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G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance.
Boortz KA, Syring KE, Lee RA, Dai C, Oeser JK, McGuinness OP, Wang JC, O'Brien RM
(2016) Endocrinology 157: 4133-4145
MeSH Terms: Animals, Blood Glucose, Cell Line, Cell Line, Tumor, Cricetinae, Dexamethasone, Fasting, Glucose-6-Phosphatase, Maf Transcription Factors, Large, Mice, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Rats, Receptors, Glucocorticoid
Show Abstract · Added March 14, 2018
The glucose-6-phosphatase catalytic subunit 2 (G6PC2) gene encodes an islet-specific glucose-6-phosphatase catalytic subunit. G6PC2 forms a substrate cycle with glucokinase that determines the glucose sensitivity of insulin secretion. Consequently, deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin. Although chronic elevation of FBG is detrimental to health, glucocorticoids induce G6PC2 expression, suggesting that G6PC2 evolved to transiently modulate FBG under conditions of glucocorticoid-related stress. We show, using competition and mutagenesis experiments, that the synthetic glucocorticoid dexamethasone (Dex) induces G6PC2 promoter activity through a mechanism involving displacement of the islet-enriched transcription factor MafA by the glucocorticoid receptor. The induction of G6PC2 promoter activity by Dex is modulated by a single nucleotide polymorphism, previously linked to altered FBG in humans, that affects FOXA2 binding. A 5-day repeated injection paradigm was used to examine the chronic effect of Dex on FBG and glucose tolerance in wild-type (WT) and G6pc2 knockout mice. Acute Dex treatment only induces G6pc2 expression in 129SvEv but not C57BL/6J mice, but this chronic treatment induced G6pc2 expression in both. In 6-hour fasted C57BL/6J WT mice, Dex treatment lowered FBG and improved glucose tolerance, with G6pc2 deletion exacerbating the decrease in FBG and enhancing the improvement in glucose tolerance. In contrast, in 24-hour fasted C57BL/6J WT mice, Dex treatment raised FBG but still improved glucose tolerance, with G6pc2 deletion limiting the increase in FBG and enhancing the improvement in glucose tolerance. These observations demonstrate that G6pc2 modulates the complex effects of Dex on both FBG and glucose tolerance.
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16 MeSH Terms
G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress.
Boortz KA, Syring KE, Dai C, Pound LD, Oeser JK, Jacobson DA, Wang JC, McGuinness OP, Powers AC, O'Brien RM
(2016) Endocrinology 157: 3002-8
MeSH Terms: Animals, Blood Glucose, Cells, Cultured, Dexamethasone, Fasting, Gene Expression Regulation, Glucose-6-Phosphatase, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreas, Promoter Regions, Genetic, Stress, Physiological
Show Abstract · Added July 16, 2016
The glucose-6-phosphatase catalytic 2 (G6PC2) gene is expressed specifically in pancreatic islet beta cells. Genome-wide association studies have shown that single nucleotide polymorphisms in the G6PC2 gene are associated with variations in fasting blood glucose (FBG) but not fasting plasma insulin. Molecular analyses examining the functional effects of these single nucleotide polymorphisms demonstrate that elevated G6PC2 expression is associated with elevated FBG. Studies in mice complement these genome-wide association data and show that deletion of the G6pc2 gene lowers FBG without affecting fasting plasma insulin. This suggests that, together with glucokinase, G6PC2 forms a substrate cycle that determines the glucose sensitivity of insulin secretion. Because genome-wide association studies and mouse studies demonstrate that elevated G6PC2 expression raises FBG and because chronically elevated FBG is detrimental to human health, increasing the risk of type 2 diabetes, it is unclear why G6PC2 evolved. We show here that the synthetic glucocorticoid dexamethasone strongly induces human G6PC2 promoter activity and endogenous G6PC2 expression in isolated human islets. Acute treatment with dexamethasone selectively induces endogenous G6pc2 expression in 129SvEv but not C57BL/6J mouse pancreas and isolated islets. The difference is due to a single nucleotide polymorphism in the C57BL/6J G6pc2 promoter that abolishes glucocorticoid receptor binding. In 6-hour fasted, nonstressed 129SvEv mice, deletion of G6pc2 lowers FBG. In response to the stress of repeated physical restraint, which is associated with elevated plasma glucocorticoid levels, G6pc2 gene expression is induced and the difference in FBG between wild-type and knockout mice is enhanced. These data suggest that G6PC2 may have evolved to modulate FBG in response to stress.
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15 MeSH Terms
Dexamethasone-suppressed Salivary Cortisol and Pain Sensitivity in Female Twins.
Godfrey KM, Herbert M, Strachan E, Mostoufi S, Crofford LJ, Buchwald D, Poeschla B, Succop A, Afari N
(2017) Clin J Pain 33: 246-253
MeSH Terms: Adult, Analgesics, Cold Temperature, Dexamethasone, Female, Hot Temperature, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Pain Measurement, Pain Perception, Pain Threshold, Pituitary-Adrenal System, Pressure, Registries, Saliva, Stress, Psychological, Twins, Dizygotic, Twins, Monozygotic, Water
Show Abstract · Added March 25, 2020
OBJECTIVES - Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is associated with chronic pain. Studying pain sensitivity and the HPA axis could elucidate the role of stress in chronic pain development, which might be influenced by familial factors, including genes.
METHODS - Associations between pain sensitivity and salivary cortisol and familial confounding in these associations were examined in 88 female, community-based twin pairs (75% monozygotic, mean age 29 y). Cortisol was assessed after 0.25 mg dexamethasone (DEX), recovery from 0.25 mg DEX, and after 0.5 mg DEX. Cold pressor task (CPT) pain ratings were obtained at threshold and at tolerance. Conditioned pain modulation (CPM) was examined using thermal heat as the testing stimulus and hot water as the conditioning stimulus. Generalized estimating equation models were used and adjusted for baseline pain rating, age, and other relevant covariates.
RESULTS - After controlling for baseline cortisol, greater cortisol suppression following DEX administration and lower recovery cortisol levels were associated with higher pain ratings at tolerance during the CPT (Bs=-2.42 to -17.82; Ps=0.031 to<0.001) as well as with reduced CPM (Bs=-0.92 to -1.68; Ps=0.003 to 0.046). Interestingly, familial confounding was evident in the CPT and CPM during recovery from DEX administration, but not immediately following DEX administration.
DISCUSSION - These findings contribute to understanding possible mechanisms underlying chronic pain by demonstrating that HPA axis response to negative feedback is related to pain sensitivity.
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MeSH Terms
Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia.
Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, Basford M, Bastarache L, Roden DM, Denny JC, Larsen E, Winick N, Carroll WL, Cheng C, Pei D, Fernandez CA, Liu C, Smith C, Loh ML, Raetz EA, Hunger SP, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Mattano LA, Relling MV
(2015) Blood 126: 1770-6
MeSH Terms: Biomarkers, Child, Cohort Studies, Dexamethasone, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucocorticoids, Humans, Male, Meta-Analysis as Topic, Neoplasm Staging, Osteonecrosis, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Receptors, N-Methyl-D-Aspartate, Risk Factors
Show Abstract · Added April 11, 2017
Glucocorticoids are important therapy for acute lymphoblastic leukemia (ALL) and their major adverse effect is osteonecrosis. Our goal was to identify genetic and nongenetic risk factors for osteonecrosis. We performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort comprising 2285 children with ALL, treated on the Children's Oncology Group AALL0232 protocol (NCT00075725), adjusting for covariates. The minor allele at SNP rs10989692 (near the glutamate receptor GRIN3A locus) was associated with osteonecrosis (hazard ratio = 2.03; P = 3.59 × 10(-7)). The association was supported by 2 replication cohorts, including 361 children with ALL on St. Jude's Total XV protocol (NCT00137111) and 309 non-ALL patients from Vanderbilt University's BioVU repository treated with glucocorticoids (odds ratio [OR] = 1.87 and 2.26; P = .063 and .0074, respectively). In a meta-analysis, rs10989692 was also highest ranked (P = 2.68 × 10(-8)), and the glutamate pathway was the top ranked pathway (P = 9.8 × 10(-4)). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR = 1.64; P = 2.5 × 10(-3)), and arterial embolism and thrombosis (OR = 1.88; P = 4.2 × 10(-3)). In conclusion, osteonecrosis was associated with inherited variations near glutamate receptor genes. Further understanding this association may allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.
© 2015 by The American Society of Hematology.
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19 MeSH Terms
Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function.
Burke SJ, May AL, Noland RC, Lu D, Brissova M, Powers AC, Sherrill EM, Karlstad MD, Campagna SR, Stephens JM, Collier JJ
(2015) J Biol Chem 290: 13401-16
MeSH Terms: 3T3-L1 Cells, Animals, Anti-Inflammatory Agents, Apoptosis, Benzimidazoles, Benzothiazoles, Blotting, Western, Cell Proliferation, Cells, Cultured, Dexamethasone, Gene Expression Profiling, Hepatocytes, Humans, Hydrocortisone, Immunoenzyme Techniques, Inflammation, Insulin, Insulin Secretion, Islets of Langerhans, Metabolomics, Mice, Mice, Inbred C57BL, Oxygen Consumption, RNA, Messenger, Rats, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Thiazoles
Show Abstract · Added July 28, 2015
Glucocorticoids signal through the glucocorticoid receptor (GR) and are administered clinically for a variety of situations, including inflammatory disorders, specific cancers, rheumatoid arthritis, and organ/tissue transplantation. However, glucocorticoid therapy is also associated with additional complications, including steroid-induced diabetes. We hypothesized that modification of the steroid backbone is one strategy to enhance the therapeutic potential of GR activation. Toward this goal, two commercially unavailable, thiobenzothiazole-containing derivatives of hydrocortisone (termed MS4 and MS6) were examined using 832/13 rat insulinoma cells as well as rodent and human islets. We found that MS4 had transrepression properties but lacked transactivation ability, whereas MS6 retained both transactivation and transrepression activities. In addition, MS4 and MS6 both displayed anti-inflammatory activity. Furthermore, MS4 displayed reduced impact on islet β-cell function in both rodent and human islets. Similar to dexamethasone, MS6 promoted adipocyte development in vitro, whereas MS4 did not. Moreover, neither MS4 nor MS6 activated the Pck1 (Pepck) gene in primary rat hepatocytes. We conclude that modification of the functional groups attached to the D-ring of the hydrocortisone steroid molecule produces compounds with altered structure-function GR agonist activity with decreased impact on insulin secretion and reduced adipogenic potential but with preservation of anti-inflammatory activity.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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28 MeSH Terms
Duration of upper and lower extremity peripheral nerve blockade is prolonged with dexamethasone when added to ropivacaine: a retrospective database analysis.
Rasmussen SB, Saied NN, Bowens C, Mercaldo ND, Schildcrout JS, Malchow RJ
(2013) Pain Med 14: 1239-47
MeSH Terms: Adult, Aged, Amides, Anesthetics, Local, Anti-Inflammatory Agents, Databases, Factual, Dexamethasone, Epinephrine, Female, Humans, Linear Models, Logistic Models, Male, Middle Aged, Nerve Block, Orthopedic Procedures, Pain, Postoperative, Patient Satisfaction, Peripheral Nerves, Postoperative Complications, Retrospective Studies, Ropivacaine, Sensation Disorders, Shoulder, Young Adult
Show Abstract · Added May 27, 2014
BACKGROUND - Dexamethasone, when added to local anesthetics, has been shown to prolong the duration of peripheral nerve blocks; however, there are limited studies utilizing large numbers of patients. The purpose of this study was to examine the effect of adding dexamethasone to ropivacaine on duration of nerve blocks of the upper and lower extremity.
METHODS - We reviewed 1,040 patient records collected in an orthopedic outpatient surgery center that had received an upper or lower extremity peripheral nerve block with ropivacaine 0.5% with or without dexamethasone and/or epinephrine. The primary outcome was duration of analgesia in upper or lower extremity blocks containing dexamethasone as an adjunct. Secondary outcomes included postoperative patient pain scores, satisfaction, and the incidence of block related complications. Linear and ordinal logistic regression models were used to examine the independent effect of dexamethasone on outcomes.
RESULTS - Dexamethasone was observed to increase median block duration by 37% (95% confidence interval: 31-43%). The increased block duration persisted within body regions (upper and lower) and across a range of block types. Dexamethasone was also observed to reduce pain scores on the day of surgery (P = 0.001) and postoperative day 1 (P < 0.001). There was no significant difference in duration of nerve blocks when epinephrine (1:400,000) was added to 0.5% ropivacaine with or without dexamethasone.
CONCLUSION - The addition of dexamethasone to 0.5% ropivacaine prolongs the duration of peripheral nerve blocks of both the upper and lower extremity.
Wiley Periodicals, Inc.
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25 MeSH Terms
Primary epiphyseal arteriopathy in a mouse model of steroid-induced osteonecrosis.
Janke LJ, Liu C, Vogel P, Kawedia J, Boyd KL, Funk AJ, Relling MV
(2013) Am J Pathol 183: 19-25
MeSH Terms: Administration, Oral, Animals, Arterioles, Dexamethasone, Disease Models, Animal, Drug Administration Schedule, Epiphyses, Femur, Glucocorticoids, Male, Mice, Mice, Inbred BALB C, Osteonecrosis
Show Abstract · Added March 20, 2014
Patients undergoing glucocorticoid therapy for a variety of disorders, including autoimmune diseases and hematological malignancies, are at risk of developing osteonecrosis. Despite extensive research in both patients and animal models, the underlying pathogenesis remains unclear. Proposed inciting mechanisms include intravascular thrombotic occlusion, marrow fat hypertrophy, osteocyte and/or endothelial cell apoptosis, hypercoagulability, and vasoconstriction of specific arteries and arterioles supplying bone. Our laboratory has developed a model of steroid-induced osteonecrosis in BALBcJ mice which reflects clinically relevant exposures to glucocorticoids in which treated mice develop osteonecrosis of the distal femoral epiphysis when administered 4 to 8 mg/L dexamethasone in drinking water for 6 weeks. We identified lesions in arterioles supplying this area, with the mildest occurring in knees without any evidence of osteonecrosis. However, arteriopathy was more common among mice that did versus did not develop osteonecrosis (P < 0.0001); in mice with osteonecrosis, the associated vessels showed transmural necrosis and thickening of the vessel wall progressing to the point of luminal obstruction. In the most severe cases of osteonecrosis, end-stage lesions consisted of fully occluded vessels with marrow and bone necrosis involving the entire epiphysis. We propose that a primary arteriopathy is the initiating event in the genesis of steroid-induced osteonecrosis and provides a basis for future investigation of this disease process.
Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Substrain-specific differences in survival and osteonecrosis incidence in a mouse model.
Kawedia JD, Janke L, Funk AJ, Ramsey LB, Liu C, Jenkins D, Boyd KL, Relling MV
(2012) Comp Med 62: 466-71
MeSH Terms: Analysis of Variance, Animals, Body Weight, Dexamethasone, Dose-Response Relationship, Drug, Mice, Mice, Inbred BALB C, Osteonecrosis, Species Specificity, Survival Analysis
Show Abstract · Added March 20, 2014
We previously reported strain-specific susceptibility to dexamethasone-induced osteonecrosis in mice. Here we report that BALB/cJ and BALB/cAnNHsd mice display substrain-specific differences in dexamethasone-induced adverse effects. As compared with BALB/cJ mice, BALB/cAnNHsd weighed more (16.6 g compared with 13.7 g) at the beginning of dexamethasone administration on postnatal day 28 and fewer died during the dexamethasone regimen (10% compared with 50%). Although the 2 substrains had similar plasma concentrations of dexamethasone, BALB/cJ mice were more susceptible to developing dexamethasone-induced osteonecrosis. A higher dose of dexamethasone (8 mg/L) throughout the treatment period compared with a lower dose (8 mg/L loading dose during week 1 followed by 4 mg/L for the remainder of the treatment period) and earlier start of treatment (postnatal day 24 compared with postnatal day 28) was required to induce osteonecrosis with a similar frequency in BALB/cAnNHsd mice as in BALB/cJ mice. Our results show, for the first time, substrain-specific differences in the development of osteonecrosis in mice.
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10 MeSH Terms
A potential role for insulin resistance in experimental pulmonary hypertension.
West J, Niswender KD, Johnson JA, Pugh ME, Gleaves L, Fessel JP, Hemnes AR
(2013) Eur Respir J 41: 861-71
MeSH Terms: Animals, Body Composition, Bone Morphogenetic Protein Receptors, Type II, Cell Line, Dexamethasone, Diet, High-Fat, Disease Models, Animal, Energy Metabolism, Humans, Hypertension, Pulmonary, Insulin Resistance, Male, Mice, Mice, Transgenic, Mutation, Phenotype, Protein Transport, Rats, Receptors, Glucocorticoid
Show Abstract · Added May 20, 2014
Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2(R899X) was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2(R899X) mice treated with dexamethasone. Compared to controls, Bmpr2(R899X) mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0 ± 0.4 versus 2.2 ± 1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2(R899X) mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.
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19 MeSH Terms
Impact of maternal dexamethasone on coronary PGE(2) production and prostaglandin-dependent coronary reactivity.
Roghair RD, Volk KA, Lamb FS, Segar JL
(2012) Am J Physiol Regul Integr Comp Physiol 303: R513-9
MeSH Terms: Angiotensin II, Animals, Cells, Cultured, Coronary Vessels, Cyclooxygenase Inhibitors, Dexamethasone, Dinoprostone, Female, Glucocorticoids, Indomethacin, Models, Animal, Muscle, Smooth, Vascular, Pregnancy, Prenatal Exposure Delayed Effects, Prostaglandins, Sheep, Vasoconstriction, Vasoconstrictor Agents, Vasodilation
Show Abstract · Added February 22, 2016
Intrauterine growth restriction is associated with increased fetal glucocorticoid exposure and an increased risk of adult coronary artery disease. Coronary arteries from sheep exposed to early gestation dexamethasone (Dex) have increased constriction to angiotensin II (ANG II). Prostaglandin E(2) (PGE(2)) helps maintain coronary dilation, but PGE(2) production is acutely decreased by Dex administration. We hypothesized early gestation Dex exposure impairs adult coronary PGE(2) production with subsequent increases in coronary reactivity. Dex was administered to ewes at 27-28 days gestation (term 145 days). Coronary reactivity was assessed by wire myography in offspring at 4 mo of age (N = 5 to 7). Coronary smooth muscle cells were cultured and prostaglandin production was measured after 90 min incubation with radiolabeled arachidonate. Coronary myocytes from Dex-exposed lambs had a significant decrease in PGE(2) production that was reversed with ANG II incubation. Dex-exposed coronary arteries had increased constriction to ANG II and attenuated dilatation to arachidonic acid, with the greatest difference seen after the endothelium was inactivated by rubbing. Preincubation with the cyclooxygenase (COX) inhibitor indomethacin altered control responses and recapitulated the heightened coronary tone seen following Dex exposure. We conclude that impaired coronary smooth muscle COX-mediated PGE(2) production contributes to the coronary dysfunction elicited by early gestation Dex. Programmed inhibition of vasodilatory prostanoid production may link an adverse intrauterine environment with adult coronary artery disease.
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19 MeSH Terms