Editors' ChoiceDiabetes

When Langerhans’ and Cajal’s worlds collide, diabetics win

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Science Translational Medicine  08 Apr 2015:
Vol. 7, Issue 282, pp. 282ec57
DOI: 10.1126/scitranslmed.aab0843

As a common chronic disease with multisystemic morbidities, type 2 diabetes is one of the most important public health issues of our times. Besides injection of insulin analogs, current therapies help normalize blood glucose levels by improving insulin sensitivity, increasing insulin secretion, reducing blood glucagon levels, or increasing the excretion of glucose in the urine. But treatment outcomes remain substandard, and so improvement requires fresh therapies with new modes of action (that is, not a “me-too” drug) or better safety profiles (for example, lower risks of hypoglycemia). Now, Marquard and colleagues present convincing evidence of an entirely new mechanism by which to control blood sugars: inhibition of N-methyl-D-aspartate receptors (NMDARs), typically found in the nervous system, that reside on the surface of insulin-secreting pancreatic β cells.

This innovative work was triggered by studies suggesting that β cells exhibit many neuronal-like features, including the expression of all three NMDAR subunits. Controversy has surrounded a role for NMDARs in the regulation of insulin secretion because in various reports, incubation of β cells with exogenous NMDA yielded unpredictable effects. The well-designed study of Marquard et al. sets the record straight. When compared with controls, mice with a genetic ablation of an NMDAR subunit (Grin1) displayed markedly elevated glucose-stimulated insulin secretion (GSIS) after a bolus injection of glucose even though baseline insulin levels were similar in the two groups. The same pattern was observed in vitro when Grin1 was silenced with siRNAs in rat insulinoma cells or when human and murine pancreatic β cells were exposed to the NMDAR inhibitors MK-801 or dextrometorphan (DXM). Addition of DXM to drinking water of obese and diabetic mice (db/db) for 8 weeks resulted in increases in β cell numbers and insulin content as well as improvements in the control of blood glucose concentrations. Because DXM is routinely used as an over-the-counter antitussive agent, the authors were able to conduct a phase 2 double-blind, placebo-controlled randomized clinical trial (n = 20) and observed higher insulin secretion and lower blood glucose with an oral glucose tolerance test performed one hour after ingestion of DXM.

The data presented by Marquard et al. make a compelling case for NMDARs as a regulator of insulin secretion. However, the source of pancreas-destined glutamate—the NMDARs' endogenous ligand—remains as a key open question. Further, the sustained benefits of DXM and the effects of its long-term exposure must be studied in patients before NMDAR antagonists become bona fide therapies for the large number of diabetes sufferers worldwide.

J. Marquard et al., Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat. Med. 10.1038/nm.3822 (2015). [Abstract]

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