The effect of antipsychotic drugs on insulin sensitivity and insulin secretion

Both conventional and second generation antipsychotics have been associated with an increased risk for impaired glucose tolerance and diabetes mellitus.

Little is known about the pathogenesis of antipsychotic-related diabetes. While mostly attributable to weight gain, there may also be a direct, receptor-mediated effect of antipsychotics on glucose tolerance.

Diabetes mellitus occurs if either insulin secretion is impaired or if peripheral tissue, particularly muscle and adipose tissue, is insensitive to the glucose lowering action of insulin (insulin resistance). Gold standard techniques to assess insulin sensitivity and secretion are the euglycemic–hyperinsulinemic and the hyperglycemic clamp techniques.

Our first study looked if insulin sensitivity (in 10 healthy subjects) may be acutely impaired by antagonism at the serotonin (5-HT)–2 receptor after single administration of ketanserin, a selective 5-HT–2 antagonist. Compared to the placebo condition, subjects showed a significantly decreased insulin sensitivity after ketanserin.

In a second study we examined acute effects of atypical antipsychotics (olanzapine and amisulpride) on insulin sensitivity and secretion in 10 healthy subjects. We found Amisulpride to have a stimulatory effect on insulin secretion by pancreatic beta cells, while olanzapine does not change insulin secretion. To the best of our knowledge, this is the first study to directly demonstrate a modulation of insulin secretion by antipsychotics.