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Glutamate Is a Positive Autocrine Signal for Glucagon Release
Over Cabrera,1,2 M. Caroline Jacques-Silva,1 Stephan Speier,2 Shao-Nian Yang,2 Martin Köhler,2 Alberto Fachado,1 Elaine Vieira,3 Juleen R. Zierath,3 Richard Kibbey,4 Dora M. Berman,1 Norma S. Kenyon,1 Camillo Ricordi,1 Alejandro Caicedo,1, and Per-Olof Berggren1,2,
1 Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
3 Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
4 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
Summary
An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic α cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human α cells express ionotropic glutamate receptors (iGluRs) that are essential for glucagon release. A lowering in glucose concentration results in the release of glutamate from the α cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca2+ channels, increase in cytoplasmic free Ca2+ concentration, and enhanced glucagon release. In vivo blockade of iGluRs reduces glucagon secretion and exacerbates insulin-induced hypoglycemia in mice. Hence, the glutamate autocrine feedback loop endows the α cell with the ability to effectively potentiate its own secretory activity. This is a prerequisite to guarantee adequate glucagon release despite relatively modest changes in blood glucose concentration under physiological conditions.
