| Summary: | Atypical antipsychotics (AAPs) are associated with metabolic sequelae including risk of type 2 diabetes. Evidence points to a weight-gain independent and direct drug effect on glucose homeostasis. While the exact mechanisms remain elusive, the heterogeneous binding profiles of AAPs likely include receptors involved in glucose metabolism. We 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 and the hyperglycemic clamp. We assessed the acute effects of several selective receptor antagonists on glucose metabolism, namely prazosin, idazoxan, MDL100907, SB242084 and WAY100635. Prazosin and MDL100907, selective α1 and 5HT2A antagonists, respectively, caused significant decreases in both insulin and C-peptide secretion. A decreased glucose infusion rate and disposition index was also found in the prazosin group. Antagonism of the α1 and 5HT2A receptors may be involved in AAP-induced glucose dysregulation, however, the responsible mechanisms remain unknown.
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