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¹ Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA² Barnard College, Columbia University, New York, New York 10027, USA³ Department of Surgery of Columbia University Medical Center, New York, New York 10032, USA⁴ Department of Surgery, Medical University of Gdansk, Gdansk 80–952, Poland⁵ Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, CNR, Naples 80131, Italy⁶ Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York 10032, USA⁷ Department of Medicine, University of Washington, Seattle, Washington 98195, USA

(Correspondence should be addressed to P E Harris; Email: peh1{at}columbia.edu)

Despite different embryological origins, islet β-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human β-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by β-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous L-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in β-cells.