D3 or 24,25(OH)2D3 levels occurred in any protocol. Thus hypocalcemia rapidly elevates 1,25(OH)2D3 levels in rats, but the increase is not caused by elevated PTH secretion, hypophosphatemia, or elevated 25(OH)D3 levels. Furthermore, the increase in 1,25(OH)2D3 levels by hypophosphatemia does not occur rapidly. These studies show that there is a calcium-dependent mechanism that is independent of changes in PTH secretion and that results in the rapid elevation of plasma 1,25(OH)2D3 levels to counteract hypocalcemia.
Insulin secretion from ob/ob mouse pancreatic islets: effects of neurotransmitters
Authors: Tassava T. M. , Okuda T. , Romsos D. R.
Published: December 2017

Effects of glucose, acetylcholine, and norepinephrine on insulin secretion from pancreatic islets of 8- to 9-wk-old female genetically obese (ob/ob) and lean mice were determined. The ob/ob islets were 60% larger in diameter than lean mouse islets, secreted fourfold more insulin in response to glucose, and secreted insulin at lower glucose concentrations than lean islets. In the presence of 15 mM glucose, ob/ob islets showed an 8-fold greater absolute increase in insulin secretion in response to acetylcholine and a 12-fold greater absolute decrease in insulin secretion in response to norepinephrine inhibition compared with lean islets. In the presence of 5 mM glucose, acetylcholine increased insulin secretion by threefold from ob/ob islets with no effect on lean islets. When both ob/ob and lean islets were stimulated by glucose to equivalent levels of insulin secretion, acetylcholine potentiated glucose-induced insulin secretion equally in ob/ob and lean islets. Enhanced glucose-induced responsiveness of ob/ob islets thus can explain the greater acetylcholine potentiation of insulin secretion and probably the greater norepinephrine inhibition of insulin secretion in ob/ob islets compared with lean islets. These data are consistent with the hypotheses that the major alteration in ob/ob mouse islets is in glucose sensitivity and responsiveness, which subsequently increases ob/ob islet susceptibility to neural regulation of insulin secretion.
Serum free fatty acids are not involved in acute exercise-induced reduction of LPL in rat tissues
Authors: Paulin A. , Deshaies Y.
Published: December 2017

The present studies were designed to verify whether preventing the rise in serum levels of nonesterified fatty acids (NEFA) by adrenergic blockade would interfere with the decrease in tissue lipoprotein lipase (LPL) activity caused by acute exercise in rats. Ninety minutes before being killed, male rats were injected intraperitoneally with either saline, the beta-adrenergic blocker propranolol (25 mg/kg body weight), or the alpha 2-adrenergic blocker yohimbine (3 mg/kg body weight). Half of each group was killed at rest and the other half immediately after a 1-h run on a treadmill. LPL was determined in white adipose tissue (WAT), heart, and red vastus lateralis muscle (VLM). Exercise enhanced serum levels of NEFA 50% over resting values in saline-injected rats. The latter increase was totally abolished in animals having received propranolol or yohimbine. The activity of LPL in WAT, heart, and red VLM was approximately 35% lower in exercised rats than in resting animals. Serum triacylglycerols were also reduced by the run. Neither propranolol nor yohimbine interfered with any of these reductions. Exercise did not change serum glucose levels in saline-injected rats but decreased it in those injected with propranolol or yohimbine. Serum insulin was unchanged by exercise and by the antagonists. These findings suggest that the beta- and alpha 2-adrenergic pathways, as well as the exercise-induced rise in serum levels of NEFA, are not responsible for the early reducing effect of a 1-h run on tissue LPL activity in untrained rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Insulin-like growth factor I stimulates sodium-phosphate cotransport in the rat osteoblastic cell line UMR-106-01
Authors: Campbell P. I. , Breedlove D. K. , Kempson S. A.
Published: December 2017

The effect of recombinant insulin-like growth factor I (IGF-I) on Pi uptake by a rat osteoblast-like cell line (UMR-106-01) in culture was investigated. IGF-I (10(-6)-10(-8) M) caused a dose-related stimulation of Na(+)-Pi cotransport. A 30-70% increase in Na(+)-dependent Pi uptake over control values was observed after 1- to 5-h exposure of these cells to 10(-7) M IGF-I. The increase was detected within 45 min, in contrast to the slower action of insulin. This effect of IGF-I was specific for Na(+)-Pi uptake, because Na(+)-independent Pi uptake and Na(+)-alanine cotransport were unaffected by IGF-I. A reversal of IGF-I induced stimulation of Na(+)-Pi cotransport was observed within 1 h of removal of the hormone. Kinetic analysis of the IGF-I effect indicates a significant change only in the apparent maximum velocity (Vmax) of Na(+)-Pi cotransport. The Vmax was 5.22 +/- 0.47 vs. 3.33 +/- 0.45 nmol Pi.mg protein-1.10 min-1 in confluent monolayers exposed to 10(-7) M IGF-I and vehicle alone, respectively, for 3 h (P less than 0.05, group t test). Blocking de novo protein synthesis with cycloheximide had no effect on this stimulatory effect of IGF-I. These observations indicate that IGF-I specifically stimulates Pi uptake in osteoblastic cells. The effect is characterized by an increase in Vmax and is not dependent on de novo protein synthesis. The mechanism remains to be determined.
Effect of prolactin on alpha-aminoisobutyric acid uptake in mouse mammary gland explants
Authors: Rillema J. A. , Golden K. , Jenkins M. A.
Published: December 2017

Studies were carried out to characterize the effect of prolactin (PRL) on amino acid uptake into mammary gland explants derived from 12- to 14-day pregnant mice. PRL approximately doubles the rate of uptake of alpha-aminoisobutyrate (AIB), arginine, and hydroxyproline but has no effect on the intracellular accumulation of unincorporated leucine. PRL increases the apparent maximum velocity of AIB uptake from 0.16 to 0.43 nmol.l intracellular water-1.min-1. No effect of PRL, however, on the apparent Michaelis constant (0.75 mM) of AIB uptake was observed. The onset of the PRL stimulation of AIB uptake occurs 4-5 h after PRL addition to the cultured mammary tissues. The lowest stimulatory concentration of PRL on AIB uptake is 5-10 ng/ml, and a maximum response is achieved with 75 ng/ml. The action of PRL on AIB uptake requires both ongoing RNA and protein synthesis, since puromycin (50 micrograms/ml), cycloheximide (5 micrograms/ml), and actinomycin D (1 microgram/ml) abolished the PRL response.
Aldosterone metabolism in the isolated perfused liver of R and S hypertension-prone Dahl rats
Authors: Egfjord M. , Olgaard K.
Published: December 2017

The effect of a chronic oral salt load on hepatic metabolism of aldosterone was examined in isolated livers of salt-resistant (R) and salt-sensitive (S) hypertension-prone male Dahl rats perfused with d-[4-14C]aldosterone (10(-9) M). Aldosterone was analyzed by radioimmunoassay and [4-14C]aldosterone radiometabolites by high-performance liquid chromatography. In salt-loaded S rats, systolic blood pressure was 30 mmHg higher than in the other three groups (P less than 0.01). In S rats, on standard and high-salt diets, plasma renin activity was 64% (P less than 0.001) and 50% (P less than 0.01) lower, and, on the standard diet, plasma aldosterone was 50% (P less than 0.01) lower than in R rats. Salt loading suppressed plasma renin activity by 42% (P less than 0.05) in R rats and plasma aldosterone by 66 and 33% (P less than 0.01) in R and S rats, respectively. In isolated perfused liver, hepatic function did not differ between various groups. Hepatic clearance of aldosterone in R rats given water and saline and in S rats given water did not differ, whereas hepatic clearance of aldosterone was 28 and 35% higher in salt-loaded S rats when compared with S rats on water (P less than 0.01) and with salt-loaded R rats (P less than 0.001), respectively. Polar and reduced metabolites of [4-14C]aldosterone were released into the circulation in livers of R and S rats on both diets, but highest relative levels of polar metabolites of aldosterone were found in salt-loaded S rats. In all groups, only polar metabolites of aldosterone were excreted in bile.(ABSTRACT TRUNCATED AT 250 WORDS)
Restoration of stable metabolic conditions during islet suppression in dogs
Authors: Bradley D. C. , Bergman R. N.
Published: December 2017

These studies were undertaken to examine the stability of metabolic conditions during islet suppression with fixed-rate insulin and glucagon replacement. Somatostatin was infused peripherally at 0.8 microgram.min-1.kg-1, insulin was infused intraportally at 200 microU.min-1.kg-1, and glucagon was infused intraportally at 0, 0.6, 1, 2, 5, or 20 ng.min-1.kg-1 in conscious overnight-fasted dogs. [3-3H]glucose was infused for measurement of glucose kinetics. During infusion, plasma insulin was 7.2 +/- 0.4 microU/ml. Plasma glucagon rose linearly with glucagon dose, achieving basal levels at 2 ng.min-1.kg-1 infusion (164 +/- 18 vs. basal = 182 +/- 57 pg/ml). Plasma glucose and hepatic glucose output (HGO) decreased from basal at doses 0, 0.6, and 1 ng.min-1.kg-1, increased from basal at doses 5 and 20 ng.min-1.kg-1, and remained close to basal at dose 2 ng.min-1.kg-1 (92 +/- 20 vs. basal = 99 +/- 3 mg/dl and 2.4 +/- 0.2 vs. basal = 2.7 +/- 0.2 mg.min-1.kg-1 for glucose and HGO, respectively; P greater than 0.47). Glucose clearance and blood lactate were also closely matched to basal at dose 2 ng.min-1.kg-1. Coefficients of variation during 2 ng.min-1.kg-1 glucagon infusion (last hour) were 3.4, 4.6, 4.9, and 4.7% for glucose, HGO, clearance, and lactate, respectively. These findings indicate that fasting metabolic conditions, as inferred from blood glucose, lactate, insulin, and glucagon levels, and the rates of glucose production and uptake can be recreated in toto during fixed-rate islet hormone replacement.
Splanchnic and whole body L-[1-13C,15N]leucine kinetics in relation to enteral and parenteral amino acid supply
Authors: Yu Y. M. , Burke J. F. , Vogt J. A. , Chambers L. , Young V. R.
Published: December 2017

The effect of the route of administration of a complete amino acid solution (0.24 g.kg-1.h-1) on leucine (Leu) and alpha-ketoisocaproate (KIC) metabolism in the splanchnic region (Sp) was assessed in nine chronically catherized mongrel dogs receiving, for 6 h, amino acids by jugular vein (PN feeding). Results were compared with those obtained previously [Y. M. Yu, D. A. Wagner, E. E. Tredget, J.A. Waleszewski, J. F. Burke, and V. R. Young. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E36-E51, 1990] in eight dogs similarly studied but given amino acids by constant enteral feeding (EN). We used primed continuous intravenous infusions of L-[1-13C,15N]Leu and measurements of arteriovenous isotope and Leu balance across the gut, liver, and Sp to estimate parameters of whole body and organ Leu metabolism [Leu-N and Leu-C flux, Leu----KIC; KIC----Leu, Leu oxidation and rates of Leu appearance (B) from and disappearance (S) into proteins]. Whole body Leu kinetics were the same for both routes of amino acid administration. With PN, KIC----Leu, Leu----KIC, and total metabolic processing were lower than for EN in Sp, and overall Leu balance (S - B) was higher in Sp for EN. Leu appearance from protein breakdown in gut was higher with PN. The rate of KIC----Leu was higher in liver for EN. These findings reveal that route of amino acid (Leu) administration, under these acute feeding conditions, alters the processing and metabolic fate of Leu in Sp but that whole body parameters of Leu metabolism are stable. The implications of these metabolic findings in relation to the maintenance of intestinal function and integrity are discussed.
Intensity of lactation modulates renal 1 alpha-hydroxylase and serum 1,25(OH)2D in rats
Authors: Lobaugh B. , Boass A. , Garner S. C. , Toverud S. U.
Published: December 2017

Renal 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-hydroxylase) activity and serum 1,25-dihydroxyvitamin D [1,25(OH)2D] concentration were measured in lactating rats suckling litters of 3, 6, or 12 pups to determine the effect of increasing lactational intensity on the biosynthesis of 1,25(OH)2D. Serum Ca2+, total Ca, Pi, and immunoreactive parathyroid hormone were also determined. The average daily litter weight gain for each litter size was calculated from the gain over the last 4-6 days of each of three experiments and was used as an index of lactational intensity. Highly significant correlation coefficients were found between 1 alpha-hydroxylase and average daily litter weight gain (rs = 0.63, n = 53, P less than 0.001), serum 1,25(OH)2D and average daily litter weight gain (rs = 0.62, n = 50, P less than 0.001), 1 alpha-hydroxylase and serum total Ca (rs = -0.52, n = 53, P less than 0.001), and average daily litter weight gain and total Ca (rs = -0.52, n = 53, P less than 0.001). Neither serum phosphorus nor immunoreactive parathyroid hormone correlated significantly with 1 alpha-hydroxylase. In addition, construction of regression models using a stepwise forward variable selection procedure revealed serum total Ca concentration to be a significant predictor for both serum 1,25(OH)2D and renal 1 alpha-hydroxylase in lactating rats. These data support the hypothesis that increasing lactational intensity leads to decreasing serum Ca concentration, resulting in stimulation of 1 alpha-hydroxylase activity and a rise in the serum 1,25(OH)2D level.(ABSTRACT TRUNCATED AT 250 WORDS)
Multiple cold air exposures change oral triiodothyronine kinetics in normal men
Authors: Reed H. L. , D'Alesandro M. M. , Kowalski K. R. , Homer L. D.
Published: December 2017

The influence of cold exposure on triiodothyronine (T3) kinetics was studied in 16 men before, during (biweekly), and after 80 (10/wk) cold (4 degrees C) air exposures. We used serum values before and up to 24 h after a pharmacological oral (o) dose of T3 [76.8 nmol (50 micrograms)] to calculate noncompartmental kinetic parameters. To assess the role of thyroxine (T4) and thyrotropin (TSH), we administered a replacement dose of T3 [46.0 nmol/day (30 micrograms)] to eight men (+T3 group) and placebo to eight others (-T3 group) for the 2-mo study. There was no group effect of T3 treatment (+T3) on oral total volume of distribution (TVdo), metabolic clearance rate (MCRo), or disposal rate (DRo). TVdo was not changed over the study. Cold increased MCRo by 5.4 +/- 2.0 l.day-1.m-2. DRo increased with cold by 10.2 +/- 4.4 nmol.day-1.m-2. Although serum TSH, total T4, and free T4 decreased by approximately 50% in the +T3 group, the changes in MCRo and DRo with cold were not different from those in -T3. We describe that human T3 kinetics are changed with brief repeated exposures to cold air and that these increases in MCRo and DRo do not appear to be dependent on TSH or T4.
Regulation of acute parathyroid hormone release in normal humans: combined calcium and citrate clamp study
Authors: Schwarz P. , Sorensen H. A. , Transbol I. , McNair P.
Published: December 2017

The objective of the present study was to elucidate the dynamics of parathyroid hormone regulation, with particular reference to the mechanism controlling the acute parathyroid hormone release. Through utilization of the citrate clamp technique and the calcium clamp technique we were able, in a standardized way, to stimulate and suppress the parathyroid hormone secretion. Precise bedside measurements of blood ionized calcium and measurements of intact parathyroid hormone were performed. Twelve healthy young volunteers participated in two trials 6-12 wk apart, a citrate clamp (delta-blood ionized calcium -0.19 mmol/l) and a calcium plus citrate clamp (delta-blood ionized calcium +0.22 mmol/l and -0.19 mmol/l). During the citrate clamp, preceded by normal calcemia, serum intact parathyroid hormone peaked to a maximum after 5-10 min, four to six times above baseline concentration and then declined to a steady state two to three times above baseline concentration. During the citrate clamp, preceded by hypercalcemia induced by a calcium clamp, serum intact parathyroid hormone also peaked immediately to about five to nine times above its suppressed level, approximately two times above the baseline concentration. Subsequently, serum intact parathyroid hormone declined to a steady state just below the baseline concentration. In conclusion, within the range studied, the mechanism eliciting the acute serum intact parathyroid hormone release from its depot is a fall in blood ionized calcium, not the absolute concentration of ionized calcium.
Leucine kinetics in fed low-birth-weight infants: importance of splanchnic tissues
Authors: Beaufrere B. , Fournier V. , Salle B. , Putet G.
Published: December 2017

Whole body Leu kinetics were determined in fed low-birth-weight (LBW) infants. To assess the importance of first-pass splanchnic extraction of ingested amino acids, two tracers were simultaneously infused by intravenous (L-[1-13C]Leu) and intragastric (L-[5,5,5-2H3]Leu) routes in 13 LBW infants [1,742 +/- 169 (SE) g] fed with protein-enriched human milk (protein intake 3.23 +/- 0.97 g.kg-1.day-1). Splanchnic extraction estimated from plasma [2H3]Leu appearance was 48.2 +/- 15.6% of Leu intake. Total Leu flux, endogenous Leu flux (index of protein catabolism), and nonoxidative Leu disposal (NOLD, index of protein synthesis) were 3.45 +/- 0.57, 1.90 +/- 0.74, and 2.54 +/- 0.62 mumol.kg-1.min-1, respectively. Higher estimates were obtained when using alpha-ketoisocaproate as a precursor pool. There was a wide individual variation of protein intake due to the use of human milk, and, over this range, Leu intake was correlated negatively with endogenous Leu flux (r = 0.88, P less than 0.01) whereas NOLD remained fairly constant. Thus, in LBW infants, 1) splanchnic extraction is two times as high as in adults and might reflect an elevated splanchnic protein turnover and 2) increasing protein intake probably promotes protein gain mainly by inhibiting protein catabolism.
Spatial and temporal thyrocyte response to TSH: a computer-assisted image analysis
Authors: Penel C. , Mauchamp J.
Published: December 2017

Pseudopods at the apical pole of porcine thyroid monolayers in culture were considered as reflecting individual thyrocyte responses to thyrotropin (TSH) stimulation. Scanning electron microscopy and computer-assisted image analysis showed that whatever TSH stimulation was used, the pseudopods were characterized by two populations: P1 with small diameters (2 microns) and P2 with greater diameters (5 microns). The density of P1 rapidly increased to reach a plateau, while P2 continuously increased during stimulation. Two-dimensional pseudopod patterns were compared with random point distributions by means of two topographical parameters: the interpseudopod distances and angles. A factorial analysis of experimental distribution of pseudopods obtained after increasing stimulation times displayed a shift from a nonrandom (10-20 min) to a random (60-90 min) distribution. Clusters of three pseudopods characterized by short distances (6-9 microns) and equilateral organization (angles 40-60 degrees) were observed after a 10-min stimulation. These results suggested that early thyrocyte response to TSH stimulation is characterized by interrelations between three adjoining cells, with the thyrocyte response later appearing as random.
Epinephrine's ketogenic effect in humans is mediated principally by lipolysis
Authors: Avogaro A. , Cryer P. E. , Bier D. M.
Published: December 2017

To quantify epinephrine's effects on acetoacetate and beta-hydroxybutyrate kinetics, we infused subjects with 0.3 and 2.5 micrograms/min epinephrine, either alone or with a concomitant somatostatin infusion with insulin, glucagon, and growth hormone replaced at postabsorptive levels (islet clamp). Additional subjects received no epinephrine but sequential infusions of heparin plus 10% Intralipid at rates of 0.5 and 3.0 ml/min. Both epinephrine and Intralipid increased ketone body appearance (unaffected by islet clamp), augmented the interconversion rates between ketone bodies and, during the 2.5 micrograms/min infusion, caused a marked increase in beta-hydroxybutyrate appearance. The fraction of plasma free fatty acid (FFA) flux appearing as plasma ketones increased from 6 to 7% in the basal state to 11% at the high-epinephrine infusion. This fraction was also unaffected by the islet clamp and was not different from values obtained at similar Intralipid plus heparin-induced elevations in plasma FFA levels. We conclude that epinephrine's ketogenic effect in humans is primarily the result of its lipolytic effect, is accompanied by a significantly increased rate of ketone body interconversion, is manifest largely as an increase in plasma beta-hydroxybutyrate appearance at high plasma epinephrine values, and is not limited by portal insulin at post-absorptive levels.
Metabolism of pregnant-lactating rats is adapted to pregnancy rather than to lactation
Authors: Wijkstra S. , Moes H. , Koiter T. R.
Published: December 2017

In pregnant-lactating rats implantation was induced on day 4 of lactation so that, as an exception, lactation coincided with the period of high fetal growth. The already present suckling litters of these animals lagged behind in growth, but the "second" litters were at birth normal in size and weight. Such pregnant-lactating rats were tested in vivo with intravenous glucose loads and compared with cyclic and lactating rats. Glucose tolerance was unaffected by the reproductive state. Pregnant-lactating rats showed, just as during their first pregnancy, low basal glucose levels. Their basal insulin levels and insulin responses, however, were decreased in comparison with the first pregnancy and resembled those of lactating rats. This may be due to an increased insulin turnover, because in vitro insulin responsiveness and insulin content of both "pregnant-lactating" and "pregnant" islets were increased in comparison with "cyclic" and "lactating" islets. It was concluded that the metabolism of pregnant-lactating rats is adapted to the pregnant rather than to the lactational state.
Suppression of central noradrenergic neuronal activity inhibits hyperglycemia
Authors: Smythe G. A. , Edwards S. R.
Published: December 2017

Hypothalamic noradrenergic neuronal activity (NNA) and hepatic glucose output are stimulated by stress. The aim of the present investigation was to examine whether the blockade of noradrenergic responses to stress might suppress the associated hyperglycemia. Mass spectrometry was used for analysis of norepinephrine (NE) and its neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) in rat hypothalamus, and the ratio DHPG/NE was used as an index of NNA. Treatment of rats with 2-deoxy-D-glucose (500 mg/kg ip, -30 min), yohimbine (10 mg/kg ip, -20 min), or neostigmine (2 micrograms icv, -60 min) increased both NNA and serum glucose (P < 0.05). When rats were additionally pretreated with pentobarbital (60 mg/kg ip; -60 min), the NNA responses were blocked (P < 0.01). At the same time the hyperglycemic responses were also inhibited (P < 0.01). In rats that had reduced NNA due to 7 days “gentling,” serum glucose levels were also significantly reduced (P < 0.001) compared with naive controls. The data demonstrate that inhibition of central noradrenergic activity is also associated with an inhibition of hyperglycemia, raising the concept that therapies aimed at reducing central NNA may have a role in the management of diseases with excessive hepatic glucose output such as non-insulin-dependent diabetes mellitus.
Role of angiotensin II and alpha-adrenergic receptors during estrogen-induced vasodilation in ewes
Authors: Davis L. E. , Magness R. R. , Rosenfeld C. R.
Published: December 2017

Estradiol-17 beta (E2 beta) produces uterine and systemic vasodilation in nonpregnant ewes without altering mean arterial pressure (MAP). Mechanisms responsible for maintaining MAP and thus uterine blood flow (UBF) may include activation of the renin-angiotensin and/or adrenergic systems. We therefore investigated the effects of systemic blockade of angiotensin II (ANG II) and/or alpha-adrenergic receptors in nonpregnant, castrated ewes, using saralasin (Sar) and/or phentolamine (Phen) in the presence or absence of intravenous E2 beta (1.0 microgram/kg). In nonestrogenized ewes neither antagonist alone had substantial cardiovascular effects; however, Sar + Phen decreased systemic vascular resistance (SVR) 20 +/- 7.4% (SE) and increased heart rate (HR) 50 +/- 19% (P < 0.01); MAP and UBF were unaffected. Following E2 beta treatment SVR fell 17 +/- 2.4% (P < 0.01), UBF increased more than fourfold, and MAP was unchanged. Compared with E2 beta alone, Phen + E2 beta decreased SVR 42 +/- 4.7%, and MAP fell 11 +/- 1.8% (P < 0.05) despite 40–50% increases in HR and cardiac output (P < 0.05). Responses to Sar + E2 beta were similar to E2 beta alone, except for a fall in MAP, whereas responses to Sar + Phen + E2 beta resembled those of Phen + E2 beta. E2 beta-induced uterine vasodilation was unaltered by Sar and/or Phen. During E2 beta-induced vasodilation, MAP is maintained by enhanced activation of the alpha-adrenergic and renin-angiotensin systems; however, uterine vascular responses to E2 beta are independent of both systems and perfusion pressure.
Oxoanions stimulate in vitro ovulation and signal transduction pathways in goldfish (Carassius auratus) follicles
Authors: Hsu S. Y. , Goetz F. W.
Published: December 2017

The present study investigated the effects of a number of oxoanion compounds on in vitro ovulation of goldfish follicles and ovarian second messenger activities. Significant levels of ovulation were induced by 0.1 mM sodium chromate, 0.1 mM sodium metavanadate, 10 mM sodium molybdate, 0.1 mM sodium orthovanadate, 5 mM sodium selenate, 0.5 mM sodium tungstate, and 0.1 mM vanadyl sulfate. At levels that significantly stimulated ovulation, metavanadate, molybdate, orthovanadate, tungstate, and vanadyl sulfate also stimulated follicular phosphatidylinositol cycling and inhibited ovarian alkaline phosphatase activity. Moreover, the ovulation induced by these oxoanions was not inhibited by indomethacin (10 micrograms/ml), while ovulation induced by selenate and chromate was. In contrast, only vanadium-containing compounds significantly stimulated prostaglandin (PG) synthesis, and, in fact, selenate significantly inhibited PG production. Finally, only sodium molybdate- and vanadium-containing compounds appeared to increase follicular adenosine 3',5'-cyclic monophosphate content. While all oxoanions stimulated in vitro ovulation, they had differential effects on certain signal transduction pathways when tested at concentrations that stimulated in vitro ovulation. From the results, two basic groups could be delineated, one containing tungstate-, molybdate-, and vanadium-containing compounds and the other selenate and chromate. Thus the mechanism by which ovulation is induced by chromate and selenate may be different from that of vanadium-containing compounds, molybdate, and tungstate.(ABSTRACT TRUNCATED AT 250 WORDS)
Platelet-activating factor stimulates resorption by rabbit osteoclasts in vitro
Authors: Zheng Z. G. , Wood D. A. , Sims S. M. , Dixon S. J.
Published: December 2017

We have shown previously that platelet-activating factor (PAF), a potent inflammatory mediator, acts directly on isolated rat osteoclasts to elevate cytosolic free Ca2+ concentration ([Ca2+]i). The purpose of this study was to examine the effects of PAF on osteoclast function. Osteoclasts were isolated from the long bones of neonatal rabbits and studied in three ways. [Ca2+]i of fura-2-loaded osteoclasts was monitored by microspectrofluorimetry. In 9 out of 16 cells tested, PAF (10–100 nM) caused elevation of [Ca2+]i that peaked then returned to baseline. In contrast, the biologically inactive precursor and metabolite of PAF, lyso-PAF, was without effect. Using time-lapse videomicroscopy, we found that PAF elicited retraction of peripheral pseudopods. Although calcitonin induced sustained retraction and immobility, the response to PAF was transient and, within 30 min, pseudopods reformed. To assess effects of PAF on resorptive activity, osteoclasts were cultured on dentin slices for 48 h in the presence of vehicle, PAF (200 nM), or calcitonin (100 ng/ml). PAF increased the area of individual resorption pits (from control values of 1,660 +/- 110 to 2,240 +/- 200 microns2, P < 0.05) and the total planar area resorbed per unit area of substrate (from 7.6 +/- 1.6 to 14.5 +/- 3.1 x 10(4) microns2/cm2, P < 0.025). As expected, calcitonin significantly decreased resorptive activity. These data indicate that PAF activates osteoclastic resorption. PAF may play a role in mediating the resorption of bone and mineralized cartilage in inflammatory diseases such as rheumatoid arthritis and periodontitis.
Analytical problems in detecting rapid insulin secretory pulses in normal humans
Authors: O'Meara N. M. , Sturis J. , Blackman J. D. , Roland D. C. , Van Cauter E. , Polonsky K. S.
Published: December 2017

The present study was undertaken to define the optimal experimental and analytical conditions necessary to reproducibly detect, in the systemic blood, small-amplitude rapid oscillations (period 8–15 min) of insulin and C-peptide. Samples for insulin, C-peptide, and glucose were drawn at 2-min intervals for 2 h from six normal subjects during constant glucose infusion and from five of the same subjects under basal conditions. To reduce measurement error, insulin and C-peptide levels were measured 16 times at each time point. Three algorithms for pulse analysis (ULTRA, Cluster, PulseFit) were used to identify significant pulses, whereas autocorrelation and spectral analysis were used to identify potential regular periodic components in the data. In three of the five subjects studied under basal conditions, regular rapid oscillations could be consistently detected by autocorrelation when the analysis was based on eight replicates but not on duplicate series. In the remaining two basal studies and in all studies during glucose infusion, the majority of profiles did not have a significant periodic component. However, formal pulse analysis demonstrated that the number of pulses was similar during glucose infusion and basal conditions. Reproducibility was enhanced by increasing the number of replicates used in the analysis. We conclude that in the analysis of small-amplitude rapid insulin and C-peptide oscillations, the sensitivity and specificity of the analysis is likely to be enhanced by performing multiple estimations at each time point and by using a minimum of two contrasting analytical approaches for pulse detection, which incorporate a method evaluating periodicity in conjunction with a pulse detection program designed to evaluate each individual oscillation separately.
Remote and chronic access to the third cerebral ventricle of the unrestrained prepubertal rhesus monkey
Authors: Gay V. L. , Mikuma N. , Plant T. M.
Published: December 2017

One channel of a commercially available standard-size three-channel fluid swivel was modified to permit continuous access to the brain of unrestrained prepubertal rhesus monkeys via a continuous length of small-bore Teflon tube originating from a swivel device on top of the animal's cage and terminating in the third cerebral ventricle. This system was employed to achieve continuous access to the third cerebroventricle in four monkeys for periods of up to 12 mo. The value of the system for studies of the neurochemical control of hypothalamic-releasing factor secretion was established by monitoring adenohypophysial responses to neurotransmitter receptor agonists infused into the third ventricle. Specifically, repetitive infusions of morphine (30 micrograms/infusion) elicited a robust train of prolactin discharges, and third ventricular administration of N-methyl-DL-aspartic acid (NMA; 20 micrograms) resulted in striking discharges of LH.
Hepatic and extrahepatic insulin action in humans: measurement in the absence of non-steady-state error
Authors: Katz H. , Butler P. , Homan M. , Zerman A. , Caumo A. , Cobelli C. , Rizza R.
Published: December 2017

The isotope dilution technique has been extensively used to assess insulin action in humans. To determine if nonsteady state (NSS) has led to erroneous estimates of hepatic and extrahepatic insulin sensitivity, we measured glucose turnover in healthy subjects during infusion of insulin at rates of 0.25, 0.6, and 2.0 mU.kg-1.min-1. Turnover was calculated using Steele's traditional NSS equations [fixed-effective volume (pV) method] as well as with methods [radioactive infused glucose (hot-GINF) or variable pV] designed to minimize NSS error. In contrast to the fixed-pV method, both the hot-GINF and variable-pV methods indicated that several hours were required for suppression of hepatic glucose release at all insulin concentrations and that small increases in plasma insulin (approximately 100 pmol/l) had comparable effects on glucose disappearance and hepatic glucose release. Nevertheless, despite these differences, when turnover during the final hour of the insulin infusions was plotted vs. the prevailing insulin concentration, all three methods yielded similar insulin dose-response curves for suppression of hepatic glucose release. Thus despite previous errors in measurement of glucose turnover, the widely accepted belief that the human liver is exquisitely sensitive to small changes in insulin is correct.
Effects of hyperinsulinemia on the subsequent hormonal response to hypoglycemia in conscious dogs
Authors: Davis S. N. , Dobbins R. , Colburn C. , Tarumi C. , Jacobs J. , Neal D. , Cherrington A. D.
Published: December 2017

The aim of this study was to determine if differing periods of prior hyperinsulinemic nonhypoglycemia can modify the subsequent counterregulatory response to hypoglycemia. Experiments were carried out on 19 normal 18-h fasted conscious dogs. Insulin was infused intraportally at 8 mU.kg-1.min-1 for 3 h on two occasions and 3.5 h on a third separate occasion. This resulted in similar steady-state arterial insulin levels during each protocol (4,370 +/- 433 pmol/l). Each animal was maintained at a similar plasma glucose nadir (2.8 +/- 0.6 mmol/l) for 2 or 2.5h, depending on the protocol. In protocol I (n = 7) plasma glucose was allowed to fall to the desired hypoglycemic plateau by 30 min. In a second group of dogs (protocol II, n = 5) there was a 30-min period of euglycemic hyperinsulinemia followed by a 30-min fall (similar to protocol I) in plasma glucose. In a third group of dogs (protocol III, n = 7), there was an initial 15-min period of euglycemic hyperinsulinemia followed by a 45-min fall in plasma glucose. Differing periods of euglycemic hyperinsulinemia had distinct effects on subsequent counterregulation. During the final 2 h of hypoglycemia the incremental area under the curve (AUC) for glucagon was significantly greater in protocol I vs. II (3.0 +/- 1.0, -0.5 +/- 0.2 micrograms.l-1.min-1, P < 0.02, respectively). Conversely, catecholamine levels were increased in protocol II (30 min prior hyperinsulinemic euglycemia) compared with protocol I (epinephrine 1,448 +/- 268, 855 +/- 119 nmol.l-1.min-1; norepinephrine 244 +/- 30, 166 +/- 23 nmol.l-1.min-1, respectively, P < 0.05). During protocol III, glucagon and catecholamine levels were intermediate between protocols I (no euglycemic hyperinsulinemia) and II (30 min euglycemic hyperinsulinemia).(ABSTRACT TRUNCATED AT 250 WORDS)
Desensitization of calcium messenger system in parathyroid hormone-stimulated opossum kidney cells
Authors: Fujimori A. , Miyauchi A. , Hruska K. A. , Martin K. J. , Avioli L. V. , Civitelli R.
Published: December 2017

We have studied the desensitization of the calcium message system to parathyroid hormone (PTH) by monitoring intracellular calcium concentration ([Ca2+]i) in an opossum kidney cell line (OKP). PTH (10(-7) M) caused a transient increase in [Ca2+]i, with an average peak height of 48.7 +/- 4.7% above baseline (n = 32). Cells stimulated with either 10(-7) or 10(-8) M PTH did not respond to a second challenge with a maximal dose (10(-7) M) of the hormone, whereas lower concentrations of PTH (10(-9) M and 10(-10) M) only partially desensitized the cells, since a [Ca2+]i transient of smaller amplitude (12.7 +/- 2.1 and 40.6 +/- 6.2% above baseline, respectively) was observed with a second stimulation. Desensitization developed within 5 min of initial hormone exposure, when PTH receptor binding was not significantly decreased. Maximal reduction of PTH binding sites (37.0 +/- 1.4%) was achieved only after 2 h. Partial desensitization was reproduced by 10(-9) M phorbol 12-myristate 13-acetate (PMA) but not by dibutyryladenosine 3',5'-cyclic monophosphate, and it was blocked by staurosporine. However, staurosporine had no effect on the complete desensitization induced by high doses of PTH. At 10(-9) M, PTH also caused a time-dependent desensitization of the adenosine 3',5'-cyclic monophosphate (cAMP) response, with maximal inhibition achieved after 2 h. PMA also decreased the cAMP response to PTH, but its inhibitory effect was less potent than that of 10(-9) M PTH. Therefore PTH induces a dose-dependent homologous desensitization of the Ca2+ message system in OKP cells, independent of receptor occupancy.(ABSTRACT TRUNCATED AT 250 WORDS)
Altered lipid kinetics in adjuvant recombinant human growth hormone-treated multiple-trauma patients
Authors: Jeevanandam M. , Petersen S. R.
Published: December 2017

Adjuvant recombinant human growth hormone therapy during the postinjury period may improve the efficiency of utilization of body energy stores. In a group of 20 severely injured highly catabolic hypermetabolic adult multiple-trauma victims, we have investigated the basic lipid kinetics of trauma (study I) and its modification after 7 days of intravenous feeding (total parenteral nutrition) with (group H, n = 10) or without (group C, n = 10) daily rhGH (0.15 mg somatotropin.kg-1.day-1) intramuscular injections (study II). Whole body lipolysis rate (2-stage primed constant infusion of 10% glycerol), substrate net oxidation rates (indirect calorimetry), and plasma levels of hormones were determined. Compared with the control group (group C) the treatment group (group H) showed significantly (P = 0.006) enhanced rates of lipolysis and free fatty acid reesterification (10 +/- 2 to 18 +/- 2 kcal.kg-1.day-1, P = 0.05). As a function of resting energy expenditure (REE), a trend of increased net glucose oxidation [32 +/- 10 vs. 56 +/- 7% REE, not significant (NS)] and decreased fat (40 +/- 8 vs. 25 +/- 5% REE, NS) and protein oxidation rates (28 +/- 2 vs. 19 +/- 2% REE, P = 0.007) were also indicated. The simultaneous operation of increased lipolytic and reesterification processes may allow the adipocyte to respond rapidly to changes in peripheral metabolic fuel requirements in injury.
Forward diastolic flow in pulmonary artery induced by right atrial contraction of pig hearts
Authors: Vengen O. A. , Ellingsen O. , Ilebekk A.
Published: December 2017

To study whether right atrial contraction can forward blood into the pulmonary artery during diastole, blood volume was expanded in anesthetized open-chest pigs until mean right atrial pressure was 13-20 mmHg (range). In the control situation, blood flow in the pulmonary artery was only observed during ventricular systole. Forward diastolic pulmonary artery flow, coinciding with right atrial contraction, was observed when diastolic pulmonary artery pressure was reduced during selectively increased left-side contractility, during bradycardia after propranolol injection (0.5 mg/kg body wt iv), and during the prolonged diastolic interval after spontaneously occurring atrial extrasystoles. The prolongation of the diastolic interval in all three series caused the diastolic pulmonary artery pressure to decline and the filling of the right atrium to increase, thus further stimulating the right atrial Frank-Starling mechanism. The diastolic blood flow in the pulmonary artery constituted 11% of the stroke volume during increased left-side inotropic stimulation, 8% during bradycardia, and 6% in beats preceded by a prolonged diastolic interval. Thus, in the normal heart, blood can be ejected into the pulmonary artery during right atrial contraction.
Pump perfusion abolishes autoregulation possibly via prostaglandin release
Authors: Borgdorff P. , Sipkema P. , Westerhof N.
Published: December 2017

The influence of pump perfusion on autoregulation was studied in the hindleg of the halothane- and chloralose-anesthetized cat. Flow was measured with an electromagnetic flow probe in a tube between aorta and the vascularly isolated, denervated leg and varied with a calibrated occluder. Perfusion pressure was measured via a T-piece distal to the occluder. The steady-state pressure-flow relations could be fit with a sigmoidal curve. The mean closed-loop gain (0 less than Gc less than 1) for autoregulation in six cats was 0.46 +/- 0.11 (SD). When in these cats a roller pump was used, an almost linear pressure-flow relation was found (Gc = 0.01 +/- 0.09), while the resistance at control flow was decreased by 15 +/- 4%. Administration of indomethacin (5 mg/kg iv), a cyclooxygenase inhibitor, partly restored autoregulation during pumping (Gc = 0.34 +/- 0.09) and slowly increased the resistance to above its original value (20 +/- 13%). In six other cats, pump perfusion had no influence on autoregulation when started after indomethacin administration but resistance increased. This increase could not be prevented with ketanserin, a specific serotonin 2 receptor blocker. We conclude that pump perfusion abolishes autoregulation and decreases resistance via a process that involves prostaglandins. Blockade of the prostaglandin synthesis unmasks a slow vasoconstrictor influence in the bed.
Chloralose alters circulatory response to alpha-receptor stimulation and blockade
Authors: Covert R. F. , Drummond W. H. , Gimotty P. A.
Published: December 2017

Chloralose anesthesia is commonly used in animals for cardiovascular research despite limited data on possible receptor-drug interactions. To investigate potential interactions with alpha-adrenergic receptors, we studied the response of chronically instrumented, spontaneously breathing young lambs to alpha-receptor stimulation (by methoxamine) and blockade (by phentolamine) after infusion of 30 mg/kg of chloralose or an equal volume of vehicle. Both experiments were performed in each animal on different days and in alternate order. Chloralose altered the systemic arterial pressure and heart rate response to both alpha-agonist challenge and to alpha-blockade when compared with control. Despite potentiating the systemic arterial pressor response to methoxamine, chloralose attenuated the reflex decrease in heart rate after alpha-agonist-induced hypertension. This observation suggests that the baroreceptor reflex was blunted. Chloralose, commonly considered an ideal anesthetic for cardiovascular studies, may have important effects on the cardiovascular response to alpha-adrenergic test agents. The potential for interactive effects should be considered in experimental designs that couple the use of chloralose and alpha-adrenergic agents.