bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyroid hormone increases the partitioning of glucose transporters to the plasma membrane in ARL 15 cells
Authors: Haber R. S. , Wilson C. M. , Weinstein S. P. , Pritsker A. , Cushman S. W.
Published: December 2017

The stimulation of glucose transport by 3,5,3'-triiodo-L-thyronine (T3) in the liver-derived ARL 15 cell line is only partly attributable to increased GLUT-1 glucose transporter gene expression. To test the hypothesis that T3 increases the partitioning of GLUT-1 to the cell surface, we quantitated surface GLUT-1 using the photolabel ATB-[3H]BMPA. In control cells only approximately 20% of total cellular GLUT-1 was present at the cell surface. T3 treatment (100 nM) for 6 h increased the rate of 2-deoxy-[3H]glucose (2-DG) uptake by 30, 92, and 95% in three experiments and increased surface GLUT-1 photolabeling by 17, 81, and 72%, respectively, with no increase in total cellular GLUT-1. T3 treatment for 48 h increased 2-DG uptake by 143, 172, and 216% in three experiments and increased cell surface GLUT-1 photolabeling by 88, 161, and 184%, respectively, with smaller increases in total cellular GLUT-1. T3 treatment for 48 h thus increased the fraction of cellular GLUT-1 at the plasma membrane from 21 +/- 2 to 35 +/- 3% (SE). We conclude that most of the early (6-h) stimulation of glucose transport by T3 in ARL 15 cells is mediated by an increase in the partitioning of GLUT-1 to the plasma membrane. With more chronic T3 treatment (48 h), the enhanced surface partitioning of GLUT-1 is persistent and is superimposed on an increase in total cellular GLUT-1, accounting for a further increase in glucose transport.
Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women
Authors: Bracco D. , Ferrarra J. M. , Arnaud M. J. , Jequier E. , Schutz Y.
Published: December 2017

The magnitude of coffee-induced thermogenesis and the influence of coffee ingestion on substrate oxidation were investigated in 10 lean and 10 obese women, over two 24-h periods in a respiratory chamber. On one occasion the subjects consumed caffeinated coffee and on the other occasion, decaffeinated coffee. The magnitude of thermogenesis was smaller in obese (4.9 +/- 2.0%) than in lean subjects (7.6 +/- 1.3%). The thermogeneic response to caffeine was prolonged during the night in lean women only. The coffee-induced stimulation of energy expenditure was mediated by a concomitant increase in lipid and carbohydrate oxidation. During the next day, in postabsorptive basal conditions, the thermogenic effect of coffee had vanished, but a significant increase in lipid oxidation was observed in both groups. The magnitude of this effect was, however, blunted in obese women (lipid oxidation increased by 29 and 10% in lean and obese women, respectively). Caffeine increased urinary epinephrine excretion. Whereas urinary caffeine excretion was similar in both groups, obese women excreted more theobromine, theophylline, and paraxanthine than lean women. Despite the high levels of urinary methylxanthine excretion, thermogenesis and lipid oxidation were less stimulated in obese than in lean subjects.
In vivo evidence of a positive role for somatostatin to optimize pulsatile growth hormone secretion
Authors: Turner J. P. , Tannenbaum G. S.
Published: December 2017

Despite convincing evidence that somatostatin (SRIF) and growth hormone (GH)-releasing factor (GRF) individually play crucial roles in GH regulation, the nature of the interplay between these two hypothalamic hormones is far from clear. In the present study, we used the long-acting SRIF analogue, octreotide, as a probe in both the normal and mutant dwarf (dw) rat 1) to further elucidate the temporal nature of the SRIF-GRF interaction in vivo and 2) to define possible mechanisms of action of SRIF in generating pulsatile GH secretion. Normal free-moving adult male rats pretreated with octreotide (25 and 50 micrograms iv) and subsequently challenged with GRF (1 micrograms iv) exhibited a markedly blunted GH response to exogenous GRF 1 h after treatment. In contrast, preexposure to octreotide for 3 h produced a two- to threefold augmentation in GH responsiveness to GRF. Compared with normal saline-pretreated controls, 3-h pretreatment with octreotide produced a 14- to 16-fold augmentation in the postinhibitory rebound release of GH after the coadministration of native SRIF-14 and GRF (P < 0.001). In dw rats, which show a selective reduction in GH synthesis and storage, 3-h preexposure to octreotide failed to significantly alter GRF-induced GH release. These results demonstrate that, in the normal male rat, a 3-h period of exposure to the SRIF analogue octreotide is sufficient to enhance GH responsiveness to GRF. Our findings suggest that this effect is due to a SRIF-mediated buildup of pituitary GH stores in a readily releasable poo.(ABSTRACT TRUNCATED AT 250 WORDS)
Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle
Authors: Mandarino L. J. , Printz R. L. , Cusi K. A. , Kinchington P. , O'Doherty R. M. , Osawa H. , Sewell C. , Consoli A. , Granner D. K. , DeFronzo R. A.
Published: December 2017

Insulin regulates the activity of key enzymes of glucose metabolism in skeletal muscle by altering transcription or translation or by producing activity-altering modifications of preexisting enzyme molecules. Because of the small size of percutaneous muscle biopsies, these phenomena have been difficult to study in humans. This study was performed to determine how physiological hyperinsulinemia regulates the activities of hexokinase (HK), glycogen synthase (GS), and GLUT-4 in human skeletal muscle in vivo. We determined mRNA abundance, protein content, and activities for these proteins in muscle biopsies before and after a hyperinsulinemic clamp in normal subjects. HK I, HK II, GS, and GLUT-4 were expressed in muscle. HK II accounted for 80% of total HK activity and was increased by insulin from a basal value of 2.11 +/- 0.26 to 3.35 +/- 0.47 pmol.min-1.mg protein-1 (P < 0.05); HK I activity was unaffected. Insulin increased GS activity from 3.85 +/- 0.82 to 6.06 +/- 0.49 nmol.min-1.mg-1 (P < 0.01). HK II mRNA was increased 3.3 +/- 1.3-fold (P < 0.05) by insulin infusion. HK I, GS, and GLUT-4 mRNA and protein were unaffected. Because insulin infusion increased HK II but not GS mRNA, we conclude that HK II and GS may be regulated by insulin by different mechanisms in human skeletal muscle.
Neonatal rat dietary carbohydrate affects pancreatic islet insulin secretion in adults and progeny
Authors: Laychock S. G. , Vadlamudi S. , Patel M. S.
Published: December 2017

Neonatal rat pups were artificially reared on isocaloric diets high in carbohydrate (HC) or high in fat (HF) or were naturally reared on mother's milk (MF). The HC adult rats were hyperinsulinemic, normoglycemic, and obese. This study investigates pancreatic islet insulin release (IR) of the adult first-generation (1-) diet-regulated animals and their second-generation (2-) progeny. Male rat 1-HC islets had higher basal IR than either 1-MF or 1-HF control groups. In addition, glucose (17 mM) failed to increase IR above basal values in 1-HC islets, whereas it stimulated IR in 1-MF and 1-HF islets. Similar secretory responses were evoked by 2-ketoisocaproic acid (2-KIC). Female rat 1-MF and 1-HF islets also had higher glucose-stimulated IR compared with 1-HC islets. Male rat 2-HC islets had higher basal IR and reduced sensitivity to glucose and 2-KIC compared with 2-MF islets, which coincided with hyperinsulinemia. Glyceraldehyde-3-phosphate dehydrogenase activity in 1-HC and 2-HC islets was higher than in MF islets. These data suggest that basal IR is higher in islets isolated from animals reared as neonates on a diet high in carbohydrate. Alterations in beta-cell metabolism and secretion probably contribute to the hyperinsulinemia, reduced glucose sensitivity, and glucose intolerance characteristic of this rat model.
Glucose production in glycogen storage disease I is not associated with increased cycling through hepatic glycogen
Authors: Rother K. I. , Schwenk W. F.
Published: December 2017

Children with glycogen storage disease type I (GSD I) lack the ability to convert glucose 6-phosphate to glucose and yet are able to produce glucose endogenously. To test the hypothesis that the source of this glucose is increased cycling of glucose moieties through hepatic glycogen, six children with GSD I were studied on two occasions during which they received enteral glucose for 6 h at 35 or 50 mumol.kg-1.min-1 along with [6,6-2H2]glucose to measure plasma glucose flux and [1-13C]galactose to label intrahepatic uridyl diphosphate (UDP)-glucose. After 3 h, acetaminophen was given to estimate UDP-glucose flux (reflecting the rate of glycogen synthesis). Mean steady-state plasma glucose concentrations (4.8 +/- 0.2 vs. 5.8 +/- 0.1 mM) and total flux (34.8 +/- 1.7 vs. 47.5 +/- 2.0 mumol.kg-1.min-1) were increased (P < 0.05 or better) on the high-infusion day. Endogenous glucose production was detectable only on the low-infusion day (2.0 +/- 0.5 mumol.kg-1.min-1). UDP-glucose flux was increased (P < 0.05) on the high-infusion day (25.8 +/- 1.6 vs. 34.7 +/- 4.1), ruling out cycling of glucose moieties through glycogen with release of glucose by debrancher enzyme as the source of glucose production.
Prevention of diabetes does not completely prevent insulin secretory defects in the ZDF rat
Authors: Sturis J. , Pugh W. L. , Tang J. , Polonsky K. S.
Published: December 2017

The rapid insulin secretory pulses that occur in the perfused rat pancreas can be entrained by an oscillatory glucose concentration in pancreata from nondiabetic rats but not from X diabetic Zucker diabetic fatty (ZDF) rats. To investigate whether this defect is present in prediabetic ZDF rats and whether treatment with either pioglitazone or acarbose can prevent or reverse this defect, 39 ZDF and 5 lean ZDF control rats were studied. The ZDF rats were divided into six groups depending on age, form of therapy used, and the time at which pioglitazone was started in relation to the onset of diabetes. The pancreas was isolated and perfused using a sine wave-shaped glucose concentration (mean 7 mM, period 10 min, amplitude 10%). The results, assessed by spectral analysis, revealed that in prediabetic animals and in controls, entrainment of pulsatile insulin secretion was normal. Initiation of pioglitazone therapy in ZDF rats at the time of weaning or before diabetes onset prevented hyperglycemia. However, entrainment was only partially retained. Thus, in these two groups, the spectral power at 10 min was greater than in untreated animals but lower than in prediabetic and control animals. Treatment with acarbose before or with pioglitazone after diabetes onset improved but did not normalize glucose levels, and it did not improve entrainment. The results demonstrate the presence of insulin secretory defects in 13-wk-old ZDF rats in which hyperglycemia was prevented.
Comparative metabolism of plasminogen glycoforms I and II in the alloxan-diabetic rabbit
Authors: Hatton M. W. , Southward S. M. , Ross-Ouellet B. , Richardson M. , Winocour P. D.
Published: December 2017

The metabolism of plasminogen glycoforms I and II was measured in alloxan-induced diabetic and in age-matched control rabbits. Radiolabeled plasminogen I and II were degraded significantly more slowly in diabetic compared with control rabbits; plasminogen II [half-time (T1/2), 1.31 days] was degraded faster than plasminogen I (T1/2), 1.86 days) in diabetic rabbits and in control rabbits (T1/2, 1.18 and 1.58 days, respectively). From the catabolic rates and relative quantities in plasma, we calculated that approximately four molecules of plasminogen II were degraded for one molecule of plasminogen I in the diabetic and control rabbits. To verify this later observation, plasminogen I and II production by diabetic rabbit livers was compared with that by the control livers in vitro. During perfusion with [3H]leucine, 3H-labeled protein was released more slowly from diabetic than from control livers, but no quantitative difference in total plasminogen yield between diabetic and control livers was found. Nevertheless, plasminogen II was produced 0.7 +/- 0.4 and 4.3 +/- 0.3 times faster than plasminogen I by diabetic and control livers, respectively. Plasminogen metabolism in the diabetic rabbit did not differ qualitatively from that in the control rabbit except that catabolism was slowed.
Postprandial free fatty acids stimulate activity of human corticosteroid binding globulin
Authors: Haourigui M. , Sakr S. , Martin M. E. , Thobie N. , Girard-Globa A. , Benassayag C. , Nunez E. A.
Published: December 2017

The effect of postprandial variation of free fatty acids (FFA) on serum corticosteroid binding globulin (CBG) properties and cortisol (hydrocortisone) concentrations were explored in 11 women (20-30 yr) during 8 h after an oral load of tallow (26% C16:0, 18% C18:0, and 43% C18:1), oleic-sunflower (oleic-SF; 73% C18:1), sunflower (SF; 67% C18:2), and mixed oil (MO; 39% C18:1 and 48% C18:2). Serum FFA increased little after SF and MO but more than doubled in the late postprandial period (6 and 8 h) after oleic-SF (due to monounsaturated FFA) or tallow (due to saturated and monounsaturated FFA). CBG concentrations remained unchanged, but in relation with the postprandial elevation of serum FFA, CBG binding activity was increased after tallow or oleic-SF as a result of a combined two- to threefold increase in affinity constant and a 50% reduction in binding sites. Immunological and in vitro binding studies showed the changes in CBG behavior to be conformational and to be mediated mainly by monounsaturated FFA, especially C18:1. The modifications of CBG properties were associated with sustained high concentrations of cortisol (suppression of midday decrease) 6 and 8 h after tallow or oleic-SF. Thus dietary FFA may have an impact on bioavailability of glucocorticoids.
Regulation of bioactive and immunoreactive ACTH secretion by CRF and AVP in sheep fetuses
Authors: Zehnder T. J. , Valego N. K. , Schwartz J. , White A. , Rose J. C.
Published: December 2017

The purpose of this study was to determine the effects of corticotropin-releasing factor (CRF) or arginine vasopressin (AVP) on the secretion of bioactive adrenocorticotropic hormone (bACTH) and immunoreactive ACTH (iACTH), the latter being measured by radioimmunoassay and separate two-site immunoradiometric assays for ACTH-(1-39) and ACTH precursors. Experiments were performed on chronically catheterized fetal sheep at 0.70 (n = 9) and 0.90 (n = 8) gestation. Each fetus received a 15-min infusion of CRF, AVP, or saline on 3 consecutive days. Blood was obtained before and 15 and 60 min after the infusion began. CRF significantly increased iACTH at 15 (younger group) and 60 min (both groups). CRF significantly increased bACTH and the bACTH-to-iACTH ratio (bACTH/iACTH) in both groups at 15 and 60 min. AVP significantly increased iACTH, bACTH, and bACTH/iACTH in both groups at 15 min. In two subgroups (n = 4/subgroup), CRF significantly increased ACTH-(1-39) and ACTH precursors at 15 and 60 min. CRF increased the ratio of ACTH-(1-39) to ACTH precursors [ACTH-(1-39)/ACTH precursors] at 15 (younger group) and 60 min (both groups). AVP increased ACTH-(1-39), ACTH precursors, and ACTH-(1-39)/ACTH precursors in both groups at 15 min. These findings show that both CRF and AVP can stimulate the secretion of bACTH, ACTH-(1-39), and ACTH precursors at 0.70 and 0.90 gestation. The proportional increments in bACTH/iACTH and ACTH-(1-39)/ACTH precursors suggest that CRF and AVP evoke selective increases in bACTH and ACTH-(1-39).
Interleukin-1 alpha stimulates dopamine release by activating type II protein kinase A in PC-12 cells
Authors: Joseph A. , Kumar A. , O'Connell N. A. , Agarwal R. K. , Gwosdow A. R.
Published: December 2017

A recent study from this laboratory [A. R. Gwosdow, N. A. O'Connell, and A. B. Abou-Samra. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E461-E466, 1992] showed that the inflammatory mediator interleukin-1 alpha (IL-1 alpha) stimulates catecholamine release from primary cultures of rat adrenal cells. The present studies were conducted to determine whether 1) IL-1 alpha stimulates catecholamine/dopamine release from the adrenal medullary cell line PC-12 and 2) the adenosine 3',5'-cyclic monophosphate (cAMP)-protein kinase A (PKA) pathway is involved in IL-1 alpha-induced dopamine release from PC-12 cells. The results indicate that IL-1 alpha significantly (P < 0.05) elevated dopamine release after a 24-h incubation period. IL-1 alpha did not stimulate cAMP accumulation at any time period between 5 min and 2 h. In contrast, forskolin-treated cells elevated (P < 0.05) intracellular cAMP levels and increased dopamine release. Because IL-1 alpha did not affect cAMP accumulation, the effect of IL-1 alpha on PKA activity was investigated. IL-1 alpha increased (P < 0.05) PKA activity at 15 and 30 min and returned to control levels by 1 h. Forskolin also increased (P < 0.05) PKA activity. The type of PKA activated (P < 0.05) by IL-1 alpha was type II PKA. In contrast, forskolin activated (P < 0.05) type I and type II PKA. Inhibition of PKA with the PKA inhibitor H-8 blocked PKA activity and dopamine secretion by both IL-1 alpha and forskolin in PC-12 cells. These observations demonstrate that 1) IL-1 alpha stimulated dopamine release from PC-12 cells by activating PKA, 2) the mechanism of IL-1 alpha activation of PKA does not involve detectable increases in intracellular cAMP accumulation, and 3) IL-1 alpha activates type II PKA, which is used by IL-1 alpha to stimulate dopamine secretion from PC-12 cells.
Altered expression of eukaryotic initiation factor 2B in skeletal muscle during sepsis
Authors: Voisin L. , Gray K. , Flowers K. M. , Kimball S. R. , Jefferson L. S. , Vary T. C.
Published: December 2017

Sepsis causes an inhibition of protein synthesis in skeletal muscles composed of fast-twitch fibers, in part, as a result of a decreased activity of the eukaryotic initiation factor 2B (eIF-2B). In the present study, we investigated the expression of two subunits of eIF-2B, i.e., the beta- and epsilon-subunits during sepsis. The expression of both beta- and epsilon-subunits of eIF-2B in gastrocnemius was decreased approximately 50% from control values during the first 5 days after induction of sepsis. The decreased expression of eIF-2B epsilon during sepsis correlated with similar reductions in eIF-2B epsilon mRNA. Restoration of protein synthesis (10 days postsurgery) was associated with a return of eIF-2B epsilon expression to values observed in control rats. Expression of eIF-2B epsilon was not altered in heart during sepsis or in gastrocnemius from nonseptic abscess animals. Amrinone, which ameliorated the inhibition of protein synthesis during sepsis, also prevented the fall in eIF-2B epsilon protein after 5 days of infection. The data provide evidence that expression of eIF-2B epsilon is markedly influenced in gastrocnemius during the course of the septic episode and support the concept that this change is a mechanism responsible for the inhibition of protein synthesis observed under this condition.
Visceral adiposity, increased adipocyte lipolysis, and metabolic dysfunction in obese postmenopausal women
Authors: Nicklas B. J. , Rogus E. M. , Colman E. G. , Goldberg A. P.
Published: December 2017

This study determines whether there are regional differences in lipolysis and whether adipocyte lipolysis is associated with the degree of visceral adiposity and its metabolic complications in 32 obese (28-37 kg/m2), nondiabetic, postmenopausal women. In vitro lipolysis was measured in the basal state and after addition of epinephrine (Epi), Epi plus yohimbine, Epi plus propranolol, and N6,2'-O-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) in abdominal (ABD) and gluteal (GLT) adipocytes. Upper body obese [UBO, waist-to-hip ratio (WHR) > or = 0.80, n = 19] women had a greater intra-abdominal fat area (IA, 199 +/- 50 vs. 142 +/- 28 cm2) and Epi-stimulated lipolysis (ABD: 1.60 +/- 1.10 vs. 0.95 +/- 0.54 mumol glycerol.10(6) cells-1.2h; GLT: 1.14 +/- 0.70 vs. 0.66 +/- 0.42 mumol glycerol.10(6) cells-1.2 h) than lower body obese (LBO, WHR < 0.80, n = 13) women. The UBO women also had lower high-density lipoprotein cholesterol (1.39 +/- 0.40 vs. 1.64 +/- 0.39 mmol/l, P < 0.05), higher plasma triglycerides (1.89 +/- 0.48 vs. 1.44 +/- 0.56 mmol/l, P < 0.05), and higher fasting insulin levels (154 +/- 57 vs. 118 +/- 33 pmol/l, P < 0.05) than LBO women. Basal, adrenergic receptor-mediated, and DBcAMP-stimulated lipolytic rates in ABD and GLT adipocytes were positively correlated with IA (r = 0.44-0.76, P < 0.05, n = 28). In both UBO and LBO women, Epi-stimulated lipolysis was higher (+30%, P < 0.05) in ABD than GLT adipocytes. These results show that, in postmenopausal women, visceral obesity is associated with increased rates of lipolysis in both ABD and GLT subcutaneous adipocytes. The findings also indicate that Epi-stimulated lipolysis is greater in ABD than GLT adipocytes regardless of fat distribution.
Regulation of muscle glycogen phosphorylase activity following short-term endurance training
Authors: Chesley A. , Heigenhauser G. J. , Spriet L. L.
Published: December 2017

The purpose of this study was to examine the regulation (hormonal, substrate, and allosteric) of muscle glycogen phosphorylase (Phos) activity and glycogenolysis after short-term endurance training. Eight untrained males completed 6 days of cycle exercise (2 h/day) at 65% of maximal O2 uptake (Vo2max). Before and after training subjects cycled for 15 min at 80% of Vo2max, and muscle biopsies and blood samples were obtained at 0 and 30 s, 7.5 and 15 min, and 0, 5, 10, and 15 min of exercise. Vo2max was unchanged with training but citrate synthase (CS) activity increased by 20%. Muscle glycogenolysis was reduced by 42% during the 15-min exercise challenge following training (198.8 +/- 36.9 vs. 115.4 +/- 25.1 mmol/kg dry muscle), and plasma epinephrine was blunted at 15 min of exercise. The Phos a mole fraction was unaffected by training. Muscle phosphocreatine utilization and free Pi and AMP accumulations were reduced with training at 7.5 and 15 min of exercise. It is concluded that posttransformational control of Phos, exerted by reductions in substrate (free Pi) and allosteric modulator (free AMP) contents, is responsible for a blunted muscle glycogenolysis after 6 days of endurance training. The increase in CS activity suggests that the reduction of muscle glycogenolysis was due in part to an enhanced mitochondrial potential.
Effects of fish oil on metabolic responses to oral fructose and glucose loads in healthy humans
Authors: Delarue J. , Couet C. , Cohen R. , Brechot J. F. , Antoine J. M. , Lamisse F.
Published: December 2017

This study examines the effect of the substitution of 6 g/day of fish oil in a saturated diet on glucose and fructose metabolism in healthy humans. Five subjects were submitted to two 3-wk controlled-diet periods (polyunsaturated/saturated = 0.21). During one period, 6 g/day of fat used for dressing were replaced by 6 g/day of fish oil [1.1 g/day of 20:5 (n-3) fatty acids and 0.7 g/day of 22:6 (n-3) fatty acids]. At the end of each period the subjects ingested a 1 g/kg fructose or glucose load 2 days apart. Plasma glucose fluxes were traced with the use of deuterated glucose and [U-13C]glucose. Substrate oxidation was measured by indirect calorimetry. Fish oil induced a 4% increase in basal and postload glycemia and a 40% decrease in insulinemia, whereas plasma C-peptide remained unaffected. Glucose fluxes were unaffected by fish oil, but carbohydrate (CHO) oxidation was reduced (fructose: 55.5 +/- 4.1 vs. 62.9 +/- 3.6 g/6 h; glucose: 36.7 +/- 4.7 vs. 50.5 +/- 4.7 g/6 h; all P < 0.05). Lipid oxidation was increased 35% by fish oil after both CHO loads. Nonoxidative glucose disposal was increased by fish oil (fructose: 9.4 +/- 2.5 vs. 2.9 +/- 1.1 g/6 h; glucose: 28.3 +/- 5.1 vs. 14.4 +/- 4.7 g/6 h; all P < 0.05). Fish oil could affect glucose transport and decrease CHO oxidation through the decrease in insulinemia and/or a specific effect on glycolytic pathway.
Differential effects of acute hypertriglyceridemia on insulin action and insulin receptor autophosphorylation
Authors: Gumbiner B. , Mucha J. F. , Lindstrom J. E. , Rekhi I. , Livingston J. N.
Published: December 2017

Experimentally induced hypertriglyceridemia (HTG) and high plasma free fatty acid (FFA) levels impair in vivo insulin action. To determine if this is a consequence of impaired in vivo insulin receptor autophosphorylation and related to defective receptor signaling, hyperinsulinemic euglycemic clamps, indirect calorimetry, and skeletal muscle biopsies were performed in nine healthy subjects. In vivo insulin action was determined from the glucose infusion rate (GINF) and glucose oxidation (Glcox) during 40 and 120 mU/m2 /min clamps with (HTG clamp) and without (control clamp) a triglyceride emulsion infusion. The percentage of receptors autophosphorylated in vivo was determined by 125I-labeled insulin tracer binding in skeletal muscle immunoprecipitates of insulin receptors and phosphorylated receptors. Compared with the control clamps, plasma triglycerides and FFA increased four- and twofold, whereas GINF and Glcox decreased 15 and 35%, respectively, during the HTG clamps (all P<0.05). However, the percentages of receptors phosphorylated after the 40 and 120 mU/m2/min HTG clamps (9.2 +/- 1.5 and 21.1 +/- 2.6%, respectively) were similar to the control clamps (9.0 +/- 0.6 and 18.6 +/- 2.2%, respectively). These results indicate that, if impaired insulin signal transduction is a mechanism by which HTG and FFA impair insulin action, it occurs at a site downstream from insulin receptor autophosphorylation.
Placental transport and fetal utilization of leucine in a model of fetal growth retardation
Authors: Ross, J. C. , Fennessey P. V. , Wilkening R. B. , Battaglia F. C. , Meschia G.
Published: December 2017

Placental transport and fetal utilization of leucine were studied at 130 days of gestation in six control ewes and in seven ewes in which intrauterine growth retardation (IUGR) had been induced by exposure to heat stress. Leucine fluxes were measured during simultaneous intravenous infusion of L-[1-13C]leucine into the mother and L-[1-14C] leucine into the fetus. In the IUGR group, the following leucine fluxes, expressed as micromol/min/kg fetus, were reduced compared with control: net uterine uptake (3.44 vs. 8.56, P<0.01), uteroplacental utilization (0.0 vs. 4.7, P<0.01), fetal disposal rate (6.4 vs. 8.9, P<0.001), flux from placenta to fetus (5.0 vs. 7.1, P<0.01), direct transport from mother to fetus (1.6 vs. 3.4, P<0.01), flux from fetus to placenta (1.5 vs. 3.2, P<0.001), and oxidation of fetal leucine by fetus plus placenta (2.1 vs. 3.2, P<0.02). Uterine uptake, uteroplacental utilization, and direct transport were also significantly reduced per gram placenta. We conclude that maternal leucine flux into the IUGR placenta is markedly reduced. Most of the reduced flux is routed into fetal metabolism via a decrease in placental leucine utilization and a decrease in the leucine flux from fetus to placenta.
Human skeletal muscle malonyl-CoA at rest and during prolonged submaximal exercise
Authors: Odland L. M. , Heigenhauser G. J. , Lopaschuk G. D. , Spriet L. L.
Published: December 2017

Previous literature has indicated that contraction-induced decreases in malonyl-CoA are instrumental in the regulation of fatty acid oxidation during prolonged submaximal exercise. This study was designed to measure malonyl-CoA in human vastus lateralis muscle at rest and during submaximal exercise. Eight males and one female cycled for 70 min (10 min at 40% and 60 min at 65% maximal O2 uptake). Needle biopsies were obtained at rest and at 10 min, 20 min, and 70 min of exercise. Malonyl-CoA content in preexercise biopsy samples determined by high-performance liquid chromatography (HPLC) was 1.53 +/- 0.18 micromol/kg dry mass (dm). Malonyl-CoA content did not change significantly during exercise (1.39 +/- 0.21 at 10 min, 1.46 +/- 0.14 at 20 min, and 1.22 +/- 0.15 micromol/kg dm at 70 min). In contrast, malonyl-CoA content determined by HPLC in perfused rat red gastrocnemius muscle decreased significantly during 20 min of stimulation at 0.7 Hz [3.44 +/- 0.54 to 1.64 +/- 0.23 nmol/g dm, (n=9)]. We conclude that human skeletal muscle malonyl-CoA content 1) is less than reported in rat skeletal muscle at rest, 2) does not decrease with prolonged submaximal exercise, and 3) is not predictive of increased fatty acid oxidation during exercise.
Hyperglucagonemia and hepatic glucose metabolism during infection in the conscious dog
Authors: McGuinness O. P. , Lacy D. B. , Eliasson K.
Published: December 2017

The chronic and acute roles of hyperglucagonemia in sustaining the increased glucose production observed in the conscious infected dog were examined. Three groups of dogs were studied: a sham group (SHAM; n = 10), an infected group (INFXN; n = 11), and a sham group in which the chronic (42-h) increase in glucagon observed in INFXN was simulated (SimGGN; n = 5). INFXN and SimGGN were studied in the presence of hyperglucagonemia. In addition, glucagon was selectively decreased for 180 min in INFXN by use of somatostatin with basal intraportal insulin replacement and in SimGGN by discontinuing the exogenous glucagon infusion. Tracer and arteriovenous difference techniques were used to assess hepatic glucose metabolism and gluconeogenesis. Whereas the rate of glucose appearance (Ra) was increased by 30% (3.3 +/- 0.1 vs. 2.5 +/- 0.1 mg.kg-1.min-1) in INFXN vs. SHAM, Ra did not increase in SimGGN (2.4 +/- 0.2 mg.kg-1.min-1). In addition, the 30% increase in net hepatic gluconeogenic precursor uptake seen in INFXN did not occur in SimGGN despite an augmented net hepatic alanine fractional extraction (0.62 +/- 0.03 vs. 0.47 +/- 0.05, SimGGN vs. INFXN). With acute removal of hyperglucagonemia, endogenous Ra decreased in SimGGN and INFXN by 1.0 +/- 0.2 and 1.4 +/- 0.3 mg.kg-1.min-1, respectively. Net hepatic alanine fractional extraction in INFXN, leading to a greater rise in arterial blood alanine levels. In summary, chronic hyperglucagonemia alone cannot explain the increase in Ra observed during an infection. The marked hyperglucagonemia seen during infection plays an essential role in sustaining normal net hepatic fractional alanine extraction to compensate for an impairment in glucagon-stimulated hepatic amino acid transport activation.
Prefeeding release of paraventricular neuropeptide Y is mediated by ascending noradrenergic neurons in rats
Authors: Yoshihara T. , Honma S. , Honma K.
Published: December 2017

The neuronal system responsible for the release of neuropeptide Y (NPY) in the paraventricular nucleus (PVN) was examined in rats under food deprivation and restricted daily feeding (RF). The ascending noradrenergic bundle (NAB) of neurons from the brain stem were destructed by microinjection of 6-hydroxydopamine (6-OHDA), and the extracellular NPY level in the PVN was measured by push-pull perfusion. 6-OHDA significantly reduced the extracellular norepinephrine level in the PVN to 15% of the control value when injected into the PVN and to 40% when injected into the midbrain ventral NAB. 6-OHDA administration into the NAB affected neither the deprivation-induced increase nor the feeding-induced decrease in the extracellular NPY. The amount of food intake after refeeding was not changed by the 6-OHDA treatment. On the other hand, 6-OHDA injection into the PVN or NAB not only decreased the extracellular NPY level, the amount of food intake was not change by the 6-OHDA treatment. It is concluded that the NAB is involved in the prefeeding NPY release in rats under RF but not in the deprivation-induced NPY release.
Protein synthesis in skeletal muscle and jejunum is more responsive to feeding in 7-than in 26-day-old pigs
Authors: Davis T. A. , Burrin D. G. , Fiorotto M. L. , Nguyen H. V.
Published: December 2017

The study aimed to determine the developmental changes in the response of peripheral and visceral tissue protein synthesis to feeding during early postnatal life and the associated changes in circulating insulin, insulin-like growth factor (IGF-I), and amino acid concentrations. Tissue protein synthesis was measured in vivo with a large dose of L-[4(-3)H]phenylalanine in 7- and 26-day-old pigs that were either fasted for 24 h or refed for 2.75 h after a 24-h fast. Fractional rates of protein synthesis (Ks) in skeletal muscle, heart, and liver were greater in 7-than in 26-day-old pigs. Refeeding stimulated Ks in skeletal muscle, pancreas, jejunum, and liver of both 7-and 26-day-old pigs. The stimulation of skeletal muscle and jejunal Ks by refeeding was greater in 7- than in 26-day-old pigs. Plasma IGF-I concentrations were lower in 7- than in 26-day-old pigs. Plasma concentrations of insulin and amino acids increased with refeeding. The increase in plasma insulin concentrations with refeeding was greater in 7- than in 26-days-old pigs. These results indicate that the stimulation in skeletal muscle and jejunal protein synthesis by feeding is elevated in young compared with older suckling pigs. This enhanced stimulation of protein synthesis by feeding in neonatal pigs is associated with elevated circulating concentrations of insulin but not amino acids or IGF-I.
Effect of aldosterone on renal potassium conservation in the rat
Authors: Ornt D. B. , Radke K. J. , Scandling J. D.
Published: December 2017

The importance of reduced plasma aldosterone concentration (PAC) in renal potassium (K) conservation is unclear. Thus we examined the effect of aldosterone on incipient, developing, and established renal K conservation. Adrenalectomized (ADX) dexamethasone-replaced rats were continuously treated with high, normal, or low dosages of aldosterone during 4 days of dietary K restriction and were compared with rats without aldosterone replacement. High and normal aldosterone replacement reduced the fall in urinary K excretion and led to significantly lower plasma [K], skeletal muscle tissue K content, renal tissue K content, and greater negative cumulative balance of K compared with low aldosterone replacement. Likewise, plasma [K] and skeletal muscle tissue K content were significantly less in intact rats after 3 days of K deprivation and chronic treatment with aldosterone. Acute aldosterone treatment significantly increased urinary K excretion by isolated perfused kidneys. We conclude that incipient, developing, and established renal K conservation is not independent of mineralocorticoid activity and that the rapid fall in PAC during K depletion is necessary for maximal renal K conservation.
Control of cell proliferation in the rat adrenal gland in vivo by the renin-angiotensin system
Authors: McEwan P. E. , Lindop G. B. , Kenyon C. J.
Published: December 2017

Adrenal cytogenesis was investigated in response to 1) subcutaneous infusions of angiotensin (ANG) II (200 ng.kg-1.min-1); 2) high and low sodium intake; and 3) captopril treatment (10 mg.kg-1.day-1). Cell proliferation was assessed as uptake of 5-bromo-2'-deoxyuridine (BrdUrd) into nuclei. BrdUrd, infused continuously throughout 2 wk of treatment, was detected immunocytochemically. ANG II and sodium restriction caused hypertrophy of the zona glomerulosa with two- to threefold increases in BrdUrd indexes. After captopril, the glomerulosa appeared atrophied with pyknotic nuclei, but the BrdUrd index was unchanged. Zonae intermedia and fasciculata were unaffected by any treatment. Zona reticularis epithelial cells proliferated in response to ANG II and sodium restriction but were unaffected by captopril. In the medulla, captopril increased BrdUrd uptake, whereas ANG II, but not low sodium, caused a decrease. In conclusion, 1) proliferation of the glomerulosa and reticularis cells is specifically controlled by ANG II, 2) captopril may cause glomerulosa cells to die, and 3) blood pressure may control proliferation of the medulla.
Relationships between sleep quality and glucose regulation in normal humans
Authors: Scheen A. J. , Byrne M. M. , Plat L. , Leproult R. , Van Cauter E.
Published: December 2017

To define the effects of sleep on glucose regulation, we analyzed plasma glucose levels, insulin secretion rates (ISR), and plasma growth hormone and cortisol levels in normal subjects receiving a constant glucose infusion during nocturnal sleep, nocturnal sleep deprivation, and daytime recovery sleep. Plasma glucose and ISR markedly increased during early nocturnal sleep and returned to presleep levels during late sleep. These changes in glucose and ISR appeared to reflect the predominance of slow-wave (SW) stages in early sleep and of rapid-eye-movement and wake stages in late sleep. Major differences in glucose and ISR profiles were observed during sleep deprivation as glucose and ISR remained essentially stable during the first part of the night and then decreased significantly, despite the persistence of bed rest and constant glucose infusion. During daytime recovery sleep, SW stages were increased, glucose levels peaked earlier than during nocturnal sleep, and the decreases of glucose and ISR in late sleep were reduced by one-half. Thus sleep has important effects on brain and tissue glucose utilization, suggesting that sleep disturbances may adversely affect glucose tolerance.
Central interleukin-1 partially mediates endotoxin-induced changes in glucose metabolism
Authors: Lang C. H. , Cooney R. , Vary T. C.
Published: December 2017

The purpose of the present study was to determine whether intracerebral interleukin (IL)-1 mediates the endotoxin [lipopolysaccharide (LPS)]-induced increase in glucose flux. To accomplish this goal, a specific receptor antagonist for IL-1 (IL-1ra) or artificial cerebrospinal fluid was infused into the lateral ventricle via an intracerebroventricular cannula before, and for 4 h after, the intravenous injection of LPS. Whole body glucose flux was measured in conscious unrestrained rats using [3-3H]glucose. LPS increased both the plasma glucose concentration and the rate of glucose production (95 and 80%, respectively). In contrast, intracerebroventricular infusion of IL-1ra (2 mg/kg + 2 mg-kg-1.h-1) attenuated by approximately 50% the LPS-induced changes in glucose metabolism. IL-1ra also blunted the increase in plasma catecholamines, but not the elevation in glucagon and corticosterone concentrations, observed after LPS. Intracerebroventricular infusion of IL-1ra greatly reduced the LPS-induced hyperlactacidemia but did not alter the increase in muscle pyruvate dehydrogenase activity. An intravenous infusion of a 10-fold greater dose of IL-1ra, however, did not antagonize the LPS-induced increase in glucose flux. These data indicate that a major portion of the stimulation of glucose flux, as well as the increase in plasma catecholamines in response to LPS, is mediated by IL-1 within the central nervous system.
Effect of glucose on uptake of radiolabeled glucose, 2-DG, and 3-O-MG by the perfused rat liver
Authors: Sweet I. R. , Peterson L. , Kroll K. , Goodner C. J. , Berry M. , Graham M. M.
Published: December 2017

In the transition from the fasting to the fed state, plasma glucose levels rise, and the liver converts from an organ producing glucose to one of storage. To determine the effect of glucose on hepatic glucose uptake, radiolabeled glucose, 2-deoxyglucose, and 3-O-methylglucose were injected into perfused rat livers during different nontracer glucose levels, and the concentrations in the outflow were measured. A mathematical model was developed that described the behavior of the injected compounds as they traveled through the liver and was used to simulate and fit the experimental results. The rates of membrane transport, glucokinase, glucose-6-phosphatase, and the consumption of glucose 6-phosphate were estimated. Membrane transport for all of the tracers decreased as nontracer glucose increased, demonstrating competitive inhibition of the glucose transporter. In contrast, the consumption of injected [2-14C]glucose increased when glucose was elevated, demonstrating that glucose caused an activation of enzyme activity that overcame the competitive inhibition of transport and phosphorylation. When glucose was elevated, the rate coefficient of glucokinase did not decrease, indicating that glucokinase was stimulated by glucose. Both changes would lead to the increased glycogen synthesis and decreased glucose production rate observed in vivo during the fasted-to-fed transition.
Modulation of vascular tone and glycerol levels measured by in situ microdialysis in rat adipose tissue
Authors: Darimont C. , Saint-Marc P. , Ailhaud G. , Negrel R.
Published: December 2017

Changes in blood flow induced by the beta-adrenoceptor agonist isoproterenol (Iso) and a stable analogue of the major metabolite of arachidonic acid in adipose tissue, carbaprostacyclin (cPGI2), have been studied in rat periepididymal fat pad with in situ microdialysis measuring the distribution ratio of 0.2% ethanol in the dialysate (outflow) to that in the perfusate (inflow) (O/I ratio). Local perfusions of 1 microM cPGI2 or 1 microM Iso led to reversible decreases of the O/I ratio that were similar to the decrease induced by the vasodilating reference drug hydralazine (Hydra, 630 microM). Interestingly, a continuous perfusion of Hydra at a submaximal vasodilating concentration (63 microM) was sufficient to prevent further vasodilatation induced by Iso or cPGI2. To take advantage of this observation, experiments were designed to evaluate the influence of the vasodilating effect of Iso or cPGI2 on the ability of either to induce lipolysis in vivo. The results showed that the vasodilating effect of Iso could contribute to glycerol removal from the extracellular fluid and demonstrate that cPGI2 was devoid of lipolytic activity.
Protein degradation and synthesis measured with multiple amino acid tracers in vivo
Authors: Tessari P. , Barazzoni R. , Zanetti M. , Vettore M. , Normand S. , Bruttomesso D. , Beaufrere B.
Published: December 2017

Whether tracers of different essential amino acids yield the same estimates of body protein turnover is still uncertain. Therefore, we have simultaneously determined leucine (Leu; using [14C]Leu), phenylalanine (Phe; using [13C]Phe), and tyrosine (Tyr; using [2H2]Tyr) rates of appearance (Ra) from proteolysis (PD), as well as Leu and Phe disposal, into protein synthesis (PS) both before and after an anabolic stimulus in healthy volunteers. Protein anabolism was stimulated by insulin plus a branched-chain amino acid-enriched aromatic amino acid-deficient amino acid solution, which increased Leu (from 145 +/- 9 to 266 +/- 10 mumol/l) but decreased Phe (from 57 +/- 2 to 46 +/- 3) and Tyr (from 58.7 +/- 5.5 to 21.0 +/- 2.2) concentrations. Postabsorptive endogenous Leu Ra (2.04 +/- 0.12 mumol.kg-1.min-1), Phe Ra (0.66 +/- 0.03), and Tyr Ra (0.45 +/- 0.06), as well as rates of PS determined with the leucine (1.65 +/- 0.10 mumol.kg-1.min-1) and the phenylalanine tracer (0.57 +/- 0.03), agreed well with the known abundance of these amino acids in body protein(s). After insulin and amino acids, PD was suppressed (P < 0.001) using all tracers. However, although percent suppression of endogenous Leu Ra (-->1.49 +/- 0.10 mumol.kg-1.min-1, 26 +/- 5%) and Phe Ra (-->0.53 +/- 0.02 mumol.kg-1.min-1, -20 +/- 2%) were comparable, endogenous Tyr Ra was suppressed to a larger extent (-->0.23 +/- 0.02 mumol.kg-1.min-1, -46 +/- 3% P = 0.038). PS was stimulated using the Leu (+24 +/- 7%, P < 0.02) but not the Phe (+6 +/- 4%, not significant) data. We conclude that isotopes of different essential amino acid: provide comparable estimates of PD and PS in the postabsorptive state. However, their responses to an anabolic stimulus may differ, possibly depending on exogenous amino acid availability and/or the resulting plasma levels.
cAMP modulates glucocorticoid-induced protein accumulation and glucocorticoid receptor in cardiomyocytes
Authors: Sato A. , Sheppard K. E. , Fullerton M. J. , Funder J. W.
Published: December 2017

Glucocorticoids have complex effects on cardiac muscle growth in vivo, and one possible reason may the regulatory cross talk between glucocorticoids and second messengers. In this study we investigated the effect of adenosine 3',5'-cyclic monophosphate (cAMP), shown to affect cardiomyocyte growth and glucocorticoid action in several systems, on glucocorticoid-induced protein accumulation and glucocorticoid receptor (GR) in neonatal rat cardiomyocytes. Dexamethasone (DEX) decreased the protein-to-DNA ratio, and 8-bromoadenosine 3',5'-cyclic monophosphate (BrcAMP) or forskolin increased this ratio. The inhibitory effect of DEX was potentiated by an elevated cAMP, despite the stimulatory effect of cAMP alone. Nuclear GR binding was increased by BrcAMP, with no change in GR mRNA or protein levels, via increased affinity of nuclear GR. H-89 blocked the effects of BrcAMP. In conclusion, glucocorticoids have an inhibitory effect on protein accumulation in cardiomyocytes via GR, an effect potentiated by elevated cAMP via increased nuclear GR binding. These results suggest that glucocorticoid effects on cardiomyocytes may be modulated by cAMP-mediated mechanisms, which may produce the complex effects of glucocorticoids on cardiomyocyte growth in vivo.
GH and IGF-I differentially increase protein synthesis in skeletal muscle and jejunum of parenterally fed rats
Authors: Lo H. C. , Ney D. M.
Published: December 2017

Growth hormone (GH) and insulin-like growth factor I (IGF-I) selectively increase tissue mass. We compared the fractional rate of protein synthesis (Ks in skeletal muscle, jejunal mucosa and muscularis, and liver to investigate the differential effects of GH and IGF-I on tissue protein synthesis. Surgically stressed rats were maintained with hypocaloric total parenteral nutrition (TPN) and given recombinant human (rh) GH (rhGH), rhIGF-I, rhGH + rhIGF-I (800 or 800 + 800 micrograms/day, respectively), or TPN alone. After 3 days, a flooding dose of valine (800 mumol with 5.56 MBq L-[3,4-3H]valine) was administered, and rats were killed 20 min later. Body weight gain, nitrogen retention, and serum IGF-I concentrations confirmed that GH plus IGF-I additively increased anabolism. Serum insulin concentrations were significantly increased by GH and decreased by IGF-I. GH significantly increased Ks in skeletal muscle and jejunal muscularis, IGF-I significantly increased Ks in jejunal mucosa and muscularis, and neither GH nor IGF-I altered Ks in liver. GH and IGF-I differentially increase tissue protein synthesis in vivo.
Regulation of rat Na+/Pi cotransporter-1 gene expression: the roles of glucose and insulin
Authors: Li H. , Ren P. , Onwochei M. , Ruch R. J. , Xie Z.
Published: December 2017

Cytosolic inorganic phosphate (P(i)) is important for glucose metabolism. It plays a role in homeostatic regulation of glucose by insulin and glucagon. Recently, we isolated two cDNA clones for rat Na+/P(i) cotransporter-1 (rNaPi-1) and demonstrated that they are expressed primarily in the rat liver and kidney. We now report that the expression of rNaPi-1 in these tissues is regulated by fasting and streptozotocin-induced diabetes. Using rat hepatocytes in primary culture, we also demonstrate that glucose and insulin upregulate rNaPi-1 expression, whereas glucagon and elevated intracellular adenosine 3',5'-cyclic monophosphate levels downregulate its expression. Because 2-deoxyglucose exhibits no effect on rNaPi-1 gene expression, we suggest that some metabolite accumulated during glucose metabolism may be responsible for the effects of glucose and insulin on rNaPi-1 gene expression. Our data also reveal that other known Na+/P(i) cotransporter genes, NaPi-2 and Ram-1 (a receptor for amphotropic murine retrovirus), are not regulated by insulin and glucose. It is therefore proposed that various subtypes of Na+/P(i) cotransporters are differentially regulated and that each subtype may be involved in a specific cellular function, rNaPi-1 may be responsible for Pi uptake by liver and kidney for glucose metabolism, whereas NaPi-2 may play a key role in P(i) reabsorption in the kidney.