bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypothalamic monoaminergic activity in obese Zucker rats in response to acute and chronic dietary stimuli
Authors: Specter S. E. , Stern J. S. , Horwitz B. A.
Published: December 2017

Monoamine neuromodulators link diet-related signals with autonomic responses in the regulation of energy balance. In view of evidence that sympathetically mediated expenditure is blunted in genetically obese (fa/fa) Zucker rats, a central defect in neurochemical activity has been proposed. This study tested the hypothesis that genotypic differences in monoaminergic activity in the hypothalamus underlie a blunted sensitivity of fa/fa rats to acute and chronic dietary stimuli, leading to less effective modulation of energy metabolism. Homozygous lean and obese Zucker rats were fed a protein-restricted (PR, protein = 8% of total dietary energy) or control (CF, 21% protein) diet from the age of 5 wk. At 10 wk of age, postprandial oxygen consumption (thermic effect of food, TEF) and levels of brown adipose tissue (BAT) uncoupling protein were significantly elevated (P < 0.0005) in PR vs. CF lean rats. Serotonin turnover was significantly (P < 0.0014) greater in the ventromedial hypothalamus (VMH) of meal-fed lean PR (vs. CF) rats, consistent with the suggestion that VMH serotonin release stimulates sympathetic outflow and may signal a heightened drive for protein intake. Serotonergic activity, BAT uncoupling protein, and TEF were not elevated in PR obese rats in response to a test meal, supporting the view that activation of sympathetic outflow in response to diet-related stimuli in fa/fa rats is impaired.
Differential regulation of renal glomerular and preglomerular vascular angiotensin II receptors
Authors: Amiri F. , Garcia R.
Published: December 2017

The activity of the renin-angiotensin system (RAS) can be influenced by sodium intake and angiotensin II (ANG II) infusion. It has been shown that ANG II can regulate the density of its receptors. Therefore, we investigated the regulation of glomerular and preglomerular vascular ANG II receptors by changes in RAS activity. Sprague-Dawley rats were fed a low- or high-sodium diet or were infused with nonpressor or pressor doses of ANG II for 7 days. ANG II receptor characteristics were determined by radioligand binding assays with use of ANG II antagonists losartan and PD-123319. AT1 was the only receptor type found in membrane preparations from all groups. Glomerular ANG II receptor characteristics in all groups were unchanged compared with their controls, whereas vascular receptor density was significantly downregulated by sodium restriction. We conclude that glomerular and preglomerular vascular ANG II receptors are differentially regulated such that AT1 receptors in preglomerular vessels can be regulated by changes in endogenous RAS. ANG II infusion did not induce any modification of either glomerular or vascular AT1 receptors, suggesting a predominant role of the endogenous local renal RAS.
Glucose metabolism and insulin release in mouse beta HC9 cells, as model for wild-type pancreatic beta-cells
Authors: Liang Y. , Bai G. , Doliba N. , Buettger C. , Wang L. , Berner D. K. , Matschinsky F. M.
Published: December 2017

Glucose metabolism and its relationship with glucose-induced insulin release were studied in beta HC9 and beta TC3 cells to identify and characterize key factors controlling the intermediary metabolism of glucose and glucose-induced insulin release. The beta HC9 cell line, derived from pancreatic islets with beta-cell hyperplasia, is characterized by a normal concentration-dependency curve for glucose-stimulated insulin release, whereas the beta TC3 cell line, derived from pancreatic beta-cell tumors, shows a marked leftward shift of this curve. Maximum velocity and the Michaelis-Menten constant of glucose uptake in beta HC9 and beta TC3 cells were similar, even though GLUT-2 expression in these two cell lines differed. In both cell lines, the kinetic characteristics of glucose usage, glucose oxidation, and glucose-induced oxygen consumption were similar to those of glucose phosphorylation, indicating that the kinetics of glucose metabolism from the glucose phosphorylation step in the cytosol to the mitochondrial process of oxidative phosphorylation are determined by the glucose-phosphorylating enzyme, that is, by glucokinase in beta HC9 cells and by hexokinase in beta TC3 cells. Thus beta HC9 cells provide an opportunity for the quantitative analysis of glucose metabolism, the associated generation of coupling factors, and other essential beta-cell functions involved in glucose sensing and insulin secretion.
Eliminating metabolic abnormalities of portacaval shunting by restoring normal liver blood flow
Authors: Hawkins P. A. , DeJoseph M. R. , Hawkins R. A.
Published: December 2017

Portacaval shunting causes a variety of anatomic, metabolic, and physiological changes. However, it has not been determined whether, and to what degree, these changes are permanent after a sustained period of shunting. We prepared three groups of rats for study of the recovery process. One group had side-to-side shunts for 3 wk, one group had side-to-side shunts for 2 wk followed by the restoration of normal liver circulation for 1 wk, and one group (control) had sham operations. Side-to-side shunting causes liver atrophy, increased plasma ammonia, altered plasma and brain amino acid spectra, decreased plasma glucose, and increased transport of neutral amino acids across the blood-brain barrier. After restoration of the normal pattern of liver circulation by shunt repair, the liver regained its normal size within 1 day. All abnormalities associated with liver dysfunction disappeared with the exception of plasma glucose, which remained approximately 15% lower than control values.
Impact of early growth retardation on glucoregulatory control and insulin action in mature rats
Authors: Holness M. J.
Published: December 2017

Glucoregulation and insulin action were examined in adult female progeny of dams fed an 8% protein diet during gestation and lactation. Progeny were provided with standard (20% protein) diet at weaning (24 days), at which time body weight was reduced by 21%. Basal (postabsorptive) endogenous glucose production (Ra) and glucose utilization by oxidative muscles was decreased in offspring that had experienced early growth retardation. The glucose disappearance rate after intravenous glucose and the glucose infusion rate required to maintain euglycemia during insulin infusion were both increased (by 35 and 24%, respectively) by early growth retardation. Insulin secretion was unimpaired. During euglycemic-hyperinsulinemic clamp, Ra was suppressed further, and there was a twofold greater increment in the stimulation of whole body glucose clearance rate in the offspring that experienced early growth retardation. Insulin-stimulated glucose utilization by peripheral tissues was unaffected.
Fetal substrate uptake during increased ovine fetal cortisol concentration
Authors: Milley J. R.
Published: December 2017

Corticosteroid administration adversely affects fetal growth and consequently, unless metabolic rate increases (thereby increasing the need for fetal metabolic substrates), reduces fetal need for exogenous substrates. To find whether the uptake of all or only certain metabolic substrates was affected by fetal hypercortisolemia, we measured exogenous uptake of glucose, lactate, and alpha-amino nitrogen during fetal hypercortisolemia in seven late-gestation sheep fetuses. Hydrocortisone infusion increased fetal cortisol concentrations from normal to values usually associated with late gestation (4.3 +/- 0.9 vs. 72.5 +/- 5.0 ng/ml; P < 0.001). In association with increased fetal cortisol concentration, both fetal metabolic rate and the uptakes of glucose and lactate remained constant. However, the uptake of alpha-amino nitrogen-containing substances fell (39.6 +/- 3.1 vs. 28.5 +/- 3.4 mumol.kg-1.min-1; P < 0.002) as did the proportion of metabolic rate (0.45 +/- 0.04 vs. 0.32 +/- 0.04; P < 0.002) that could be supported by metabolism of these substances. The proportion of fetal metabolic rate that could be supported by complete metabolism of all substrates taken up across the placenta decreased (1.09 +/- 0.07 vs. 0.95 +/- 0.06; P < 0.02). In conclusion, hypercortisolemia alters the composition of oxidative substrates taken up by the sheep fetus and decreases total fetal substrate uptake. These changes occur within hours of exposure to increased cortisol concentration.
Effect of glutamine on leucine metabolism in humans
Authors: Hankard R. G. , Haymond M. W. , Darmaun D.
Published: December 2017

The aim of this study was to determine whether the putative protein anabolic effect of glutamine 1) is mediated by increased protein synthesis or decreased protein breakdown and 2) is specific to glutamine. Seven healthy adults were administered 5-h intravenous infusions of L-[1-14C]leucine in the postabsorptive state while receiving in a randomized order an enteral infusion of saline on one day or L-glutamine (800 mumol.kg-1.h-1, equivalent to 0.11 g N/kg) on the other day. Seven additional subjects were studied using the same protocol except they received isonitrogenous infusion of glycine. The rates of leucine appearance (RaLeu), an index of protein degradation, leucine oxidation (OxLeu), and nonoxidative leucine disposal (NOLD), an index of protein synthesis, were measured using the 14C specific activity of plasma alpha-ketoisocaproate and the excretion rate of 14CO2 in breath. During glutamine infusion, plasma glutamine concentration doubled (673 +/- 66 vs. 1,184 +/- 37 microM, P < 0.05), whereas RaLeu did not change (122 +/- 9 vs. 122 +/- 7 mumol. kg-1.h-1), OxLeu decreased (19 +/- 2 vs. 11 +/- 1 mumol.kg-1.h-1, P < 0.01), and NOLD increased (103 +/- 8 vs. 111 +/- 6 mumol. kg-1.h-1, P < 0.01). During glycine infusion, plasma glycine increased 14-fold (268 +/- 62 vs. 3,806 +/- 546 microM, P < 0.01), but, in contrast to glutamine, RaLeu (124 +/- 6 vs. 110 +/- 4 mumol. kg-1.h-1, P = 0.02), OxLeu (17 +/- 1 vs. 14 +/- 1 mumol.kg-1.h-1, P = 0.03), and NOLD (106 +/- 5 vs. 96 +/- 3 mumol.kg-1.h-1, P < 0.05) all decreased. We conclude that glutamine enteral infusion may exert its protein anabolic effect by increasing protein synthesis, whereas an isonitrogenous amount of glycine merely decreases protein turnover with only a small anabolic effect resulting from a greater decrease in proteolysis than protein synthesis.
Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide
Authors: Fattinger K. E. , Verotta D. , Porchet H. C. , Munafo A. , Le Cotonnec J. Y. , Sheiner L. B.
Published: December 2017

A pharmacodynamic analysis of the input-response relationship between the gonadotropin-releasing hormone antagonist antide and luteinizing hormone (LH) and testosterone concentrations is presented. A control compartmental model is developed using pharmacokinetic and pharmacodynamic data from experiments in which different short intravenous antide infusions were given to healthy male volunteers. Because of the control interdependence between serum LH and testosterone a separation principle similar to one we have used previously to analyze physiological pharmacokinetic data is used for model exploration: testosterone and LH are first modeled separately, conditioning on the other observed response. This reveals that the LH effect on testosterone depends on previous LH exposure and that LH depends not on current but on previous testosterone exposure, resulting in an LH overshoot after antide-induced suppression. Both submodels are combined into one global model, which in addition includes a model for testosterone circadian variation. This model describes the data well and can be used to predict responses for some nonstudied antide dosages. However, the sensitivity of predictions to model assumptions limits the range of valid extrapolation, and this, too, is illustrated.
Alterations of plasma lactate and glucose metabolism in obese children
Authors: Stunff C. L. , Bougneres P. F.
Published: December 2017

Using a double stable isotope infusion method, we quantified plasma glucose and lactate inter-relationships in five recently obese children. Compared with five age-matched controls, obese children had an approximately 50% increase of total body lactate turnover [167 +/- 20 vs. 111 +/- 20 (SE) mg/min, P < 0.05]. The rate of lactate conversion to glucose was double the normal rate (96 +/- 21 vs. 46 +/- 10 mg/min, P < 0.05). Increased gluconeogenesis from plasma lactate correlated with total glucose production (r = 0.74), with plasma lactate contributing to 58% of glucose production in obese children vs. 38% in normal children (P < 0.05). Conversion into glucose correlated with the rate of lactate release in the circulation (r = 0.76). In turn, the obese children converted a larger fraction (35 +/- 2 vs. 27 +/- 2%, P < 0.02) and amount (58 +/- 10 vs. 34 +/- 5 mg/min, P < 0.05) of glucose into plasma lactate. The amount of lactate originating from plasma glucose correlated (r = 0.70) with lipid oxidation, which was increased in the obese children (58 +/- 4 vs. 23 +/- 5 mg/min, P < 0.02). Our data suggest that increased gluconeogenesis from lactate is associated with increased lipid oxidation and could contribute to the progressive development of insulin resistance and glucose intolerance in juvenile obesity.
Energy expenditure in obstructive sleep apnea: effects of treatment with continuous positive airway pressure
Authors: Stenlof K. , Grunstein R. , Hedner J. , Sjostrom L.
Published: December 2017

We examined 24-h energy expenditure (EE) in a chamber for indirect calorimetry in five male patients with obstructive sleep apnea (OSA) and six snoring control subjects (snorers). The 24-h EE was remeasured in patients with OSA after 3-mo treatment with nasal continuous positive airway pressure (CPAP). Patients with OSA had a greater degree of severe sleep-breathing disturbance than snorers. Patients with OSA had higher 24-h EE [39.2 +/- 3.0 vs. 33.9 +/- 2.7 kcal.24 h-1.kg fat-free mass (FFM)-1, P < 0.05], daytime urinary norepinephrine and vanillylmandelic acid (VMA), and aminoterminal procollagen III peptide (PIIIp) levels, and they tended to have higher sleeping EE (32.4 +/- 4.1 vs. 26.3 +/- 1.9 kcal.24 h-1.kg FFM-1, P < 0.1) than snorers. CPAP treatment normalized sleep architecture and breathing. CPAP treatment also decreased sleep EE (from 32.4 +/- 4.1 to 27.2 +/- 1.4 kcal.24 h-1.kg FFM-1, P < 0.05) and EE variability during sleep (from 1.6 +/- 0.5 to 1.0 +/- 0.5 kcal.24 h-1.kg FFM-1, P < 0.05) and increased the basal metabolic rate-to-sleep EE ratio in all subjects. Serum PIIIp and plasma norepinephrine decreased after CPAP in all patients. We conclude that OSA is associated with an increased sleep EE, which is normalized by treatment with CPAP.
Aging alters calcium regulation of serum concentration of parathyroid hormone in healthy men
Authors: Portale A. A. , Lonergan E. T. , Tanney D. M. , Halloran B. P.
Published: December 2017

We examined the effect of aging on the relationship between the concentrations of blood ionized calcium and of serum parathyroid hormone (PTH) in 22 healthy men [9 elderly (age 74 +/- 2 yr) and 13 young (age 39 +/- 1 yr)] in whom the glomerular filtration rate was > 70 ml/min. Throughout a 24-h period, serum concentrations of PTH in the elderly men were twice those in the young men, whereas blood ionized calcium did not differ between the two groups. With intravenous infusion of calcium gluconate, the minimum PTH concentration was two- to threefold higher in the elderly men. With infusion of NaEDTA. the maximum PTH concentration was 20% higher in the elderly men. The calcium set point for PTH release was higher in the elderly than in the young men (4.71 +/- 0.04 vs. 4.54 +/- 0.03 mg/dl, respectively, P < 0.005). In these healthy men, the age-related increase in serum PTH could not be attributed to a sustained decrease in concentration of either blood ionized calcium or 1,25-hydroxyvitamin D. These findings suggest that, with aging, the relationship between calcium and PTH is altered such that at any given level of calcium, the concentration of PTH is higher.
Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats
Authors: Hellerstein M. K. , Neese R. A. , Schwarz J. M. , Turner S. , Faix D. , Wu K.
Published: December 2017

The net release of glucose from the liver, or hepatic glucose production (HGP), and apparent gluconeogenesis (GNG) are reduced by exogenous glucose. We investigated the changes in metabolic fluxes responsible. Flux through the hepatic GNG pathway was quantified by mass isotopomer distribution analysis (MIDA) from [2-13C]glycerol. Unidirectional flux across hepatic glucose-6-phosphatase (G-6-Pase), or total hepatic glucose output (THGO), and hepatic glucose cycling (HGC) were also measured by using glucuronate (GlcUA) to correct for glucose 6-phosphate (G-6-P) labeling. Infusion of glucose (15-30 mg.kg-1.min-1 iv) to 24 h-fasted rats caused two important metabolic alterations. First was a significant increase in hepatic glucose uptake and HGC: > 60% of THGO was from HGC. Second, although flux through hepatic G-6-P increased (from 15.7 to 17.7-22.7 mg.kg-1.min-1), the partitioning of G-6-P flux changed markedly [from 30-35% to 55-60% entering UDP-glucose (UDP-Glc), P < 0.01]. Total flux through the GNG pathway remained active during intravenous glucose, but increased partitioning into UDP-Glc lowered GNG flux plasma glucose by 50%. In summary, the suppression of HGP and GNG flux into glucose is not primarily due to reduced carbon flow through hepatic G-6-Pase or the hepatic GNG pathway. THGO persists, but hepatic G-6-P is derived increasingly from plasma glucose, and flow through GNG persists, but the partitioning coefficient of G-6-P into UDP-Glc doubles. These adjustments permit net HGP to fall despite increased total production of hepatic G-6-P during administration of glucose.
Effects of bis(maltolato)oxovanadium(IV) are distinct from food restriction in STZ-diabetic rats
Authors: Yuen V. G. , Orvig C. , McNeill J. H.
Published: December 2017

In association with the insulin-mimetic properties, vanadium and related compounds have been shown to normalize hyperphagia associated with diabetes mellitus. The objective of this study was to clarify the effects of an organic vanadium compound, bis(maltolato)oxovanadium(IV) (BMOV), vs. food restriction on the metabolic abnormalities that occur in diabetes. BMOV was administered daily in drinking water to streptozotocin (STZ)-diabetic rats for 6 wk. Pair-fed groups were fed based on the intake for their respective counterparts from the previous day. Plasma parameters were measured weekly after a carefully controlled 5-h fasting period. BMOV reduced plasma glucose (diabetic = 31.2 +/- 1.9, diabetic treated = 10.2 +/- 1.8, and diabetic pair fed = 34.2 +/- 1.1 mM), triglyceride, and cholesterol levels to normal without a concomitant increase in plasma insulin levels. There was no body weight gain in the diabetic pair-fed group compared with all other groups. BMOV but not pair feeding was effective in preventing the decreased cardiac function observed in STZ-diabetic rats. These data suggest that the glucose-lowering properties of BMOV are independent of the effects of dietary restriction and reinforce the efficacy of BMOV as an effective antihyperglycemic agent.
Separate and joint effects of arginine and glucose on ovine fetal insulin secretion
Authors: Gresores A. , Anderson S. , Hood D. , Zerbe G. O. , Hay W. W.
Published: December 2017

To determine separate and joint effects of increases (delta) in fetal plasma concentrations of arginine (Af) and glucose (Gf) on fetal insulin (If) secretion (delta If), 15 late-gestation fetal sheep were given 5-min arginine bolus infusions (40, 86, 144, 201, and 402 mumol/kg estimated fetal wt) at 90 min of 120 min steady-state glucose clamps (basal Gf, basal + 0.6 mM Gf, and basal + 1.1 mM Gr), producing absolute and percent increases above basal Af of 25.8 +/- 1.3 microM (+33%), 50.9 +/- 6.3 microM (+66%), 83.8 +/- 7.1 microM (+108%), 122.1 +/- 9.4 microM (+156%), and 302.2 +/- 28.2 microM (+386%), respectively. Acute hyperglycemia alone produced an increase above basal If of 9 +/- I microU/ml (+80%) and 19 +/- 2 microU/ml (+170%) after basal + 0.6 mM Gf and basal + 1.1 mM Gf, respectively. Increasing values of delta Af showed separate but lesser effects on delta If, which were significant only at very high values of Af (> 100% above mean normal Af) unless marked hyperglycemia (1.5- to 2-fold normal) was also present, demonstrating joint effects of delta Af and delta Gf on delta If according to a best-fit inverse polynomial response surface. We conclude that physiological increases in Af at normal glucose concentrations are not a potent-stimulus to insulin secretion in fetal sheep.
Persistent glucose production and greater peripheral sensitivity to insulin in the neonate vs. the adult
Authors: Farrag H. M. , Nawrath L. M. , Healey J. E. , Dorcus E. J. , Rapoza R. E. , Oh W. , Cowett R. M.
Published: December 2017

Insulin resistance has been reported to partially explain the clinical appearance of neonatal hyperglycemia. To determine the relative resistance to insulin of glucose production vs. glucose utilization, the euglycemic hyperinsulinemic clamp technique was employed for the first time in the human neonate and was combined with stable isotopic determination of glucose production and glucose utilization. The basal rates of glucose production and glucose utilization were determined, after which each neonate was clamped at his or her own euglycemic glucose concentration while receiving regular human insulin at one rate of 0.2, 0.5, 1.0, 2.0, or 4.0 mU. kg-1.min-1. Persistent glucose production (> or = 1 mg.kg-1.min-1) during the clamp was recorded for all groups. A significant increase in the glucose infusion rate (P < 0.001) and in percent glucose utilization (P < 0.01) occurred in the 2.0 and 4.0 mU.kg-1.min-1 insulin groups. Metabolic clearance rate of insulin was significantly greater in the neonate compared with the adult at the 2.0 mU.kg-1.min-1 insulin infusion rate (P = 0.036). Our results indicate that, in contrast to the adult, the neonate has persistent glucose production (P = 0.001) and greater peripheral sensitivity to insulin (P = 0.015).
Site selectivity of osteoblast gene expression response to thyroid hormone localized by in situ hybridization
Authors: Suwanwalaikorn S. , Van Auken M. , Kang M. I. , Alex S. , Braverman L. E. , Baran D. T.
Published: December 2017

We have previously reported that thyroid-stimulating hormone (TSH)-suppressive doses of L-thyroxine (L-T4) decrease femoral, but not vertebral, bone mineral density (BMD) in rats. L-T4-induced decreases in BMD were associated with increased expression of genes, reflecting osteoblast activity in mRNA extracted from whole femurs but not from vertebrae. To document that this skeletal selectivity reflected altered osteoblast activity, we studied gene expression by in situ hybridization in 8-wk-old rats treated with L-T4 (20 microg x 100 g body wt(-1) x day(-1)) for 4 wk. TSH-suppressive doses of L-T4 were associated with decreased femoral (0.299 +/- 0.005 vs. 0.273 +/- 0.005 g/cm2, P < 0.01), but not vertebral (0.222 +/- 0.004 vs. 0.218 +/- 0.003 g/cm2), BMD. In situ hybridization documented that L-T4 administration for 4 wk increased expression of osteocalcin and alkaline phosphatase mRNA in femoral, but not vertebral, osteoblasts. This study demonstrates a differential gene expression response of vertebral and femoral osteoblasts to L-T4. This altered degree of gene expression markers of osteoblast activity documented by in situ hybridization may in part explain the apparent clinical differences in the effect of L-T4 on femoral and vertebral BMD.
C-peptide does not alter carbohydrate metabolism in isolated mouse muscle
Authors: Shashkin P. N. , Jiao Y. , Westerblad H. , Katz A.
Published: December 2017

The effects of C-peptide on carbohydrate metabolism in isolated mouse soleus muscle were studied. C-peptide, at concentrations up to 1,000 nM, had no effect on [14C]glucose incorporation into glycogen, glycogen synthase activity, or 2-deoxyglucose uptake. These data demonstrate that C-peptide has no direct effect on the measured parameters of carbohydrate metabolism in isolated mouse muscle.
Glucoregulation during progressive starvation in late pregnancy in the rat
Authors: Holness M. J. , Sugden M. C.
Published: December 2017

The response of glucose utilization (transport and phosphorylation) by individual skeletal muscles to progressive starvation in late pregnancy in the rat was investigated in relation to changes in whole body glucose turnover. Compared with insulin-stimulated values, the decline in muscle glucose utilization evoked by short-term (6-h) starvation was about twofold greater in pregnancy. Suppression of glucose utilization by slow-twitch muscles was observed as the starvation period was extended from 6 to 24 h only in unmated rats. Extending starvation to 24 h did not further reduce glucose utilization by fast-twitch skeletal muscles in either group. Suppression of whole body glucose disposal was observed between 6 and 24 h of starvation in unmated, but not pregnant, rats. The results demonstrate that metabolic adaptation of almost complete suppression of glucose utilization by slow-twitch muscle, normally elicited only by prolonged (24-h) starvation, is already established after acute (6-h) starvation in late pregnancy. The present study supports the concept of "accelerated starvation" in late pregnancy with respect to muscle glucose utilization after short-term food withdrawal but demonstrates that further glucose conservation cannot be achieved after more prolonged starvation.
Amino acids suppress proteolysis independent of insulin throughout the neonatal period
Authors: Poindexter B. B. , Karn C. A. , Ahlrichs J. A. , Wang J. , Leitch C. A. , Liechty E. A. , Denne S. C.
Published: December 2017

To determine how increased amino acid availability alters rates of whole body proteolysis and the irreversible catabolism of the essential amino acids leucine and phenylalanine throughout the neonatal period, leucine and phenylalanine kinetics were measured under basal conditions and in response to intravenous amino acids in two separate groups of healthy, full-term newborns (at 3 days and 3 wk of age). The endogenous rates of appearance of leucine and phenylalanine (reflecting proteolysis) were suppressed equally in both groups and in a dose-dependent fashion (by approximately 10% with 1.2 g x kg(-1) x day(-1) and by approximately 20% with 2.4 g x kg(-1) x day(-1)) in response to intravenous amino acid delivery. Insulin concentrations remained unchanged from basal values during amino acid administration. The irreversible catabolism of leucine and phenylalanine increased in a stepwise fashion in response to intravenous amino acids; again, no differences were observed between the two groups. This study clearly demonstrates that the capacity to acutely increase rates of leucine oxidation and phenylalanine hydroxylation is fully present early in the neonatal period in normal newborns. Furthermore, these data suggest that amino acid availability is a primary regulator of proteolysis in normal newborns throughout the neonatal period.
Insulin receptor mRNA splicing and altered metabolic control in aged and mildly insulin-deficient rats
Authors: Wiersma M. M. , Auboeuf D. , Nieuwenhuizen-Bakker I. M. , Radder J. K. , Riou J. P. , Vidal H.
Published: December 2017

Using reverse transcription-competitive polymerase chain reaction, we measured the abundance of the mRNAs encoding the two spliced isoforms of insulin receptor in aged and mildly insulin-deficient rats. Twelve-month-old rats were characterized by peripheral insulin resistance and decreased glucose tolerance. Mild insulin deficiency, obtained by neonatal streptozotocin treatment, was associated with glucose intolerance due to reduced glucose-stimulated insulin response. Both models were associated with a decrease in the relative abundance of the mRNA with exon 11 in liver, heart, adipose tissue, and tibialis muscle, whereas a slight increase was seen in the extensor digitorum longus and no change in the soleus muscle. In the three muscles, the expression of the form without exon 11 largely predominated (>90%). In heart and adipose tissue, the two isoforms were expressed at a similar level in control rats. In both tissues, the form without exon 11 increased in streptozotocin-treated rats, whereas the absolute level of the form with exon 11 decreased in old rats. Although a decreased level of the variant with exon 11 correlated with insulin resistance of whole body glucose uptake, our results indicated that changes in the expression of the insulin receptor variants were secondary events and thus not the cause of the insulin resistance in old and mildly insulin-deficient rats.
Role of glycogen concentration and epinephrine on glucose uptake in rat epitrochlearis muscle
Authors: Jensen J. , Aslesen R. , Ivy J. L. , Brors O.
Published: December 2017

The effects of diet-manipulated variations in muscle glycogen concentration and epinephrine on glucose uptake were studied in epitrochlearis muscles from Wistar rats. Both basal and insulin-stimulated glucose uptake [measured with a tracer amount of 2-[1,2-3H(N)]deoxy-D-glucose] inversely correlated with initial glycogen concentration (glycogen concentration vs. basal glucose uptake: Spearman's rho = -0.76, n = 84, P < 0.000001; glycogen concentration vs. insulin-stimulated glucose uptake: Spearman's rho = -0.67, n = 44, P < 0.00001). Two fasting-refeeding procedures were used that resulted in differences in muscle glycogen concentrations, although with similar treatment for the last 48 h before the experiment. In the rats with the lower glycogen concentration, basal as well as insulin-stimulated glucose uptake was elevated. The muscle glycogen concentration had no effect on epinephrine-stimulated glycogenolysis. Epinephrine, however, was found to reduce basal glucose uptake in all groups. These results suggest that 1) the glycogen concentration participates in the regulation of both basal and insulin-stimulated glucose uptake in skeletal muscle, 2) the magnitude of epinephrine-stimulated glycogen breakdown is independent of the glycogen concentration, and 3) epinephrine inhibits basal glucose uptake at all glycogen concentrations.
Measurement and modeling of glucose-6-phosphatase in pancreatic islets
Authors: Sweet I. R. , Najafi H. , Li G. , Grodberg J. , Matschinsky F. M.
Published: December 2017

In the beta-cells of the pancreas, glucose phosphorylation carried out by glucokinase is the rate-controlling step in glycolysis, and the kinetic characteristics of glucokinase govern to a high degree the dose-response relationship between glucose and insulin release. Because glucose-6-phosphatase (G-6-Pase) opposes the action of glucokinase, it may have a regulatory role in the release of insulin in response to glucose if the enzyme is present in the beta-cells. A number of researchers have reported finding high levels of G-6-Pase in islets, but quantitation of its activity remains controversial, mainly because of difficulties in solubilizing a particulate enzyme. Therefore a method developed to measure functional glucose phosphorylation activity in intact brain was applied (Chi, M. M.-Y., M. E. Pusateri, J. G. Carter, B. J. Norris, D. B. McDougal, Jr., and O. H. Lowry. Anal. Biochem. 161: 508-513, 1987), and the rates of accumulation and disappearance of 2-deoxyglucose 6-phosphate (DG-6-P) in freshly harvested islets were determined as a measure of glucose cycling. Islets were incubated in the presence of 30 mM 2-deoxyglucose (DG) for 60 min, and subsequently the incubation medium was replaced with medium containing no DG, but instead high levels of mannoheptulose as a blocker of phosphorylation. The content of DG-6-P in the islets was measured at strategic times during the protocol. As predicted by a mathematical model, DG-6-P accumulated in the presence of DG and decayed after its washout. Both of these results are consistent with islets containing dephosphorylation activity for this substrate. The kinetic curves were fit using a mathematical model, and the maximal G-6-Pase activity was estimated to be 0.13 +/- 0.005 micromol x g(-1) x min(-1). However, when the physiological effect of this amount of G-6-Pase activity was assessed by use of a model of glycolysis, it was found that the impact on glucose cycling and usage was insignificant. It was concluded that normal islets do contain measurable activity for dephosphorylating glucose 6-phosphate but that this enzymatic reaction does not play a role in glucose metabolism and sensing by the normal beta-cell.
Chronic insulin hypoglycemia induces GLUT-3 protein in rat brain neurons
Authors: Uehara Y. , Nipper V. , McCall A. L.
Published: December 2017

Near-normalization of glycemia reduces the risks of chronic diabetic complications but increases the risk of serious hypoglycemia. Hypoglycemia can impair neuronal function in the brain and diminish awareness of subsequent hypoglycemic episodes, yet little is known about how neurons adapt to hypoglycemia. This study tests the hypothesis that isoform-specific alterations in brain glucose transport proteins occur in response to chronic hypoglycemia. To study this, groups of rats were injected with approximately 25 U/kg ultralente insulin daily at 1700 for 8 days to maintain hypoglycemia. Vascular-free and microvessel membrane fractions from brain were prepared for immunoblot analysis of GLUT-1 and GLUT-3 by use of isoform-specific antisera. Insulin treatment reduced blood glucose levels from 4.0 +/- 0.1 (vehicle-injected controls) to 1.7 +/- 0.1 mmol/l on day 8 (P < 0.001) and increased GLUT-3 protein expression (175.6% of control; P < 0.05). Microvascular GLUT-1 (55 kDa) tended to increase (195.6% of controls; P = 0.08) variably, whereas nonvascular GLUT-1 (45 kDa) was unchanged. We conclude that neuronal glucose transport protein (GLUT-3) expression adapts to chronic hypoglycemia. This adaptation may spare neuronal energy metabolism but could dampen neuronal signaling of glucose deprivation.
Impaired phosphoinositide metabolism in glucose-incompetent islets of neonatally streptozotocin-diabetic rats
Authors: Morin L. , Giroix M. H. , Gangnerau M. N. , Bailbe D. , Portha B.
Published: December 2017

The effects of nutrient and neurotransmitter stimuli on insulin release, loss of phosphoinositides (PI), and production of inositol phosphates (InsP) were investigated in islets from neonatally streptozotocin-injected (nSTZ) rats. In islets from nSTZ rats, insulin secretory responses to 16.7 mM D-glucose and 10.0 mM D-glyceraldehyde were reduced compared with controls. Contents in phosphatidylinositol 4-monophosphate [PtdIns(4)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], but not in phosphatidylinositol, were diminished. Glucose effects on breakdown of PtdIns(4)P and PtdIns(4,5)P2 and on total InsP accumulation were both reduced. D-Glucose was unable to increase the levels of both inositol trisphosphate isomers, Ins(1,3,4)P3 and Ins(1,4,5)P3. Glyceraldehyde also failed to promote InsP formation. By contrast, the ability of 1.0 mM carbachol or 300 nM cholecystokinin to stimulate insulin secretion and InsP generation was still observed. Thus a disturbed coupling between nutrient recognition and activation of phospholipase C, possibly together with a shortage of available polyphosphoinositides, could be responsible for the altered islet PI turnover in the nSTZ rats. It is proposed that such defects may contribute to the impairment of glucose-stimulated insulin secretion in this model of non-insulin-dependent diabetes mellitus.
Regulation of plasma fatty acid oxidation during low- and high-intensity exercise
Authors: Sidossis L. S. , Gastaldelli A. , Klein S. , Wolfe R. R.
Published: December 2017

In the present study we examined the hypothesis that fatty acid oxidation is less during high-intensity exercise than during moderate-intensity exercise because of inhibition of long-chain fatty acid entry into the mitochondria. Six volunteers exercised at 40% peak oxygen consumption (VO2peak) for 60 min and at 80% VO2peak for 30 min on two different occasions. [1-13C]oleate, a long-chain fatty acid, and [1-14C]octanoate, a medium-chain fatty acid, were infused for the duration of the studies. Lipids and heparin were infused during exercise at 80% VO2peak to prevent the expected decrease in plasma free fatty acid (FFA) concentration. Plasma oleate and total FFA availability were similar in the two experiments. Oleate oxidation decreased from 2.8 +/- 0.6 (40% VO2peak) to 1.8 +/- 0.2 mumol.kg-1.min-1 (80% VO2peak, P < 0.05), whereas octanoate oxidation increased from 1.0e-05 +/- 1.0e-06 (40% VO2peak) to 1.3e-05 +/- 5.1e-06 mumol.kg-1.min-1 (80% VO2peak, P < 0.05). Furthermore, the percentage of oleate uptake oxidized decreased from 67.7 +/- 2.8% (40% VO2peak) to 51.8 +/- 4.6% (80% VO2peak, P < 0.05), whereas the percentage of octanoate oxidized was similar during exercise at 40 and 80% VO2peak (84.8 +/- 2.7 vs. 89.3 +/- 2.7%, respectively). Our data suggest that, in addition to suboptimal FFA availability, fatty acid oxidation is likely limited during high-intensity exercise because of direct inhibition of long-chain fatty acid entry into mitochondria.
Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats
Authors: Gerhart D. Z. , Enerson B. E. , Zhdankina O. Y. , Leino R. L. , Drewes L. R.
Published: December 2017

A polyclonal affinity-purified antibody to the carboxyl-terminal end of the rat monocarboxylate transporter 1 (MCT1) was generated in chickens and used in immunocytochemical studies of brain tissue sections from adult and suckling rats. The antibody identified a 48-kDa band on immunoblots and stained tissue sections of heart, cecum, kidney, and skeletal muscle, consistent with the reported molecular mass and cellular expression for this transporter. In tissue sections from adult brains, the antibody labeled brain microvessel endothelial cells, ependymocytes, glial-limiting membranes, and neuropil. In brain sections from 3- to 14-day-old rats, microvessels were much more strongly labeled and neuropil was weakly labeled compared with sections from adults. Immunoelectron microscopy indicated that labeling was present on both luminal and abluminal endothelial cell plasma membranes. These results suggest that MCT1 may play an important role in the passage of lactate and other monocarboxylates across the blood-brain barrier and that suckling rats may be especially dependent on this transporter to supply energy substrates to the brain.
Physiological changes in circulating glucagon alter hepatic glucose disposition during portal glucose delivery.
Authors: Holste L C , Connolly C C , Moore M C , Neal D W , Cherrington A D
Published: December 2017

This study examined whether physiological changes in glucagon alter net hepatic glucose uptake (NHGU) or glycogen synthesis under conditions of hyperglycemia, hyperinsulinemia, and portal vein glucose concentrations exceeding those in the arterial circulation. Somatostatin was infused into 42-h-fasted dogs, insulin and glucagon were replaced intraportally at basal rates, and peripheral infusion of glucose maintained the hepatic glucose load twofold basal for 90 min (period 1). In period 2 (240 min) the insulin infusion was increased fourfold, glucose was infused intraportally, the hepatic glucose load was twofold basal, and glucagon was infused to create levels 150% basal (HiGGN, n = 6) or 40% basal (LoGGN, n = 6). NHGU rates (mg.kg-1.min-1) were low during period 1 (-0.9 +/- 0.7 in LoGGN and -0.2 +/- 0.4 in HiGGN, not significant) but increased during period 2 (-4.1 +/- 0.6 in LoGGN and -1.9 +/- 0.2 in HiGGN, P < 0.05). Endogenous glucose production (Endo Ra) declined during period 2 in LoGGN (P < 0.01 vs. basal) but did not change in HiGGN. Tracer-determined hepatic glucose uptake did not differ between groups. The poststudy increment in liver glycogen synthase I (12.5 +/- 3 vs. 6.5 +/- 2% of total) was greater in LoGGN (P < 0.05), as was net glycogen synthesis (27 +/- 8 vs. 13 +/- 3 mg/g liver, P = 0.06). An elevation in glucagon reduced NHGU (because of failure to suppress Endo Ra) and glycogen synthase activation and tended to reduce glycogen deposition.
More marked stimulation by lithium than insulin of the glycogenic pathway in rat skeletal muscle.
Authors: Fürnsinn C , Noe C , Herdlicka R , Roden M , Nowotny P , Leighton B , Waldhäusl W
Published: December 2017

Lithium's impact on glucose metabolism was compared with that of insulin in isolated rat soleus muscle. Lithium chloride (20 mmol/l) induced a 4.8-fold more pronounced increment over basal glycogen synthase activity than insulin (10 nmol/l) (nmol UDP-glucose into glycogen in synthase activity assay.g-1.min-1: lithium, +22.1 +/- 1.8 vs. insulin, +4.6 +/- 3.9; P < 0.01). In parallel, lithium was less efficient than insulin in stimulating glucose transport (counts per minute 2-deoxy-D-[3H]glucose.mg-1.h-1: lithium, +211 +/- 19 vs. insulin, +311 +/- 57; P < 0.05) and lactate release (mumol.g-1.h-1: lithium, +1.0 +/- 0.5 vs. insulin, +3.9 +/- 0.5; P < 0.01), and similar increments were induced in glycogen synthesis (mumol glucose into glycogen.g-1.h-1: lithium, +3.32 +/- 0.43 vs. insulin, +3.46 +/- 0.47; not significant). Full additivity of glycogenic effects and divergent dependency on phosphatidylinositol 3-kinase activation provided further evidence for different mechanisms of action. In muscle from insulin-resistant obese Zucker rats (fa/fa), failure of lithium to reverse deficits in glucose metabolism suggested a primary deficit in muscle glucose uptake rather than glycogen synthesis. Hence lithium distinctly stimulates glycogen synthase activity in skeletal muscle and may therefore be regarded as a candidate for the treatment of disorders associated with primary deficits in the glycogenic pathway.
Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle.
Authors: Meyer C , Nadkarni V , Stumvoll M , Gerich J
Published: December 2017

To determine the relationship between free fatty acids (FFA) and glucose uptake by the human kidney, 12 postabsorptive normal volunteers underwent renal vein catheterization and were infused to isotopic steady state with [6-3H]glucose and [9,10-3H]palmitate. Arterial and renal vein palmitate specific activities were not significantly different (3,533 +/- 219 vs. 3,549 +/- 220 dpm/mumol, P = 0.64). Palmitate renal fractional extraction and uptake determined isotopically (7.2 +/- 1.1% and 9.1 +/- 1.4 mumol/min) were not significantly different from those calculated by net balance measurements (8.3 +/- 1.2% and 9.7 +/- 1.2 mumol/min, P > 0.07 and P > 0.7, respectively). Renal palmitate uptake accounted for 8.7 +/- 1.3% of its systemic turnover. Renal linoleate and oleate fractional extraction calculated by net balance measurements (8.0 +/- 0.9 and 7.7 +/- 1.2%, respectively) were not significantly different from each other and that of palmitate (all P > 0.7). Renal uptake of palmitate, linoleate (7.9 +/- 1.0 mumol/min), and oleate (10.9 +/- 2.0 mumol/min) were all directly proportional to their arterial concentrations (r = 0.70, 0.68, and 0.63, respectively, all P < 0.025). Renal glucose uptake (93 +/- 10 mumol/min) accounted for 12.6 +/- 1.5% of its systemic turnover and was inversely related to the sum of palmitate, linoleate, and oleate uptake (r = -0.74, P < 0.01). These data indicate that in postabsorptive humans: 1) the kidney is an important site of FFA and glucose disposal, 2) a renal glucose-fatty acid cycle may exist, and 3) there appears to be little or no release into the circulation of stored renal FFA.
[Pro11,d-Ala12]angiotensin I has rapid onset vasoconstrictor activity in the cat
Authors: Garrison Etoi A. , Champion Hunter C. , Kadowitz Philip J.
Published: December 2017

Responses to the synthetic substrate [Pro11,d-Ala12]angiotensin I were investigated in the hindlimb vascular bed of the cat, a system in which local angiotensin-converting enzyme activity is high. Under constant-flow conditions, injections of [Pro11,d-Ala12]angiotensin I into the perfusion circuit in doses of 1–300 μg caused dose-related increases in perfusion pressure that were rapid in onset and that were not changed by the presence of a time-delay coil in the perfusion circuit upstream from the site of peptide injection. The synthetic substrate was ∼100-fold less potent than angiotensin I and II, and responses to [Pro11,d-Ala12]angiotensin I were not altered by captopril in a dose that inhibited pressor responses to angiotensin I but did not alter responses to angiotensin II. Responses to [Pro11,d-Ala12]angiotensin I, angiotensin I, and angiotensin II were inhibited by DUP-532 and candesartan but were not altered by the angiotensin AT2receptor antagonist PD-123319. The present data show that [Pro11,d-Ala12]angiotensin I has significant vasoconstrictor activity in the hindlimb vascular bed of the cat and suggest that responses are mediated by the activation of AT1receptors and that activation of AT2receptors is not involved. The present data show that the onset of responses to [Pro11,d-Ala12]angiotensin I and angiotensin II are similar and are not dependent on the action of the angiotensin-converting enzyme. The present data suggest that conversion of the synthetic substrate to an active peptide occurs rapidly within the hindlimb vascular bed or that the peptide may have direct AT1receptor-stimulating activity.
Insulinotropic action of α-d-glucose pentaacetate: functional aspects
Authors: Malaisse Willy J. , Sánchez-Soto Carmen , Larrieta M. Elena , Hiriart Marcia , Jijakli Hassan , Viñambres Concepción , Villanueva-Peñacarrillo María L. , Valverde Isabel , Kirk Ole , Kadiata Marcel M. , Sener Abdullah
Published: December 2017

The functional determinants of the insulinotropic action of α-d-glucose pentaacetate were investigated in rat pancreatic islets. The ester mimicked the effect of nutrient secretagogues by recruiting individual B cells into an active secretory state, stimulating proinsulin biosynthesis, inhibiting86Rb outflow, and augmenting45Ca efflux from prelabeled islets. The secretory response to the ester was suppressed in the absence of Ca2+ and potentiated by theophylline or cytochalasin B. The generation of acetate from the ester apparently played a small role in its insulinotropic action. Thus acetate, methyl acetate, ethyl acetate, α-d-galactose pentaacetate, and β-d-galactose pentaacetate all failed to stimulate insulin release. The secretory response to α-d-glucose pentaacetate was reproduced by β-d-glucose pentaacetate and, to a lesser extent, by β-l-glucose pentaacetate. It differed from that evoked by unesterifiedd-glucose by its resistance to 3- O-methyl-d-glucose,d-mannoheptulose, and 2-deoxy-d-glucose. It is concluded that the insulinotropic action of α-d-glucose pentaacetate, although linked to the generation of the hexose from its ester, entails a coupling mechanism that is not identical to that currently implied in the process of glucose-induced insulin release.