DOCSLIB.ORG

Mechanisms Underlying Cardiovascular Benefits of Sodium Glucose Co-Transporter-2 Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mechanisms Underlying Cardiovascular Benefits of Sodium Glucose Co-Transporter-2 Inhibitors MECHANISMS UNDERLYING CARDIOVASCULAR BENEFITS OF SODIUM GLUCOSE CO-TRANSPORTER-2 INHIBITORS: MYOCARDIAL SUBSTRATE OR SODIUM/HYDROGEN EXCHANGER? Hana Elisabeth Baker Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Cellular and Integrative Physiology, Indiana University January 2020 Accepted by the Graduate Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee ______________________________________ Johnathan D. Tune, Ph.D., Chair ______________________________________ David Basile, PhD December 2, 2019 ______________________________________ Adam Goodwill, PhD ______________________________________ Mark Kowala, PhD ______________________________________ Kieren Mather, MD ______________________________________ Mervyn (Dod) Michael, PhD ii © 2020 Hana Elisabeth Baker iii DEDICATION This work is dedicated to my husband, Mike, and our daughters, Audrey and Margret. Without their love, help, patience, and encouragement, this would have never been possible. iv ACKNOWLEDGEMENT The author would like to express her sincere gratitude to her advisor, Dr. Johnathan Tune, for the valuable discussions, encouragement, advice, guidance, and the freedom to set the directions of her research. Also, the author is grateful for the guidance provided by her thesis committee members including Drs. David Basile, Adam Goodwill, Mark Kowala, Kieren Mather and Dod Michael. Additionally, the author would like to thank her collaborator at the University of Alberta, Dr. Larry Fliegel for his help with NHE-1 activity assay in wild type NHE-1 transfected AP-1 cells and her collaborators at Eli Lilly and Company, Ajit Regmi and Dr. William Roell for their help with mRNA expression of SGLT-1 vs. SGLT-2 and to Fang Li for her help with the NHE-1 activity assay in iCell™ human IPSc-derived cardiomyocytes. v Hana Elisabeth Baker MECHANISMS UNDERLYING CARDIOVASCULAR BENEFITS OF SODIUM GLUCOSE CO-TRANSPORTER-2 INHIBITORS: MYOCARDIAL SUBSTRATE OR SODIUM/HYDROGEN EXCHANGER? Recent clinical outcome studies demonstrate that Sodium glucose cotransporter 2 inhibitors (SGLT2i) significantly reduce major adverse cardiovascular events and heart failure outcomes in subjects with type 2 diabetes mellitus. At present, several hypotheses have been proposed to explain the observed cardiovascular benefit of SGLT2i, however, the mechanisms responsible remain to be elucidated. This investigation tested the hypothesis that SGLT2i improves cardiac function and efficiency during acute, regional ischemia/reperfusion injury via preferential shifts in myocardial substrate selection and/or inhibition of cardiac sodium/hydrogen exchanger-1 (NHE-1). Our initial investigation evaluated the effects of 24 hour pretreatment of the SGLT2i canagliflozin on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in healthy swine. At the onset of ischemia, canagliflozin increased left ventricular end diastolic and systolic volumes which returned to baseline with reperfusion. This increased end diastolic volume was directly associated with increased stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial substrate uptake of glucose, lactate, fatty acids or ketones were detected between groups. In separate experiments using a longer 60 min coronary occlusion, canagliflozin significantly diminished myocardial infarct size. Subsequent studies investigated the effect of an acute administration (15-30 min pre-treatment) of canagliflozin and the NHE-1i cariporide on cardiac contractile function vi efficiency in response to myocardial ischemia/reperfusion injury. Similar to our initial studies, canagliflozin increased diastolic filling, stroke work and improved cardiac work efficiency relative to untreated control hearts during the ischemic period. In contrast, cariporide did not alter ventricular filling volume, cardiac output or work efficiency at any time point. Additional examination of AP-1 cells transfected with wild-type NHE-1 showed dose-dependent inhibition of NHE-1 activity by cariporide, while canagliflozin had minimal effect on overall activity. This investigation demonstrates that SGLT2i improves cardiac function and efficiency during acute, regional ischemia in healthy swine. However, the present data fail to support the hypothesis that these SGLT2i-mediated improvements involve either preferential alterations in myocardial substrate utilization or the inhibition of NHE-1 activity. Johnathan Tune, PhD, Chair vii TABLE OF CONTENTS List of Tables .................................................................................................................. xi List of Figures ................................................................................................................ xii List of Abbreviations ..................................................................................................... xvi Chapter 1: Introduction ................................................................................................... 1 Population at risk for cardiovascular disease ............................................................. 1 Cardiovascular disease in obesity and diabetes ........................................................ 3 Anti-hyperglycemic therapies and cardiovascular risk ................................................ 5 Sodium glucose Transporter 2 ................................................................................... 9 SGLT2i and cardiovascular events .......................................................................... 11 SGLT2 expression ................................................................................................... 13 Proposed mechanisms of cardiovascular protection ................................................ 14 Thrifty fuel hypothesis .............................................................................................. 23 Sodium hypothesis .................................................................................................. 25 Summary and proposed experimental aims ............................................................. 28 Chapter 2: Inhibition of Sodium Glucose Cotransporter-2 Preserves Cardiac Function During Regional Myocardial Ischemia Independent of Alterations in Myocardial Substrate Utilization..................................................................................... 32 Introduction .............................................................................................................. 32 Methods ................................................................................................................... 33 Animal model and surgical preparation .............................................................. 33 Left Circumflex Ischemia Protocol ...................................................................... 34 Metabolic Analysis ............................................................................................. 35 Infarct protocol ................................................................................................... 36 Infarct Quantification .......................................................................................... 36 RNA Isolation and cDNA synthesis .................................................................... 37 viii RT PCR ............................................................................................................. 37 Statistical Analyses ............................................................................................ 38 Results .................................................................................................................... 39 mRNA expression of SGLT-1 vs. SGLT-2 in swine heart and kidney ................. 39 Systemic effects of SGLT-2i during ischemia/reperfusion injury of the LCX ....... 39 Effects of SGLT2i on cardiac contractile function during ischemia/reperfusion injury of the LCX ................................................................................................ 40 Effects of SGLT2i on myocardial substrate selection during ischemia/reperfusion injury of the LCX ............................................................... 43 Effect of SGLT2i on myocardial infarct size and cardiac function in response to 60-minute LAD occlusion ............................................................................... 44 Discussion ............................................................................................................... 46 Cardiac effects of SGLT2i .................................................................................. 46 Potential mechanisms underlying cardiac effects of SGLT2i .............................. 48 Conclusion ............................................................................................................... 50 Chapter 3: Inhibition of Sodium Glucose Cotransporter-2 Improves Cardiac Efficiency During Regional Myocardial Ischemia Independent of Sodium/Hydrogen Exchanger-1 ............................................................................................................... 55 Introduction .............................................................................................................
Load more

Recommended publications
  • New Advances in Urea Transporter UT-A1 Membrane Trafficking
    Int. J. Mol. Sci. 2013, 14, 10674-10682; doi:10.3390/ijms140510674 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review New Advances in Urea Transporter UT-A1 Membrane Trafficking Guangping Chen Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA; E-Mail: [email protected]; Tel.: +1-404-727-7494; Fax: +1-404-727-2648. Received: 22 April 2013; in revised form: 9 May 2013 / Accepted: 9 May 2013 / Published: 21 May 2013 Abstract: The vasopressin-regulated urea transporter UT-A1, expressed in kidney inner medullary collecting duct (IMCD) epithelial cells, plays a critical role in the urinary concentrating mechanisms. As a membrane protein, the function of UT-A1 transport activity relies on its presence in the plasma membrane. Therefore, UT-A1 successfully trafficking to the apical membrane of the polarized epithelial cells is crucial for the regulation of urea transport. This review summarizes the research progress of UT-A1 regulation over the past few years, specifically on the regulation of UT-A1 membrane trafficking by lipid rafts, N-linked glycosylation and a group of accessory proteins. Keywords: lipid rafts; glycosylation; accessory proteins; SNARE protein; cytoskeleton protein 1. Introduction Urea is the major end product of amino acid metabolism. It is generated from the ornithine cycle in liver, and is ultimately excreted by the kidney representing 90% of total nitrogen in urine. The physiological significance of urea in the production of concentrated urine was recognized by Gamble in the 1930s [1,2]. Urea reabsorbed in the kidney inner medullary collecting duct (IMCD) contributes to the development of the osmolality in the medullary interstitium.
    [Show full text]
  • Does Addition of Vildagliptin to Metformin Monotherapy Improve Glycemic Control in Patients with Type 2 Diabetes Mellitus?
    PRACTICE pOINT www.nature.com/clinicalpractice/endmet Does addition of vildagliptin to metformin monotherapy improve glycemic control in patients with type 2 diabetes mellitus? Original article Bosi E et al. (2007) Effects of vildagliptin on OUTCOME MEASURES glucose control over 24 weeks in patients with type 2 diabetes The primary outcome measure was the change inadequately controlled with metformin. Diabetes Care 30: 890–895 in HbA1c level from baseline to study end. Secondary outcome measures included FPG SYNOPSIS levels, lipid profiles, β-cell function, and the KEYWORDS dipeptidyl peptidase 4 inhibitor, incidence and severity of adverse events. glycemic control, HbA1c, type 2 diabetes mellitus, vildagliptin RESULTS BACKGROUND The 50 mg vildagliptin, 100 mg vildagliptin Metformin is frequently prescribed as the and placebo groups comprised 177, 185, and first-line treatment for type 2 diabetes mellitus 182 patients, respectively. Participants were (T2DM); however, additional antidiabetic agents predominantly white and obese, with a mean might be required when glycemic control is age of 54 years. The mean duration of T2DM poor. was 6.2 years, the mean duration of metformin monotherapy was 17 months, and the mean OBJECTIVE metformin dose was 2,100 mg daily. The study To assess the efficacy and safety of the dipeptidyl was completed by >83% of patients in each peptidase 4 (DPP4) inhibitor vildagliptin as group. The mean baseline HbA1c level was 8.4% an add-on to metformin monotherapy. and the mean baseline FPG level was 9.9 mmol/l. Treatment with vildagliptin improved both of DESIGN AND INTERVENTION these parameters. The between-treatment This was a 24-week, multicenter, double- difference (vildagliptin minus placebo) in HbA1c blind, placebo-controlled, randomized study at study end was –0.7% and –1.1% with 50 mg of patients with T2DM inadequately controlled and 100 mg vildagliptin, respectively (P <0.001 with metformin monotherapy.
    [Show full text]
  • (Glut1ds): Methylxanthines Potentiate GLUT1 Haploinsufficiency in Vitro
    0031-3998/01/5002-0254 PEDIATRIC RESEARCH Vol. 50, No. 2, 2001 Copyright © 2001 International Pediatric Research Foundation, Inc. Printed in U.S.A. Glucose Transporter Type 1 Deficiency Syndrome (Glut1DS): Methylxanthines Potentiate GLUT1 Haploinsufficiency In Vitro YUAN-YUAN HO, HONG YANG, JÖRG KLEPPER, JORGE FISCHBARG, DONG WANG, AND DARRYL C. DE VIVO Department of Neurology, Columbia University, New York, New York 10032, U.S.A. [Y.Y.H., H.Y., D.W., D.C.D.]; Department of Pediatrics, University of Essen, Essen, Germany 45122 [J.K.]; and Departments of Physiology and Cellular Biophysics, and Ophthalmology, Columbia University, New York, New York 10032, U.S.A. [J.F.] ABSTRACT Methylxanthines such as caffeine and theophylline are known substrate for Glut1. The combined effects of caffeine (3 mM) and to inhibit glucose transport. We have studied such inhibition in phenobarbital (10 mM) on glucose transport, as determined in the glucose transporter type 1 deficiency syndrome (Glut1DS) by patient 15 and the maternal control, show no additive or syner- erythrocyte glucose transport assays. Data from four patients gistic inhibition. These data indicate that caffeine and phenobar- with individual mutations in the GLUT1 gene are discussed: bital have similar Glut1 inhibitory properties in these two sub- patient 1 (hemizygosity), 3 (S66F), 15 (368Ins23), and 17 jects. Our study suggests that Glut1DS patients may have a (R333W). Zero-trans influx of 14C-labeled 3-O-methyl glucose reduced safety margin for methylxanthines. Consumption of (3-OMG) into erythrocytes of patients is reduced (patient 1, 51%; methylxanthine-containing products may aggravate the neuro- 3, 45%; 15, 31%; 17, 52%) compared with maternal controls.
    [Show full text]
  • Galvus Data Sheet
    1 NEW ZEALAND DATA SHEET 1 GALVUS (50 mg tablets) 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Vildagliptin: 1-[(3-Hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(S)-carbonitrile. One tablet of Galvus® contains 50 mg of vildagliptin. For the full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM Galvus 50 mg: white to light yellowish, round (8 mm diameter) flat faced with beveled edges, unscored tablet. One side is debossed with "NVR", and the other side with "FB". 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Galvus is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus. • as monotherapy. • in dual combination with metformin, a sulphonylurea (SU), or a thiazolidinedione (TZD) when diet, exercise and a single antidiabetic agent do not result in adequate glycaemic control. • In triple combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. • In combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycaemic control. 4.2 Dosage and method of administration Dose The management of antidiabetic therapy should be individualized. The recommended dose of Galvus is 50 mg once or twice daily. The maximum daily dose of Galvus is 100 mg. For monotherapy, and for combination with metformin, with a TZD or with insulin (with or without metformin), the recommended dose of Galvus is 50 mg or 100 mg daily. When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg once daily.
    [Show full text]
  • Cystine–Glutamate Antiporter Xct Deficiency Suppresses Tumor Growth While Preserving Antitumor Immunity
    Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity Michael D. Arensmana, Xiaoran S. Yanga, Danielle M. Leahya, Lourdes Toral-Barzaa, Mary Mileskia, Edward C. Rosfjorda, Fang Wanga, Shibing Dengb, Jeremy S. Myersa, Robert T. Abrahamb, and Christina H. Enga,1 aOncology Research & Development, Pfizer, Pearl River, NY 10965; and bOncology Research & Development, Pfizer, San Diego, CA 92121 Edited by William G. Kaelin Jr., Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and approved April 2, 2019 (received for review September 1, 2018) T cell-invigorating cancer immunotherapies have near-curative Thus, tumor cells may rely on xCT to fulfill the majority of their potential. However, their clinical benefit is currently limited, as cysteine and GSH needs by importing cystine. only a fraction of patients respond, suggesting that these regimens Inhibition of xCT has been investigated as a therapeutic may benefit from combination with tumor-targeting treatments. As strategy for cancer based on observations that elevated xCT ex- oncogenic progression is accompanied by alterations in metabolic pression on tumor cells correlates with poor prognosis (10–12) pathways, tumors often become heavily reliant on antioxidant and that inhibition of xCT in preclinical studies suppresses tumor machinery and may be susceptible to increases in oxidative stress. growth (10, 12–14). However, these studies relied heavily on the The cystine–glutamate antiporter xCT is frequently overexpressed in use of sulfasalazine, a clinical compound used for the treatment cancer and fuels the production of the antioxidant glutathione; thus, of rheumatoid arthritis, ulcerative colitis, and Crohn’s disease.
    [Show full text]
  • Effect of Hydrolyzable Tannins on Glucose-Transporter Expression and Their Bioavailability in Pig Small-Intestinal 3D Cell Model
    molecules Article Effect of Hydrolyzable Tannins on Glucose-Transporter Expression and Their Bioavailability in Pig Small-Intestinal 3D Cell Model Maksimiljan Brus 1 , Robert Frangež 2, Mario Gorenjak 3 , Petra Kotnik 4,5, Željko Knez 4,5 and Dejan Škorjanc 1,* 1 Faculty of Agriculture and Life Sciences, University of Maribor, Pivola 10, 2311 Hoˇce,Slovenia; [email protected] 2 Veterinary Faculty, Institute of Preclinical Sciences, University of Ljubljana, Gerbiˇceva60, 1000 Ljubljana, Slovenia; [email protected] 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia; [email protected] 4 Department of Chemistry, Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia; [email protected] (P.K.); [email protected] (Ž.K.) 5 Laboratory for Separation Processes and Product Design, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, 2000 Maribor, Slovenia * Correspondence: [email protected]; Tel.: +386-2-320-90-25 Abstract: Intestinal transepithelial transport of glucose is mediated by glucose transporters, and affects postprandial blood-glucose levels. This study investigates the effect of wood extracts rich in hydrolyzable tannins (HTs) that originated from sweet chestnut (Castanea sativa Mill.) and oak (Quercus petraea) on the expression of glucose transporter genes and the uptake of glucose and HT constituents in a 3D porcine-small-intestine epithelial-cell model. The viability of epithelial cells CLAB and PSI exposed to different HTs was determined using alamarBlue®. qPCR was used to analyze the gene expression of SGLT1, GLUT2, GLUT4, and POLR2A. Glucose uptake was confirmed Citation: Brus, M.; Frangež, R.; by assay, and LC–MS/ MS was used for the analysis of HT bioavailability.
    [Show full text]
  • Vildagliptin/Metformin Hydrochloride Novartis, INN-Vildagliptin/Metformin
    European Medicines Agency Evaluation of Medicines for Human Use Doc.Ref.: EMEA/CHMP/656453/2008 ASSESSMENT REPORT FOR Vildagliptin/metformin hydrochloride Novartis International Nonproprietary Name: vildagliptin / metformin hydrochloride Procedure No. EMEA/H/C/001050 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 16 E-mail: [email protected] http://www.emea.europa.eu © European Medicines Agency, 2008. Reproduction is authorised provided the source is acknowledged TABLE OF CONTENTS 1. BACKGROUND INFORMATION ON THE PROCEDURE........................................... 3 1.1 Submission of the dossier ........................................................................................................ 3 1.2 Steps taken for the assessment of the product.......................................................................... 3 2. SCIENTIFIC DISCUSSION................................................................................................. 4 2.1 Introduction.............................................................................................................................. 4 2.2 Quality aspects......................................................................................................................... 4 2.3 Non-clinical aspects................................................................................................................. 4 2.4 Clinical
    [Show full text]
  • Transport of Sugars
    BI84CH32-Frommer ARI 29 April 2015 12:34 Transport of Sugars Li-Qing Chen,1,∗ Lily S. Cheung,1,∗ Liang Feng,3 Widmar Tanner,2 and Wolf B. Frommer1 1Department of Plant Biology, Carnegie Institution for Science, Stanford, California 94305; email: [email protected] 2Zellbiologie und Pflanzenbiochemie, Universitat¨ Regensburg, 93040 Regensburg, Germany 3Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305 Annu. Rev. Biochem. 2015. 84:865–94 Keywords First published online as a Review in Advance on glucose, sucrose, carrier, GLUT, SGLT, SWEET March 5, 2015 The Annual Review of Biochemistry is online at Abstract biochem.annualreviews.org Soluble sugars serve five main purposes in multicellular organisms: as sources This article’s doi: of carbon skeletons, osmolytes, signals, and transient energy storage and as 10.1146/annurev-biochem-060614-033904 transport molecules. Most sugars are derived from photosynthetic organ- Copyright c 2015 by Annual Reviews. isms, particularly plants. In multicellular organisms, some cells specialize All rights reserved in providing sugars to other cells (e.g., intestinal and liver cells in animals, ∗ These authors contributed equally to this review. photosynthetic cells in plants), whereas others depend completely on an ex- Annu. Rev. Biochem. 2015.84:865-894. Downloaded from www.annualreviews.org ternal supply (e.g., brain cells, roots and seeds). This cellular exchange of Access provided by b-on: Universidade de Lisboa (UL) on 09/05/16. For personal use only. sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is criti- cal for plants, animals, and humans.
    [Show full text]
  • Low Affinity Uniporter Carrier Proteins Can Increase Net Substrate Uptake
    www.nature.com/scientificreports OPEN Low afnity uniporter carrier proteins can increase net substrate uptake rate by reducing efux Received: 10 November 2017 Evert Bosdriesz 1,3, Meike T. Wortel 1,4, Jurgen R. Haanstra 1, Marijke J. Wagner1, Accepted: 9 March 2018 Pilar de la Torre Cortés2 & Bas Teusink 1 Published: xx xx xxxx Many organisms have several similar transporters with diferent afnities for the same substrate. Typically, high-afnity transporters are expressed when substrate is scarce and low-afnity ones when it is abundant. The beneft of using low instead of high-afnity transporters remains unclear, especially when additional nutrient sensors are present. Here, we investigate two hypotheses. It was previously hypothesized that there is a trade-of between the afnity and the catalytic efciency of transporters, and we fnd some but no defnitive support for it. Additionally, we propose that for uptake by facilitated difusion, at saturating substrate concentrations, lowering the afnity enhances the net uptake rate by reducing substrate efux. As a consequence, there exists an optimal, external-substrate- concentration dependent transporter afnity. A computational model of Saccharomyces cerevisiae glycolysis shows that using the low afnity HXT3 transporter instead of the high afnity HXT6 enhances the steady-state fux by 36%. We tried to test this hypothesis with yeast strains expressing a single glucose transporter modifed to have either a high or a low afnity. However, due to the intimate link between glucose perception and metabolism, direct experimental proof for this hypothesis remained inconclusive. Still, our theoretical results provide a novel reason for the presence of low-afnity transport systems.
    [Show full text]
  • Dipeptidyl Peptidase-4 Inhibitor Switching
    abetes & Di M f e t o a Tanaka et al., J Diabetes Metab 2016, 7:9 l b a o n l r i DOI: 10.4172/2155-6156.1000701 s u m o J Journal of Diabetes & Metabolism ISSN: 2155-6156 Research Article Open Access Dipeptidyl Peptidase-4 Inhibitor Switching as an Alternative Add-on Therapy to Current Strategies Recommended by Guidelines: Analysis of a Retrospective Cohort of Type 2 Diabetic Patients Masami Tanaka*, Takeshi Nishimura, Risa Sekioka and Hiroshi Itoh Department of Internal Medicine, School of Medicine, Keio University 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Abstract Objective: This retrospective cohort study aimed to investigate the significance of dipeptidyl peptidase-4 (DPP- 4) inhibitor switch therapy, which is currently not recommended by major diabetes guidelines. Methods: The subjects were 238 outpatients with type 2 diabetes who had been prescribed sitagliptin 50 mg daily, which was subsequently changed in one of three ways. Patients whose sitagliptin was switched to vildagliptin 50 mg twice daily were defined as the switched group. Patients whose sitagliptin was increased to 100 mg once daily were defined as the increased group. Patients who received an additional alfa-glucosidase inhibitor (α-GI) three times daily prior to meals and sitagliptin 50 mg once daily were defined as the added group. The primary endpoint was the glycated hemoglobin (HbA1c) value at 6 months after the medication change. Patients whose oral hypoglycemic agents were changed within 6 months after switching to vildagliptin, increasing sitagliptin, or adding α-GI were excluded from the full analysis set and the remaining patients were included in the per protocol analysis.
    [Show full text]
  • Renal Membrane Transport Proteins and the Transporter Genes
    Techno e lo n g Gowder, Gene Technology 2014, 3:1 e y G Gene Technology DOI; 10.4172/2329-6682.1000e109 ISSN: 2329-6682 Editorial Open Access Renal Membrane Transport Proteins and the Transporter Genes Sivakumar J T Gowder* Qassim University, College of Applied Medical Sciences, Buraidah, Kingdom of Saudi Arabia Kidney this way, high sodium diet favors urinary sodium concentration [9]. AQP2 has a role in hereditary and acquired diseases affecting urine- In humans, the kidneys are a pair of bean-shaped organs about concentrating mechanisms [10]. AQP2 regulates antidiuretic action 10 cm long and located on either side of the vertebral column. The of arginine vasopressin (AVP). The urinary excretion of this protein is kidneys constitute for less than 1% of the weight of the human body, considered to be an index of AVP signaling activity in the renal system. but they receive about 20% of blood pumped with each heartbeat. The Aquaporins are also considered as markers for chronic renal allograft renal artery transports blood to be filtered to the kidneys, and the renal dysfunction [11]. vein carries filtered blood away from the kidneys. Urine, the waste fluid formed within the kidney, exits the organ through a duct called the AQP4 ureter. The kidney is an organ of excretion, transport and metabolism. This gene encodes a member of the aquaporin family of intrinsic It is a complicated organ, comprising various cell types and having a membrane proteins. These proteins function as water-selective channels neatly designed three dimensional organization [1]. Due to structural in the plasma membrane.
    [Show full text]
  • Eucreas, INN-Vildagliptin / Metformin Hydrochloride
    SCIENTIFIC DISCUSSION 1. Introduction The pathophysiology of Type 2 diabetes mellitus (T2DM) is characterised by deficient insulin activity arising from decreased insulin secretion secondary to beta cell failure, and/or compromised insulin action in peripheral target tissues (insulin resistance). This abnormal metabolic state is exacerbated by excess hepatic glucose production and altered metabolism of proteins and lipids, which along with hyperglycaemia, contribute to microvascular and macrovascular complications. T2DM accounts for approximately 85% to 95% of diabetes cases in developed regions like the European Union. Age and weight are established risk factors for T2DM. The majority of patients with T2DM are overweight or obese. Diet modification and exercise is the first line of treatment for T2DM. Pharmacologic intervention with one oral antidiabetic drug (OAD) is usually the next step in treatment. After 3 to 9 years of OAD monotherapy, patients typically require an additional intervention. The recommended first line treatment is metformin, which restrains hepatic glucose production and decreases peripheral insulin resistance. Sulphonylureas, which are insulin secretagogues, may be used as an alternative to patients intolerant to metformin, or as an addition to metformin. Other second line oral treatment alternatives include alpha-glucosidase inhibitors, meglitinides and thiazolidinediones. Recently the first GLP-1 analogue, exenatide, and the first DPP-4 inhibitors, sitagliptin and vildagliptin, were approved by the CHMP. Vildagliptin belongs to a new class of oral anti-diabetic drugs and is a selective and reversible inhibitor of Dipeptidyl peptidase 4 (DPP-4), the enzyme which inactivates the incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), hormones which significantly contribute to the maintenance of glucose homeostasis.
    [Show full text]