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The New England Journal of Medicine Nov 2004Term infants who are small for gestational age appear prone to the development of insulin resistance during childhood. We hypothesized that insulin resistance, a marker...
BACKGROUND
Term infants who are small for gestational age appear prone to the development of insulin resistance during childhood. We hypothesized that insulin resistance, a marker of type 2 diabetes mellitus, would be prevalent among children who had been born prematurely, irrespective of whether they were appropriate for gestational age or small for gestational age.
METHODS
Seventy-two healthy prepubertal children 4 to 10 years of age were studied: 50 who had been born prematurely (32 weeks' gestation or less), including 38 with a birth weight that was appropriate for gestational age (above the 10th percentile) and 12 with a birth weight that was low (i.e., who were small) for gestational age, and 22 control subjects (at least 37 weeks' gestation, with a birth weight above the 10th percentile). Insulin sensitivity was measured with the use of paired insulin and glucose data obtained by frequent measurements during intravenous glucose-tolerance tests.
RESULTS
Children who had been born prematurely, whether their weight was appropriate or low for gestational age, had an isolated reduction in insulin sensitivity as compared with controls (appropriate-for-gestational-age group, 14.2x10(-4) per minute per milliunit per liter [95 percent confidence interval, 11.5 to 16.2]; small-for-gestational-age group, 12.9x10(-4) per minute per milliunit per liter [95 percent confidence interval, 9.7 to 17.4]; and control group, 21.6x10(-4) per minute per milliunit per liter [95 percent confidence interval, 17.1 to 27.4]; P=0.002). There were no significant differences in insulin sensitivity between the two premature groups (P=0.80). As compared with controls, both groups of premature children had a compensatory increase in acute insulin release (appropriate-for-gestational-age group, 2002 pmol per liter [95 percent confidence interval, 1434 to 2432] [corrected]; small-for-gestational-age group, 2253 pmol per liter [95 percent confidence interval, 1622 to 3128]; and control group, 1148 pmol per liter [95 percent confidence interval, 875 to 1500]; P<0.001).
CONCLUSIONS
Like children who were born at term but who were small for gestational age, children who were born prematurely have an isolated reduction in insulin sensitivity, which may be a risk factor for type 2 diabetes mellitus.
Topics: Blood Glucose; Child; Child, Preschool; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Insulin Resistance; Linear Models; Male; Risk Factors
PubMed: 15548778
DOI: 10.1056/NEJMoa042275 -
Hypertension (Dallas, Tex. : 1979) Apr 2012Early-generation β-blockers lower blood pressure and reduce cardiovascular morality in coronary artery disease and congestive heart failure but worsen glucose... (Randomized Controlled Trial)
Randomized Controlled Trial
Early-generation β-blockers lower blood pressure and reduce cardiovascular morality in coronary artery disease and congestive heart failure but worsen glucose homeostasis and fibrinolytic balance. Nebivolol is a third-generation β-blocker that increases the bioavailability of nitric oxide. We compared the effect of nebivolol (5 mg/d) and the β(1)-selective antagonist metoprolol (100 mg/d) on glucose homeostasis and markers of fibrinolysis in 46 subjects with metabolic syndrome. Subjects underwent a frequently sampled IV glucose tolerance test after 3-week washout and placebo treatment and after randomized treatment with study drug. After 12-week treatment, nebivolol and metoprolol equivalently decreased systolic blood pressure, diastolic blood pressure, and heart rate. Neither drug affected β-cell function, disposition index, or acute insulin response to glucose. Metoprolol significantly decreased the insulin sensitivity index. In contrast, nebivolol did not affect insulin sensitivity, and the decrease in sensitivity was significantly greater after metoprolol than after nebivolol (-1.5±2.5×10(-4)×min(-1) per milliunit per liter versus 0.04±2.19×10(-4)×min(-1) per milliunit per liter after nebivolol; P=0.03). Circulating plasminogen activator inhibitor also increased after treatment with metoprolol (from 9.8±6.8 to 12.3±7.8 ng/mL) but not nebivolol (from 10.8±7.8 to 10.5±6.2 ng/mL; P=0.05 versus metoprolol). Metoprolol, but not nebivolol, increased F(2)-isoprostane concentrations. In summary, treatment with metoprolol decreased insulin sensitivity and increased oxidative stress and the antifibrinolytic plasminogen activator inhibitor 1 in patients with metabolic syndrome, whereas nebivolol lacked detrimental metabolic effects. Large clinical trials are needed to compare effects of nebivolol and the β(1) receptor antagonist metoprolol on clinical outcomes in patients with hypertension and the metabolic syndrome.
Topics: Adrenergic beta-Antagonists; Adult; Benzopyrans; Blood Glucose; Blood Pressure; Double-Blind Method; Ethanolamines; F2-Isoprostanes; Female; Heart Rate; Homeostasis; Humans; Insulin Resistance; Male; Metabolic Syndrome; Metoprolol; Middle Aged; Nebivolol; Oxidative Stress; Plasminogen Inactivators
PubMed: 22353614
DOI: 10.1161/HYPERTENSIONAHA.111.189589 -
BMC Pregnancy and Childbirth Mar 2023The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment...
Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum - a systematic review with implications for the function of the oxytocinergic system.
BACKGROUND
The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding.
AIM
To systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems.
METHODS
Systematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables.
RESULTS
Infusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2-3 times physiological levels. Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher. Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus.
CONCLUSIONS
Synthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2-3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Oxytocin; Parturition; Postpartum Period; Labor, Obstetric; Postpartum Hemorrhage
PubMed: 36864410
DOI: 10.1186/s12884-022-05221-w -
American Journal of Obstetrics and... Nov 2023The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta's glucose consumption exhibits considerable...
BACKGROUND
The principal fetal energy source is glucose provided by the placental transfer of maternal glucose. However, the placenta's glucose consumption exhibits considerable variation. Hexokinase is the first and one of the rate-limiting enzymes of glycolysis that phosphorylates glucose to glucose-6-phosphate. The role of placental hexokinase activity in human placental glucose metabolism is unknown.
OBJECTIVE
This study aimed to test the hypothesis that placental hexokinase activity is related to maternal body mass index, placental glucose uptake and consumption, and birthweight.
STUDY DESIGN
Overall, 67 healthy pregnant participants at term were included in this study at Oslo University Hospital, Oslo, Norway. Placental hexokinase activity was measured by using a colorimetric assay. The mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arteriovenous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from the maternal radial artery, uterine vein, and umbilical artery and vein. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptakes. The Spearman rank correlation was performed for statistical analyses to study the correlation of placental hexokinase activity (milliunit per milligram of protein) with prepregnancy body mass index, maternal glucose and insulin, birthweight, uteroplacental glucose uptake and consumption, and fetal glucose uptake (micromole per minute). Partial rank correlation analysis was performed when controlling for hours of fasting or placental weight.
RESULTS
Hexokinase activity was detectable in all placental tissue samples. The mean activity was 19.6 (standard deviation, 4.64) mU/mg protein. Placental hexokinase activity correlated positively with prepregnancy body mass index (Spearman rho=0.33; P=.006). On controlling for hours of fasting, hexokinase activity showed positive correlations with both maternal glucose (r=0.30; P=.01) and insulin (r=0.28; P=.02). Hexokinase activity was positively correlated with uteroplacental glucose uptake (Spearman rho=0.31; P=.01) and consumption (Spearman rho=0.28; P=.02). Hexokinase activity did not correlate with fetal glucose uptake. On controlling for placental weight, hexokinase activity showed a positive correlation with birthweight (r=0.31; P=.01).
CONCLUSION
Our findings suggest that placental hexokinase, being crucial for uteroplacental retention of glucose for disposition, is related to both maternal body mass index and birthweight independent of placental weight. Placental hexokinase may play a central role in the relationship between maternal glucose dysregulation and fetal growth. Thus, the current study supports the need to develop clinically useful tools to assess the metabolic properties of the placenta.
PubMed: 37925123
DOI: 10.1016/j.ajog.2023.10.043 -
The Journal of Biological Chemistry Jun 1979It is well documented that adipose tissue glycogen content decreases during fasting and increases above control during refeeding. We now present evidence that these... (Comparative Study)
Comparative Study
It is well documented that adipose tissue glycogen content decreases during fasting and increases above control during refeeding. We now present evidence that these fluctuations result from adaptations intrinsic to adipose tissue glycogen metabolism that persist in vitro: in response to insulin (1 milliunit/ml), [3H]glucose incorporation into rat fat pad glycogen was reduced to 10% of control after a 3-day fast; incorporation increased 6-fold over fed control on the 4th day of refeeding following a 3-day fast. We have characterized this adaptation with regard to alterations in glycogen synthase and phosphorylase activity. In addition, we found that incubation of fat pads from fasted rats with insulin (1 milliunit/ml) increased glucose-6-P content, indicating that glucose transport was not the rate-limiting step for glucose incorporation into glycogen in the presence of insulin. In contrast, feeding a fat-free diet resulted in dramatic increases in glycogen content of fat pads without a concomitant increase in glucose incorporation into glycogen in response to insulin (1 milliunit/ml). Thus, fasting and refeeding appeared to alter insulin action on adipose tissue glycogen metabolism more than this dietary manipulation.
Topics: Adipose Tissue; Animals; Eating; Fasting; Glucose; Glucosephosphates; Glycogen; Glycogen Synthase; Insulin; Kinetics; Male; Phosphorylases; Rats
PubMed: 108280
DOI: No ID Found -
Frontiers in Neurology 2022This study aimed to construct an animal model of intracranial arterial dolichoectasia (IADE) applying the modified modeling protocol.
BACKGROUND AND PURPOSE
This study aimed to construct an animal model of intracranial arterial dolichoectasia (IADE) applying the modified modeling protocol.
MATERIALS AND METHODS
Twenty five milliunits elastase and inactivated elastase were, respectively, injected into the cerebellomedullary cistern of 60 C57/BL6 mice which were divided into experimental group (EG, = 30) and control group (CG, = 30) by using a computer-based random order generator. The modified modeling protocol clarified these aspects including brain three-dimensional parameters of mouse head fixation, angle of head inclination, fixed position of taper ear, needle holding technique, needle entry depth, prevention of liquid drug back flow, and storage conditions of elastase. And it was observed for the following parts such as mortality, inflammatory factors, craniocerebral arteries scanning, vascular tortuosity index, artery diameter, pathology of the cerebrovascular.
RESULTS
Within differently surveyed stage, the total mortality of mice in EG was 20%. ELISA illustrated that the levels of matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor α (TNF-α) in peripheral blood were increased significantly after modeling. Angiography indicated that 100% of IADE in EG were observed and the diameter and tortuosity index of the basilar artery were significantly increased ( < 0.01). EVG histological processing and staining showed the disrupted internal elastic lamina, the atrophied muscle layer, and the hyalinized connective tissue of the basilar artery with the vascular wall tunica media in EG. Micro-computed tomography reported that the craniocerebral arteries of the mice in EG were outstandingly elongated, tortuous, and dilated.
CONCLUSION
The modified modeling protocol can reduce the mortality, improve the success rate, and provide a stable animal model for IADE.
PubMed: 35518204
DOI: 10.3389/fneur.2022.860541 -
The Journal of Biological Chemistry Apr 1997The effects of increased plasma free fatty acids (FFA) on insulin-dependent whole body glucose disposal, skeletal muscle glycolysis, glycogen synthesis, pyruvate versus...
The effects of increased plasma free fatty acids (FFA) on insulin-dependent whole body glucose disposal, skeletal muscle glycolysis, glycogen synthesis, pyruvate versus FFA/ketone oxidation, and glucose 6-phosphate (Glu-6-P) were investigated in the awake rat. A control group (glycerol-infused) and high plasma FFA group (Liposyn-infused) were clamped at euglycemia (approximately 6 mM)-hyperinsulinemia (10 milliunits/kg/min) throughout the experiment (180-240 min). In the initial experiment, 13C NMR was used to observe [1-13C]glucose incorporation into [1-13C]glycogen in the rat hindlimb for glycogen synthesis calculations and into [3-13C]lactate and [3-13C]alanine for glycolytic flux calculations. These experiments were followed by 31P NMR measurements of Glu-6-P changes under identical conditions of the initial experiment. Plasma FFA concentrations were 2.25 +/- 0.36 and 0.20 +/- 0.03 mM in the high plasma FFA and control groups respectively (p < 0.0005). Glucose infusion rates (Ginf) decreased significantly in the Liposyn-infused rats (29.5 +/- 0.7 and 27.2 +/- 1.2 mg/kg/min for control and high plasma FFA group, respectively, at 15 min to 30.7 +/- 2.3 and 17.7 +/- 1.3 mg/kg/min, respectively, at the end of the experiment, p < 0.002). Glycogen synthesis rates were 163 +/- 32 and 104 +/- 17 nmol/g/min, and glycolytic rates were 57.9 +/- 8.0 and 19. 5 +/- 3.6 nmol/g/min (p < 0.002) in the control and high plasma FFA groups, respectively. The relative flux of pyruvate versus free fatty acids and ketones entering the tricarboxylic acid cycle was greater in the control (57 +/- 9%) versus high plasma FFA group (25 +/- 4%) (p < 0.005) as assessed by [4-13C]glutamate/[3-13C]lactate steady state isotopic enrichment measurements. Finally, Glu-6-P concentrations increased by 29.8 +/- 7.0 and 52.8 +/- 12.3% (p < 0. 05) in the control and high plasma FFA groups, respectively, above their basal concentrations by 180 min. In conclusion, we have demonstrated the ability to use in vivo NMR to elucidate the metabolic fate of glucose within skeletal muscle of an awake rat during a euglycemic-hyperinsulinemic clamp and increased levels of plasma FFA. These data suggest that increased concentrations of plasma FFA inhibit insulin-stimulated muscle glucose metabolism in the rat through inhibition of glycolysis.
Topics: Alanine; Animals; Carbon Isotopes; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glucose-6-Phosphate; Glycogen; Glycolysis; Hyperinsulinism; Infusions, Intravenous; Insulin; Ketones; Kinetics; Lactates; Magnetic Resonance Spectroscopy; Models, Biological; Muscle, Skeletal; Phosphorus; Pyruvates; Rats; Rats, Sprague-Dawley; Wakefulness
PubMed: 9099689
DOI: 10.1074/jbc.272.16.10464 -
The Journal of Biological Chemistry Nov 1990This study was carried out to clarify the way in which thyrotropin (TSH) and forskolin regulate the adenylylcyclase complex in thyroid follicle cells. We examined the...
This study was carried out to clarify the way in which thyrotropin (TSH) and forskolin regulate the adenylylcyclase complex in thyroid follicle cells. We examined the effects of chronic treatment of pig thyroid follicles with TSH or forskolin on the state of G proteins by (a) assaying adenylylcyclase activity, (b) analyzing the ADP-ribosylation of stimulatory G protein (Gs) by cholera toxin, and (c) quantifying the Gs subunits by Western blotting with antipeptide antibodies. Chronic exposure (18 h) of thyroid follicles to a low concentration of TSH (0.01-0.1 milliunit/ml) enhanced the subsequent response of adenylylcyclase to TSH. Higher concentration of TSH (1 milliunit/ml) induced a homologous desensitization of this response. In cells pretreated with forskolin, the TSH-stimulated adenylylcyclase activity was higher than in control cells. The forskolin-or guanosine 5'-(beta, gamma-imido) triphosphate (Gpp(NH)p)-stimulated adenylylcyclase activity was always significantly increased after chronic treatment of cells with TSH or forskolin. Treatment of cultured thyroid follicle membranes with [32P]NAD and cholera toxin resulted in labeling of the Gs alpha (45-52-kDa) component. Culturing follicles with TSH (0.001-1 milliunit/ml) or forskolin (0.01-10 microM) greatly affected the cholera toxin-mediated ADP-ribosylation of the Gs alpha subunit. Gs alpha labeling increased progressively to level off at 1 milliunit/ml TSH or 1 microM forskolin (150-200%). Gs alpha immunoreactivity was increased in parallel (200-300%). The immunoreactivity of G beta subunits in cells cultured with TSH or forskolin was also increased compared with control cells. Cycloheximide abolished the effects of TSH and forskolin on the follicles, suggesting that new protein synthesis is required. These results indicate that Gs protein subunits are up-regulated by TSH and forskolin and suggest that their synthesis in thyroid cells is mediated, at least in part, by a cyclic AMP-dependent mechanism.
Topics: Adenosine Diphosphate Ribose; Adenylyl Cyclases; Animals; Blotting, Western; Cell Membrane; Cells, Cultured; Cholera Toxin; Colforsin; Cyclic AMP; Cycloheximide; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Immunoblotting; NAD; Swine; Thyroid Gland; Thyrotropin
PubMed: 2174058
DOI: No ID Found -
Proceedings of the National Academy of... May 1977The location of the somatostatin-containing D-cells of the pancreatic islets between the A- and B-cells suggests that their function might be to inhibit insulin and/or...
The location of the somatostatin-containing D-cells of the pancreatic islets between the A- and B-cells suggests that their function might be to inhibit insulin and/or glucagon secretion by these neighboring cells. To determine if insulin and/or glucagon, in concentrations that might be present in the extracellular space surrounding the D-cells, stimulate immunoreactive somatostatin (IRS) release, we perfused 10 microng of glucagon or 10 milliunits of insulin per ml in 11 isolated dog pancreases, for 40 min in seven experiments and for 100 min in four experiments. In eight of the nine experiments in which glucagon was perfused, a prompt and significant rise in mean IRS release, ranging from 71 to 128% above the control level, was observed. In the eight experiments in which insulin was perfused. IRS did not increase during the first 40 min; in the two 100-min insulin experiments, it did rise during the final 50 min, however. To determine the effect of an A- and B-cell secretogogue on IRS release, we perfused 20 mM arginine for 60 min in six experiments. In all, IRS rose within 3 min and reached a level 71-465% above the control, remaining significantly elevated throughout the perfusion, while glucagon and insulin rose to peak levels at 2 min and then declined somewhat despite continuing arginine perfusion. The results indicate that perfusion of the normal dog pancreas with high doses of glucagon or arginine is accompanied by a prompt increase in IRS release and are compatible with a local feedback circuit involving A- and D-cells. Insulin appears not to augment IRS release, at least not promptly, but IRS stimulated by local endogenous glucagon could inhibit the B-cell response to locally secreted glucagon and thereby influence the composition of the insulin/glucagon secretion mixture.
Topics: Animals; Arginine; Dogs; Glucagon; Insulin; Islets of Langerhans; Male; Secretory Rate; Somatostatin
PubMed: 325567
DOI: 10.1073/pnas.74.5.2140 -
The Journal of Biological Chemistry Aug 1984Neutrophilic granulocytes contain an oxidase system in their plasma membrane that can be activated to generate superoxide radicals and hydrogen peroxide. Cytochrome b,...
Neutrophilic granulocytes contain an oxidase system in their plasma membrane that can be activated to generate superoxide radicals and hydrogen peroxide. Cytochrome b, flavoprotein, and ubiquinone-50 have been proposed as components of this oxidase system. These components have been quantitated, but the results are obscured by different isolation procedures for plasma membranes from resting and activated neutrophils. This problem has now been avoided by the use of enucleated neutrophils (polymorphonuclear leukocyte cytoplasts), which are almost completely devoid of intracellular structures but contain an intact, activatable oxidase system (Roos, D., Voetman, A.A., and Meerhof, L.J. (1983) J. Cell Biol. 97, 368-377). Membranes of resting and phorbol myristate acetate-stimulated cytoplasts contain equal amounts of cytochrome b (4 pmol/milliunit of alkaline phosphatase) and also equal amounts of noncovalently bound FAD (2 pmol/milliunit of alkaline phosphatase). These findings refute the hypothesis that incorporation of cytochrome b and/or a flavoprotein into the plasma membrane constitutes the mechanism of activation of the oxidase system. Ubiquinone-50 is present neither in intact neutrophils nor in cytoplasts, excluding a role for this compound in the generation of bactericidal oxygen species by neutrophils.
Topics: Cell Fractionation; Coenzymes; Cytochrome b Group; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flavins; Humans; Hydrogen Peroxide; Neutrophils; Ubiquinone
PubMed: 6746662
DOI: No ID Found