Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine.
Despite different embryological origins, islet beta-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 beta-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 beta-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 beta-cells.
Raffo
Anthony
A
Department of Medicine, BB 20-06, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032, USA.
Hancock
Kolbe
K
Polito
Teresa
T
Xie
Yuli
Y
Andan
Gordon
G
Witkowski
Piotr
P
Hardy
Mark
M
Barba
Pasquale
P
Ferrara
Caterina
C
Maffei
Antonella
A
Freeby
Matthew
M
Goland
Robin
R
Leibel
Rudolph L
RL
Sweet
Ian R
IR
Harris
Paul E
PE
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004298:Dopamine / Q000032:analysis; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D013747:Tetrabenazine / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D018759:Adrenergic Uptake Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D012333:RNA, Messenger; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D005947:Glucose; D004298:Dopamine; D013747:Tetrabenazine