bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of dopamine on total oxygen consumption and oxygen delivery in healthy men
Authors: Ruttimann Y. , Chiolero R. , Jequier E. , Breitenstein E. , Schutz Y.
Published: December 2017

The effect of acute intravenous dopamine (DA) administration at three sequential (but randomized) infusion rates was studied in eight young male volunteers. DA was infused at 2.5, 5, and 10 micrograms.kg-1.min-1. O2 consumption (VO2) and CO2 production (VCO2) were measured continuously by means of a computerized indirect calorimeter (blood system). In response to the 5- and 10-micrograms.kg-1.min-1 DA infusion rates, a significant increase (P less than 0.01) in VO2 corresponding to a 6% (range, 3-10) and 15% (range, 12-23) increase, respectively, of preinfusion values was observed. In contrast, at the low dose (2.5 micrograms.kg-1.min-1), DA induced no significant change in VO2. Cardiac output (Qc) increased significantly after the three DA administration rates [19% (range, 0-42), 34% (range, 17-71), and 25% (range, -3 to +47)] for the doses 2.5, 5, and 10 micrograms.-kg-1.min-1, respectively. The increase in O2 delivery (QO2) outweighed VO2 at all administration rates despite the relative drop in QO2 at the maximal DA administration rate. These results indicate that in humans DA improves net O2 supply to tissues proportionally more than it increases VO2 at all doses used in the present study.
Atrial natriuretic hormone and aldosterone regulation in salt-depleted state
Authors: Shenker Y.
Published: December 2017

To evaluate the effect of very low-dose infusion of atrial natriuretic hormone (ANH) on aldosterone regulation, seven normal young men were infused for 2.5 h with 0.47 pmol.kg-1.min-1 of human [Ser-Tyr28]ANH or placebo. During the last 0.5 h 4 pmol.kg-1.min-1 of angiotensin II were also infused. ANH plasma levels increased from 3.46 +/- 0.25 to a maximum of 6.80 +/- 0.88 pmol/l, which is well within normal limits. Plasma aldosterone decreased almost 40%, from 40.7 +/- 5.7 to 25.9 +/- 4.9 ng/dl after 2 h. ANH infusion caused a slight decrease in blood pressure and slight increase in renal excretion of sodium and potassium. These results suggest that even small changes in ANH levels, within the normal range, have physiological significance, particularly in aldosterone regulation.
Oral verapamil and calcium and vitamin D metabolism in rats: effect of dietary calcium
Authors: Fox J. , Della-Santina C. P.
Published: December 2017

Prior studies showed that chronic oral verapamil administration increased plasma immunoreactive parathyroid hormone (irPTH) but decreased 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels in rats fed a high (1.2%)-Ca diet. These and other findings suggested that verapamil may induce target-organ PTH resistance. This study determined the effects of verapamil (4, 20, or 100 mumol.kg-1.day-1 for 2 wk) in rats fed high (1.2%)-, low-normal (0.47%)-, and low (0.02%)-Ca diets (higher irPTH levels). With 1.2 and 0.47% Ca diets, verapamil administration was associated with increases in irPTH (92 and 44%, respectively) and decreases in 1,25(OH)2D3 levels (22 and 21%, respectively), increases in duodenal Ca transport (13 and 8%, respectively), and increases in tibia mineral content (1.3 and 2.8%, respectively). The decrease in 1,25(OH)2D3 levels was caused by decreased production, not by increased clearance. In contrast, verapamil was without effect in rats fed the 0.02% Ca diet. Thus severe dietary Ca deficiency abolished the stimulatory effects of verapamil on irPTH levels, Ca absorption, and tibia mineral content. Importantly, these results indicate that verapamil, in contrast to nifedipine, appears not to have adverse effects on Ca homeostasis in rats, irrespective of dietary Ca intake.
The glucose-galactose paradox in neonatal murine hepatic glycogen synthesis
Authors: Kunst C. , Kliegman R. , Trindade C.
Published: December 2017

In adults glucose incorporation to glycogen is indirect after recycling from lactate. In neonates galactose entry to glycogen exceeds that for glucose, but the pathway is unknown. The pathway of hexose incorporation to glycogen was studied in 5-7-day-old rats and 6-h-old rats injected intraperitoneally (IP) with either double-labeled [6-3H]glucose (nonrecycling), [U-14C]glucose (recycling), or [6-3H]glucose and [U-14C]galactose in saline. In another group of pups, 1 g/kg of glucose or galactose was administered in addition to tracers to determine glycemia and net glycogen synthesis between 15 and 180 min after injection. Blood glucose increased from 3.4 +/- 0.4 to 8.5 +/- 1.5 mM in 5-7-day-old pups in response to IP glucose; there was no glycemic response to galactose, although galactose levels increased from 0.5 to 6.3 mM at 15 min. Hepatic glycogen increased after IP glucose from 14 +/- 2 at 15 min to 30 +/- 3 at 120 min (P less than 0.01), whereas after IP galactose glycogen was 44 +/- 6 mumol/g at 120 min (P less than 0.05). After IP glucose, 3H and 14C disintegration per minute in glycogen increased slowly with 14C exceeding 3H at 120 and 180 min. In contrast IP [14C]galactose resulted in a much greater peak of 14C incorporation into glycogen. The ratio of 3H to 14C in glycogen relative to the injectate after IP glucose decreased from 0.69 +/- 0.12 to 0.36 +/- 0.03 (P less than 0.01) between 15 to 180 min, whereas the ratio after galactose was 0.20 +/- 0.007 to 0.15 +/- 0.02 at these times. The 6-h-old pups also demonstrated augmented incorporation of [14C]galactose in glycogen relative to [3H-14C]glucose. In contrast to 5-7-day-old pups there was no evidence of glucose recycling in 6-h-old pups. In conclusion galactose entry into glycogen exceeds that for glucose and is not dependent on recycling. Direct incorporation of galactose exceeds that for direct incorporation from [3H]glucose, suggesting a preferential utilization of galactose for neonatal glycogen synthesis.
Glucocorticosteroids increase leucine oxidation and impair leucine balance in humans
Authors: Beaufrere B. , Horber F. F. , Schwenk W. F. , Marsh H. M. , Matthews D. , Gerich J. E. , Haymond M. W.
Published: December 2017

High-dose glucocorticoid treatment results in protein wasting. To determine whether such therapy affects leucine oxidation in the postabsorptive state and the disposal of dietary amino acids, eight normal subjects were studied twice in random order, once after 5 days of prednisone (20 mg three times daily) and on a second occasion without prednisone as a control. In the postabsorptive state prednisone therapy increased (P less than 0.05) plasma concentrations of leucine, alpha-ketoisocaproate, glucose, insulin, and C-peptide, as well as leucine carbon flux and oxidation calculated by means of isotope dilution techniques and [1-13C]leucine. During infusion of a chemically defined meal, total leucine carbon flux and oxidation increased similarly on both study days, but leucine oxidation was greater (P less than 0.01) during prednisone treatment; net leucine balance became positive on the control day but remained negative or zero on the prednisone study day despite higher (P less than 0.05) plasma insulin concentrations. These studies demonstrate that high-dose glucocorticoid treatment impairs the balance of the essential amino acid leucine in both the postabsorptive and absorptive states in humans.
Growth hormone secretory rates in children as estimated by deconvolution analysis of 24-h plasma concentration profiles
Authors: Albertsson-Wikland K. , Rosberg S. , Libre E. , Lundberg L. O. , Groth T.
Published: December 2017

The kinetics of growth-hormone (GH) distribution and elimination was estimated in five GH-deficient children who received 11 intravenous single injections of GH. The plasma disappearance data were analyzed in terms of a two-compartment model. The kinetic parameters obtained were then used in calculating the GH-secretory rate by a numerical deconvolution technique. A simple formula was derived for calculation of the cumulated secretion from the area under the concentration curve of 145 healthy children of various ages, heights, and stages of puberty. The estimated 24-h GH secretion increased with age, corresponding to a two- to fourfold increase during the adolescence period. The highest secretions were found in pubertal stages 3-4. In prepubertal children the heights correlated markedly with the secretion of GH (r = 0.83). Thus an indication of the range of the GH secretion in normal growing children is found, which is important to estimate substitution doses for treatment of GH-deficient children.
Influence of hepatic vagus nerve on pancreatic hormone secretion during exercise
Authors: Lavoie J. M. , Cardin S. , Doiron B.
Published: December 2017

There has been recent evidence that the liver through the hepatic vagus nerve may influence the resting levels of plasma insulin in adrenalectomized rats. The present investigation was designed to evaluate whether such a relationship exists during physical exercise. To this end, the effects of a selective hepatic vagotomy on portal and peripheral insulin and on peripheral glucagon concentrations were studied after a 30-min treadmill run (26 m/min, 0% grade) in adrenodemelludated rats. Hepatic vagotomy was associated with small but significantly higher (P less than 0.05) levels of liver glycogen and blood glucose at rest and after exercise. No significant differences were observed between hepatic-vagotomized and sham-operated rats in resting insulin, glucagon, and plasma norepinephrine concentrations. Peripheral plasma insulin levels after exercise were significantly higher (P less than 0.01) in hepatic-vagotomized than in sham-operated rats [172 +/- 20 vs. 108 +/- 10 (SE) pmol/l]. Exercise was also associated with a significantly lower peripheral glucagon (P less than 0.01) and norepinephrine (P less than 0.05) levels in hepatic-vagotomized compared with sham-operated rats. These results indicate a role for the hepatic vagus nerve in the regulation of pancreatic islet secretion during exercise, possibly by contributing to the increase in sympathetic activity.
Norepinephrine inhibits islet lipid metabolism, 45Ca2+ uptake, and insulin secretion
Authors: Vara E. , Tamarit-Rodriguez J.
Published: December 2017

We have previously shown that palmitate potentiates, in isolated islets, glucose-induced stimulation of insulin release, "de novo" lipid synthesis, and 45Ca2+ turnover in a correlative manner. Norepinephrine, a known inhibitor of the secretory response, has now been used to further investigate the relationships among the three phenomena. The amine decreased insulin secretion dose dependently in response to glucose and palmitate with alpha 2-adrenergic specificity. It also reduced similarly the oxidation of 1 mmol/l [U-14C]palmitate as well as the incorporation of 20 mmol/l D-[U-14C]glucose into islet phospholipids and neutral lipids through an alpha 2-adrenergic mechanism. These results indirectly suggest that alpha 2-adrenoceptor stimulation inhibits in islets both palmitate oxidation and esterification through an inactivation of long-chain acyl-CoA synthetase and other enzymes of glycerolipid synthesis. Islet uptake of 45Ca2+ was also decreased by norepinephrine with a similar sensitivity to that shown by insulin release and de novo lipid synthesis. Therefore, it is suggested that alpha 2-adrenoceptor-mediated reduction of the potentiation by palmitate of the secretory response to glucose depends on the inhibition of fatty acid metabolism and the resulting impairment of de novo lipid synthesis and 45Ca2+ turnover.
Pregnancy does not alter the metabolic clearance of 1,25-dihydroxyvitamin D in rats
Authors: Paulson S. K. , Ford K. K. , Langman C. B.
Published: December 2017

Increased circulating levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] during pregnancy could be due to an increase in production or decrease in the metabolic clearance rate of 1,25(OH)2D. To answer this question an isotope dilution method was used to determine the clearance rate of 1,25(OH)2D in pregnant and aged-matched nonpregnant female rats. A bolus of 0.146 muCi 1,25(OH)2[3H]D3 was given to 60 pregnant and 60 aged-matched nonpregnant rats and the disappearance of the isotope was followed in these animals over the next 48 h. In 12 pregnant rats vs. 14 nonpregnant controls not injected with tracer, plasma calcium (9.6 +/- 0.41 vs. 10.7 +/- 0.17 mg/ml) and 25(OH)D (17.1 +/- 1.15 vs. 25.4 +/- 1.58 ng/ml) levels were significantly lower (P less than 0.01 and P less than 0.001), whereas plasma 1,25(OH)2D levels (110 +/- 16.1 pg/ml vs. 77 +/- 6.0 pg/ml) were significantly higher (P less than 0.05). Clearance rates of 1,25(OH)2D of 25.8 +/- 1.31 microliters/min in pregnant rats and 20.2 20.2 +/- 1.38 microliters/min in nonpregnant aged-matched rats were not significantly different. Similarly, the apparent volume of distribution of 1,25(OH)2D in the pregnant rats (15 +/- 1.0 ml) was not significantly different from that in the nonpregnant control animals (18 +/- 2.1 ml). Production rates of.1,25(OH)2D were elevated in the pregnant rats (2.83 pg/min) compared with the nonpregnant controls (1.55 pg/min). In conclusion, the elevated maternal plasma 1,25(OH)2D level during pregnancy is a result of increased production and is not due to a decreased clearance.
Measurement of myocardial glycogen synthesis in diabetic and fasted rats
Authors: Laughlin M. R. , Petit W. A. , Shulman R. G. , Barrett E. J.
Published: December 2017

Diabetes and fasting provoke an increase in heart glycogen content, despite a decline in the amount of active glycogen synthase present. To determine if the activity of glycogen synthase i is still rate limiting for glycogen synthesis, we used 13C-nuclear magnetic resonance to measure the in vivo rate of glycogen synthesis and compared this with the activity of glycogen synthase and phosphorylase measured in tissue extracts using physiological concentrations of substrates and activators. In the basal state the activity of glycogen synthase i was depressed in the diabetic and fasted hearts (P less than 0.01). The rate of heart glycogen synthesis was measured during a 50-min infusion of D-[1-13C]-glucose (10 mg/min) and insulin (1 U/min) and averaged 0.32 +/- 0.04 mumol.min-1.g wet wt-1 in controls and was diminished in both the diabetic (0.18 +/- 0.04 mumol.min-1.g wet wt-1) and fasted (0.16 +/- 0.03 mumol.min-1.g wet wt-1) and fasted (0.16 +/- 0.03 mumol.min-1.g wet wt-1) rats (P less than 0.05 for each). During the glucose and insulin infusion the average activity of glycogen synthase i was greater in control than diabetic or fasted hearts (P less than 0.01 for each) and approximated the rates of net glycogen synthesis in each group. In contrast, there were no significant differences in phosphorylase alpha activity, measured in tissue extracts, among the three groups. Furthermore, although this phosphorylase alpha activity greatly exceeded synthase activity, it did not appear to be expressed in vivo. We conclude that in normal, diabetic, and fasted rats, glycogen synthase is rate limiting for glycogen synthesis.
Androgen receptor of rat penis is down-regulated by androgen
Authors: Takane K. K. , George F. W. , Wilson J. D.
Published: December 2017

To provide insight into the factors that control androgen receptor levels in rat penis, we assessed 5 alpha-[3H]-dihydrotestosterone binding in low-salt [10 mM tris(hydroxymethyl)aminomethane (Tris), 10 mM Na2M0O4] and high-salt (10 mM Tris, 10 mM Na2M0O4, 0.5 M KCl) extracts of rat penis using sucrose density gradients. Total receptor content decreased from approximately 729 +/- 114 fmol/g tissue at 3 wk of age to less than 50 fmol/g tissue at 10 wk of age. Castration of 3-wk-old rats prevented penile growth and the age-related decline in penile androgen receptor. Treatment of 3-wk-old castrated rats with 5 alpha-dihydrotestosterone caused an acceleration in the decline in receptor levels compared with intact animals. Castration of 10-wk-old rats (after androgen receptor levels had decreased) did not result in an increase in the amount of total androgen receptor by 16 wk of age. To determine the specificity of the androgen-mediated decline in receptor levels, the amounts of prostate androgen receptor were compared with those of the penis at different ages. When expressed as femtomoles per organ, the total androgen receptor level in the prostate increased fourfold from 3 to 10 wk of age, whereas the total androgen receptor in the penis declined approximately threefold. We conclude that the downregulation of the penile androgen receptor content that occurs in the rat between 3 and 10 wk of age is androgen mediated, does not occur in all androgen target tissues, and is prevented but not reversed by castration.
Effect of hypoxia on atrial natriuretic factor and aldosterone regulation in humans
Authors: Lawrence D. L. , Skatrud J. B. , Shenker Y.
Published: December 2017

To evaluate the possible physiological role of atrial natriuretic factor (ANF) on the observed dissociation of aldosterone from the renin-angiotensin system during acute hypoxia, 7 men, ages 18-27 yr, were studied on two separate days for 1 h under hypoxic (12% O2) and normoxic (room air) conditions. Subjects were on a low-salt diet (urinary sodium 67 +/- 13 meq/24 h) and suppressed with dexamethasone. Hemoglobin saturation decreased during hypoxemia to 68 +/- 1% (P less than 0.01), whereas heart rate increased from 65 +/- 3 to 89 +/- 5 beats/min (P less than 0.01). Plasma aldosterone levels decreased 43% from basal during hypoxemia (P less than 0.01), whereas ANF levels increased by 50% (P less than 0.05). Levels of both were unchanged during normoxemia. Plasma renin activity, angiotensin II, blood pressure, and pH did not change under either condition, and plasma cortisol levels were totally suppressed. These results indicate that acute hypoxemia is a potent stimulus for ANF release and that ANF is probably a major factor responsible for the dissociation of aldosterone from the renin-angiotensin system under these conditions.
Low-calcium diets increase both production and clearance of 1,25-dihydroxyvitamin D3 in rats
Authors: Fox J. , Bunker J. E. , Kamimura M. , Wong P. F.
Published: December 2017

Administration of large doses of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] to animals induces 1,25(OH)2D3 side-chain oxidative pathways. This study determined if the elevated plasma 1,25(OH)2D3 seen in rats fed low-Ca diets is associated not only with an increased production rate (PR) but also with an increased metabolic clearance rate (MCR) of the hormone. In vitamin D-replete rats fed a Ca-deficient diet for 3-4 wk, the PR increased 21-fold, plasma levels 15-fold, and the MCR by 37%. The increased MCR in Ca-deficient rats was associated with a 48% increase in hepatic microsomal UDP glucuronyl transferase enzyme activity, whereas 1,25(OH)2D3 catabolism by homogenates of liver and small intestinal mucosa was unchanged. In contrast to the effects of low-Ca diets, acute (7 h) pharmacological elevation of plasma 1,25(OH)2D3 to 1.5 ng/ml in normal rats did not influence the MCR. Thus chronically elevated 1,25(OH)2D3 levels are necessary to stimulate clearance. In conclusion, 1,25(OH)2D3 clearance in rats can be stimulated not only by chronic pharmacological doses of 1,25(OH)2D3 but also by the physiological stimulus of a low-Ca diet. Hence, plasma 1,25(OH)2D3 levels can be regulated by changes in both PR and MCR.
Paradoxically slow preadipocyte replication and differentiation in corpulent rats
Authors: Shillabeer G. , Forden J. M. , Russell J. C. , Lau D. C.
Published: December 2017

We have investigated the in vitro rate of replication and differentiation of preadipocytes derived from lean (+/+) and obese (cp/cp) male JCR:LA-corpulent (cp) rats in an attempt to identify mechanisms that regulate adipose tissue growth. Cp/cp rats were twofold heavier than age-matched lean rats by 9-10 mo. Cp/cp-derived preadipocytes demonstrated an inherently slower rate of replication than +/+ preadipocytes (population doubling time: cp/cp 52.3 +/- 9.6 h vs. +/+ 19.7 +/- 1.6 h), although the preadipocyte pool in the cp/cp was significantly greater. Cp/cp preadipocytes were resistant to hormonally induced differentiation (19.9 +/- 9.4% of cells accumulated lipid) but differentiated when cocultured with mature adipocytes to the same extent as preadipocytes derived from Sprague-Dawley (SD) rats (cp/cp 48.4 +/- 15.2% vs. SD 52.2 +/- 11.9%). In contrast, SD preadipocytes did not differentiate in response to mature adipocytes from +/+ rats (13.8 +/- 5.2%). Our observations suggest that preadipocyte replication and maturation may not be controlled in a coordinated manner.
Influences of thyroid status and sympathoadrenal system on extrarenal potassium disposal
Authors: Kubota K. , Ingbar S. H.
Published: December 2017

Effects of hyper- and hypothyroidism on the ability of rats to transfer acute intravenous loads of potassium from the extracellular to the intracellular milieu (extrarenal potassium disposal, ERPD) were studied. We also examined the effects of the sympathoadrenal system on ERPD, as well as the manner in which it interacts with thyroid status. Experiments were performed in thyroidectomized (hypothyroid), sham-operated (euthyroid), or 3,5,3'-triiodo-L-thyronine-treated (thyrotoxic) rats. In anesthetized, acutely nephrectomized animals given a constant infusion of KCl over a 90-min period, ERPD was assessed as an inverse function of the increase in plasma potassium concentration. Some animals were subjected to chemical sympathectomy, adrenalectomy, the administration of adrenergic antagonists, or the infusion of adrenergic agonists. The effects of these treatments in various combinations on ERPD in animals of differing thyroid status were determined and the following conclusions could be drawn: 1) beta 2-adrenergic influences increase ERPD; 2) alpha 1- and alpha 2-adrenergic influences decrease ERPD; 3) these influences of the sympathoadrenal system on ERPD are qualitatively independent of thyroid status, and in all three thyroid states, beta-adrenergic enhancement predominates over alpha-adrenergic inhibition; 4) thyrotoxicosis increases and hypothyroidism decreases ERPD, and these effects are qualitatively independent of the presence of sympathoadrenal activity; 5) the intrinsic effect of thyroid hormone insufficiency and increased alpha-adrenergic tone and/or responsiveness together account for the decreased ERPD observed in hypothyroid animals; and 6) the intrinsic effect of thyroid hormone excess and increased beta-adrenergic tone and/or responsiveness, as well as decreased alpha-adrenergic tone and/or responsiveness, together account for the increased ERPD found in thyrotoxic animals.
Coupling of mitochondrial metabolism and protein synthesis in heart mitochondria
Authors: McKee E. E. , Grier B. L. , Thompson G. S. , Leung A. C. , McCourt J. D.
Published: December 2017

Although much is now known with regard to the processes of mammalian mitochondrial gene expression, relatively little is known concerning the quantitative regulation of this pathway in response to hormones or other physiological stimuli. In this paper the potential coupling of mitochondrial metabolism to mitochondrial protein synthesis was investigated and the concentration of nucleotides and substrates for optimal translation in isolated rat heart mitochondria was determined. It was demonstrated that optimal isolated heart mitochondrial protein synthesis required the presence of an oxidizable substrate. Of the substrates tested, glutamate (20 mM) supported translation best followed by malate, succinate, and alpha-ketoglutarate, whereas pyruvate supported synthesis poorly. Unlike other recent mammalian mitochondrial systems, the presence of an oxidizable substrate was required for translation even in the presence of medium ATP and an exogenous energy-generating system. Mitochondrial translation also required the presence of adenine nucleotide that could be added as ADP or ATP; however, ATP added above 0.5 mM became progressively inhibitory. As a result, synthesis was supported significantly better by ATP synthesized by the system from added ADP, than by ATP added directly to the system. However, if the phosphorylation of ADP was prevented by limiting the phosphate concentration, ADP itself strongly inhibited mitochondrial protein synthesis. This inhibition appeared to be closely related to the energy charge of the system rather than to absolute levels of ADP, indicating for the first time that mitochondrial translation, like its cytoplasmic counterpart is regulated by energy charge. Last, this system did not require the inhibition of guanine nucleotide or exogenous energy-generating systems.(ABSTRACT TRUNCATED AT 250 WORDS)
IGF-II receptors and IGF-II-stimulated glucose transport in human fat cells
Authors: Sinha M. K. , Buchanan C. , Raineri-Maldonado C. , Khazanie P. , Atkinson S. , DiMarchi R. , Caro J. F.
Published: December 2017

Insulin-like growth factor II (IGF-II) receptors have been described in rat but not in human adipocytes. In both species, IGF-II has been reported to stimulate glucose transport by interacting with the insulin receptor. In this study, we have unequivocally demonstrated the presence of IGF-II receptors in human adipocytes. 125I-labeled IGF-II specifically binds to intact adipocytes, membranes, and lectin-purified detergent solubilized extracts. Through the use of 0.5 mM disuccinimidyl suberate, 125I-IGF-II is cross-linked to a 260-kDa protein that is identified as the IGF-II receptor by displacement experiments with unlabeled IGF-II, IGF-I, and insulin and either by immunoprecipitation or by Western blot analysis with mannose 6-phosphate receptor antibodies. The concentrations of IGF-II required for half-maximal and maximal stimulation of glucose transport in human adipocytes are 35 and 100 times more than that of insulin. The possibility of IGF-II stimulating glucose transport by interacting predominantly with the insulin receptor is suggested by the following: 1) the concentration of IGF-II that inhibits half of insulin binding is only 20 times more than that of insulin; 2) the lack of an additive effect of IGF-II and insulin for maximal stimulation of glucose transport; 3) the ability of monoclonal insulin receptor antibodies to decrease glucose transport stimulated by submaximal concentrations of both IGF-II and insulin; and 4) the ability of IGF-II to stimulate insulin receptor autophosphorylation albeit at a reduced potency when compared with insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Contractile activity increases plasma membrane glucose transporters in absence of insulin
Authors: Goodyear L. J. , King P. A. , Hirshman M. F. , Thompson C. M. , Horton E. D. , Horton E. S.
Published: December 2017

To study the interactions between insulin and contraction on the skeletal muscle glucose transport system, the hindquarters of male rats were perfused in the absence of insulin, in the presence of insulin (30 mU/ml), during contractions induced by sciatic nerve stimulation, or during contractions plus insulin. Compared with control preparations, rates of glucose uptake in the perfused hindquarter were increased by 2.5- and 2.6-fold in the insulin and insulin plus contraction groups, respectively, but not significantly increased in the contraction only preparations. After perfusion, soleus and red and white gastrocnemius muscles from the hindquarter were pooled and used for the preparation of plasma membranes. Skeletal muscle plasma membrane vesicle glucose transport rates were 2.2 +/- 0.5, 7.9 +/- 1.7, 9.0 +/- 2.2, and 10.8 +/- 2.0 nmol.mg protein-1.s-1 (40 mM glucose), and plasma membrane glucose transporter numbers were 4.7 +/- 0.5, 8.1 +/- 0.9, 9.1 +/- 1.0, and 8.6 +/- 0.6 pmol/mg protein in the control, contraction, insulin, and insulin plus contraction groups, respectively. The transport-transporter ratio, an indication of plasma membrane glucose transporter intrinsic activity, was increased by contraction, insulin, and insulin plus contraction. These results demonstrate that contractile activity in the absence of insulin increases muscle plasma membrane glucose transport by increasing transporter number and intrinsic activity. In addition, under these experimental conditions, the effects of insulin and contraction to increase muscle glucose transport are not additive.
Neural control of glutamine synthetase activity in rat skeletal muscles
Authors: Feng B. , Konagaya M. , Konagaya Y. , Thomas J. W. , Banner C. , Mill J. , Max S. R.
Published: December 2017

The mechanism of glutamine synthetase induction in rat skeletal muscle after denervation or limb immobilization was investigated. Adult male rats were subjected to midthigh section of the sciatic nerve. At 1, 2, and 5 h and 1, 2, and 7 days after denervation, rats were killed and denervated, and contralateral control soleus and plantaris muscles were excised, weighted, homogenized, and assayed for glutamine synthetase. Glutamine synthetase activity increased approximately twofold 1 h after denervation in both muscles. By 7 days postdenervation enzyme activity had increased to three times the control level in plantaris muscle and to four times the control level in soleus muscle. Increased enzyme activity after nerve section was associated with increased maximum velocity with no change in apparent Michaelis constant. Immunotitration with an antiglutamine synthetase antibody suggested that denervation caused an increase in the number of glutamine synthetase molecules in muscle. However, Northern-blot analysis revealed no increase in the steady-state level of glutamine synthetase mRNA after denervation. A mixing experiment failed to yield evidence for the presence of a soluble factor involved in regulating the activity of glutamine synthetase in denervated muscle. A combination of denervation and dexamethasone injections resulted in additive increases in glutamine synthetase. Thus the mechanism underlying increased glutamine synthetase after denervation appears to be posttranscriptional and is distinct from that of the glucocorticoid-mediated glutamine synthetase induction previously described by us.
Failure of insulin to antagonize cAMP-mediated glycogenolysis in rat ventricular cardiomyocytes
Authors: Redmon J. B. , Gettys T. W. , Sheorain V. S. , Corbin J. D. , Taylor I. L.
Published: December 2017

Isolated rat ventricular cardiomyocytes were used to study the effects of insulin on glycogen metabolism in cells treated with various agents that activate adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. Incubation of myocytes with isoproterenol produced a rapid concentration-dependent increase in cAMP concentration, cAMP-dependent protein kinase activity, and phosphorylase activity and a simultaneous decrease in the glycogen synthase activity ratio. Various cAMP analogues also produced a concentration-dependent increase in phosphorylase activity and a decline in the glycogen synthase activity ratio. Incubation of cells with insulin produced no change in basal phosphorylase activity but produced a rapid 40% increase in the glycogen synthase activity ratio. Inclusion of insulin in cell incubations containing increasing concentrations of isoproterenol did not modify the increases in cAMP concentration, protein kinase activity, or phosphorylase activity. Insulin also did not antagonize the ability of any of the cAMP analogues tested to activate phosphorylase, irrespective of the suitability of the particular cAMP analogue as a substrate for cAMP phosphodiesterases. The failure of insulin to antagonize the glycogenolytic effects of isoproterenol or cAMP analogues was paralleled by its failure to activate low-Km phosphodiesterase activity, but the cAMP analogue, 8-parachlorophenylthio-cAMP produced a small reproducible activation of the low-Km enzyme. In contrast to hepatocytes and adipocytes, where some effects of insulin appear to be due to activation of the phosphodiesterase and hydrolysis of cAMP, the effects in cardiomyocytes appear to be independent of an insulin-sensitive phosphodiesterase or of the effects on other components of the cAMP cascade.
Subcutaneous adipose tissue: a source of lactate production after glucose ingestion in humans
Authors: Hagstrom E. , Arner P. , Ungerstedt U. , Bolinder J.
Published: December 2017

The in vivo kinetics of lactate and pyruvate in the extracellular space of subcutaneous adipose tissue after glucose ingestion were investigated in healthy volunteers by the use of a microdialysis sampling technique. Comparison was made with the metabolite levels in venous plasma. The absolute subcutaneous tissue concentrations of lactate and pyruvate were estimated in the fasting state by perfusion with varying lactate- and pyruvate-containing solutions. An equilibrium with the surrounding extracellular fluid was found for both lactate and pyruvate in concentrations similar to those in venous plasma. After glucose ingestion there was an increase in the circulating levels of glucose, lactate, and pyruvate, which returned to base-line values within 3 h. There was a more marked increase in lactate in subcutaneous adipose tissue than in venous blood, and the adipose tissue lactate remained elevated for at least 3 h. In contrast, pyruvate levels increased much less in subcutaneous fat than in venous blood. The addition of isoproterenol (which inhibits adipose tissue glucose metabolism) to the tissue perfusate lowered the subcutaneous tissue lactate levels significantly but did not affect the subcutaneous pyruvate levels. These data suggest that human subcutaneous adipose tissue is a source of in vivo lactate production after glucose ingestion. Since lactate is thought to be a major substrate for glycogen synthesis in the liver, the present findings may provide evidence of a new and important role of the adipose tissue metabolism in the regulation of whole body glucose homeostasis in humans.
Hippocampal glutamine synthetase: insensitivity to glucocorticoids and stress
Authors: Tombaugh G. C. , Sapolsky R. M.
Published: December 2017

Glucocorticoids enhance the neurotoxic potential of several insults to the rat hippocampus that involve overactivation of glutamatergic synapses. These hormones also stimulate the synthesis of glutamine synthetase (GS) in peripheral tissue. Because this enzyme helps regulate glutamate metabolism in the central nervous system, glucocorticoid induction of GS in the brain may underlie the observed synergy. We have measured GS activity in the hippocampus and skeletal muscle (plantaris) of adult rats after bilateral adrenalectomy (ADX), corticosterone (Cort) replacement, or stress. No significant changes in GS were observed in hippocampal tissue, whereas muscle GS was significantly elevated after Cort treatment or stress and was reduced after ADX. These results suggest that Cort-induced shifts in GS activity probably do not explain Cort neurotoxicity, although the stress-induced rise in muscle GS may be relevant to certain types of myopathy.
Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans
Authors: Kelley D. E. , Reilly J. P. , Veneman T. , Mandarino L. J.
Published: December 2017

The effects of physiological hyperinsulinemia (approximately 75 mU/l) on glucose storage, oxidation, and glycolysis in skeletal muscle were assessed with euglycemic clamps performed in seven healthy volunteers, in conjunction with leg balance for glucose, lactate, alanine, O2, and CO2. Infusion of insulin increased leg glucose uptake, storage, and oxidation but did not alter net release of lactate and alanine. The respiratory quotient (RQ) across the leg increased from a basal value of 0.74 +/- 0.02 to 0.99 +/- 0.02 during hyperinsulinemia. Under conditions of insulin stimulation, 49 +/- 5% of leg glucose uptake was stored, 37 +/- 4% was oxidized, and 14 +/- 2% was released as lactate and alanine. We conclude that during physiological hyperinsulinemia and euglycemia 1) skeletal muscle lipid oxidation is nearly entirely suppressed and glucose becomes the primary oxidative substrate of muscle, 2) glucose storage and oxidation are the major pathways of skeletal muscle glucose metabolism and are quantitatively similar at physiological insulin levels, and 3) the majority of insulin-stimulated glycolysis is oxidized, with only a small portion released as lactate or alanine.
Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans
Authors: Nyomba B. L. , Ossowski V. M. , Bogardus C. , Mott D. M.
Published: December 2017

To investigate the relationship of insulin receptor kinase with insulin resistance in humans, we studied insulin-sensitive tyrosine kinase activity in muscle biopsies taken from 20 Pima Indians [14 nondiabetics, 6 with non-insulin-dependent mellitus (NIDDM)] during euglycemic clamps, at insulin concentrations of approximately 68 microU/ml (low dose) and approximately 1,170 microU/ml (high dose). In the nondiabetics, the low dose, insulin-induced kinase activation in vivo was 1.5-fold the activity in the fasting state (P less than 0.05), whereas in the diabetics, the kinase activity actually decreased by 40% relative to fasting (P less than 0.05). The difference in delta-kinase in vivo was significant (P less than 0.01) between the two groups. Similarly, the kinase activation in vitro in response to 1 nM insulin was lower in diabetic subjects compared with nondiabetics (P less than 0.01). These data indicate that, in NIDDM, both in vitro and in vivo insulin-stimulated tyrosine kinase activity is impaired. Among nondiabetics, the kinase sensitivity to insulin, calculated as the ratio of the kinase activity at 1 nM insulin in vitro to the kinase activity at 100 nM insulin, was positively correlated with plasma insulin concentrations 2 h after an oral glucose load (r = 0.69, P less than 0.01). Thus, in nondiabetic subjects with insulin resistance, insulin activation of the kinase is not reduced, but the kinase sensitivity to insulin increases with increasing plasma insulin levels. Therefore, the site of insulin resistance in nondiabetic subjects is distal to the insulin receptor kinase. Furthermore, it is possible that circulating insulin, by increasing the kinase sensitivity to insulin, is a determinant of the receptor kinase activity.
Altered blood flow regulation in autotransplanted pancreatic islets of rats
Authors: Jansson L. , Sandler S.
Published: December 2017

Adult rats were partially depancreatized, and approximately 500 islets were isolated from each excised pancreas, maintained in tissue culture for 7 days, and subsequently transplanted back to the same animals beneath the renal capsule. Four weeks after transplantation the animals were anesthetized and given an intravenous injection of 1 ml of either saline, 30% (wt/vol) D-glucose, 30% (wt/vol) D-galactose, DL-propranolol (15 mg/kg body wt) dissolved in saline, or terbutaline (1 mg/kg body wt) dissolved in saline. Five minutes later blood perfusion of the islet grafts and the pancreatic remnant were measured with a microsphere technique. Islet blood flow was also measured in animals with pancreas intact and no islet grafts after administration of saline, glucose, or galactose. These animals demonstrated a significant and preferential increase in islet blood flow after glucose administration, whereas galactose caused a selective decrease in islet blood perfusion. Both whole pancreatic blood flow and islet blood flow in the pancreatic remnant were decreased by terbutaline administration, whereas the other substances had no effect. Blood flow to the transplanted islets was decreased by glucose and galactose, whereas propranolol and terbutaline had no effect compared with the saline-injected animals. These results suggest that blood flow regulation differs between transplanted pancreatic islets, islets in the normal pancreas, and islets in the pancreatic remnant after partial pancreatectomy. Whether this reflects lack of innervation or an altered reactivity of the newly formed blood vessels in islet grafts is presently unknown.
Influence of age and endurance training on metabolic rate and hormones in healthy men
Authors: Poehlman E. T. , McAuliffe T. L. , Van Houten D. R. , Danforth E.
Published: December 2017

The associations among age, maximal aerobic capacity (VO2max), and body composition with resting metabolic rate (RMR), and fasting plasma hormones were examined in endurance-trained and untrained older and younger men. A higher RMR (approximately 6%; P less than 0.05), normalized per kilogram of fat-free weight (FFW), was found in endurance-trained younger and older men relative to untrained men. VO2max, independent of FFW, accounted for a significant portion of the variation in RMR. Fasting insulin and the fasting insulin-to-glucose ratio were higher in older men relative to younger men. This difference was diminished when differences in percent body fat were taken into account. Plasma thyroid hormones and glucagon were not associated with age, VO2max, or percent body fat. We conclude that endurance-trained and older men have a higher RMR than untrained younger and older men that is independent of differences in FFW. Plasma levels of thyroid hormones and glucagon are not influenced by age, VO2max, or adiposity in healthy nonobese men.
Na(+)-K+ pump in rat muscle: effects of hypophysectomy, growth hormone, and thyroid hormone
Authors: Everts M. E. , Dorup I. , Flyvbjerg A. , Marshall S. M. , Jorgensen K. D.
Published: December 2017

We investigated the effects of growth hormone and thyroid hormone on the synthesis of Na(+)-K+ pumps in rat soleus muscle. Hypophysectomized rats were treated for 11 days with saline, human growth hormone (hGH; 140 micrograms/day), thyroxine (T4; 3 micrograms/day), or hGH plus T4. Age-matched nonhypophysectomized control rats received no treatment. The concentration of Na(+)-K+ pumps was reduced by 75% in the hypophysectomized rats. Treatment with hGH alone or combined with T4 restored the growth rate, whereas T4 alone did not stimulate growth. In contrast, the synthesis of Na(+)-K+ pumps was only responsive to T4 treatment when given alone or in combination with hGH. The concentration of Na(+)-K+ pumps increased around threefold in the T4-treated groups and showed full normalization to the control level after 11 days of treatment. It is concluded that growth hormone does not play any major role in the de novo synthesis of Na(+)-K+ pumps in skeletal muscle. More important, thyroid hormone, also at physiological doses, seems to be the major endocrine factor determining the concentration of Na(+)-K+ pumps in skeletal muscle.
Maternal diet and insulin secretion in islets of lactating, nonlactating, and young rats
Authors: Bliss C. R. , Wiedenkeller D. E. , Sharp G. W.
Published: December 2017

The effects of dietary phosphorus (P) on insulin secretion by pancreatic islets of rats at peak lactation (14 days after parturition) and by islets of nonlactating previously pregnant rats have been determined. In addition, the effects of changed dietary P in the maternal diet on insulin secretion by islets of the 1- and 14-day-old offspring were studied. Lactating rats had increased food intake relative to nonlactating rats and correspondingly increased P intake on the 0.4 and 0.7% P diets. Serum P levels were elevated in lactating rats consuming the 0.7% P feed relative to those on the 0.4% P feed and also relative to the nonlactating rats on the 0.7% P feed. Lactating rats had decreased bone calcium compared with the nonlactating rats. Islets from lactating rats on the 0.7% P feed secreted more insulin in response to glucose or to 3-isobutyl-1-methylxanthine (IBMX) than lactating rats on the 0.4% P feed. Additionally, lactating rats on the 0.7% P feed secreted more insulin in response to glucose than nonlactating rats on the same 0.7% P feed. The maternal diet had no influence on the endocrine pancreatic responses of the 1- and 14-day-old offspring in response to glucose or IBMX.
Role of corticosterone in adaptive changes in energy expenditure during refeeding after low calorie intake
Authors: Dulloo A. G. , Seydoux J. , Girardier L.
Published: December 2017

We examined the importance of corticosterone in elevated efficiency of energy utilization during refeeding after low food consumption. Energy balance studies during refeeding (over periods of 14 or 16 days) were conducted in rats previously food restricted for 16 days at 50% of normal food intake. Comparisons made with nonrestricted weight-matched controls after validation studies indicated that 2-wk-younger weight-matched controls had similar maintenance energy requirements and similar efficiency of energy utilization above maintenance (i.e., net efficiency) to nonrestricted age-matched controls. Results indicate that relative to controls refeeding after low food consumption was associated with enhanced energy conservation underlain by a 16-18% reduction (P less than 0.001) in total energy expenditure over a 14-day period. This metabolic adaptation for energy conservation resulted in a threefold increase (P less than 0.001) in body fat accretion but no difference in body protein deposition. Bilateral adrenalectomy (ADX) 2 days before refeeding reduced differences in energy expenditure between refed group and controls from 18 to 8% (P less than 0.01) and attenuated body fat gain from a three- to twofold increase (P less than 0.001) above control group. Effects of ADX were prevented by daily corticosterone replacement. Data suggest that after a period of low calorie intake an adaptive neurohormonal switching mechanism facilitates replenishment of fat stores during refeeding. This metabolic reorientation (characterized by an adaptive fall in energy expenditure) has both an adrenal as well as a nonadrenal component, because it is partially reversed by prior bilateral ADX, an effect attributed to removal of corticosterone-induced inhibition of thermogenesis.
Insulin- and thyroid hormone-independent adaptation of myofibrillar proteolysis to glucocorticoids
Authors: Kayali A. G. , Goodman M. N. , Lin J. , Young V. R.
Published: December 2017

Myofibrillar protein breakdown in skeletal muscle progresses through two distinct phases in response to chronic glucocorticoid administration in the rat, i.e., an early phase lasting 4–5 days, during which proteolysis increases followed by a later phase during which proteolysis decreases. The possible involvement of insulin and the iodothyronines in this phenomenon has now been examined. Diabetic, thyroidectomized, and normal rats were treated with corticosteroid for 10–11 days, and at timed intervals muscle proteolysis was evaluated by measuring the release of 3-methyl-L-histidine (3-MH) and tyrosine from the perfused hindquarter as well as the excretion of 3-MH in the urine. Corticosterone (CTC) administration to normal rats increased plasma insulin, whereas plasma 3,5,3'-triiodothyronine responded with an early rise followed by a fall after 4–5 days. However, the biphasic response of myofibrillar proteolysis to chronic glucocorticoid treatment was not abolished in CTC-treated diabetic or thyroidectomized rats. CTC treatment increased release of tyrosine by perfused muscle of diabetic rats but, unlike 3-MH release, did not diminish later. Thus the adaptation of myofibrillar proteolysis to chronic glucocorticoid treatment appears to be independent of insulin and thyroid hormones. However, insulin may play a role in curtailing glucocorticoid-induced breakdown of nonmyofibrillar proteins.