Need for Better Diabetes Treatment: The Therapeutic Potential of NMDA Receptor Antagonists

A. Welters; E. Lammert; E. Mayatepek; T. Meissner

doi:10.1055/s-0042-117831

Klinische Pädiatrie, Table of Contents

Klin Padiatr 2017; 229(01): 14-20
DOI: 10.1055/s-0042-117831

Review

Need for Better Diabetes Treatment: The Therapeutic Potential of NMDA Receptor Antagonists

Bessere Diabetesmedikamente sind erforderlich: therapeutisches Potenzial von NMDAR Antagonisten

Authors

A. Welters

¹Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital Düsseldorf, Germany
E. Lammert

²Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital Düsseldorf, Germany
E. Mayatepek

¹Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital Düsseldorf, Germany
T. Meissner

¹Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital Düsseldorf, Germany

Abstract

Diabetes mellitus is the most common metabolic disorder in children and adolescents. Optimal control of blood glucose concentration is essential to prevent acute and diabetic long-term complications. The options to treat diabetes have clearly improved over the last decades, however, to date neither type 1 diabetes nor type 2 diabetes mellitus can be cured. Therefore, diabetes research aims at developing β-cell protective agents that prevent or even reverse diabetes onset. N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are widely expressed in the central nervous system (CNS) where they hold central roles in CNS function. NMDAR dysfunction is associated with several neurological and psychiatric disorders and therefore NMDAR modulators have several potential therapeutic indications. Only little is known about the role of pancreatic NMDA receptors. Our data provide evidence that inhibition of pancreatic NMDARs, either genetically or pharmacologically with the over-the-counter drug dextromethorphan, increases glucose-stimulated insulin secretion from mouse and human pancreatic islets, improves glucose tolerance in mice and individuals with diabetes and promotes islet cell survival under diabetogenic conditions. Thus, our data indicate for the first time that NMDAR antagonists could serve as adjunct treatment for diabetes mellitus. The development of a safe, blood glucose lowering and particularly β-cell protective medication would significantly enhance current diabetes treatment.

Zusammenfassung

Diabetes mellitus ist die häufigste Stoffwechselerkrankung des Kindes- und Jugendalters. Eine optimale Blutzuckereinstellung ist essentiell, um Akut- sowie diabetische Langzeitkomplikationen zu verhindern. Die Möglichkeiten Diabetes zu behandeln haben sich in den letzten Jahrzehnten zwar deutlich verbessert, jedoch ist bis heute weder der Typ 1 Diabetes noch der Typ 2 Diabetes mellitus heilbar. Ziel der Diabetesforschung ist es daher, betazellprotektive Medikamente zu entwickeln, die das Auftreten eines Diabetes verhindern, oder sogar einen bestehenden Diabetes heilen können. N-Methyl-D-Aspartat Rezeptoren (NMDAR) sind Glutamat gesteuerte Ionenkanäle, die in großer Zahl im zentralen Nervensystem (ZNS) exprimiert werden, wo sie zentrale Rollen für die Funktionen des ZNS einnehmen. Fehlfunktionen der NMDAR sind mit mehreren neurologischen und psychiatrischen Erkrankungen assoziiert und NMDAR Modulatoren haben daher verschiedene potentielle therapeutische Indikationen. Bisher ist nur wenig über die Funktion pankreatischer NMDAR bekannt. Unsere Daten deuten erstmals darauf hin, dass die Inhibition pankreatischer NMDAR, entweder genetisch oder pharmakologisch mit dem frei verkäuflichen NMDAR Antagonisten Dextromethorphan, die glukose-stimulierte Insulinsekretion muriner und menschlicher Langerhans-Inseln steigert, in Mausmodellen sowie bei Diabetikern die Glukosetoleranz verbessert und unter diabetogenen Bedingungen Inselzellschutz vermittelt. Zusammenfassend deuten unsere Arbeiten erstmals darauf hin, dass NMDAR Antagonisten die Therapie des Diabetes mellitus ergänzen könnten. Die Entwicklung eines nebenwirkungsarmen, blutzuckersenkenden und vor allem betazellprotektiven Medikamentes würde die Therapie des Diabetes mellitus signifikant aufwerten.

Full Text

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