Contribution of parasympathetic muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia

Abstract

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers

“…Olanzapine-induced hyperinsulinemia has been observed previously in studies of patients with schizophrenia [32,33] and healthy volunteers [30,34]. The findings of this study are consistent with reports that hyperinsulinemia results from increases in insulin secretion from the pancreas.…”

“…Multiple mechanisms may account for olanzapine-mediated increases in insulin secretion, including alterations in neuronal modulation of the pancreas and even direct effects of dopamine receptor antagonism on pancreatic β-cells [35][36][37]. One study of intravenous glucose tolerance tests in healthy volunteers treated with olanzapine demonstrated an essential role of sympathetic input via muscarinic receptors in mediating the olanzapine-induced hyperinsulinemic response to glucose challenge [34]. More recently, it has been reported that pancreatic αand β-cells not only express D2-like dopamine receptors but also are capable of local catecholamine synthesis [36].…”

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

“…On this aspect, the effect of AAPs is controversial because besides blocking muscarinic receptors, clozapine and olanzapine seem to increase the parasympathetic cholinergic output that probably leads to a rebound on the vagal system with compensatory stimulation of the β-cells [ 63 , 89 ]. In a study, olanzapine administrated for 9 days increased insulin and C peptide secretion that was reduced by atropine treatment, thus confirming the role of muscarinic receptor stimulation [ 90 ]. Clozapine and olanzapine-induced insulin dysregulation may also be partly due to blockade of hypothalamic M 3 receptors [ 91 ].…”

An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

“…59 Finally, OLZ/SAM consistently mitigated olanzapine-associated weight gain across a range of species/populations (eg, rodents, nonhuman primates, healthy individuals, and patients with schizophrenia), 60,62,71 and antipsychotic-associated weight gain and metabolic dysregulation occur independently of disease. [102][103][104]…”