title: Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: an animal model.
abstract: The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n=10), a selective M(3) muscarinic antagonist; ketanserin 2mg/kg (n=10), a 5HT(2A) antagonist; raclopride 0.3mg/kg (n=11) a selective D(2)/D(3) antagonist; terfenadine 20mg/kg (n=9) a selective H(1) antagonist; or, vehicle (n=11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic β-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H(1) blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M(3)) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D(2)-like receptors in β-cells, which mediate inhibition of insulin secretion, we propose that prolonged D(2) blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation.
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Canada. maggie.hahn@utoronto.ca
authors.forename: Margaret
authors.initials: M
authors.lastname: Hahn
authors.forename: Araba
authors.initials: A
authors.lastname: Chintoh
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Loretta
authors.initials: L
authors.lastname: Lam
authors.forename: Steve
authors.initials: S
authors.lastname: Mann
authors.forename: Paul
authors.initials: P
authors.lastname: Fletcher
authors.forename: Melanie
authors.initials: M
authors.lastname: Guenette
authors.forename: Tony
authors.initials: T
authors.lastname: Cohn
authors.forename: Tom
authors.initials: T
authors.lastname: Wolever
authors.forename: Tamara
authors.initials: T
authors.lastname: Arenovich
authors.forename: Gary
authors.initials: G
authors.lastname: Remington
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D002096:C-Peptide / Q000097:blood; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism* / Q000517:prevention & control; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D011863:Radioimmunoassay / Q000379:methods; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D043587:Receptor, Muscarinic M3; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011968:Receptors, Histamine; D005947:Glucose