IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
artículos
Título:
Disruption of the Dopamine D2 Receptor impairs insulin secretion and causes glucose intolerance.
Autor/es:
GARCIA-TORNADU,I; ORNSTEIN AM; CHAMSON-REIG,A.; WHEELER, MB; HILL, DJ; ARANY,E; RUBINSTEIN M; BECU-VILLALOBOS, D.
Revista:
ENDOCRINOLOGY
Editorial:
The Endocrine Society
Referencias:
Lugar: EEUU; Año: 2009
ISSN:
0013-7227
Resumen:
The relationship between
antidopaminergic drugs and glucose has not been extensively studied, even
though chronic neuroleptic treatment causes hyperinsulinemia in normal
subjects, or is associated with diabetes in psychiatric patients. We sought to
evaluate dopamine D2 receptor (D2R) participation in pancreatic function.
Glucose homeostasis was studied in D2R knockout mice (Drd2-/-) mice, and in isolated islets from wild-type
and Drd2-/- mice, using different
pharmacological tools. Pancreas immunohistochemistry was performed.
Drd2-/- male mice exhibited an impairment of
insulin response to glucose, high fasting glucose levels, and were glucose
intolerant. Glucose intolerance resulted from a blunted insulin secretory
response, rather than insulin resistance, as shown by glucose stimulated
insulin secretion tests (GSIS) in vivo and in vitro, and by a conserved insulin
tolerance test in vivo. On the other hand, short-term treatment with
cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased
insulin response to glucose in wild-type but not in Drd2-/- mice; this effect
was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was
impaired in islets from Drd2-/- mice, and that only in wild-type islets
dopamine inhibited GSIS, an effect which was blocked by a D2R but not a D1R
antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta
cell mass in Drd2-/- mice, and decreased β cell replication in two month-old
Drd2-/- mice.
Pancreatic
D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic
inhibition throughout development may exert a gradual deteriorating effect on
insulin homeostasis, so that eventually glucose intolerance develops.