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 M₃ muscarinic antagonist; ketanserin 2 mg/kg (n = 10), a 5HT_2A antagonist; raclopride 0.3 mg/kg (n = 11) a selective D₂/D₃ antagonist; terfenadine 20 mg/kg (n = 9) a selective H₁ 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. H₁ 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 (M₃) and serotonergic (5HT₂) antagonism on insulin secretion. Based on the expression of D₂-like receptors in β-cells, which mediate inhibition of insulin secretion, we propose that prolonged D₂ blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation.

Introduction

Increasing evidence suggests that ‘atypical’ antipsychotics (AAPs), as a class, are associated with increased liability for weight gain, lipid abnormalities, and development of type 2 diabetes (DM2) (Newcomer, 2005). Clinical evidence suggests considerable variability in individual risk of metabolic aberrations, with clozapine and olanzapine conferring the greatest risk. Weight gain, a well-documented side effect of these agents (Pi-Sunyer, 1993), is a leading risk factor for glucose dysregulation, suggesting that weight gain could account for the observed metabolic disturbances.

However, consistent evidence of a) acute metabolic effects of certain atypical agents on glucose homeostasis in animal models (Houseknecht et al., 2007, Chintoh et al., 2008, Chintoh et al., 2009), b) impaired glucose regulation in patients with schizophrenia independent of adiposity (Newcomer, et al., 2002) and c) numerous reports of diabetic ketoacidosis (DKA) occurring early in treatment and without weight gain (Jin et al., 2002), have suggested that direct, weight-independent mechanisms may be involved. Further, the reports of DKA imply acute effects on insulin secretory mechanisms, which may also share common pathophysiologic pathways with failure of β-cell compensation implicated in longer-term risk of diabetes associated with these agents. Our group recently demonstrated that acute effects on insulin sensitivity appear to mirror risk of weight gain, suggesting some common pharmacological mechanisms between the 2 processes (Chintoh et al., 2009). Our findings also highlighted clozapine and olanzapine-induced deficits in β-cell functioning. This is in keeping with data suggesting that the normal compensatory increase in insulin secretion elicited in obesity-induced insulin resistance may be prevented by olanzapine in dogs (Ader et al., 2005), as well as the observation that olanzapine induces impaired insulin secretion in atypical antipsychotic-naïve patients with schizophrenia (Chiu et al., 2006).

Although the mechanisms underlying antipsychotic-induced glucose regulation remain poorly understood, it has been proposed that the heterogeneous receptor binding pharmacology differentiating the atypical agents not only from each other, but also from their more selective high-potency “conventional” counterparts, may be implicated. As reviewed elsewhere, antipsychotic binding to dopaminergic, serotonergic, adrenergic, and cholinergic sites is understood to influence receptors and transporters in essential body tissues implicated in glucose metabolism (Richelson, 1999, Starrenburg and Bogers, 2009). To this point, correlation studies, within the limitation of not always controlling for weight gain, have implicated affinity for histaminergic, muscarinic, and serotonergic binding sites in the increased risk of diabetes associated with these agents (Matsui-Sakata et al., 2005, Silvestre and Prous, 2005).

The aim of the present study was to ‘deconstruct’ the pharmacological binding profile of high liability AAPs (e.g. clozapine, olanzapine) and examine acute mechanisms underlying AAP-induced glucose dysregulation through single dosing of various representative antagonists. The in vivo effect of the antagonists on secretory capacity of pancreatic β-cells was assessed using hyperglycemic clamps, which also allows for estimation of peripheral sensitivity (Elahi, 1996).