Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat

Aims/hypothesis  Use of the second-generation antipsychotic drugs (SGAs) results in the development of obesity and a type 2 diabetes-like syndrome. We hypothesised that, in addition to the insulin resistance associated with the obesity, the SGAs might have acute effects on glucose metabolism that could contribute to the derangements in glucose metabolism. Methods  We investigated the effects of therapeutically relevant levels of three different antipsychotic medications (haloperidol, quetiapine and clozapine) on glucose tolerance, measures of insulin resistance and hepatic glucose production, and on insulin and glucagon secretion in rats. Results  We found that these drugs induce impaired glucose tolerance in rats that is associated with increased insulin secretion (clozapine>quetiapine>haloperidol) but is independent of weight gain. However, Akt/protein kinase B activation is normal, and at these levels of drug there was no effect on insulin action in fat cells or soleus muscle, and no effect on insulin sensitivity as evaluated by insulin tolerance tests. We show that clozapine induces increased glucose levels following pyruvate and glycerol challenges, indicating an increase in hepatic glucose output (HGO). Increased HGO would in turn increase insulin release and would explain the apparent phenotype mimicking insulin resistance. We provide evidence that this effect could at least in part be mediated by a stimulation of glucagon secretion. Conclusions/interpretation  Our findings indicate that SGAs can cause acute derangements in glucose metabolism that are not caused by a direct induction of insulin resistance but act via an increase in glucagon secretion and thus stimulation of hepatic glucose production. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.