Glutamate is a positive autocrine signal for glucagon release.
An important feature of glucose homeostasis is the effective release of glucagon from the pancreatic alpha cell. The molecular mechanisms regulating glucagon secretion are still poorly understood. We now demonstrate that human alpha 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 alpha cell. Glutamate then acts on iGluRs of the AMPA/kainate type, resulting in membrane depolarization, opening of voltage-gated Ca(2+) channels, increase in cytoplasmic free Ca(2+) 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 alpha 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.
Cabrera
Over
O
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Jacques-Silva
M Caroline
MC
Speier
Stephan
S
Yang
Shao-Nian
SN
Köhler
Martin
M
Fachado
Alberto
A
Vieira
Elaine
E
Zierath
Juleen R
JR
Kibbey
Richard
R
Berman
Dora M
DM
Kenyon
Norma S
NS
Ricordi
Camillo
C
Caicedo
Alejandro
A
Berggren
Per-Olof
PO
D000818:Animals; D019898:Autocrine Communication; D001786:Blood Glucose; D002478:Cells, Cultured; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D000882:Haplorhini; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018091:Receptors, AMPA / Q000378:metabolism; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate
D001786:Blood Glucose; D005934:Glucagon; D018698:Glutamic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate