bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of a negative arterial-portal venous glucose gradient in the postexercise state
Authors: Galassetti Pietro , Koyama Yoshiharu , Coker Robert H. , Lacy Drury B. , Cherrington Alan D. , Wasserman David H.
Published: December 2017

Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs. Experimental protocol: exercise (−180 to −30 min), transition (−30 to −20 min), basal period (−20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 ± 1 in Pe and −10 ± 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg ⋅ kg−1⋅ min−1, negative = uptake) was 4.2 ± 0.3 (basal period) and −1.2 ± 0.3 (glucose infusion); in Po it was 4.1 ± 0.5 and −3.2 ± 0.4, respectively ( P < 0.005 vs. Pe). Total glucose infusion (mg ⋅ kg−1⋅ min−1) was 11 ± 1 in Po and 8 ± 1 in Pe ( P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar. Conclusions: the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.
Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in human skeletal muscle
Authors: Houmard Joseph A. , Shaw Christopher D. , Hickey Matthew S. , Tanner Charles J.
Published: December 2017

The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, ≈75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15–17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased ( P < 0.05) significantly (means ± SE, 7.8 ± 0.5 vs. 9.8 ± 0.8 mg ⋅ kg−1 ⋅ min−1), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly ( P < 0.05) with exercise (3.1 ± 0.8-fold) compared with the sedentary condition (1.3 ± 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.
A dietary intervention (high carbohydrate) during the neonatal period causes islet dysfunction in rats
Authors: Aalinkeel Ravikumar , Srinivasan Malathi , Kalhan Satish C. , Laychock Suzanne G. , Patel Mulchand S.
Published: December 2017

Artificial rearing of 4-day-old rat pups on a high-carbohydrate (HC) milk formula results in the immediate onset of hyperinsulinemia. To evaluate these early changes, studies on pancreatic function were carried out on 12-day-old HC rats and compared with age-matched mother-fed (MF) pups. The plasma insulin and glucagon contents were increased sixfold and twofold, respectively, in HC rats compared with MF rats. There was a distinct leftward shift in the glucose-stimulated insulin secretory pattern for HC islets. HC islets secreted insulin in the absence of any added glucose and in the presence of Ca2+channel inhibitors. The activities of glucokinase, hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate dehydrogenase complex were significantly increased in HC islets compared with MF islets. The protein contents of GLUT-2 and hexokinase were significantly increased in HC islets. These findings indicate that a nutritional intervention in the form of a HC formula only during the suckling period has a profound influence on pancreatic function, causing the onset of hyperinsulinemia.
Contraction-stimulated muscle glucose transport and GLUT-4 surface content are dependent on glycogen content
Authors: Derave Wim , Lund Sten , Holman Geoffrey D. , Wojtaszewski Jørgen , Pedersen Oluf , Richter Erik A.
Published: December 2017

The influence of muscle glycogen content on basal and contraction-induced glucose transport and cell surface GLUT-4 content was studied in rat skeletal muscle. Wistar rats were preconditioned by a combination of swimming exercise and diet, resulting in 40% lower (LG) or threefold higher (HG) muscle glycogen content compared with nonexercised controls (NG). At rest and during contractions, 2-deoxy-d-glucose uptake in perfused fast-twitch muscle, but not slow-twitch muscle, was significantly lower in HG compared with LG. Cell surface GLUT-4 content in the fast-twitch plantaris was 994 ± 180, 1,173 ± 311, and 2,155 ± 243 dpm/g in the basal condition and increased ( P < 0.05) to 2,285 ± 239, 3,230 ± 464, and 4,847 ± 654 dpm/g during contractions with HG, NG, and LG, respectively, the increase being significantly smaller in HG compared with LG. The contraction-induced increments in glucose transport and in cell surface GLUT-4 content were negatively correlated with the initial glycogen content (P <0.01). In conclusion, glucose transport and cell surface GLUT-4 content in resting and contracting fast-twitch muscle are dependent on the muscle glycogen content.
Neuroendocrine modulation of the “menopause”: insights into the aging brain
Authors: Wise Phyllis M.
Published: December 2017

The menopause marks the permanent end of fertility in women. It was once thought that this dramatic physiological change could be explained simply by the exhaustion of the reservoir of ovarian follicles. New data from studies performed in women and animal models make us reassess this assumption. An increasing body of evidence suggests that there are multiple pacemakers that contribute to the transition to irregular cycles, decreasing fertility, and the timing of the menopause. We will present evidence that lends credence to the possibility that a dampening and desynchronization of the precisely orchestrated neural signals lead to miscommunication between the brain and the pituitary-ovarian axis, and that this constellation of hypothalamic-pituitary-ovarian events leads to the deterioration of regular cyclicity and heralds menopausal transition.
Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice
Authors: Ahrén Bo , Pacini Giovanni
Published: December 2017

We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance in anesthetized mice. GLP-1 dose dependently potentiated insulin secretion after glucose administration, with the half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area under the glucose curve (AUCglucose) and increased the glucose elimination rate (KG) but did not affect the glucose effectiveness (SG). Furthermore, the insulin sensitivity index (SI) was reduced after administration of GLP-1. Because insulin secretion was stimulated to a larger degree than SIwas reduced, the peptide increased the global disposition index (GDI = AUCinsulin× SI). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced the influences of GLP-1 on AUCglucose, KG, SI, and GDI. Finally, the GLP-1 receptor antagonist exendin-3-(9—39) inhibited the actions of GLP-1. We conclude that GLP-1 increases glucose tolerance in the mouse mainly by potently stimulating insulin secretion.
Adaptations in skeletal muscle exercise metabolism to a sustained session of heavy intermittent exercise
Authors: Green H. , Tupling R. , Roy B. , O'Toole D. , Burnett M. , Grant S.
Published: December 2017

The purpose of this study was to investigate the hypothesis that a single, extended session of heavy exercise would be effective in inducing adaptations in energy metabolism during exercise in the absence of increases in oxidative potential. Ten healthy males [maximal aerobic power (V˙o2 peak) = 43.4 ± 2.2 (SE) ml ⋅ kg−1⋅ min−1] participated in a 16-h training session involving cycling for 6 min each hour at ∼90% of maximal oxygen consumption. Measurements of metabolic changes were made on tissue extracted from the vastus lateralis during a two-stage standardized submaximal cycle protocol before (Pre) and 36–48 h after (Post) the training session. At Pre, creatine phosphate (PCr) declined ( P < 0.05) by 32% from 0 to 3 min and then remained stable until 20 min of exercise at 60%V˙o2 peakbefore declining ( P < 0.05) by a further 35% during 20 min of exercise at 75%V˙o2 peak. Muscle lactate (mmol/kg dry wt) progressively increased ( P < 0.05) from 4.59 ± 0.64 at 0 min to 17.8 ± 2.7 and 30.9 ± 5.3 at 3 and 40 min, respectively, whereas muscle glycogen (mmol glucosyl units/kg dry wt) declined ( P < 0.05) from a rest value of 360 ± 24 to 276 ± 31 and 178 ± 36 at similar time points. During exercise after the training session, PCr and glycogen were not as depressed ( P < 0.05), and increases in muscle lactate were blunted ( P < 0.05). All of these changes occurred in the absence of increases in oxidative potential as measured by the maximal activities of citrate synthase and malate dehydrogenase. These findings are consistent with other studies, namely, that muscle metabolic adaptations to regular exercise are an early adaptive event that occurs before increases in oxidative potential.
Effect of exercise training on in vivo insulin-stimulated glucose uptake in intra-abdominal adipose tissue in rats
Authors: Enevoldsen L. H. , Stallknecht B. , Fluckey J. D. , Galbo H.
Published: December 2017

Intra-abdominal obesity may be crucial in the pathogenesis of the insulin-resistance syndrome, and training may alleviate this condition. We compared insulin-mediated glucose uptake in vivo in three intra-abdominal adipose tissues (ATs; retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT and also studied the effect of training. Rats were either swim trained (15 wk, n = 9) or sedentary ( n = 16). While the rats were under anesthesia, a hyperinsulinemic (∼900 pM), euglycemic clamp was carried out and local glucose uptake was measured by both the 2-deoxy-d-[3H]glucose and microdialysis techniques. Blood flow was measured by microspheres. Upon insulin stimulation, blood flow generally decreased in AT. Flow was higher in mesenteric tissue than in other ATs, whereas insulin-mediated glucose uptake did not differ between ATs. Training doubled the glucose infusion rate during hyperinsulinemia, in part, reflecting an effect in muscle. During hyperinsulinemia, interstitial glucose concentrations were lower, glucose uptake per 100 g of tissue was higher in AT in trained compared with sedentary rats, and training influenced glucose uptake identically in all ATs. In conclusion, differences between ATs in insulin sensitivity with respect to glucose uptake do not explain that insulin resistance is associated with intra-abdominal rather than subcutaneous obesity. Furthermore, training may be beneficial by enhancing insulin sensitivity in intra-abdominal fat depots.
Testosterone and dihydrotestosterone regulate AUF1 isoforms in a tissue-specific fashion in the mouse
Authors: Sheflin Lowell G. , Spaulding Stephen W.
Published: December 2017

.—The sex difference in the metabolism of certain mRNAs in the murine submaxillary gland (SMG) prompted us to determine whether androgens regulate the expression of any of the four isoforms of AUF1, proteins that bind differentially to AU-rich RNA. We found that cytosol from female SMGs contains two major isoforms (p45 and p40), whereas cytosol from male SMGs contains a prominent p37 and a weaker p42. Injecting female mice with testosterone decreases p45 levels by 81% after 7 days ( P < 0.05, n = 4), whereas p42 and p37 increase 74 and 449% at 7 days ( P < 0.05, n = 4, for both). Orchiectomy, conversely, decreases p37 levels in the male SMG by 91% ( P < 0.006) while increasing p45 5-fold and p40 2.5-fold ( P < 0.05, n = 5 for both). Both male and female kidney cytosol contains a prominent p37 and a faint band of ∼42 kDa, but neither shows a significant change when circulating androgen levels are altered. Dihydrotestosterone (DHT) changes the pattern of AUF1 isoforms in female SMG cytosol more rapidly than does testosterone. Nuclear extracts from female SMG contain predominantly p45, and DHT decreases its level slightly (35%, P < 0.05 at 24 h). Polysomal extracts from female SMG contain p45 and p42, and DHT increases p45 levels 58% ( P < 0.02, n = 6) at 24 h. In certain nonreproductive tissues, androgens may differentially regulate AUF1 isoform levels to modulate the metabolism of AU-rich mRNAs posttranscriptionally.
Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle
Authors: Shah O. Jameel , Kimball Scot R. , Jefferson Leonard S.
Published: December 2017

Glucocorticoids are diabetogenic factors that not only antagonize the action of insulin in target tissues but also render these tissues catabolic. Therefore, in rats, we endeavored to characterize the effects in skeletal muscle of glucocorticoids on translation initiation, a regulated process that, in part, governs overall protein synthesis through the modulated activities of eukaryotic initiation factors (eIFs). Four hours after intraperitoneal administration of dexamethasone (100 μg/100 g body wt), protein synthesis in skeletal muscle was reduced to 59% of the value recorded in untreated control animals. Furthermore, translation initiation factor eIF4E preferred association with its endogenous inhibitor 4E-BP1 rather than eIF4G. Dexamethasone treatment resulted in dephosphorylation of both 4E-BP1 and the 40S ribosomal protein S6 kinase concomitant with enhanced phosphorylation of eIF4E. Moreover, the guanine nucleotide exchange activity of eIF2B was unaffected as was phosphorylation of the α-subunit of eIF2. Hence glucocorticoids negatively modulate the activation of a subset of the protein synthetic machinery, thereby contributing to the catabolic properties of this class of hormones in vivo.
Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers
Authors: Azpiazu Iñaki , Manchester Jill , Skurat Alexander V. , Roach Peter J. , Lawrence John C.
Published: December 2017

The effects of transgenic overexpression of glycogen synthase in different types of fast-twitch muscle fibers were investigated in individual fibers from the anterior tibialis muscle. Glycogen synthase was severalfold higher in all transgenic fibers, although the extent of overexpression was twofold greater in type IIB fibers. Effects of the transgene on increasing glycogen and phosphorylase and on decreasing UDP-glucose were also more pronounced in type IIB fibers. However, in any grouping of fibers having equivalent malate dehydrogenase activity (an index of oxidative potential), glycogen was higher in the transgenic fibers. Thus increasing synthase is sufficient to enhance glycogen accumulation in all types of fast-twitch fibers. Effects on glucose transport and glycogen synthesis were investigated in experiments in which diaphragm, extensor digitorum longus (EDL), and soleus muscles were incubated in vitro. Transport was not increased by the transgene in any of the muscles. The transgene increased basal [14C]glucose into glycogen by 2.5-fold in the EDL, which is composed primarily of IIB fibers. The transgene also enhanced insulin-stimulated glycogen synthesis in the diaphragm and soleus muscles, which are composed of oxidative fiber types. We conclude that increasing glycogen synthase activity increases the rate of glycogen synthesis in both oxidative and glycolytic fibers, implying that the control of glycogen accumulation by insulin in skeletal muscle is distributed between the glucose transport and glycogen synthase steps.
Combined effects of hyperaminoacidemia and oxandrolone on skeletal muscle protein synthesis
Authors: Sheffield-Moore Melinda , Wolfe Robert R. , Gore Dennis C. , Wolf Steven E. , Ferrer Dennis M. , Ferrando Arny A.
Published: December 2017

We investigated whether the normal anabolic effects of acute hyperaminoacidemia were maintained after 5 days of oxandrolone (Oxandrin, Ox)-induced anabolism. Five healthy men [22 ± 3 (SD) yr] were studied before and after 5 days of oral Ox (15 mg/day). In each study, a 5-h basal period was followed by a 3-h primed-continuous infusion of a commercial amino acid mixture (10% Travasol). Stable isotopic data from blood and muscle sampling were analyzed using a three-compartment model to calculate muscle protein synthesis and breakdown. Model-derived muscle protein synthesis increased after amino acid infusion in both the control [basal control (BC) vs. control + amino acids (C+AA); P < 0.001] and Ox study [basal Ox (BOx) vs. Ox + amino acids (Ox+AA); P < 0.01], whereas protein breakdown was unchanged. Fractional synthetic rates of muscle protein increased 94% (BC vs. C+AA; P = 0.01) and 53% (BOx vs. Ox+AA; P < 0.01), respectively. We conclude that the normal anabolic effects of acute hyperaminoacidemia are maintained in skeletal muscle undergoing oxandrolone-induced anabolism.
Oxidation of glutamine by the splanchnic bed in humans
Authors: Haisch M. , Fukagawa N. K. , Matthews D. E.
Published: December 2017

[1,2-13C2]glutamine and [ ring-2H5]phenylalanine were infused for 7 h into five postabsorptive healthy subjects on two occasions. On one occasion, the tracers were infused intravenously for 3.5 h and then by a nasogastric tube for 3.5 h. The order of infusion was reversed on the other occasion. From the plasma tracer enrichment measurements at plateau during the intravenous and nasogastric infusion periods, we determined that 27 ± 2% of the enterally delivered phenylalanine and 64 ± 2% of the glutamine were removed on the first pass by the splanchnic bed. Glutamine flux was 303 ± 8 μmol ⋅ kg−1⋅ h−1. Of the enterally delivered [13C]glutamine tracer, 73 ± 2% was recovered as exhaled CO2compared with 58 ± 1% of the intravenously infused tracer. The fraction of the enterally delivered tracer that was oxidized specifically on the first pass by the splanchnic bed was 53 ± 2%, comprising 83% of the total tracer extracted. From the appearance of13C in plasma glucose, we estimated that 7 and 10% of the intravenously and nasogastrically infused glutamine tracers, respectively, were converted to glucose. The results for glutamine flux and first-pass extraction were similar to our previously reported values when a [2-15N]glutamine tracer [Matthews DE, Morano MA, and Campbell RG, Am J Physiol Endocrinol Metab 264: E848–E854, 1993] was used. The results of [13C]glutamine tracer disposal demonstrate that the major fate of enteral glutamine extraction is for oxidation and that only a minor portion is used for gluconeogenesis.
Insulin increases NO-stimulated guanylate cyclase activity in cultured VSMC while raising redox potential
Authors: Kahn Andrew M. , Allen Julius C. , Seidel Charles L. , Lichtenberg Daniel S. , Song Tom , Zhang Sui
Published: December 2017

Insulin acutely stimulates cyclic guanosine monophosphate (cGMP) production in primary confluent cultured vascular smooth muscle cells (VSMC) from canine femoral artery, but the mechanism is not known. These cells contain the inducible isoform of nitric oxide (NO) synthase (iNOS), and insulin-stimulated cGMP production in confluent cultured cells is blocked by the NOS inhibitor, NG-monomethyl-l-arginine (l-NMMA). In the present study, it is shown that iNOS is also present in freshly dispersed VSMC from this artery, indicating that iNOS expression in cultured VSMC is not an artifact of the culture process. Insulin did not stimulate NOS activity in primary confluent cultured cells because it did not affect citrulline or combined[Formula: see text]/[Formula: see text]production. To see whether insulin required the permissive presence of NO to stimulate cGMP production, iNOS and basal cGMP production were inhibited with l-NMMA, and the cells were incubated with or without 1 nM insulin and/or the NO donor, S-nitroso- N-acetyl-d,l-penicillamine (SNAP) at a concentration (0.1 μM) that restored cGMP production to the basal value. In the presence of l-NMMA, insulin no longer affected cGMP production but when insulin was added tol-NMMA plus SNAP, cGMP production was increased by 69% ( P < 0.05 vs. l-NMMA plus SNAP). Insulin, which increases glucose uptake by these cells, increased the cell lactate content and the lactate-to-pyruvate ratio (LPR) by 81 and 97%, respectively (both P < 0.05), indicating that the hormone increased aerobic glycolysis and the redox potential. The effects of insulin on LPR and cGMP production were blocked by removing glucose or by adding 2-deoxyglucose to the incubation media and were duplicated by the reducing substrate, β-hydroxybutyrate. We conclude that insulin does not acutely affect iNOS activity in these VSMC but it does augment cGMP production induced by the NO already present in the cell while increasing aerobic glycolysis and the cell redox potential.
Effects of plasma epinephrine on fat metabolism during exercise: interactions with exercise intensity
Authors: Mora-Rodriguez Ricardo , Coyle Edward F.
Published: December 2017

This study determined the effects of elevated plasma epinephrine on fat metabolism during exercise. On four occasions, seven moderately trained subjects cycled at 25% of peak oxygen consumption (V˙o2 peak) for 60 min. After 15 min of exercise, subjects were intravenously infused with low (0.96 ± 0.10 nM), moderate (1.92 ± 0.24 nM), or high (3.44 ± 0.50 nM) levels (all P < 0.05) of epinephrine to increase plasma epinephrine above control (Con; 0.59 ± 0.10 nM). During the interval between 35 and 55 min of exercise, lipolysis [i.e., rate of appearance of glycerol] increased above Con (4.9 ± 0.5 μmol ⋅ kg−1⋅ min−1) with low, moderate, and high (6.5 ± 0.5, 7.1 ± 0.8, and 10.6 ± 1.2 μmol ⋅ kg−1⋅ min−1, respectively; all P < 0.05) levels of epinephrine despite simultaneous increases in plasma insulin. The release of fatty acid into plasma also increased progressively with the graded epinephrine infusions. However, fatty acid oxidation was lower than Con (11.1 ± 0.8 μmol ⋅ kg−1⋅ min−1) during moderate and high levels (8.7 ± 0.7 and 8.1 ± 0.9 μmol ⋅ kg−1⋅ min−1, respectively; P < 0.05). In one additional trial, the same subjects exercised at 45%V˙o2 peakwithout epinephrine infusion, which produced a plasma epinephrine concentration identical to low levels. However, lipolysis was lower (i.e., 5.5 ± 0.6 vs. 6.5 ± 0.5 μmol ⋅ kg−1⋅ min−1; P < 0.05). In conclusion, elevations in plasma epinephrine concentration during exercise at 25% ofV˙o2 peakprogressively increase whole body lipolysis but decrease fatty acid oxidation. Last, increasing exercise intensity from 25 to 45%V˙o2 peakattenuates the lipolytic actions of epinephrine.
Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats
Authors: Suga Asako , Hirano Tsutomu , Kageyama Haruaki , Osaka Toshimasa , Namba Yoshio , Tsuji Masatomi , Miura Masakazu , Adachi Mitsuru , Inoue Shuji
Published: December 2017

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.
Different effects of IGF-I on insulin-stimulated glucose uptake in adipose tissue and skeletal muscle
Authors: Frick Fredrik , Oscarsson Jan , Vikman-Adolfsson Kerstin , Ottosson Malin , Yoshida Noriko , Edén Staffan
Published: December 2017

The effect of insulin-like growth factor I (IGF-I) on insulin-stimulated glucose uptake was studied in adipose and muscle tissues of hypophysectomized female rats. IGF-I was given as a subcutaneous infusion via osmotic minipumps for 6 or 20 days. All hypophysectomized rats received l-thyroxine and cortisol replacement therapy. IGF-I treatment increased body weight gain but had no effect on serum glucose or free fatty acid levels. Serum insulin and C-peptide concentrations decreased. Basal and insulin-stimulated glucose incorporation into lipids was reduced in adipose tissue segments and isolated adipocytes from the IGF-I-treated rats. In contrast, insulin treatment of hypophysectomized rats for 7 days increased basal and insulin-stimulated glucose incorporation into lipids in isolated adipocytes. Pretreatment of isolated adipocytes in vitro with IGF-I increased basal and insulin-stimulated glucose incorporation into lipids. These results indicate that the effect of IGF-I on lipogenesis in adipose tissue is not direct but via decreased serum insulin levels, which reduce the capacity of adipocytes to metabolize glucose. Isoproterenol-stimulated lipolysis, but not basal lipolysis, was enhanced in adipocytes from IGF-I-treated animals. In the soleus muscle, the glycogen content and insulin-stimulated glucose incorporation into glycogen were increased in IGF-I-treated rats. In summary, IGF-I has opposite effects on glucose uptake in adipose tissue and skeletal muscle, findings which at least partly explain previous reports of reduced body fat mass, increased body cell mass, and increased insulin responsiveness after IGF-I treatment.
Hyperbaric oxygen treatment attenuates cytokine induction after massive hemorrhage
Authors: Yamashita Masatomo , Yamashita Mamoru
Published: December 2017

We investigated the effect of hyperbaric oxygen treatment (HBO) on cytokine induction after hemorrhage, because hypoxia induces cytokines in vitro. Chronically cannulated conscious rats were subjected to 40 ml/kg of hemorrhage and resuscitated with the shed blood and twice the volume of saline either under room air (room air group) or under 100% oxygen at 3 atmospheres absolute (hyperbaric group). Rats exposed to HBO with no hemorrhage served as controls. Time course changes in plasma endotoxin level, arterial ketone body ratio (AKBR), serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and their hepatic mRNA were detected in the three groups. Plasma endotoxin levels increased significantly after hemorrhage, and there were no significant differences between the room air group and the hyperbaric group. In the room air group, AKBR dropped rapidly after hemorrhage and became minimal at hour 1, which was associated with significant increases in TNF-α and IL-6 at both mRNA and circulating levels. HBO significantly attenuated decreases in AKBR after hemorrhage with a significant reduction of mortality and cytokine induction. These results indicate that HBO attenuated the cytokine induction after hemorrhage by improving liver ischemia, and they suggest that tissue hypoxia may be responsible, at least in part, for cytokine induction after massive hemorrhage.
Oxoproline kinetics and oxoproline urinary excretion during glycine- or sulfur amino acid-free diets in humans
Authors: Metges Cornelia C. , Yu Yong-Ming , Cai Wei , Lu Xiao-Ming , Wong Sue , Regan Meredith M. , Ajami Alfred , Young Vernon R.
Published: December 2017

l-5-oxoproline (l-5-OP) is an intermediate in glutathione synthesis, possibly limited by cysteine availability. Urinary 5-OP excretion has been proposed as a measure of glycine availability. We investigated whether 5 days of dietary sulfur amino acid (SAA-free) or glycine (Gly-free) restriction affects plasma kinetics of 5-OP and urinary excretion of l- andd-5-OP in 6 healthy men. On day 6, l-5-[1-13C]oxoproline and [3,3-2H2]cysteine were infused intravenously for 8 h (3 h fast/5 h fed). In a control study (adequate amino acid mixture), plasma oxoproline fluxes were 37.8 ± 13.8 (SD) and 38.4 ± 14.8 μmol ⋅ kg−1⋅ h−1; oxidation accounted for 85% of flux. Cysteine flux was 47.9 ± 8.5 and 43.2 ± 8.5 μmol ⋅ kg−1⋅ h−1for fast and fed phases, respectively. Urinary excretion ofl- and d-5-OP was 70 ± 34 and 31.1 ± 13.3 μmol/mmol creatinine, respectively, during days 3–5, and 46.4 ± 13.9 and 22.4 ± 8.3 μmol/mmol over the 8-h tracer study. The 5-OP flux for the Gly-free diet was higher ( P = 0.018) and tended to be higher for the SAA-free diet ( P = 0.057) when compared with the control diet. Oxidation rates were higher on the Gly-free ( P = 0.005) and SAA-free ( P = 0.03) diets. Cysteine fluxes were lower on the the Gly-free ( P= 0.01) and the SAA-free diets ( P = 0.001) compared with the control diet. Rates of l-5-OP excretion were unchanged by withdrawal of SAA or Gly for 5 days but increased on day 6( P = 0.005 and P = 0.019, respectively). Thus acute changes in the dietary availability of SAA and Gly alter oxoproline kinetics and urinary 5-OP excretion.
Role of adrenal renin-angiotensin system in the control of aldosterone secretion in sodium-restricted rats
Authors: Mazzocchi Giuseppina , Malendowicz Ludwik K. , Markowska Anna , Albertin Giovanna , Nussdorfer Gastone G.
Published: December 2017

This study examined the effect of the pharmacological manipulation of adrenal renin-angiotensin system (RAS) on aldosterone secretion from in situ perfused adrenals of rats kept on a normal diet and sodium restricted for 14 days. Neither the angiotensin-converting enzyme inhibitor captopril nor the nonselective angiotensin II receptor antagonist saralasin and the AT1 receptor-selective antagonist losartan affected basal aldosterone output in normally fed rats. In contrast, they concentration dependently decreased aldosterone secretion in sodium-restricted animals, with maximal effective concentration ranging from 10− 7 to 10− 6 M. Captopril (10− 6 M), saralasin (10− 6 M), and losartan (10− 7 M) counteracted aldosterone response to 10 mM K+ in sodium-restricted rats but not in normally fed animals. Collectively, these findings provide evidence that adrenal RAS plays a role in the regulation of aldosterone secretion, but only under conditions of prolonged stimulation of zona glomerulosa probably leading to overexpression of adrenal RAS.
Effect of early dietary restriction on insulin action and secretion in the GK rat, a spontaneous model of NIDDM
Authors: Alvarez Carmen , Bailbe Danielle , Picarel-Blanchot Françoise , Bertin Eric , Pascual-Leone Ana-Maria , Portha Bernard
Published: December 2017

The availability of the Goto-Kakisaki (GK) rat model of non-insulin-dependent diabetes mellitus prompted us to test the effect of a limited period of undernutrition in previously diabetic young rats on their insulin secretion and insulin action during adult age. Four-week-old female GK rats were either food restricted (35% restriction, 15% protein diet) or protein and energy restricted (35% restriction, 5% protein diet) for 4 wk. Food restriction in the young GK rat lowered weight gain but did not aggravate basal hyperglycemia or glucose intolerance, despite a decrease in basal plasma insulin level. Furthermore, the insulin-mediated glucose uptake by peripheral tissues in the GK rat was clearly improved. We also found that food restriction, when it is coupled to overt protein deficiency in the young GK rat, altered weight gain more severely and slightly decreased basal hyperglycemia but conversely aggravated glucose tolerance. Improvement of basal hyperglycemia was related to repression of basal hepatic glucose hyperproduction, despite profound attenuation of basal plasma insulin level. Deterioration of tolerance to glucose was related to severe blunting of the residual glucose-induced insulin secretion. It is, however, likely that the important enhancement of the insulin-mediated glucose uptake helped to limit the deterioration of glucose tolerance.
Immunochemical studies on the putative plasmalemmal receptor for 1,25(OH)2D3. I. Chick intestine
Authors: Nemere Ilka , Ray Rahul , McManus William
Published: December 2017

Antisera were raised against the NH2-terminus of the putative basal lateral membrane (BLM) receptor for 1,25-dihydroxyvitamin D3[1,25(OH)2D3; BLM-VDR]. In Western analyses of BLM proteins, antibody (Ab) 099 was monospecific for a 64.5-kDa band. A protein of 64.5 kDa was also labeled by the affinity ligand [14C]1,25(OH)2D3-bromoacetate; label was diminished in the presence of excess unlabeled secosteroid. The monoclonal antibody against the nuclear VDR (9A7) failed to detect an appropriate band in BLM fractions. Preincubation of isolated intestinal cells with Ab 099, but not 9A7, affected the following two 1,25(OH)2D3-mediated signal transduction events: augmented intracellular calcium and protein kinase C activity. Subcellular distribution of Ab 099 reactivity by Western analyses and fluorescence microscopy revealed the highest concentrations in BLM followed by the endoplasmic reticulum. Exposure of isolated intestinal cells to 1,25(OH)2D3for 10 s or vascular perfusion of duodena for 5 min resulted in a time-dependent increase in nuclear localization of the BLM-VDR antigen, as judged by electron microscopy, whereas 24,25-dihydroxyvitamin D3failed to increase antigenic labeling in nuclei. Densitometric quantitation of Western blots of subcellular fractions prepared from isolated intestinal cells treated with vehicle or 1,25(OH)2D3confirmed a hormone-induced increase of putative BLM-VDR in the nucleus. It is concluded that a novel cell surface binding protein for 1,25(OH)2D3has been identified.
Control of ovine hepatic growth hormone receptor and insulin-like growth factor I by thyroid hormones in utero
Authors: Forhead A. J. , Li J. , Saunders J. C. , Dauncey M. J. , Gilmour R. S. , Fowden A. L.
Published: December 2017

By use of RNase protection assays, hepatic growth hormone receptor (GHR) and insulin-like growth factor I (IGF-I) mRNA abundances were measured in sheep fetuses after experimental manipulation of fetal plasma thyroid hormone concentrations by fetal thyroidectomy (TX) and exogenous infusion of triiodothyronine (T3) and cortisol. TX abolished the normal prepartum rise in hepatic GHR abundance but had little effect on hepatic GHR gene expression at 127–130 days (term 145 ± 2 days). By contrast, it upregulated basal IGF-I expression in immature fetal liver by increasing both Class 1 and Class 2 transcript abundance but had no further effects on IGF-I gene mRNA levels at 142–145 days. Raising plasma T3 to prepartum values by exogenous infusion of either T3 or cortisol into immature intact fetuses prematurely raised hepatic GHR and IGF-I mRNA abundances to values similar to those seen in intact fetuses at 142–145 days. In TX fetuses, cortisol infusion increased hepatic GHR mRNA but not total IGF-I mRNA abundance at 127–130 days. These findings show that thyroid hormones have an important role in the regulation of hepatic GHR and IGF-I gene expression in fetal sheep during late gestation and suggest that T3 mediates the maturational effects of cortisol on the hepatic somatotropic axis close to term.
Mechanism of coronary vasodilation to insulin and insulin-like growth factor I is dependent on vessel size
Authors: Oltman Christine L. , Kane Neal L. , Gutterman David D. , Bar Robert S. , Dellsperger Kevin C.
Published: December 2017

Insulin and insulin-like growth factor I (IGF-I) influence numerous metabolic and mitogenic processes; these hormones also have vasoactive properties. This study examined mechanisms involved in insulin- and IGF-I-induced dilation in canine conduit and microvascular coronary segments. Tension of coronary artery segments was measured after constriction with PGF2α. Internal diameter of coronary microvessels (resting diameter = 112.6 ± 10.1 μm) was measured after endothelin constriction. Vessels were incubated in control (Krebs) solution and were treated with N ω-nitro-l-arginine (l-NA), indomethacin, or K+ channel inhibitors. After constriction, cumulative doses of insulin or IGF-I (0.1–100 ng/ml) were administered. In conduit arteries, insulin produced modest maximal relaxation (32 ± 5%) compared with IGF-I (66 ± 12%). Vasodilation was attenuated by nitric oxide synthase (NOS) and cyclooxygenase inhibition and was blocked with KCl constriction. Coronary microvascular relaxation to insulin and IGF-I was not altered by l-NA, indomethacin, tetraethylammonium chloride, glibenclamide, charybdotoxin, and apamin; however, tetrabutylammonium chloride attenuated the response. In conclusion, insulin and IGF-I cause vasodilation in canine coronary conduit arteries and microvessels. In conduit vessels, NOS/cyclooxygenase pathways are involved in the vasodilation. In microvessels, relaxation to insulin and IGF-I is not mediated by NOS/cyclooxygenase pathways but rather through K+-dependent mechanisms.
Amelioration of denervation-induced atrophy by clenbuterol is associated with increased PKC-α activity
Authors: Sneddon A. A. , Delday M. I. , Maltin C. A.
Published: December 2017

Rat soleus muscle was denervated for 3 or 7 days, and total membrane protein kinase C (PKC) activity and translocation and immunocytochemical localization of PKC isoforms were examined. Dietary administration of clenbuterol concomitant with denervation ameliorated the atrophic response and was associated with increased membrane PKC activity at both 3 (140%) and 7 (190%) days. Of the five PKC isoforms (α, ɛ, θ, ζ, and μ) detected in soleus muscle by Western immunoblotting, clenbuterol treatment affected only the PKC-α and PKC-θ forms. PKC-α was translocated to the membrane fraction upon denervation, and the presence of clenbuterol increased membrane-bound PKC-α and active PKC-α as assayed by Ser657phosphorylation. PKC-θ protein was downregulated upon denervation, and treatment with clenbuterol further decreased both cytosolic and membrane levels. Immunolocalization of PKC-θ showed differences for regulatory and catalytic domains, with the latter showing fast-fiber type specificity. The results suggest potential roles of PKC-α and PKC-θ in the mechanism of action of clenbuterol in alleviating denervation-induced atrophy.
Energetic response to repeated restraint stress in rapidly growing mice
Authors: Laugero Kevin D. , Moberg Gary P.
Published: December 2017

There is a cost of stress that may result in the loss of normal biological function (e.g., growth). Repeated, and even single, applications of stressors have been shown to induce negative energy balance in rodents. However, here we addressed whether this energetic response changes during multiple stress exposure and whether there is complete recovery subsequent to the cessation of stress exposure. These questions were addressed in growing C57Bl/6 mice (31 day) by determining at different times the energetic and endocrine responses after the exposure to restraint (R) stress for 4 h applied once (R1), repeatedly over 3 days (R3), or repeatedly over 7 days (R7). Compared with control values, R elevated ( P < 0.05) plasma corticosterone and reduced plasma insulin-like growth factor I on all days of exposure to the stressor. Seven days, but not 1 or 3 days of R, decreased the net growth (126%, P < 0.05) and deposition of fat (71%, P < 0.05) and lean (60%, P < 0.05) energy over the 7 days. Only R7 depressed the 7-day metabolizable energy intake ( P < 0.05), and R7, but not R1 or R3, increased the overall energy expenditure (10%, P < 0.05). Our results demonstrate that repeated episodes of stress are energetically costly to the rapidly growing animal, but compensatory mechanisms mitigate this cost of repeated stress exposure and permit complete recovery of energy balance after the cessation of stress application.
Glucocorticoids abate p70S6kand eIF4E function in L6 skeletal myoblasts
Authors: Shah O. Jameel , Kimball Scot R. , Jefferson Leonard S.
Published: December 2017

The catabolic properties of glucocorticoid hormones are largely attributable to dual regulation of protein degradation and synthesis. With regard to the latter, glucocorticoids modulate the translational machinery, namely that component functional in translation initiation. This investigation revealed that in L6 myoblasts, dexamethasone, a synthetic glucocorticoid, deactivated the ribosomal protein S6 kinase (p70S6k) within 4 h, as evidenced by diminished phosphorylation of its physiological substrate, the 40S ribosomal protein S6. This deactivation correlated with dephosphorylation of p70S6kat Thr389, whereas phosphorylation of Ser411was unaffected. Furthermore, glucocorticoid administration induced dephosphorylation of the cap-dependent translational repressor, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), thereby facilitating conjunction of the inhibitor and eIF4E. The mechanism of action is reminiscent of classical transcriptional regulation by steroid hormone receptors in that these effects were preceded by a temporal lag and were sensitive to inhibitors of glucocorticoid receptor function as well as transcriptional and translational inhibition. Okadaic acid and calyculin A corrected the dexamethasone-induced dephosphorylation of p70S6kand 4E-BP1, implicating a PP1- and/or PP2A-like protein phosphatase(s) in the observed phenomena. Hence, glucocorticoids attenuate distal constituents of the phosphatidylinositol-3 kinase signaling pathway and thereby encumber the protein synthetic apparatus.
Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release
Authors: Henningsson Ragnar , Alm Per , Lindström Erik , Lundquist Ingmar
Published: December 2017

Islet production of nitric oxide (NO) and CO in relation to islet hormone secretion was investigated in mice given the NO synthase (NOS) inhibitor N G-nitro-l-arginine methyl ester (l-NAME) in their drinking water. In these mice, the total islet NO production was paradoxically increased, reflecting induction of inducible NOS (iNOS) in background of reduced activity and immunoreactivity of constitutive NOS (cNOS). Unexpectedly, normal mice fasted for 24 h also displayed iNOS activity, which was further increased in l-NAME-drinking mice. Glucose-stimulated insulin secretion in vitro and in vivo was increased in fasted but unaffected in fed mice after l-NAME drinking. Glucagon secretion was increased in vitro. Control islets incubated with different NOS inhibitors at 20 mM glucose displayed increased insulin release and decreased cNOS activity. These NOS inhibitors potentiated glucose-stimulated insulin release also from islets ofl-NAME-drinking mice. In contrast, glucagon release was suppressed. In islets from l-NAME-drinking mice, cyclic nucleotides were upregulated, and forskolin-stimulated hormone release, CO production, and heme oxygenase (HO)-2 expression increased. In conclusion, chronic NOS blockade evoked iNOS-derived NO production in pancreatic islets and elicited compensatory mechanisms against the inhibitory action of NO on glucose-stimulated insulin release by inducing upregulation of the islet cAMP and HO-CO systems.
Importance of the hepatic arterial glucose level in generation of the portal signal in conscious dogs
Authors: Hsieh Po-Shiuan , Moore Mary Courtney , Neal Doss W. , Cherrington Alan D.
Published: December 2017

The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs ( n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol·kg−1·min−1) and glucagon (0.65 ng·kg−1·min−1). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 μmol·kg−1·min−1). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 ± 2.2 and 12.8 ± 2.1 vs. 11.5 ± 1.6 and 23.8 ± 3.3* vs. 9.0 ± 2.4 and 13.8 ± 4.2 μmol · kg−1·min−1 in the two periods of CONT, PD, and PD+HAD, respectively (*  P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 ± 1.2 and 39.5 ± 4.3 vs. 26.3 ± 3.7 and 24.5 ± 3.7* vs. 36.1 ± 3.8 and 53.3 ± 8.5 μmol·kg−1·min−1 in the first and second periods of CONT, PD, and PD+HAD, respectively (*  P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.
Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients
Authors: Biolo Gianni , Iscra Fulvio , Bosutti Alessandra , Toigo Gabriele , Ciocchi Beniamino , Geatti Onelio , Gullo Antonino , Guarnieri Gianfranco
Published: December 2017

We determined the effects of 24-h recombinant human growth hormone (rhGH) infusion into a femoral artery on leg muscle protein kinetics, amino acid transport, and glutamine metabolism in eight adult hypercatabolic trauma patients. Metabolic pathways were assessed by leg arteriovenous catheterization and muscle biopsies with the use of stable amino acid isotopes. Muscle mRNA levels of selected enzymes were determined by competitive PCR. rhGH infusion significantly accelerated the inward transport rates of phenylalanine and leucine and protein synthesis, whereas the muscle protein degradation rate and cathepsin B and UbB polyubiquitin mRNA levels were not significantly modified by rhGH. rhGH infusion decreased the rate of glutamine de novo synthesis and glutamine precursor availability, total branched-chain amino acid catabolism, and nonprotein glutamate utilization. Thus net glutamine release from muscle into circulation significantly decreased after rhGH administration (∼50%), whereas glutamine synthetase mRNA levels increased after rhGH infusion, possibly to compensate for reduced glutamine precursor availability. We conclude that, after trauma, the anticatabolic action of rhGH is associated with a potentially harmful decrease in muscle glutamine production.