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Mechanisms of thiazide-induced glucose intolerance

English title Mechanisms of thiazide-induced glucose intolerance
Applicant Fuster Daniel Guido
Number 172974
Funding scheme Project funding
Research institution Klinik für Nephrologie und Hypertonie Universitätsklinik Inselspital Bern
Institution of higher education University of Berne - BE
Main discipline Physiology : other topics
Start/End 01.05.2017 - 31.05.2022
Approved amount 496'000.00
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All Disciplines (5)

Discipline
Physiology : other topics
Cellular Biology, Cytology
Biochemistry
Biophysics
Molecular Biology

Keywords (7)

Islets; Diabetes mellitus; Insulin secretion; Thiazides; Insulin resistance; Glucose intolerance; Diuretics

Lay Summary (German)

Lead
In diesem Projekt werden die molekularen Ursachen der Glukosestoffwechselstörungen erforscht, welche durch eine häufig eingesetzte Klasse von Medikamenten, den sogenannten Thiaziddiuretika, ausgelöst werden können.
Lay summary

Inhalt und Ziele des Forschungsprojektes:
Thiaziddiuretika (“Thiazide”) werden sehr häufig eingesetzt bei der Behandlung von Bluthochdruck, in der Rezidivprophylaxe von kalziumhaltigen Nierensteinen oder der Salz-und Wasserretention bei Herz-, Leber- und Nierenerkrankungen. Thiazide sind äusserst günstige, weltweit verfügbare und effektive Medikamente, die aus dem klinischen Alltag nicht mehr wegzudenken sind. Obwohl Thiazide in der Regel gut verträglich und nebenwirkungsarm sind, kann es unter der Behandlung mit Thiaziden zu einem Anstieg des Blutzuckers ("Glukoseintoleranz") oder sogar zur Entwicklung eines Diabetes mellitus kommen. Die Ursachen dieser bereits vor 60 Jahren erkannten, gefürchteten Nebenwirkung sind leider immer noch unbekannt.
Ziel dieses Forschungsprojektes ist es, die zellulären und molekularen Ursachen der Thiazid-induzierten Glukosestoffwechselstörungen zu erforschen. Dabei werden Experimente in Zellkulturen und mit genetisch veränderten Mäusen durchgeführt werden.

3. Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts:
Das Projekt befasst sich mit der Grundlagenforschung. Ein besseres, mechanistisches Verständnis von Thiazid-induzierten Glukosestoffwechselstörungen wird den verschreibenden Aerzten helfen, Patienten mit einem erhöhtem Risiko für diese gefürchtete Nebenwirkung frühzeitig zu identifizieren. Daneben werden die gewonnenen Erkenntnisse die Entwicklung diagnostischer Hilfsmittel und effektiver Strategien zur Verhinderung dieser Nebenwirkung fördern und eine wissenschaftliche Grundlage sein für zukünftige Studien im Menschen.

Direct link to Lay Summary Last update: 17.04.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Urinary tetrahydroaldosterone is associated with circulating FGF23 in kidney stone formers
Moor Matthias B., Dhayat Nasser A., Schietzel Simeon, Grössl Michael, Vogt Bruno, Fuster Daniel G. (2022), Urinary tetrahydroaldosterone is associated with circulating FGF23 in kidney stone formers, in Urolithiasis, 50(3), 333-340.
Lack of NHE6 and Inhibition of NKCC1 Associated With Increased Permeability in Blood Labyrinth Barrier-Derived Endothelial Cell Layer
Sekulic-Jablanovic Marijana, Paproth Jessica, Sgambato Cinzia, Albano Giuseppe, Fuster Daniel G., Bodmer Daniel, Petkovic Vesna (2022), Lack of NHE6 and Inhibition of NKCC1 Associated With Increased Permeability in Blood Labyrinth Barrier-Derived Endothelial Cell Layer, in Frontiers in Cellular Neuroscience, 16, 1.
Predictors of Bone Mineral Density in Kidney Stone Formers
Dhayat Nasser A., Schneider Lisa, Popp Albrecht W., Lüthi David, Mattmann Cedric, Vogt Bruno, Fuster Daniel G. (2022), Predictors of Bone Mineral Density in Kidney Stone Formers, in Kidney International Reports, 7(3), 558-567.
Association of urinary sex steroid hormones with urinary calcium, oxalate and citrate excretion in kidney stone formers
Fuster Daniel G, Morard Gaétan A, Schneider Lisa, Mattmann Cedric, Lüthi David, Vogt Bruno, Dhayat Nasser A (2022), Association of urinary sex steroid hormones with urinary calcium, oxalate and citrate excretion in kidney stone formers, in Nephrology Dialysis Transplantation, 37(2), 335-348.
Mechanisms Underlying Calcium Nephrolithiasis
Alexander R.T., Fuster D.G., Dimke H. (2022), Mechanisms Underlying Calcium Nephrolithiasis, in Annual Review of Physiology, 84(1), 559-583.
Thiazides induce glucose intolerance through inhibition of mitochondrial carbonic anhydrase 5b in β-cells
(2022), Thiazides induce glucose intolerance through inhibition of mitochondrial carbonic anhydrase 5b in β-cells, 1.
Deletion of the sodium/hydrogen exchanger 6 causes low bone volume in adult mice
Schnyder Daniela, Albano Giuseppe, Kucharczyk Patrycja, Dolder Silvia, Siegrist Mark, Anderegg Manuel, Pathare Ganesh, Hofstetter Willy, Baron Roland, Fuster Daniel G. (2021), Deletion of the sodium/hydrogen exchanger 6 causes low bone volume in adult mice, in Bone, 153, 116178-116178.
Solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney
Verouti Sophia N., Lambert Delphine, Mathis Déborah, Pathare Ganesh, Escher Geneviève, Vogt Bruno, Fuster Daniel G. (2021), Solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney, in American Journal of Physiology-Renal Physiology, 320(3), F351-F358.
The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney
Anderegg Manuel A., Albano Giuseppe, Hanke Daniela, Deisl Christine, Uehlinger Dominik E., Brandt Simone, Bhardwaj Rajesh, Hediger Matthias A., Fuster Daniel G. (2021), The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney, in Kidney International, 99(2), 350-363.
Sodium-hydrogen exchanger 6 (NHE6) deficiency leads to hearing loss, via reduced endosomal signalling through the BDNF/Trk pathway
Kucharava Krystsina, Brand Yves, Albano Giuseppe, Sekulic-Jablanovic Marijana, Glutz Andrea, Xian Xunde, Herz Joachim, Bodmer Daniel, Fuster Daniel G., Petkovic Vesna (2020), Sodium-hydrogen exchanger 6 (NHE6) deficiency leads to hearing loss, via reduced endosomal signalling through the BDNF/Trk pathway, in Scientific Reports, 10(1), 3609-3609.
Quality of Life in Autosomal Dominant Polycystic Kidney Disease Patients Treated With Tolvaptan
Anderegg Manuel A., Dhayat Nasser A., Sommer Grit, Semmo Mariam, Huynh-Do Uyen, Vogt Bruno, Fuster Daniel G. (2020), Quality of Life in Autosomal Dominant Polycystic Kidney Disease Patients Treated With Tolvaptan, in Kidney Medicine, 1-30.
Parathyroid hormone and plasma phosphate are predictors of soluble α-klotho levels in adults of European descent
Dhayat Nasser A, Pruijm Menno, Ponte Belen, Ackermann Daniel, Leichtle Alexander Benedikt, Devuyst Olivier, Ehret Georg, Guessous Idris, Pechère-Bertschi Antoinette, Pastor Johanne, Martin Pierre-Yves, Burnier Michel, Fiedler Georg-Martin, Vogt Bruno, Moe Orson W, Bochud Murielle, Fuster Daniel G (2019), Parathyroid hormone and plasma phosphate are predictors of soluble α-klotho levels in adults of European descent, in The Journal of Clinical Endocrinology & Metabolism, 1-28.
A preliminary survey of practice patterns across several European kidney stone centers and a call for action in developing shared practice
Ferraro Pietro Manuel, Arrabal-Polo Miguel Ángel, Capasso Giovambattista, Croppi Emanuele, Cupisti Adamasco, Ernandez Thomas, Fuster Daniel G., Galan Juan Antonio, Grases Felix, Hoorn Ewout J., Knauf Felix, Letavernier Emmanuel, Mohebbi Nilufar, Moochhala Shabbir, Petkova Kremena, Pozdzik Agnieszka, Sayer John, Seitz Christian, Strazzullo Pasquale, Trinchieri Alberto, Vezzoli Giuseppe, Vitale Corrado, Vogt Liffert, Unwin Robert J., et al. (2019), A preliminary survey of practice patterns across several European kidney stone centers and a call for action in developing shared practice, in Urolithiasis, 47(3), 219-224.
Unraveling the structural elements of pH sensitivity and substrate binding in the human zinc transporter SLC39A2 (ZIP2)
Gyimesi Gergely, Albano Giuseppe, Fuster Daniel G., Hediger Matthias A., Pujol-Giménez Jonai (2019), Unraveling the structural elements of pH sensitivity and substrate binding in the human zinc transporter SLC39A2 (ZIP2), in Journal of Biological Chemistry, 294(20), 8046-8063.
Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism
Stergachis Andrew B., Pujol‐Giménez Jonai, Gyimesi Gergely, Fuster Daniel, Albano Giusppe, Troxler Marina, Picker Jonathan, Rosenberg Paul A., Bergin Ann, Peters Jurriaan, El Achkar Christelle Moufawad, Harini Chellamani, Manzi Shannon, Rotenberg Alexander, Hediger Matthias A., Rodan Lance H. (2019), Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism, in Annals of Neurology, 85(6), 921-926.
Distinct phenotype of kidney stone formers with renal phosphate leak
Dhayat Nasser A, Lüthi David, Schneider Lisa, Mattmann Cedric, Vogt Bruno, Fuster Daniel G (2019), Distinct phenotype of kidney stone formers with renal phosphate leak, in Nephrology Dialysis Transplantation, 34(1), 129-137.
Impact of potassium citrate on urinary risk profile, glucose and lipid metabolism of kidney stone formers in Switzerland
Wiegand Anna, Fischer Gioia, Seeger Harald, Fuster Daniel, Dhayat Nasser, Bonny Olivier, Ernandez Thomas, Kim Min-Jeong, Wagner Carsten A, Mohebbi Nilufar (2019), Impact of potassium citrate on urinary risk profile, glucose and lipid metabolism of kidney stone formers in Switzerland, in Clinical Kidney Journal, 1-12.
Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules
Faller Nicolas, Dhayat Nasser A., Fuster Daniel G. (2019), Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules, in Urolithiasis, 47(1), 43-56.
Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
Pathare Ganesh, Anderegg Manuel, Albano Giuseppe, Lang Florian, Fuster Daniel G. (2018), Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC), in Scientific Reports, 8(1), 3590-3590.
Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial
Dhayat Nasser A., Faller Nicolas, Bonny Olivier, Mohebbi Nilufar, Ritter Alexander, Pellegrini Lisa, Bedino Giulia, Schönholzer Carlo, Venzin Reto M., Hüsler Carina, Koneth Irene, Del Giorno Rosaria, Gabutti Luca, Amico Patrizia, Mayr Michael, Odermatt Urs, Buchkremer Florian, Ernandez Thomas, Stoermann-Chopard Catherine, Teta Daniel, Rintelen Felix, Roumet Marie, Irincheeva Irina, Trelle Sven, et al. (2018), Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial, in BMC Nephrology, 19(1), 349-349.
Incomplete Distal Renal Tubular Acidosis and Kidney Stones
Fuster Daniel G., Moe Orson W. (2018), Incomplete Distal Renal Tubular Acidosis and Kidney Stones, in Advances in Chronic Kidney Disease, 25(4), 366-374.
Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis
Pathare Ganesh, Dhayat Nasser A., Mohebbi Nilufar, Wagner Carsten A., Bobulescu Ion A., Moe Orson W., Fuster Daniel G. (2018), Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis, in Kidney International, 93(4), 871-880.
Acute regulated expression of pendrin in human urinary exosomes
Pathare Ganesh, Dhayat Nasser, Mohebbi Nilufar, Wagner Carsten A., Cheval Lydie, Neuhaus Thomas J., Fuster Daniel G. (2018), Acute regulated expression of pendrin in human urinary exosomes, in Pflügers Archiv - European Journal of Physiology, 470(2), 427-438.
Thiazide Diuretic Dose and Risk of Kidney Stones in Older Adults: A Retrospective Cohort Study.
(2018), Thiazide Diuretic Dose and Risk of Kidney Stones in Older Adults: A Retrospective Cohort Study., in Can J Kidney Health Dis, 1-10.
Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers
Dhayat Nasser A., Gradwell Michael W., Pathare Ganesh, Anderegg Manuel, Schneider Lisa, Luethi David, Mattmann Cedric, Moe Orson W., Vogt Bruno, Fuster Daniel G. (2017), Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers, in Clinical Journal of the American Society of Nephrology, 12(9), 1507-1517.
Antihypertensive medication and risk of kidney stones: a Canadian wake-up call
Fuster Daniel G (2017), Antihypertensive medication and risk of kidney stones: a Canadian wake-up call, in Hypertension Research, 40(9), 807-808.

Collaboration

Group / person Country
Types of collaboration
Department of Anatomy, University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Department of Nephrology, UTSouthwestern Medical Center, Dallas TX United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Service d'Explorations Fonctionnelles Rénales, Hôpital Felix Guyon, CHU de la Réunion, St Denis, Ile France (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Graduate School Symposium University of Bern Poster Mechanisms of thiazide induced glucose intolerance 27.01.2022 Bern, Switzerland Fuster Daniel Guido; Patrycja Kucharczyk;
Graduate School Symposium University of Bern Poster Mechanisms of thiazide induced glucose intolerance 28.01.2021 Bern, Switzerland Fuster Daniel Guido; Patrycja Kucharczyk;
Graduate School Symposium University of Bern Poster Mechanisms of thiazide-induced glucose intolerance 30.01.2020 Bern, Switzerland Patrycja Kucharczyk;
BioMedical Transporters Conference Poster Mechanisms of thiazide-induced glucose intolerance 06.08.2019 Luzern, Switzerland Patrycja Kucharczyk;


Associated projects

Number Title Start Funding scheme
152829 Physiological role of the sodium/hydrogen exchanger NHE6 01.05.2014 Project funding
166785 Randomized double-blind placebo-controlled trial assessing the efficacy of standard and low dose hydrochlorothiazide treatment in the prevention of recurrent calcium nephrolithiasis 01.06.2016 Investigator Initiated Clinical Trials (IICT)
135503 Sodium/hydrogen exchanger NHA2 - quest for biological function 01.05.2011 Project funding

Abstract

Background and rationale: Thiazides belong to the most commonly prescribed drugs worldwide. Treatment indications include arterial hypertension, recurrent calcareous nephrolithiasis and fluid overload states. Since their introduction into clinical medicine in the 1960ies, thiazide diuretics are known to cause impaired glucose tolerance or even overt diabetes mellitus. Several hypotheses have been put forth to explain thiazide-induced glucose intolerance, but the underlying mechanisms remain elusive until today. Unfortunately, however, these unpredictable and poorly understood side effects have caused many physicians to avoid the use of these clinically effective and cheap drugs. The classical molecular thiazide target is the Na+/Cl- co-transporter NCC (also known as SLC12A3) in the distal tubules of the kidney. Inhibition of Na+ and Cl- reabsorption by NCC is responsible for the diuretic action of the drug. Additional known thiazide targets include carbonic anhydrase and the Na+-driven Cl-/bicarbonate exchanger NDCBE (also known as SLC4A8). The relevance of the currently known thiazide targets with respect to the metabolic side effects of thiazides has not been studied. We have performed transcript analysis and found that all currently known thiazide targets are expressed in the three key organs involved in glucose homeostasis, i.e. Langerhans islets, liver and adipose tissue. Mice treated with hydrochlorothiazide showed an acute impairment of glucose tolerance following intraperitoneal glucose challenge, thus demonstrating the clinical relevance of this model. Furthermore, primary murine islets or Min6 cells exposed to submicromolar concentrations of hydrochlorothiazide and other thiazides displayed significantly reduced insulin secretion. This reduction was independent of NCC, as islets of NCC-deficient and wild-type mice were equally sensitive to thiazides. Peripheral insulin sensitivity, assessed by intraperitoneal insulin tolerance test, was unaltered upon acute hydrochlorothiazide administration, thereby further indicating that thiazides induce glucose intolerance by impairing insulin secretion. However, additional experiments revealed that thiazides can induce hyperglycemia even in the fasting state, in the absence of a concomitant glucose challenge and without demonstrable alterations in serum insulin or plasma glucagon. These results suggested that thiazides induce glucose intolerance by an additional, islet-independent mechanism, possibly by inducing hepatic insulin resistance, with an upregulation of hepatic glucose production.Working hypothesis: Based on our preliminary data, we hypothesize that thiazides induce glucose intolerance by both islet-dependent and islet-independent mechanisms. Objective: With this proposal we aim to definitively establish the sites of acute and chronic thiazide induced glucose intolerance and to elucidate the underlying cellular and molecular mechanisms. We will address our hypothesis by studying genetically modified mice subjected to acute or chronic thiazide treatments and applying complementary ex vivo and in vitro studies. Expected significance: A mechanistic understanding of thiazide-induced glucose intolerance will help clinicians in better identifying patients at risk for this feared side effect, foster the implementation of diagnostic tools and enable the development of therapeutic strategies to minimize risk of occurrence. In addition, we hope that our preclinical studies may pave the way for prospective and mechanistic trials in humans in this clinically relevant but scientifically neglected area.
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