Inactivation of Corticotropin- Releasing Hormone–Induced Insulinotropic Role by High- Altitude Hypoxia

Total Page:16

File Type:pdf, Size:1020Kb

Inactivation of Corticotropin- Releasing Hormone–Induced Insulinotropic Role by High- Altitude Hypoxia Diabetes Volume 64, March 2015 785 Ke Hao,1 Fan-Ping Kong,1 Yu-Qi Gao,2 Jia-Wei Tang,1 Jian Chen,2 A. Mark Evans,3 Stafford L. Lightman,4 Xue-Qun Chen,1 and Ji-Zeng Du1 Inactivation of Corticotropin- Releasing Hormone–Induced Insulinotropic Role by High- Altitude Hypoxia Diabetes 2015;64:785–795 | DOI: 10.2337/db14-0500 We have shown that hypoxia reduces plasma insulin, dysfunction and illness, particularly acute mountain sick- which correlates with corticotropin-releasing hormone ness (AMS) (1). During the construction of the Qinghai- (CRH) receptor 1 (CRHR1) in rats, but the mechanism Tibet railway (at altitudes of 3,000–5,000 m) in China, remains unclear. Here, we report that hypobaric hypoxia at .100,000 construction workers were involved, and 51% an altitude of 5,000 m for 8 h enhances rat plasma CRH, of them developed AMS (2). Moreover, since the railway METABOLISM corticosterone, and glucose levels, whereas the plasma began service, .10 million travelers have visited the Tibet insulin and pancreatic ATP/ADP ratio is reduced. In islets region in 2012, of whom 31% developed AMS despite cultured under normoxia, CRH stimulated insulin release in traveling with an oxygen supply on the train (3). Increas- a glucose- and CRH-level–dependent manner by activat- ing CRHR1 and thus the cAMP-dependent protein kinase ing evidence in both humans and animals suggests that pathway and calcium influx through L-type channels. In exposure to either high-altitude or hypobaric hypoxia fl islets cultured under hypoxia, however, the insulinotropic in uences plasma insulin levels and glucose homeostasis, effect of CRH was inactivated due to reduced ATP and depending on the oxygen level and duration of exposure cAMP and coincident loss of intracellular calcium oscilla- (4–9). We previously showed that subacute hypoxia at an tions. Serum and glucocorticoid-inducible kinase 1 (SGK1) altitude of 5,000 m for 5 days reduces plasma insulin in also played an inhibitory role. In human volunteers rapidly rats, and this effect is blocked by a corticotropin-releasing ascended to 3,860 m, plasma CRH and glucose levels in- hormone (CRH) receptor 1 (CRHR1) antagonist in vivo creased without a detectable change in plasma insulin. By (10). However, the underlying mechanisms have not been contrast, volunteers with acute mountain sickness (AMS) clearly addressed. exhibited a marked decrease in HOMA insulin sensitivity Insulin, the unique hypoglycemic hormone, plays a (HOMA-IS) and enhanced plasma CRH. In conclusion, hyp- crucial role in maintaining glucose sensing in pancreatic oxia may attenuate the CRH-insulinotropic effect by re- b-cells and regulating glucose uptake in a variety of tis- ducing cellular ATP/ADP ratio, cAMP and calcium influx, sues and cells during health and disease (11,12). Apart and upregulated SGK1. Hypoxia may not affect HOMA-IS in healthy volunteers but reduces it in AMS volunteers. from glucose, many neural and endocrine hormones reg- ulate pancreatic insulin release (13). In particular, CRH is the key regulator of the hypothalamic-pituitary-adrenal To enjoy social activities, millions of people travel to high (HPA) axis; is activated by a variety of stressors, including altitudes every year. High-altitude hypoxia often induces hypoxia; and mediates a variety of neural and endocrine 1Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Corresponding authors: Ji-Zeng Du, [email protected], and Xue-Qun Chen, School of Medicine, Key Laboratory of Medical Neurobiology of the Ministry of [email protected]. Health of China, Zhejiang University, Hangzhou, China Received 27 March 2014 and accepted 25 September 2014. 2Department of Pathophysiology and High Altitude Physiology, College of High This article contains Supplementary Data online at http://diabetes Altitude Military Medicine, Third Military Medical University, Chongqing, China .diabetesjournals.org/lookup/suppl/doi:10.2337/db14-0500/-/DC1. 3Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, U.K. © 2015 by the American Diabetes Association. Readers may use this article as 4Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, long as the work is properly cited, the use is educational and not for profit, and University of Bristol, Bristol, U.K. the work is not altered. 786 Hypoxia Inactivates Insulinotropic Role of CRH Diabetes Volume 64, March 2015 response to stress (14). Studies have shown that CRHR1 day, starting 2 days before the flight to Rikaze, China, at exists in human, mouse, and rat islets (15,16) and that 3,860 m altitude, volunteers were given a Rhodiola capsule CRH enhances calcium influx (17), increases insulin con- (Z10980020, Tibet Nuodikang Medicine, Lhasa, China) to tent, and elevates insulin secretion in a glucose-dependent improve endurance and resistance to hypoxia. On the manner in cultured islets (15,16,18). Furthermore, CRH third morning at Rikaze, SpO2 was measured, and fasting modulates development, proliferation, and antiapoptosis blood samples were collected again. The AMS score was in islets (15,16,19). These findings suggest that CRH and obtained using the Lake Louise Score $3 (23). Plasma was CRHR1 play significant roles in regulating insulin release obtained by centrifugation as soon as possible and stored under normal conditions. We previously showed that at 280°C until use. hypobaric hypoxia results in upregulated CRH in the para- ventricular nucleus and corticosterone (CORT) in the Hypoxia Exposure of Animals and Isolated Islets plasma of rats (20,21), which was associated with reduced The rats in the hypoxia group were placed in a hypobaric plasma insulin (reversed by a CRHR1 antagonist) and chamber (FLYDWC-50-IIC; AVIC Guizhou Fenglei Avia- glucose levels in vivo (10). tion Armament Co., Ltd., Guizhou, China) and exposed to In the current study, we address the mechanisms by hypoxia of 2,000 m altitude (79.97 kPa, equivalent to which CRHR1 mediates insulin secretion and glucose 16.0% O2 at sea level) or 5,000 m altitude (54.02 kPa, homeostasis during hypoxia. To achieve this goal, we 10.8% O2). The chamber was opened daily for 30 min to completed comparative studies on rats under hypobaric clean and replenish food and water during the 5 days of hypoxia and on humans following a rapid ascent to the exposure. The normoxia group was placed in an identical Tibetan plateau. Under hypoxia, the cell metabolic state chamber at sea level (100.08 kPa, 20.9% O2). Rats re- switches from aerobic metabolism toward anaerobic ceived intraperitoneal injections of the CRHR1 antagonist fi glycolysis, which may lead to reduced ATP production cp-154,526 (30 mg/kg) (donated by P zer, Groton, CT), the fi and plasma insulin levels (10). In the present article, the glucocorticoid receptor (GR)-speci c antagonist RU486 data suggest that a fall in the ATP/ADP ratio and loss of (50 mg/kg) (Tocris, Bristol, U.K.), or vehicle 30 min before cAMP signaling capacity during hypoxia attenuate voltage- exposure. After exposure, rats were killed by decapitation – gated calcium influx and, thus, inactivate insulinotropic at 1300 1400 h, and trunk blood was collected. Plasma was 2 action of CRH. obtained by centrifugation and stored at 80°C. The liver and pancreas were immediately removed, frozen in liquid RESEARCH DESIGN AND METHODS nitrogen, and stored at 280°C until use. Isolated islets in Animals the hypoxia group were incubated in 5% CO2 and various Male Sprague-Dawley rats weighing 200–220 g were pur- O2 conditions delivered by the hypoxia chamber (ProOx chased from the Laboratory Animal Center of Zhejiang model P110 and ProCO2 model P120 systems; BioSpherix, Province, China (certification no. SCXK2008-0033), and Lacona, NY) (24). maintained in a 12-h light/dark cycle (lights on at 0600 h) Insulin Secretion 6 at 20 2°C with food and water ad libitum. Rats were Size-matched islets were washed and preincubated for 1 h adapted for 1 week before experiments. All animal experi- in RPMI 1640 medium containing 2.8 mmol/L glucose, ments were approved by the Animal Care and Use Com- 10 mmol/L HEPES, and 0.1% BSA. Ten islets per well were mittee of the School of Medicine, Zhejiang University. then incubated in testing RPMI 1640 medium containing Islet Isolation 10 mmol/L HEPES and 0.1% BSA with the indicated glucose Pancreatic islets were isolated by collagenase digestion and drugs under hypoxia or normoxia. At the end of the from rats as previously described (22). Intact islets were experiments, the testing medium was collected for insulin cultured in RPMI 1640 medium (containing 8.3 mmol/L measurement using a rat insulin enzyme immunosorbent glucose) supplemented with 10% FBS, 10 mmol/L HEPES, assay kit (Mercodia, Uppsala, Sweden), whereas islets were and penicillin/streptomycin (Invitrogen, Carlsbad, CA) at placed in lysis buffer for quantitative PCR (qPCR) assay. 37°C under 5% CO and 21% O for overnight recovery 2 2 Calcium Imaging before experiments. Islets were washed and loaded with 5 mmol/L Fluo-4 AM Human Hypoxia Exposure (Molecular Probes, Eugene, OR) in Krebs-Ringer bicarbon- Sixty-seven healthy male volunteers (18–23 years old) ate HEPES buffer comprising (in mmol/L) 129 NaCl, 4.7 were recruited in Chengdu, China, at 540 m altitude, as KCl, 1.2 KH2PO4, 5.0 NaHCO3, 2.0 CaCl2, 1.2 MgSO4,10 basal lowland control subjects. They were informed about HEPES, and 0.1% BSA at pH 7.4 containing 5.6 mmol/L the objectives of the study and agreed to the experimental glucose for 1 h at 37°C. Calcium-free conditions were protocols. All studies were approved by the Ethics Com- achieved by use of calcium-free Krebs-Ringer bicarbonate mittee of the Third Military Medical University.
Recommended publications
  • Protection of Insulin‑Like Growth Factor 1 on Experimental Peripheral Neuropathy in Diabetic Mice
    MOLECULAR MEDICINE REPORTS 18: 4577-4586, 2018 Protection of insulin‑like growth factor 1 on experimental peripheral neuropathy in diabetic mice HUA WANG, HAO ZHANG, FUMING CAO, JIAPING LU, JIN TANG, HUIZHI LI, YIYUN ZHANG, BO FENG and ZHAOSHENG TANG Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China Received December 24, 2017; Accepted July 19, 2018 DOI: 10.3892/mmr.2018.9435 Abstract. The present study investigated whether insulin-like the IGF-1-PPP group compared with the IGF-1 group; however, growth factor-1 (IGF-1) exerts a protective effect against no significant difference was observed in the expression neuropathy in diabetic mice and its potential underlying levels of p-p38 following treatment with IGF-1. The results mechanisms. Mice were divided into four groups: Db/m of the present study demonstrated that IGF-1 may improve (control), db/db (diabetes), IGF-1-treated db/db and neuropathy in diabetic mice. This IGF-1-induced neurotrophic IGF-1-picropodophyllin (PPP)-treated db/db. Behavioral effect may be associated with the increased phosphorylation studies were conducted using the hot plate and von Frey levels of JNK and ERK, not p38; however, it was attenuated by methods at 6 weeks of age prior to treatment. The motor nerve administration of an IGF-1R antagonist. conduction velocity (NCV) of the sciatic nerve was measured using a neurophysiological method at 8 weeks of age. The Introduction alterations in the expression levels of IGF-1 receptor (IGF-1R), c-Jun N-terminal kinase (JNK), extracellular signal-regulated An epidemiological survey demonstrated that the prevalence kinase (ERK), p38 and effect of IGF-1 on the sciatic nerve of diabetes in adults ≥18 years old in China was ≤11.6% (1).
    [Show full text]
  • Receptor Activity Modifying Proteins (Ramps) Interact with the VPAC2 Receptor and CRF1 Receptors and Modulate Their Function
    British Journal of DOI:10.1111/j.1476-5381.2012.02202.x www.brjpharmacol.org BJP Pharmacology RESEARCH PAPER Correspondence David R Poyner, School of Life and Health Sciences, Aston University, Birmingham, Receptor activity modifying B4 7ET, UK. E-mail: [email protected] ---------------------------------------------------------------- proteins (RAMPs) interact Current address: *Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, 381 with the VPAC2 receptor Royal Parade, Parkville, Victoria 3052 Australia; †Discovery Sciences, AstraZeneca R&D, and CRF1 receptors and Mölndal, Sweden; ‡R&I iMED, AstraZeneca R&D, Mölndal, Sweden. modulate their function ---------------------------------------------------------------- Keywords D Wootten1*, H Lindmark2†, M Kadmiel3, H Willcockson3, KM Caron3, receptor activity-modifying proteins (RAMPs); RAMP1; J Barwell1, T Drmota2‡ and DR Poyner1 RAMP2; RAMP3; VPAC2 receptor; +/- CRF1 receptor; Ramp2 mice; 1 2 School of Life and Health Sciences, Aston University, Birmingham, UK, Department of Lead G-protein coupling; biased Generation, AstraZeneca R&D, Mölndal, Sweden, and 3Department of Cellular and Molecular agonism Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA ---------------------------------------------------------------- Received 10 July 2012 Revised 15 August 2012 Accepted 28 August 2012 BACKGROUND AND PURPOSE Although it is established that the receptor activity modifying proteins (RAMPs) can interact with a number of GPCRs, little is known about the consequences of these interactions. Here the interaction of RAMPs with the glucagon-like peptide 1 receptor (GLP-1 receptor), the human vasoactive intestinal polypeptide/pituitary AC-activating peptide 2 receptor (VPAC2) and the type 1 corticotrophin releasing factor receptor (CRF1) has been examined. EXPERIMENTAL APPROACH GPCRs were co-transfected with RAMPs in HEK 293S and CHO-K1 cells.
    [Show full text]
  • Secretin and Autism: a Clue but Not a Cure
    SCIENCE & MEDICINE Secretin and Autism: A Clue But Not a Cure by Clarence E. Schutt, Ph.D. he world of autism has been shaken by NBC’s broadcast connections could not be found. on Dateline of a film segment documenting the effect of Tsecretin on restoring speech and sociability to autistic chil- The answer was provided nearly one hundred years ago by dren. At first blush, it seems unlikely that an intestinal hormone Bayless and Starling, who discovered that it is not nerve signals, regulating bicarbonate levels in the stomach in response to a but rather a novel substance that stimulates secretion from the good meal might influence the language centers of the brain so cells forming the intestinal mucosa. They called this substance profoundly. However, recent discoveries in neurobiology sug- “secretin.” They suggested that there could be many such cir- gest several ways of thinking about the secretin-autism connec- culating substances, or molecules, and they named them “hor- tion that could lead to the breakthroughs we dream about. mones” based on the Greek verb meaning “to excite”. As a parent with more than a decade of experience in consider- A simple analogy might help. If the body is regarded as a commu- ing a steady stream of claims of successful treatments, and as a nity of mutual service providers—the heart and muscles are the pri- scientist who believes that autism is a neurobiological disorder, I mary engines of movement, the stomach breaks down foods for have learned to temper my hopes about specific treatments by distribution, the liver detoxifies, and so on—then the need for a sys- seeing if I could construct plausible neurobiological mechanisms tem of messages conveyed by the blood becomes clear.
    [Show full text]
  • Alteration in Phosphorylation of P20 Is Associated with Insulin Resistance Yu Wang,1 Aimin Xu,1 Jiming Ye,2 Edward W
    Alteration in Phosphorylation of P20 Is Associated With Insulin Resistance Yu Wang,1 Aimin Xu,1 Jiming Ye,2 Edward W. Kraegen,2 Cynthia A. Tse,1 and Garth J.S. Cooper1,3 We have recently identified a small phosphoprotein, P20, insulin action, such as the activation of insulin receptors, as a common intracellular target for insulin and several postreceptor signal transduction, and the glucose trans- of its antagonists, including amylin, epinephrine, and cal- port effector system, have been implicated in this disease citonin gene-related peptide. These hormones elicit phos- (3,4). Defective insulin receptor kinase activity, reduced phorylation of P20 at its different sites, producing three insulin receptor substrate-1 tyrosine phosphorylation, and phosphorylated isoforms: S1 with an isoelectric point (pI) decreased phosphatidylinositol (PI)-3 kinase activity were value of 6.0, S2 with a pI value of 5.9, and S3 with a pI observed in both human type 2 diabetic patients as well as value of 5.6 (FEBS Letters 457:149–152 and 462:25–30, animal models, such as ob/ob mice (5,6). 1999). In the current study, we showed that P20 is one In addition to the intrinsic defects of the insulin receptor of the most abundant phosphoproteins in rat extensor digitorum longus (EDL) muscle. Insulin and amylin an- and postreceptor signaling components, other circulating tagonize each other’s actions in the phosphorylation of factors, such as tumor necrosis factor-␣, leptin, free fatty this protein in rat EDL muscle. Insulin inhibits amylin- acids, and amylin, may also contribute to the pathogenesis evoked phosphorylation of S2 and S3, whereas amylin of insulin resistance (7–11).
    [Show full text]
  • Clinical Policy: Mecasermin (Increlex) Reference Number: ERX.SPA.209 Effective Date: 01.11.17 Last Review Date: 11.17 Revision Log
    Clinical Policy: Mecasermin (Increlex) Reference Number: ERX.SPA.209 Effective Date: 01.11.17 Last Review Date: 11.17 Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Mecasermin (Increlex®) is an insulin growth factor-1 (IGF-1) analogue. FDA Approved Indication(s) Increlex is indicated for the treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Limitation(s) of use: Increlex is not a substitute to GH for approved GH indications. Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria It is the policy of health plans affiliated with Envolve Pharmacy Solutions™ that Increlex is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Severe Primary IGF-1 Deficiency (must meet all): 1. Diagnosis of IGF-1 deficiency growth failure and associated growth failure with one of the following (a or b): a. Severe primary IGF-1 deficiency as defined by all (i through iii): i. Height standard deviation score (SDS) ≤ –3.0; ii. Basal IGF-1 SDS ≤ –3.0; iii. Normal or elevated GH level; b. GH gene deletion with development of neutralizing antibodies to GH; 2. Prescribed by or in consultation with an endocrinologist; 3. Age ≥ 2 and <18 years; 4. At the time of request, member does not have closed epiphyses; 5. Dose does not exceed 0.12 mg/kg twice daily.
    [Show full text]
  • Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function
    Upsala J Med Sci 77: 183-188, 1972 Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function HENRY JOHANSSON and ANDERS SEGERSTROM From the Department of Surgery, University Hospital, Uppsala, Sweden ABSTRACT MATERIAL Gastrointestinal propulsive motility was studied after The material consisted of 109 male albino rats (Sprague- inhgastric deposition of a non-absorbable isotope in Dawley) fed on laboratory food and with free access to rats after subcutaneous glucagon injections. Glucagon water. The animals were distributed at random in fol- administration was followed by retardation of gastric lowing series: emptying. The results indicated that the retarding effect Series I of glucagon on gastrointestinal propulsion was independent The influence of glucagon on gastrointestinal motility in of the presence of both thyroid and parathyroid tissue. intact rats. The observation period was 7 days. The hypocalcemic effect of glucagon was exerted in- dependently of the presence of thyroid tissue, Le. thyro- 1. Intact rats given 1.2 mg glucagon/kg body weight calcitonin. (GN-A, n= 6) 2. Intact rats given 4.8 mg glucagon/kg body weight (GN-B, n= 5) 3. Intact rats given 9.6 mg glucagon/kg body weight INTRODUCTION (GN-C, n= 12) 4. Intact rats given glucine buffert (GLY, n= 10). Glucagon is known to influence gastrointestinal Series I1 motility. In man, Dotevall & Kock (2) observed The influence of glucagon on gastrointestinal motility in that glucagon retarded gastrointestinal motility parathyroidectomized rats. The animals were given 4.8 independently of the hyperglucemia. In dogs, mg glucagon/kg body weight. The observation period glucagon retarded motility of the stomach ani was 90 days.
    [Show full text]
  • AVP-Induced Counter-Regulatory Glucagon Is Diminished in Type 1 Diabetes
    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.30.927426; this version posted January 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes Angela Kim1,2, Jakob G. Knudsen3,4, Joseph C. Madara1, Anna Benrick5, Thomas Hill3, Lina Abdul Kadir3, Joely A. Kellard3, Lisa Mellander5, Caroline Miranda5, Haopeng Lin6, Timothy James7, Kinga Suba8, Aliya F. Spigelman6, Yanling Wu5, Patrick E. MacDonald6, Ingrid Wernstedt Asterholm5, Tore Magnussen9, Mikkel Christensen9,10,11, Tina Vilsboll9,10,12, Victoria Salem8, Filip K. Knop9,10,12,13, Patrik Rorsman3,5, Bradford B. Lowell1,2, Linford J.B. Briant3,14,* Affiliations 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. 2Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX4 7LE, UK. 4Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen. 5Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Göteborg, 405 30, Göteborg, Sweden. 6Alberta Diabetes Institute, 6-126 Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, T6G 2E1, Canada. 7Department of Clinical Biochemistry, John Radcliffe, Oxford NHS Trust, OX3 9DU, Oxford, UK. 8Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, W12 0NN, UK.
    [Show full text]
  • Localization of Glucokinase Gene Expression in the Rat Brain Ronald M
    Localization of Glucokinase Gene Expression in the Rat Brain Ronald M. Lynch, Linda S. Tompkins, Heddwen L. Brooks, Ambrose A. Dunn-Meynell, and Barry E. Levin The brain contains a subpopulation of glucosensing neu- rons that alter their firing rate in response to elevated glucose concentrations. In pancreatic ␤-cells, gluco- ammalian feeding behavior and general energy kinase (GK), the rate-limiting enzyme in glycolysis, medi- homeostasis appear to be regulated by circu- ates glucose-induced insulin release by regulating intra- lating levels of nutrients (glucose) and pep- cellular ATP production. A similar role for GK is pro- tides (e.g., leptin, insulin). Sensors to detect lev- posed to underlie neuronal glucosensing. Via in situ M els of these factors have been found to reside within specific hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large popu- nuclei of the hypothalamus (1–8), where central regulation of lations of glucosensing neurons (the arcuate, ventrome- energy homeostasis is believed to be coordinated. For exam- dial, dorsomedial, and paraventricular nuclei and the lat- ple, large changes in blood glucose are correlated with cen- eral area). GK also was found in brain areas without trally mediated responses such as thermogenesis through known glucosensing neurons (the lateral habenula, the activation of the sympathetic nervous system. These changes bed nucleus stria terminalis, the inferior olive, the are monitored by the brain (9–11), and such responses are retrochiasmatic and medial preoptic areas, and the thal- altered in obesity-prone animals (11–13). Moreover, lesions amic posterior paraventricular, interpeduncular, oculo- of the ventromedial hypothalamus (VMH) prevent the hypo- motor, and anterior olfactory nuclei).
    [Show full text]
  • And Oxytocin-Induced Glucagon Secretion in V1b Vasopressin Receptor Knockout Mice
    361 Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice Yoko Fujiwara, Masami Hiroyama, Atsushi Sanbe, Junji Yamauchi, Gozoh Tsujimoto1 and Akito Tanoue Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan 1Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan (Requests for offprints should be addressed to A Tanoue; Email: [email protected]) Abstract [Arg8]-vasopressin (AVP) and oxytocin (OT) are neurohy- CL-14-26 further inhibited AVP- and OT-induced glucagon pophysial hormones which exert various actions, including secretions in islets of V1bRC/C mice (57 and 69% of the the control of blood glucose, in some peripheral tissues. To stimulation values respectively). In addition, both AVP and investigate the type of receptors involved in AVP- and OT stimulated glucagon secretion with the same efficacy in OT-induced glucagon secretion, we investigated the effect V1bRK/K mice as in V1bRC/C mice. AVP- and of these peptides on glucagon secretion in islets of OT-induced glucagon secretion in V1bRK/K mice was wild-type (V1bRC/C) and vasopressin V1b receptor significantly inhibited by CL-14-26. These results demonstrate knockout (V1bRK/K) mice. AVP-induced glucagon that V1b receptors can mediate OT-induced glucagon secretion secretion was significantly inhibited by the selective V1b and OTreceptors can mediate AVP-induced glucagon secretion receptor antagonist, SSR149415 (30%), and OT-induced in islets from V1bRC/C mice in the presence of a heterologous glucagon secretion by the specific OT receptor antagonist, antagonist, while AVP and OT can stimulate glucagon secretion ð Þ ½ ð Þ2; 4; 9 d CH2 5 Tyr Me Thr Tyr-NH2 OVT (CL-14-26) through the OTreceptors in V1bRK/K mice, suggesting that C C (45%), in islets of V1bR / mice.
    [Show full text]
  • Biomoleculesbiomolecules
    1414Unit Objectives BiomoleculesBiomolecules After studying this Unit, you will be able to • explain the characteristics of “It is the harmonious and synchronous progress of chemical biomolecules like carbohydrates, reactions in body which leads to life”. proteins and nucleic acids and hormones; • classify carbohydrates, proteins, A living system grows, sustains and reproduces itself. nucleic acids and vitamins on the The most amazing thing about a living system is that it basis of their structures; is composed of non-living atoms and molecules. The • explain the difference between pursuit of knowledge of what goes on chemically within DNA and RNA; a living system falls in the domain of biochemistry. Living • describe the role of biomolecules systems are made up of various complex biomolecules in biosystem. like carbohydrates, proteins, nucleic acids, lipids, etc. Proteins and carbohydrates are essential constituents of our food. These biomolecules interact with each other and constitute the molecular logic of life processes. In addition, some simple molecules like vitamins and mineral salts also play an important role in the functions of organisms. Structures and functions of some of these biomolecules are discussed in this Unit. 14.114.114.1 Carbohydrates Carbohydrates are primarily produced by plants and form a very large group of naturally occurring organic compounds. Some common examples of carbohydrates are cane sugar, glucose, starch, etc. Most of them have a general formula, Cx(H2O)y, and were considered as hydrates of carbon from where the name carbohydrate was derived. For example, the molecular formula of glucose (C6H12O6) fits into this general formula, C6(H2O)6. But all the compounds which fit into this formula may not be classified as carbohydrates.
    [Show full text]
  • Insulin Products and the Cost of Diabetes Treatment
    November 19, 2018 Insulin Products and the Cost of Diabetes Treatment Insulin is a hormone that regulates the storage and use of would involve a consistent insulin level between meals sugar (glucose) by cells in the body. When the pancreas combined with a mealtime level of insulin that has a rapid does not make enough insulin (type 1 diabetes) or it cannot onset and duration of action to match the glucose peak that be used effectively (type 2 diabetes), sugar builds up in the occurs after a meal. The original insulin, also called regular blood. This may lead to serious complications, such as heart insulin, is a short-acting type of product with a duration of disease, stroke, blindness, kidney failure, amputation of action of about 8 hours, making it less suitable for toes, feet, or limbs. Prior to the discovery of insulin providing 24-hour coverage. treatment, type 1 diabetics usually died from this disease. In the late 1930s through the 1950s, regular insulin was There were 23.1 million diagnosed cases of diabetes in the altered by adding substances (protamine and zinc) to gain United States in 2015 according to the Centers for Disease longer action; these are called intermediate-acting insulins. Control and Prevention (CDC). Adding an estimated 7.2 One such advance (neutral protamine Hagedorn, or NPH) million undiagnosed cases brings the total to 30.3 million was patented in 1946 and is still in use today. It allowed for (9.4% of U.S. population). People with type 1 diabetes, the combination of two types of insulin in premixed vials about 5% of U.S.
    [Show full text]
  • Celastrol Suppresses Experimental Autoimmune Encephalomyelitis Via MAPK/SGK1-Regulated Mediators of Autoimmune Pathology
    Inflammation Research (2019) 68:285–296 https://doi.org/10.1007/s00011-019-01219-x Inflammation Research ORIGINAL RESEARCH PAPER Celastrol suppresses experimental autoimmune encephalomyelitis via MAPK/SGK1-regulated mediators of autoimmune pathology Shivaprasad H. Venkatesha1,2 · Kamal D. Moudgil1,2,3 Received: 17 November 2018 / Revised: 10 January 2019 / Accepted: 11 February 2019 / Published online: 28 February 2019 © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019 Abstract Objective and design Multiple sclerosis (MS) is a debilitating autoimmune disease involving immune dysregulation of the pathogenic T helper 17 (Th17) versus protective T regulatory (Treg) cell subsets, besides other cellular aberrations. Studies on the mechanisms underlying these changes have unraveled the involvement of mitogen-activated protein kinase (MAPK) pathway in the disease process. We describe here a gene expression- and bioinformatics-based study showing that celastrol, a natural triterpenoid, acting via MAPK pathway regulates the downstream genes encoding serum/glucocorticoid regulated kinase 1 (SGK1), which plays a vital role in Th17/Treg differentiation, and brain-derived neurotrophic factor (BDNF), which is a neurotrophic factor, thereby offering protection against experimental autoimmune encephalomyelitis (EAE) in mice. Methods We first tested the gene expression profile of splenocytes of EAE mice in response to the disease-related antigen, myelin oligodendrocyte glycoprotein (MOG), and then examined the effect of celastrol on that profile. Results Interestingly, celastrol reversed the expression of many MOG-induced genes involved in inflammation and immune pathology. The MAPK pathway involving p38MAPK and ERK was identified as one of the mediators of celastrol action.
    [Show full text]