Does Olanzapine Inhibit the Secretory Response to Insulin Resistance?

Objectives: The use of atypical antipsychotics has been associated with increased weight gain, the development of type-2 diabetes, and, in rare cases, diabetic ketoacidosis. It is not clear if these changes are a direct function of antipsychotics on either insulin action or insulin secretion, or simply related to their ability to induce weight gain in a population at increased risk to develop hyperglycemia. The objective of this investigation is to determine if treatment with the atypical antipsychotics olanzapine impairs the ability of the pancreatic beta cell to increase its insulin secretory response to graded increases in plasma glucose concentration in non-diabetic, insulin resistant individuals. In addition, we will compare the range of insulin-mediated glucose uptake (IMGU) in olanzapine-treated versus non-antipsychotic treated patients.

Research Plan and Methods: 120 subjects with psychiatric disorders will be enrolled; 60 patients on olanzapine and 60 patients with similar psychiatric diagnoses on a different antipsychotic medication (ziprasidone, risperidone or aripiprazole). All subjects will have a fasting plasma glucose concentration <126 mg/dL, and on no medication with a direct effect on IMGU. Subjects will be admitted to the General Clinical Research Center (GCRC) at Stanford Medical Center and evaluated by an insulin suppression test (IST) to determine their IMGU. Subjects with a steady state plasma glucose (SSPG) concentration during the IST that is >180 mg/dL will be defined as being insulin resistant. From this population of subjects, 15 patients on olanzapine and 15 patients not on any antipsychotic, will return to the GCRC to determine their glucose-stimulated insulin secretory dose-response curves (GS-ISR). The GS-ISR at the same glucose concentration will be compared between the subjects on olanzapine (n=15) and the not on an antipsychotic (n=15) by analysis of variance. Analyses of the 120 subjects screened for insulin resistance will compare 1) the means and distribution of the SSPG concentrations in olanzapine and non-olanzapine treated patients with psychiatric diagnoses; and 2) the means of the two experimental groups with psychiatric diagnoses to Dr. Reaven's data base of volunteers without psychiatric disorders.