Disruption of the Dopaminergic D2 Receptor impairs insulin secretion and causes glucose intolerance

GARCIA- TORNADU, I.; ORNSTEIN, A.M.; CHAMSON - REIG , A.; WHEELER, M.B.;HILL,D.; ARANY, E.; RUBINSTEIN, M.; BECU- VILLALOBOS, D.;

ENDOCRINOLOGY

ENDOCRINE SOC

Año: 2010 vol. 151 p. 1441 - 1450

0013-7227

The relationship between antidopaminergic drugs and glucose has not been extensively studied,even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associatedwith 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 pharmacologicaltools. Pancreas immunohistochemistry was performed. Drd2
/
male mice exhibited animpairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant.Glucose intolerance resulted from a blunted insulin secretory response, rather than insulinresistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and bya 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 toglucose in wild-type but not in Drd2
/
mice; this effect was partially prevented by haloperidol, aD2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2
/
mice andthat only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but nota D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic
-cell mass inDrd2
/
miceanddecreased
-cell replication in 2-month-old Drd2
/
mice. Pancreatic D2Rs inhibitglucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development mayexert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerancedevelops. (Endocrinology 151: 1441–1450, 2010)