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

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

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 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 â cell mass in Drd2-/- mice, and decreased â 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.