This study will examine the effects of two different antipsychotic medications on control of blood sugar in people who are at risk of diabetes but mentally healthy.

Antipsychotic medications are those that treat the most severe psychiatric symptoms, such as hallucinations, paranoid thoughts, and delusions. Research shows that some of these medications may put people at a higher risk of metabolic derangements, such as insulin resistance. Certain antipsychotics, like clozapine and olanzapine, are associated with a higher risk of metabolic side effects than others, like aripiprazole and ziprasidone. Because people with schizophrenia may experience adverse side effects from switching antipsychotic medications and because it is difficult to find people with schizophrenia who do not have experience taking antipsychotics, this study will use people without psychiatric disorders who are at risk for diabetes in place of people with schizophrenia. The study will compare the effects of single doses of two antipsychotic medications, olanzapine and aripiprazole, on insulin action in this population. In addition to determining metabolic effects of these medications, this study will also seek to demonstrate the feasibility of using mentally healthy people at risk of diabetes as a substitute for people with schizophrenia in studying these effects.

Participation in this study will last 4 weeks. Participants will first complete a screening visit that will include the following: an oral glucose tolerance test (OGTT), which involves a blood draw, consumption of a sugar drink, and then a second blood draw; a review of medical and psychiatric history, including use of medicines and psychiatric medications; and measurement of participants' height and weight. The second visit, scheduled 2 weeks after screening, will include a tracer-clamp study to test how participants' bodies handle sugar. The tracer-clamp study will be conducted over the course of one night and morning and will require participants to stay at the study location overnight. At 3 AM, participants will receive an intravenous line (IV) with a sugar solution. Just before 8 AM, they will receive a second IV in the opposite arm that will draw blood and monitor blood sugar levels.

At 8 AM, participants will begin receiving insulin in the first IV; blood samples will be drawn and blood sugar levels will be monitored during this time to ensure they remain within a healthy range. At 11 AM, participants will receive an injection of an antipsychotic medication into their arm muscles. The antipsychotic, which will be randomly assigned, will be either olanzapine or aripiprazole. Participants will be monitored for 3 hours after receiving the injection of antipsychotic medication; during this time, more blood samples will be drawn, blood sugar levels will be monitored to ensure they are within a healthy range, and secondary medications will be available to counteract certain side effects of the antipsychotics. After 2 more weeks, participants will undergo a third study visit in which they repeat the OGTT.

Inclusion Criteria:

• Prediabetic, defined as 2-hour post-load serum glucose between 140 and 199 mg/dl on a 75-gram standard oral glucose tolerance test (OGTT) within the past 90 days
• Family history of type 2 diabetes mellitus
• Body mass index (BMI) between 25 and 35 kg/m2
• English speaker
• Nonsmoker

Exclusion Criteria:

• History of Axis I mood, anxiety, or psychotic disorder, confirmed by Structured Clinical Interview for DSM-IV
• Use of psychotropic drugs

Male subjects ages 40-65 with impaired glucose tolerance as measured by oral glucose tolerance testing.

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