Atypical antipsychotics and effects of adrenergic and serotonergic receptor binding on insulin secretion in-vivo: An animal model

Atypical antipsychotics (AAPs) are associated with several metabolic sequelae including increased risk of type 2 diabetes. Growing evidence points to a direct drug effect of these compounds on glucose homeostasis, independent of weight gain. While the responsible mechanisms have yet to be elucidated, the heterogeneous binding profiles of AAPs likely include receptors involved in glucose metabolism. This study aimed to clarify weight-gain independent mechanisms of AAP-induced alterations in insulin secretion. Deconstruction of the receptor binding profiles of these agents was done using representative antagonists. Healthy rats were pre-treated with a single subcutaneous dose of prazosin 0.25 mg/kg (n = 16), a selective α1 antagonist; idazoxan 0.5 mg/kg (n = 10), a selective α2 antagonist; SB242084 0.5 mg/kg (n = 10), a selective 5HT2C antagonist; WAY100635 0.1 mg/kg (n = 10), a selective 5HT1A antagonist; MDL100907 0.5 mg/kg (n = 8), a selective 5HT2A antagonist; or vehicle: 0.9% NaCl saline (n = 8), DMSO (n = 8), or cyclodextrin (n = 5). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic β-cells. Treatment with prazosin and MDL100907 resulted in significant decreases in both insulin and C-peptide secretion compared to their respective controls, DMSO and saline. These findings were corroborated with decreased glucose infusion rate and disposition index in the prazosin group. Results suggest that α1 and 5HT2A receptor antagonism may be involved in glucose dysregulation with AAP treatment, however, the exact mechanisms involved remain unknown.