Translational research at Profil Neuss exploring the anti-diabetic effect of the cough suppressant dextromethorphan published in Nature Medicine
A curative therapy of diabetes is still missing. This calls not only for new inventions in the area of drug development but also for the exploration of new avenues improving the effectiveness of translational research. The joined publication in Nature Medicine discussed here stands as a paradigm for bridging the gap between groundbreaking basic research and clinical development by early entering into a strategic partnership between top level academia and full service clinical contract research. By adding the clinical dimension to excellent basic research four members from Profil’s interdisciplinary scientific team critically contributed to this publication in Nature Medicine.
Background
Scientific work published by different research groups indicated that pancreatic alpha and beta cells may display neuronal activities. Accordingly it has been suggested that the neurotransmitter glutamate acts as an inter- and intracellular signaling metabolite in the islets of Langerhans. Whether a chronic hyperglutamataemia may contribute to the pathogenesis and epidemic spread of (pre)diabetes is also part of the debate. In people with diabetes a chronic excitation of beta cell glutamate receptors due to an extracellular accumulation of the amino acid in the islet may contribute to the loss of beta cell functioning in people with (pre)diabetes.
This is why the internationally renowned diabetes researcher Eckhard Lammert (Heinrich-Heine-University Düsseldorf, Institute for Metabolic Physiology) investigated the expression of N-methyl-D-aspartate (NMDA)-type glutamate receptors in beta cells. His key question was how NMDA receptor activity could affect fasting and glucose-stimulated insulin secretion.
Here the OTC cough suppressant dextromethorphan (DXM) came into the play, which was one of the pharmacological tools used for inhibtion of NMDA receptors. In collaboration with high level academic partners from all over Europe the Lammert lab provided strong evidence that pancreatic N-methyl-D-aspartate (NMDA) receptors play a key role in the control of insulin secretion and glucose homeostasis.
A cough suppressant for diabetes treatment? Translating preclinincal findings to people with diabetes
By using sophisticated islet culture and animal models the basic researchers were able to demonstrate that DXM via inhibition of beta cell NMDA receptors increases glucose-stimulated insulin secretion, glucose tolerance and islet cell survival. The impact of these new and exiting findings for the treatment of people with type 2 diabetes naturally remained an unanswered issue. Here Profil complemented the academic partnership by supporting a collaborative effort translating the peclinical findings to people with diabetes. Using the preclinical data set and safety information from the literature we designed a clinical trial investigating the glucose lowering effect of DXM and amantadine (a comparator) in subjects with T2DM during an oral glucose tolerance test (OGTT).
Figure 1: Design of the phase IIa, double-blind, placebo-controlled, randomised, fourfold crossover clinical trial in people with type 2 diabetes performed in the clinical research unit at Profil Neuss.
As discussed extensively in the Nature Medicine publication the key results of the trial
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DXM 270 mg (single dose) reduces OGTT-related glucose excursions in people with T2DM
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DXM 270 and 60 mg increase insulin levels during an OGTT
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DXM does not affect fasting insulin & glucose levels
are largely consistent with the picture evolving from the preclinical data set. Neither serious or severe adverse events, nor clinically significant abnormal findings in laboratory parameters, vital signs, physical examination or electrocardiogram have been recorded during the trial.
Perspective: NMDA receptor inhibition as a new therapeutic approach for people with diabetes
We see a high potential for drugs that protect pancreatic beta cell functioning by preventing beta cell death, supporting beta cell mass adaptation, and stimulating endogenous resources for beta cell regeneration in people with (pre)diabetes.
Figure 2 depicts potential mechanisms contributing to the development of glutamate excitotoxicity to the pancreatic beta cells. Our vision is to enable a peripheral or even beta cell specific NMDA receptor blockade preventing the excitotoxic action of glutamate, thereby protecting beta cell functioning in people with (pre)diabetes.
Figure 2: Protection of beta cell function by NMDA receptor inhibition - working hypothesis.
