bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of epinephrine on muscle glycogenolysis and insulin-stimulated muscle glycogen synthesis in humans
Authors: Laurent Didier , Petersen Kitt Falk , Russell Raymond R. , Cline Gary W. , Shulman Gerald I.
Published: December 2017

To examine the effects of a physiological increase in plasma epinephrine concentration (∼800 pg/ml) on muscle glycogenolysis and insulin-stimulated glycogenesis, we infused epinephrine [1.2 μg ⋅ (m2body surface)−1⋅ min−1] for 2 h and monitored muscle glycogen and glucose 6-phosphate (G-6- P) concentrations with13C/31P nuclear magnetic resonance (NMR) spectroscopy. Epinephrine caused an increase in plasma glucose (Δ ∼50 mg/dl), lactate (Δ ∼1.4 mM), free fatty acids (Δ ∼1,200 μM at peak), and whole body glucose oxidation (Δ ∼0.85 mg ⋅ kg−1⋅ min−1) compared with levels in a group of control subjects ( n = 4) in the presence of slight hyperinsulinemia (∼13 μU/ml, n = 8) or basal insulin (∼7 μU/ml, n = 7). However, epinephrine did not induce any detectable changes in glycogen or G-6- P concentrations, whereas muscle inorganic phosphate (Pi) decreased by 35%. Epinephrine infusion during a euglycemic-hyperinsulinemic clamp ( n = 8) caused a 45% decrease in the glucose infusion rate that could be mostly attributed to a 73% decrease in muscle glycogen synthesis rate. After an initial increase to ∼160% of basal values, G-6- Plevels decreased by ∼30% with initiation of the epinephrine infusion. We conclude that a physiological increase in plasma epinephrine concentration 1) has a negligible effect on muscle glycogenolysis at rest, 2) decreases muscle Pi, which may maintain phosphorylase activity at a low level, and 3) causes a major impairment in insulin-stimulated muscle glycogen synthesis, possibly due to inhibition of glucose transport-phosphorylation activity.
Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis
Authors: Chu Chang An , Sindelar Dana K. , Neal Doss W. , Allen Eric J. , Donahue E. Patrick , Cherrington Alan D.
Published: December 2017

To determine the effect of a selective rise in liver sinusoidal norepinephrine (NE) on hepatic glucose production (HGP), norepinephrine (50 ng ⋅ kg−1⋅ min−1) was infused intraportally (Po-NE) for 3 h into five 18-h-fasted conscious dogs with a pancreatic clamp. In the control protocol, NE (0.2 ng ⋅ kg−1⋅ min−1) and glucose were infused peripherally to match the arterial NE and blood glucose levels in the Po-NE group. Hepatic sinusoidal NE levels rose ∼30-fold in the Po-NE group but did not change in the control group. The arterial NE levels did not change significantly in either group. During the portal NE infusion, HGP increased from 1.9 ± 0.2 to 3.5 ± 0.4 mg ⋅ kg−1⋅ min−1(15 min; P < 0.05) and then gradually fell to 2.4 ± 0.4 mg ⋅ kg−1⋅ min−1by 3 h. HGP in the control group did not change (2.0 ± 0.2 to 2.0 ± 0.2 mg ⋅ kg−1⋅ min−1) for 15 min but then gradually fell to 1.1 ± 0.2 mg ⋅ kg−1⋅ min−1by the end of the study. Because the fall in HGP from 15 min on was parallel in the two groups, the effect of NE on HGP (the difference between HGP in the two groups) did not decline over time. Gluconeogenesis did not change significantly in either group. In conclusion, elevation in hepatic sinusoidal NE significantly increases HGP by selectively stimulating glycogenolysis. Compared with the previously determined effects of epinephrine or glucagon on HGP, the effect of NE is, on a molar basis, less potent but nore sustained over time.
Exogenous growth hormone stimulates somatotropic axis function and growth in neonatal pigs
Authors: Wester Timothy J. , Davis Teresa A. , Fiorotto Marta L. , Burrin Douglas G.
Published: December 2017

We studied the effects of exogenous porcine growth hormone (pGH) administration on circulating insulin-like growth factor I (IGF-I) concentration, IGF-binding proteins (IGFBP), tissue growth, and protein synthesis in neonatal pigs. One-day-old pigs were given daily intramuscular injections of either pGH (1 mg/kg body wt) ( n = 6) or saline ( n = 5) for 7 days, after which time we measured in vivo protein synthesis using a bolus of [3H]-phenylalanine. Mean plasma pGH concentration in pGH-treated pigs measured on day 7was 22-fold higher than in controls. The plasma IGF-I concentration in pGH-treated pigs was significantly greater than in controls after 1 day of treatment and plateaued at 285% of control values after 4 days. After 7 days of treatment, plasma IGFBP-3 concentrations and the plasma glucose response to a meal were also greater in pGH-treated than control pigs. pGH treatment significantly increased body weight gain and food conversion efficiency and the protein synthesis rate in several visceral organs. Our results demonstrate that exogenous pGH increases circulating IGF-I and IGFBP-3 concentrations and visceral organ growth in neonatal pigs, suggesting that the somatotrophic axis is functional in the neonate.
Total daily energy expenditure in free-living older African-Americans and Caucasians
Authors: Carpenter William H. , Fonong Tekum , Toth Michael J. , Ades Philip A. , Calles-Escandon Jorge , Walston Jeremy D. , Poehlman Eric T.
Published: December 2017

Low rates of daily energy expenditure, increased energy intake, or a combination of both contribute to obesity in African-Americans. We examined whether African-Americans have lower rates of free-living daily energy expenditure than Caucasians. One hundred sixty-four (>55 yr) volunteers (37 African-American women, 52 Caucasian women, 28 African-American men, and 47 Caucasian men) were characterized for total daily energy expenditure, resting metabolic rate, and physical activity energy expenditure from the doubly labeled water method and indirect calorimetry. Absolute total daily energy expenditure was lower in women than men but was not different between African-Americans and Caucasians. However, we found race and gender differences in total daily energy expenditure after controlling for differences in fat-free mass. Total daily energy expenditure was 10% lower ( P < 0.01) in African-Americans compared with Caucasians due to a 5% lower resting metabolic rate ( P < 0.01) and 19% lower physical activity energy expenditure ( P = 0.08). Moreover, total daily energy expenditure was 16% lower ( P < 0.01) in women compared with men due to a 6% lower resting metabolic rate ( P = 0.09) and a 37% lower physical activity energy expenditure ( P = 0.06). Low rates of energy expenditure may be a predisposing factor for obesity, particularly in African-American women.
Metabolic-cytokine responses to a second immunological challenge with LPS in mice withT. gondiiinfection
Authors: Arsenijevic D. , Girardier L. , Seydoux J. , Pechere J. C. , Garcia I. , Lucas R. , Chang H. R. , Dulloo A. G.
Published: December 2017

Injection of 10 cysts of Toxoplasma gondii (Me49 strain) into Swiss Webster mice results in 1) an acute phase of infection lasting for 2–3 wk, characterized by weight loss, and 2) a chronic phase in which surviving mice show either partial weight recovery (Gainers) or persistent, although stable, cachexia (Nongainers). In response to a second immunological stimulation with lipopolysaccharide (LPS) in the chronic phase of the infection, it is shown that 1) the increase in energy expenditure was more prolonged in both groups of infected mice than in controls, 2) the intensity and duration of hypophagia were also differently affected with Nongainers > Gainers > controls, and 3) the infected mice had higher serum levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-10 and a lower ratio of IL-10 to TNF-α than controls. In contrast, serum IL-4 increased to the same level in all three groups. Evaluation of the permeability of the blood-brain barrier by intravenous injection of Evans blue revealed a marked staining in the brain of only the infected Nongainers. Taken together, these results indicate that, in mice with chronic toxoplasmosis, a second nonspecific challenge (with LPS) exacerbates the hypophagic and hypermetabolic states, the latter being associated with hyperresponsiveness in TNF-α and IL-10 production. Furthermore, the greater exacerbation of the hypophagic state in mice showing persistent cachexia may be due to a preexisting higher permeability of the blood-brain barrier, which would allow a greater access of plasma-borne cytokines and/or other neuroimmunologically active substances to the central nervous system.
Circulatory model in metabolic studies of rapidly renewed hormones: application to ANP kinetics
Authors: Pilo A. , Iervasi G. , Clerico A. , Vitek F. , Berti S. , Palmieri C. , Biagini A. , Donato L.
Published: December 2017

In an attempt to identify and quantify the sites of atrial natriuretic peptide (ANP) degradation, a new tracer experiment has been developed.125I-ANP was injected as a bolus just upstream from the right atrium, and blood was sampled from two different sites (pulmonary artery and aorta) in eight cardiac patients. Data were analyzed using a physiologically based circulatory model consisting of three blocks in series (right heart, lungs and left heart, and periphery) supplied by the same flow (cardiac output, measured by thermodilution); the extraction coefficients of the three blocks and of the whole body could be determined from the areas under tracer concentration curves in plasma (AUCs). The values for AUCs (means ± SD) were 64.8 ± 9.4 and 65.5 ± 10.7% dose ⋅ l−1⋅ min−1for pulmonary artery and aorta curves, respectively; the area under the pulmonary artery curve could be subdivided into the area under the first-pass curve (30.6 ± 4.7% dose ⋅ l−1⋅ min−1) and the area under the recirculating curve (34.0 ± 7.7% dose ⋅ l−1⋅ min−1). The metabolic clearance rate of125I-ANP, computed as dose divided by the area under the recirculating curve, was 3.1 ± 0.7 l/min, and the whole body extraction was 47.6 ± 6.6%. In our patients with myocardial dysfunction, neither right heart block nor lungs and left heart block significantly extracted ANP, and periphery block accounted for almost all removal of the hormone from the blood.
Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates phosphorylation of the IGFBP-5 receptor
Authors: Andress Dennis L.
Published: December 2017

The finding that insulin-like growth factor (IGF)-binding protein-5 (IGFBP-5) binding to mouse osteoblasts was capable of being downregulated by IGFBP-5 suggested that the 420-kDa membrane protein, which interacted with IGFBP-5, may be a signaling receptor (Andress, D. L. J. Biol. Chem. 270: 28289–28296, 1995). In the current study, a carboxy-terminal IGFBP-5 peptide, IGFBP-5-(201—218), which was found to competitively inhibit125I-IGFBP-5 binding and to specifically bind to osteoblast monolayers, was used to affinity-purify the 420-kDa membrane protein. Coincubation of the affinity-purified membrane protein with [32P]ATP resulted in autophosphorylation at serine residues. Serine phosphorylation of the 420-kDa protein was enhanced by intact IGFBP-5, IGFBP-5-(1—169), and IGFBP-5-(201—218). When the IGFBP-5 receptor was incubated with dephosphorylated casein in the presence of [32P]ATP, casein became phosphorylated on serine residues. These data indicate that IGFBP-5 stimulates the phosphorylation of the IGFBP-5 receptor and suggest that serine/threonine kinase activation may be important in mediating some of the IGF-independent effects of IGFBP-5.
Dissociation of the effects of amylin on osteoblast proliferation and bone resorption
Authors: Cornish J. , Callon K. E. , Lin C. Q.-X. , Xiao C. L. , Mulvey T. B. , Coy D. H. , Cooper G. J. S. , Reid I. R.
Published: December 2017

This study assesses the structure-activity relationships of the actions of amylin on bone. In fetal rat osteoblasts, only intact amylin and amylin-(1—8) stimulated cell proliferation (half-maximal concentrations 2.0 × 10−11 and 2.4 × 10−10 M, respectively). Amylin-(8—37), COOH terminally deamidated amylin, reduced amylin, and reduced amylin-(1—8) (reduction results in cleavage of the disulfide bond) were without agonist effect but acted as antagonists to the effects of both amylin and amylin-(1—8). Calcitonin gene-related peptide-(8—37) also antagonized the effects of amylin and amylin-(1—8) on osteoblasts but was substantially less potent in this regard than amylin-(8—37). In contrast, inhibition of bone resorption in neonatal mouse calvariae only occurred with the intact amylin molecule and was not antagonized by any of these peptides. The rate of catabolism of the peptides in calvarial cultures was not accelerated in comparison with that of intact amylin. This dissociation of the actions of amylin suggests that it acts through two separate receptors, one on the osteoclast (possibly the calcitonin receptor) and a second on the osteoblast.
Effects of thiopental anesthesia on local rates of cerebral protein synthesis in rats
Authors: Smith C. Beebe , Eintrei C. , Kang J. , Sun Y.
Published: December 2017

We have examined the effects of a surgical level of thiopental anesthesia in adult male rats on local rates of cerebral protein synthesis with the quantitative autoradiographicl-[1-14C]leucine method. The relative contribution of leucine derived from protein breakdown to the intracellular precursor amino acid pool for protein synthesis was found to be statistically significantly decreased in the anesthetized rats compared with controls. In the brain as a whole and in 30 of the 35 brain regions examined, rates of protein synthesis were decreased (1–11%) in the anesthetized rats. Decreases were statistically significant ( P ≤ 0.05) in the brain as a whole and in six of the regions, and they approached statistical significance in an additional 13 regions, indicating a tendency for a generalized but small effect.
Total body lipid and triglyceride response to energy deficit: relevance to body composition models
Authors: Comizio Renee , Pietrobelli Angelo , Tan Yan Xiu , Wang Zimian , Withers Robert T. , Heymsfield Steven B. , Boozer Carol N.
Published: December 2017

Although the study of human body composition is advancing rapidly, confusion still prevails regarding the molecular-level lipid component. Most molecular-level body composition models are presently based on the overall hypothesis that nontriglyceride lipids constitute an insignificant proportion of total body lipid. A single lipid or “fat” component consisting of triglycerides is thus assumed in most molecular-level body composition models. To test this hypothesis, the present study, carried out in adult rats, was designed to examine two questions: 1) What is the proportion of total lipids as triglycerides? and 2) Is this proportion constant or does it change with negative energy balance and weight loss produced by calorie restriction and increased exercise? Results indicated that with negative energy balance and weight loss there were progressive losses of total body triglyceride and lipid. The proportion of total lipids as triglyceride was 0.83 ± 0.08 (SD) in control animals, with reductions at 2 and 9 wk of energy restriction [0.82 ± 0.04 ( P = NS vs. control) and 0.70 ± 0.15 ( P = 0.05)] and at 9 wk for energy restriction plus exercise [0.67 ± 0.09 ( P = 0.003)]. Nontriglyceride lipids comprised 2.8% of carcass weight at baseline and decreased to 2.2% by 9 wk of energy restriction and exercise ( P = NS). Substantial differences were observed between body composition ratios expressed as percentages of the lipid-free body mass (LFM) and triglyceride-free body mass (TGFM); (e.g., total body water/LFM and TGFM in controls = 72.7 ± 0.7 and 70.4 ± 2.2, respectively; P = 0.02). These observations strongly support the existence and importance of nontriglyceride lipids as a body composition component that responds independently from storage triglycerides, with negative energy balance produced by food restriction and exercise.
Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow
Authors: Rosdahl H. , Hamrin K. , Ungerstedt U. , Henriksson J.
Published: December 2017

To identify a perfusion flow at which the interstitial fluid completely equilibrates with the microdialysis perfusion fluid, a protocol with successively lower perfusion flows was used. A colloid was included in the perfusion fluid to make sampling possible at the lowest perfusion flows. At 0.16 μl/min, the measured metabolites had reached a complete equilibration in both tissues, and the measured concentrations of glucose, glycerol, and urea were in good agreement with expected tissue-specific levels. The glucose concentration in adipose tissue (4.98 ± 0.14 mM) was equal to that of plasma (5.07 ± 0.07 mM), whereas the concentration in muscle (4.41 ± 0.11 mM) was lower than in plasma and adipose tissue ( P < 0.001). The concentration of lactate was higher ( P< 0.001) in muscle (2.39 ± 0.22 mM) than in adipose tissue (1.30 ± 0.12 mM), whereas the glycerol concentration in adipose tissue (233 ± 19.7 μM) was higher ( P< 0.001) than in muscle (40.8 ± 3.0 μM) and in plasma (68.7 ± 3.97 μM). The concentration of urea was equal in the two tissues. Overall, the study indicates that microdialysis at a low perfusion flow may be a tool to continuously monitor tissue interstitial concentrations.
Genetic variability in melatonin concentrations in ewes originates in its synthesis, not in its catabolism
Authors: Zarazaga Luis A. , Malpaux Benoît , Guillaume Daniel , Bodin Loys , Chemineau Philippe
Published: December 2017

We investigated whether the genetic difference in plasma melatonin concentration in ewes was due to differences in the synthesis pathway from the pineal gland or in the catabolism of the hormone. Two groups of ewes [9 low (L) and 10 high (H)] were selected according to the breeding value of their mean nighttime plasma melatonin concentrations estimated at winter and summer solstices. In response to an identical dose of melatonin administered intravenously at 9:00 AM, no differences between groups were observed for any of the kinetic parameters: clearance rate, steady-state volume of distribution, terminal half-lives, and mean residence times. In the second experiment, two series of frequent blood samples were performed, one in the middle of the dark phase with samples taken every 5 min, and the other over 24 h with hourly samples. Highly significant differences between groups in nocturnal melatonin production rate were observed (L: 25.7 ± 2.8 vs. H: 63.1 ± 8.9 μg ⋅ kg−1⋅ h−1, P < 0.01). Thus the genetic differences in plasma melatonin concentrations in ewes originate in the synthesis pathway of the melatonin from the pineal gland rather than from differences in the catabolism of the hormone.
Response of normal and osteoporotic human bone cells to mechanical stress in vitro
Authors: Sterck Jozien G. H. , Klein-Nulend Jenneke , Lips Paul , Burger Elisabeth H.
Published: December 2017

Bone adapts to mechanical stress, and bone cell cultures from animal origin have been shown to be highly sensitive to mechanical stress in vitro. In this study, we tested whether bone cell cultures from human bone biopsies respond to stress in a similar manner as animal bone cells and whether bone cells from osteoporotic patients respond similarly to nonosteoporotic donors. Bone cell cultures were obtained as outgrowth from collagenase-stripped trabecular bone fragments from 17 nonosteoporotic donors between 7 and 77 yr of age and from 6 osteoporotic donors between 42 and 72 yr of age. After passage, the cells were mechanically stressed by treatment with pulsating fluid flow (PFF; 0.7 ± 0.03 Pa at 5 Hz for 1 h) to mimic the stress-driven flow of interstitial fluid through the bone canaliculi, which is likely the stimulus for mechanosensation in bone in vivo. Similar to earlier studies in rodent and chicken bone cells, the bone cells from nonosteoporotic donors responded to PFF with enhanced release of prostaglandin E2(PGE2) and nitric oxide as well as a reduced release of transforming growth factor-β (TGF-β). The upregulation of PGE2but not the other responses continued for 24 h after 1 h of PFF treatment. The bone cells from osteoporotic donors responded in a similar manner as the nonosteoporotic donors except for the long-term PGE2release. The PFF-mediated upregulation of PGE2release during 24 h of postincubation after 1 h of PFF was significantly reduced in osteoporotic patients compared with six age-matched controls as well as with the whole nonosteoporotic group. These results indicate that enhanced release of PGE2and nitric oxide, as well as reduced release of TGF-β, is a characteristic response of human bone cells to fluid shear stress, similar to animal bone cells. The results also suggest that bone cells from osteoporotic patients may be impaired in their long-term response to mechanical stress.
Acetogenesis does not replace ketogenesis in fasting piglets infused with hexanoate
Authors: Adams Sean H. , Odle Jack
Published: December 2017

The current studies were performed to better understand the physiological relevance of acetate in the poorly ketogenic piglet and to determine if endogenous acetogenesis rises with increased mitochondrial fatty acid β-oxidation, analogous to ketogenesis. Plasma acetate concentration values in newborn, fasted, or suckled piglets (230–343 μM) were at least 10-fold higher than the ketone bodies, a pattern opposite to that in 24- to 48-h suckled rats (77–175 μM). Employing continuous infusion techniques with sodium [3H]acetate tracer in fasting ∼40-h-old piglets, acetate rate of appearance (Ra) was found to be 34 ± 4 μmol ⋅ min−1⋅ kg body wt−1. This basal Rawas double that observed in animals coinfused with sodium [1-14C]hexanoate ( P < 0.001), despite active oxidation of the latter as determined by14CO2production. Active acetogenesis in vivo and relatively abundant acetate in piglet blood are consistent with the hypothesis that acetate plays an important physiological role in piglets. However, the negative impact of hexanoate oxidation upon acetate Raand the lack of significant changes in circulating acetate in newborn, suckled, and fasted piglets draws into question the extent of analogy between acetogenesis and ketogenesis in vivo.
Endotoxin-induced alteration in the expression of leptin and β3-adrenergic receptor in adipose tissue
Authors: Berkowitz Dan E. , Brown Daniel , Lee Kyoung Min , Emala Charles , Palmer David , An Ying , Breslow Michael
Published: December 2017

Cytokines, such as tumor necrosis factor (TNF) and interleukin-6, may contribute to the anorexia and cachexia of infection, cancer, and AIDS. The present study tests the hypothesis that endotoxin alters the expression of two key fat cell proteins, leptin and β3-adrenergic receptor (β3-AR), through a mechanism involving TNF-α. Increasing doses of Escherichia coli endotoxin (lipopolysaccharide, LPS) resulted in dose-dependent elevations of plasma leptin (maximal response ∼7-fold, half-maximal effective dose of ∼16 μg/100 g body wt) and white fat leptin mRNA in C3/HeOUJ mice. LPS also produced a large decrease in adipose tissue β3-AR mRNA and a parallel reduction in β-agonist-induced activation of adenylyl cyclase. Changes in plasma leptin and β3-AR mRNA were preceded by an approximately threefold increase in white fat TNF mRNA. TNF administration resulted in changes similar to those seen with LPS. We conclude that endotoxemia results in an induction of leptin mRNA and a decrease in β3-AR mRNA in adipose tissue, an effect that may be mediated by alterations in TNF-α.
Role of free fatty acids and glucagon in the peripheral effect of insulin on glucose production in humans
Authors: Lewis Gary F. , Vranic Mladen , Giacca Adria
Published: December 2017

We have shown previously that the greater suppression of endogenous glucose production (GP) with equimolar peripheral vs. portal insulin cannot be detected or is minimally reversed when the insulin-induced suppression of either free fatty acids (FFA) or glucagon alone is prevented. The present experiments were designed to minimize the insulin suppression of both glucagon and FFA in an attempt to further examine the mechanism of insulin’s peripheral effect on GP. In nine healthy men, we investigated the effect of limiting the insulin suppression of both FFA and glucagon by infusing heparin (250 U/h), Intralipid 10% (25 ml/h), and glucagon (0.65 ng ⋅ kg−1⋅ min−1) during 1) portal ( n = 9), 2) equimolar peripheral ( n = 9), and 3) half-dose peripheral insulin delivery ( n = 4) by use of our previously published tolbutamide infusion method, with calculation and matching of insulin secretion rate. GP decreased by 57.2 ± 2.6% with portal, 39.0 ± 4.1% with equimolar peripheral, and 31.5 ± 2.7% with half-dose peripheral insulin delivery ( P < 0.001 for portal vs. peripheral and P < 0.001 for portal vs. half-dose peripheral). In contrast, in six control subjects in whom glucagon and FFA were not replaced, GP decreased by 62.6 ± 2.4% with portal ( n = 6), 75.7 ± 3.0% with peripheral ( n = 6), and 56.3 ± 3.0% with half-dose peripheral ( n = 4) insulin delivery ( P < 0.01 for portal vs. peripheral and P = not significant for portal vs. half-dose peripheral). In summary, the greater suppression of GP with equimolar peripheral vs. portal insulin is eliminated and markedly reversed if the acute insulin-induced suppression of both plasma FFA and glucagon is minimized. This suggests that the insulin-induced suppression of glucagon and FFA has additive or cooperative effects in mediating the acute extrahepatic effect of insulin on GP.
Pulsatile cortisol secretion and EEG delta waves are controlled by two independent but synchronized generators
Authors: Gronfier Claude , Chapotot Florian , Weibel Laurence , Jouny Christophe , Piquard François , Brandenberger Gabrielle
Published: December 2017

We have previously described a temporal relationship between plasma cortisol pulses and slow-wave sleep and, more recently, an inverse significant cross-correlation between cortisol secretory rates and delta wave activity of the sleep electroencephalogram (EEG). The aim of this study was to observe ACTH, cortisol, and sleep delta wave activity variations throughout 24 h to get a better insight into their initiating mechanisms. Two groups of 10 subjects participated in a 24-h study, one group with a night sleep (2300–0700) and the other with a day sleep (0700–1500). Cortisol secretory rates were calculated by a deconvolution procedure from plasma levels measured at 10-min intervals. Delta wave activity was computed during sleep by spectral analysis of the sleep EEG. When delta waves and cortisol were present at the same time at the end of the night sleep as well as during the daytime sleep, they were negatively correlated, cortisol changes preceding variations in delta wave activity by ∼10 min. Increases in delta wave activity occurred in the absence of cortisol pulses, as observed at the beginning of the night. Cortisol pulses occurred without any concomitant variations of sleep delta wave activity, as observed during wakefulness and intrasleep awakenings. In no case did delta wave activity increase together with an increase in cortisol secretory rates. In conclusion, cortisol secretion and delta wave activity have independent generators. They can oscillate independently from each other, but when they are present at the same time, they are oscillating in phase opposition.
Transduction pathways involved in rapid hormone receptor regulation in the mammary epithelium
Authors: Bolander Franklyn F.
Published: December 2017

Previous studies have shown that the envelope protein of the mouse mammary tumor virus (MMTV) rapidly upregulates prolactin (PRL) receptors by shifting them from internal pools to the cell surface and downregulates epidermal growth factor (EGF) receptors by inducing their internalization and degradation. This study shows that the effect on PRL receptors is mediated by the nitric oxide (NO)/cGMP pathway, since it can be mimicked by an NO donor or 8-bromo-cGMP and can be blocked by an NO synthase inhibitor. In contrast, the effect on EGF receptors is mediated by tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3K), since it can be blocked by either a tyrosine kinase inhibitor or by a PI3K inhibitor. Both of these pathways can be activated by a calcium ionophore and inhibited by calcium chelation. Therefore, it appears that the mouse mammary tumor virus envelope protein, like other retroviral envelope proteins, initially elevates cytoplasmic calcium, which can then stimulate both the NO/cGMP and the tyrosine phosphorylation/PI3K pathways, leading to PRL receptor upregulation and EGF receptor downregulation, respectively.
Skeletal muscle phosphatidylcholine fatty acids and insulin sensitivity in normal humans
Authors: Clore John N. , Li Jing , Gill Ranjodh , Gupta Shona , Spencer Robert , Azzam Amin , Zuelzer Wilhelm , Rizzo William B. , Blackard William G.
Published: December 2017

The fatty acid composition of skeletal muscle membrane phospholipids (PL) is known to influence insulin responsiveness in humans. However, the contribution of the major PL of the outer (phosphatidylcholine, PC) and inner (phosphatidylethanolamine, PE) layers of the sarcolemma to insulin sensitivity is not known. Fatty acid composition of PC and PE from biopsies of vastus lateralis from 27 normal men and women were correlated with insulin sensitivity determined by the hyperinsulinemic euglycemic clamp technique at insulin infusion rates of 0.4, 1.0, and 10.0 mU ⋅ kg−1⋅ min−1. Significant variation in the half-maximal insulin concentration (ED50) was observed in the normal volunteers (range 24.0–146.0 μU/ml), which correlated directly with fasting plasma insulin ( r = 0.75, P < 0.0001). ED50was inversely correlated with the degree of membrane unsaturation (C20-C22polyunsaturated fatty acids; r = 0.58, P < 0.01) and directly correlated with fatty acid elongation (ratio of 16:0 to 18:0, r = 0.45, P < 0.05) in PC. However, no relationship between fatty acid composition and insulin sensitivity was observed in PE (NS). These studies suggest that the fatty acid composition of PC may be of particular importance in the relationship between fatty acids and insulin sensitivity in normal humans.
Low-density lipoproteins supply phospholipid-bound arachidonic acid for platelet eicosanoid production
Authors: Dobner Petra , Engelmann Bernd
Published: December 2017

After the rapid extracorporal reduction of plasma low-density lipoprotein (LDL) by LDL apheresis, the percentages of arachidonic acid (AA)-containing species of phosphatidylcholine (PC) were lowered in the plasma of patients with hypercholesterolemia. The same PC species with AA were also decreased in the patient’s platelets. Thus the supply of phospholipid-bound AA from LDL to the platelets was probably diminished after the apheresis. We therefore analyzed the concentration dependence of the transfer of phospholipid-bound AA from LDL to the platelets under in vitro conditions. The amount of [14C]AA-PC transferred to platelets strongly increased upon elevation of LDL from 0.1 to 1 mg protein/ml, with a less marked elevation being noted at higher LDL concentrations. After stimulation with thrombin (0.5 U/ml), 7.1% ([14C]AA-PC) and 10.6% ([14C]AA-phosphatidylethanolamine) of the14C transferred from LDL to the platelets were recovered in the eicosanoids [14C]thromboxane B2(TxB2) plus 12-[14C]hydroxyeicosatetraenoic acid. Experimental increases and reductions of the [14C]AA-PC import were associated with comparable modifications in the [14C]TxB2production of the platelets. Accordingly, the import of phospholipid-bound [14C]AA is a necessary prerequisite for the formation of14C-labeled eicosanoids. In summary, the transfer of phospholipids from LDL to the platelets markedly varies within the physiological range of lipoprotein concentrations. LDL contributes to platelet eicosanoid formation by supplying platelets with phospholipid-bound AA.
Human aging is associated with parallel reductions in insulin and amylin release
Authors: Dechenes Cynthia J. , Verchere C. Bruce , Andrikopoulos Sofianos , Kahn Steven E.
Published: December 2017

Aging is associated with an increased risk of type 2 diabetes. To determine whether the insulin resistance of aging is associated with an increase in amylin release or whether amylin release parallels the reduction in insulin release, we studied 10 older (72 ± 2 yr) and 9 young (25 ± 1 yr) subjects. Insulin sensitivity was quantified as the insulin sensitivity index (SI) and B cell function as the acute insulin and amylin responses to iv glucose (AIRg and AARg, respectively) and iv arginine at a glucose level of >25 mM (AIRmax and AARmax). To account for the effect of SIto modulate B cell function, we calculated SI× B cell function. Older subjects were insulin resistant (SI: 4.6 ± 0.8 vs. 8.6 ± 1.4 × 10−5min−1/pM, P < 0.05). Acute responses to glucose [AIRg (older vs. young): 420 ± 106 vs. 537 ± 87 pM; AARg: 6.5 ± 1.7 vs. 9.0 ± 1.5 pM] and arginine (AIRmax: 1,096 ± 203 vs. 1,572 ± 307 pM; AARmax: 14.0 ± 3.5 vs. 16.5 ± 2.4 pM) did not differ despite the difference in SI. When adjusted for SI, insulin responses were reduced in older subjects (SI× AIRg: 1.54 ± 0.29 vs. 4.10 ± 0.63 × 10−2min−1, P = 0.001; SI× AIRmax: 4.03 ± 0.52 vs. 12.7 ± 2.9 × 10−2min−1, P < 0.01), as was amylin release (SI× AARg: 2.46 ± 0.59 vs. 6.85 ± 0.95 × 10−4min−1, P < 0.001; SI× AARmax: 4.71 ± 0.52 vs. 13.5 ± 2.2 × 10−4min−1, P < 0.001). Amylin and insulin release was proportionate, with a molar ratio of 1.5% in older and 1.4% in young subjects. Thus aging is associated with parallel impairments in the adaptation of insulin and amylin release to insulin resistance. It is unlikely that an alteration in amylin release contributes to the increased risk of type 2 diabetes.
Overestimation of minimal model glucose effectiveness in presence of insulin response is due to undermodeling
Authors: Cobelli Claudio , Bettini Francesca , Caumo Andrea , Quon Michael J.
Published: December 2017

Glucose effectiveness is an important determinant of glucose tolerance that can be derived from minimal model analysis of an intravenous glucose tolerance test (IVGTT). However, recent evidence suggests that glucose effectiveness is overestimated by minimal model analysis. Here we compare a new model-independent estimate of glucose effectiveness with the minimal model estimate by reanalyzing published data in which insulin-dependent diabetic subjects were each given IVGTTs under two conditions (Quon, M. J., C. Cochran, S. I. Taylor, and R. C. Eastman. Diabetes 43: 890–896, 1994). In one case, a basal insulin level was maintained (BI-IVGTT). In the second case, a dynamic insulin response was recreated (DI-IVGTT). Our results show that minimal model glucose effectiveness is very similar to the model-independent measurement during a BI-IVGTT but is three times higher during a DI-IVGTT. To investigate the causes of minimal model overestimation in the presence of a dynamic insulin response, Monte Carlo simulation studies on a two-compartment model of glucose kinetics with various insulin response patterns were performed. Results suggest that minimal model overestimation is due to single-compartment representation of glucose kinetics that results in a critical oversimplification in the presence of increasingly dynamic insulin secretion patterns.
Insulinotropic action of β-l-glucose pentaacetate
Authors: Malaisse Willy J. , Best Leonard C. , Herchuelz André , Hiriart Marcia , Jijakli Hassan , Kadiata Marcel M. , Larrieta-Carasco Elena , Laghmich Aouatif , Louchami Karim , Mercan Dany , Olivares Elizabeth , Sànchez-Soto Carmen , Scruel Olivier , Sener Abdullah , Valverde Isabel , Villanueva-Peñacarrillo María L. , Viñambres Concepción , Zawalich Walter S.
Published: December 2017

The metabolism of β-l-glucose pentaacetate and its interference with the catabolism ofl-[U-14C]glutamine, [U-14C]palmitate,d-[U-14C]glucose, andd-[5-3H]glucose were examined in rat pancreatic islets. Likewise, attention was paid to the effects of this ester on the biosynthesis of islet peptides, the release of insulin from incubated or perifused islets, the functional behavior of individual B cells examined in a reverse hemolytic plaque assay of insulin secretion, adenylate cyclase activity in a membrane-enriched islet subcellular fraction, cAMP production by intact islets, tritiated inositol phosphate production by islets preincubated with myo-[2-3H]inositol, islet cell intracellular pH,86Rb and45Ca efflux from prelabeled perifused islets, and electrical activity in single isolated B cells. The results of these experiments were interpreted to indicate that the insulinotropic action of β-l-glucose pentaacetate is not attributable to any nutritional value of the ester but, instead, appears to result from a direct effect of the ester itself on a yet unidentified receptor system, resulting in a decrease in K+conductance, plasma membrane depolarization, and induction of electrical activity.
The metabolic consequences of critical illness: acute effects on glutamine and protein metabolism
Authors: Jackson N. C. , Carroll P. V. , Russell-Jones D. L. , Sönksen P. H. , Treacher D. F. , Umpleby A. M.
Published: December 2017

Net protein loss and large decreases in plasma glutamine concentration are characteristics of critical illness. We have used [2-15N]glutamine and [1-13C]leucine to investigate whole body glutamine and leucine kinetics in a group of critically ill patients and matched healthy controls. Glutamine appearance rate (Ra,Gln) was similar in both groups. However, in the patients, the proportion of Ra,Gln arising from protein breakdown was higher than in the control group (43 ± 3 vs. 32 ± 2%, P < 0.05). Glutamine metabolic clearance rate (MCR) was 92 ± 8% higher ( P < 0.001), whereas plasma glutamine concentration was 38 ± 5% lower ( P < 0.001) than in the control group. Leucine appearance rate (whole body proteolysis) and nonoxidative leucine disposal (whole body protein synthesis) were 59 ± 14 and 49 ± 15% higher in the patients ( P < 0.001). Leucine oxidation and MCR were increased in the patients by 104 ± 37 and 129 ± 39%, respectively ( P < 0.05). These results demonstrate that critical illness is associated with a major increase in protein turnover. The acute decrease in plasma glutamine concentration and the unaltered plasma Ra,Gln suggest that the increase in proteolysis is insufficient to meet increased demand for glutamine in this severe catabolic state.
Effects of hyper- and hypoosmolality on whole body protein and glucose kinetics in humans
Authors: Berneis Kaspar , Ninnis Ronald , Häussinger Dieter , Keller Ulrich
Published: December 2017

To investigate the effect of acute changes of extracellular osmolality on whole body protein and glucose metabolism, we studied 10 male subjects during three conditions: hyperosmolality was induced by fluid restriction and intravenous infusion of hypertonic NaCl [2–5%; (wt/vol)] during 17 h; hypoosmolality was produced by intravenous administration of desmopressin, liberal water drinking, and infusion of hypotonic saline (0.4%); and the isoosmolality study consisted of ad libitum oral water intake by the subjects. Leucine flux ([1-13C]leucine infusion technique), a parameter of whole body protein breakdown, decreased during the hypoosmolality study ( P < 0.02 vs. isoosmolality). The leucine oxidation rate decreased during the hypoosmolality study ( P < 0.005 vs. isoosmolality). Metabolic clearance rate of glucose during hyperinsulinemic-euglycemic clamping increased less during the hypoosmolality study than during the isoosmolality study ( P < 0.04). Plasma insulin decreased, and plasma nonesterified fatty acids, glycerol, and ketone body concentrations and lipid oxidation increased during the hypoosmolality study. It is concluded that acute alterations of plasma osmolality influence whole body protein, glucose, and lipid metabolism; hypoosmolality results in protein sparing associated with increased lipolysis and lipid oxidation and impaired insulin sensitivity.
Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding
Authors: Holness Mark J. , Sugden Mary C.
Published: December 2017

The study investigated whether a persistent impairment of insulin secretion resulting from mild protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of the diabetogenic challenge of high-fat feeding. Offspring of dams provided with either control (20% protein) diet (C) or an isocaloric restricted (8%) protein diet (PR) were weaned onto the maintenance diet with which their mothers had been provided. At 20 wk of age, protein restriction enhanced glucose tolerance despite impaired insulin secretion and an augmented and sensitized lipolytic response to norepinephrine in adipocytes. C and PR rats were then transferred to a high-fat diet (HF, 19% protein, 22% lipid, 34% carbohydrate) and sampled after 8 wk. These groups are termed C-HF and PR-HF. Glucose tolerance was impaired in PR-HF, but not C-HF, rats. Insulin-stimulated glucose disposal rates were significantly lower (by 30%; P < 0.01) in the PR-HF group than in the C-HF group, and a specific impairment of antilipolytic response of insulin was unmasked in adipocytes from PR-HF, but not C-HF, rats. The study demonstrates that antecedent protein restriction accelerates and augments the development of impaired glucoregulation and insulin resistance after high-fat feeding.
Proinsulin stimulates growth of small intestinal crypt-like cells acting via specific receptors
Authors: Jehle Peter M. , Fussgaenger Rolf D. , Angelus Niklas K. O. , Jungwirth Robert J. , Saile Bernhard , Lutz Manfred P.
Published: December 2017

The mechanisms that regulate cell turnover in the intestinal epithelium are incompletely understood. Here we tested the hypothesis that proinsulin, present in serum and pancreatic juice in picomolar concentrations, stimulates growth of the rat small intestinal crypt-like cell line IEC-6 under serum-free conditions. Proinsulin binding was assessed by competitive ligand binding studies. Proinsulin and insulin-like growth factor I (IGF-I) stimulated cell proliferation up to threefold above controls, with half-maximal action already in the picomolar range and with additive effects. In early confluent cell monolayers, proinsulin bound with higher affinity (IC501.3 ± 0.05 nM) and capacity (87,200 ± 2,500 receptors/cell) than IGF-I (4.0 ± 0.6; 23,700 ± 2,200, P < 0.05). C-peptide competed with 10-fold lower affinity for binding of125I-proinsulin but not for125I-IGF-I or125I-insulin, suggesting a specific binding epitope of the proinsulin molecule within or close to the C-peptide region. In contrast, insulin showed ∼100-fold lower binding affinity and growth-promoting potency than proinsulin or IGF-I. We conclude that proinsulin stimulates growth of small intestinal crypt cells through specific binding and may play a physiological role in the regulation of intestinal epithelial cell proliferation.
Differential effect of amino acid infusion route on net hepatic glucose uptake in the dog
Authors: Moore Mary Courtney , Hsieh Po-Shiuan , Flakoll Paul J. , Neal Doss W. , Cherrington Alan D.
Published: December 2017

Concomitant portal infusion of gluconeogenic amino acids (GNGAA) and glucose significantly reduces net hepatic glucose uptake (NHGU), in comparison with NHGU during portal infusion of glucose alone. To determine whether this effect on NHGU is specific to the portal route of GNGAA delivery, somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and intraportal glucose (to increase the hepatic glucose load by ∼50%) were infused for 240 min. GNGAA were infused peripherally into a group of dogs (PeAA), at a rate to match the hepatic GNGAA load in a group of dogs that were given the same GNGAA mixture intraportally (PoAA) at 7.6 μmol ⋅ kg−1 ⋅ min−1(9). The arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups, but NHGU (−0.9 ± 0.2 PoAA and −2.1 ± 0.5 mg ⋅ kg−1 ⋅ min−1in PeAA, P < 0.05) and net hepatic fractional extraction of glucose (2.6 ± 0.7% in PoAA vs. 5.9 ± 1.4% in PeAA, P < 0.05) differed. Neither the hepatic loads nor the net hepatic uptakes of GNGAA were significantly different in the two groups. Net hepatic glycogen synthesis was ∼2.5-fold greater in PeAA than PoAA ( P < 0.05). Intraportal, but not peripheral, amino acid infusion suppresses NHGU and net hepatic glycogen synthesis in response to intraportal glucose infusion.
Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein
Authors: Xie Chonglun , Turley Stephen D. , Pentchev Peter G. , Dietschy John M.
Published: December 2017

Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5,442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg ⋅ day−1⋅ kg−1. Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular.
Endotoxin-induced changes in IGF-I differ in rats provided enteral vs. parenteral nutrition
Authors: Wojnar Margaret M. , Fan Jie , Li Yue Hua , Lang Charles H.
Published: December 2017

The purpose of the present study was to determine whether acute changes in the insulin-like growth factor (IGF) system induced by mild surgical trauma/fasting or endotoxin [lipopolysaccharide (LPS)] are differentially modulated by total enteral nutrition (TEN) or total parenteral nutrition (TPN). Rats had vascular catheters and a gastrostomy tube surgically placed and were fasted overnight. The next morning animals randomly received an isocaloric, isonitrogenous (250 kcal ⋅ kg−1 ⋅ day−1, 1.6 g N ⋅ kg−1 ⋅ day−1) infusion of either TEN or TPN for 48 h. Then rats were injected intravenously with Escherichia coliLPS (1 mg/kg) while nutritional support was continued. Time-matched control animals were injected with saline. After mild surgical trauma and an 18-h fast, TEN was more effective at increasing plasma IGF-I levels than TPN. Subsequent injection of LPS decreased IGF-I in blood, liver, and muscle in both TEN- and TPN-fed rats compared with saline-injected control animals. However, this decrease was ∼30% greater in rats fed TPN compared with those fed TEN. LPS-induced downregulation of IGF-I mRNA expression in liver and muscle was also more prominent in TPN-fed rats. The LPS-induced increase in plasma corticosterone and tumor necrosis factor-α was greater (2- and 1.6-fold, respectively) in TPN-fed rats, and these changes were consistent with the greater reduction in IGF-I seen in these animals. In similarly treated rats allowed to survive for 24 h after LPS injection, the LPS-induced increase in the urinary 3-methylhistidine-to-creatinine ratio was smaller in TEN-fed rats. In summary, LPS reduced systemic levels of IGF-I as well as IGF-I protein and mRNA in critical target organs. Enteral feeding greatly attenuated this response. Maintenance of higher IGF-I levels in TEN-fed rats was associated with a reduction in inflammatory cytokine levels and lower rates of myofibrillar degradation.