title: Insulin secretion in patients receiving clozapine, olanzapine, quetiapine and risperidone.
abstract: BACKGROUND
  Second-generation antipsychotics (SGAs) increase the risk of type 2 diabetes. The mechanism is thought to center on drug-induced weight gain, which starts the dysmetabolic cascade of insulin resistance, increased insulin production and pancreatic beta-cell failure. An independent effect of SGAs on insulin secretion has been suggested in animal models, but has not been demonstrated in clinical samples.
  
  
  OBJECTIVE
  To determine the post-challenge insulin secretion in patients treated with SGAs.
  
  
  METHODS
  We identified 520 non-diabetic individuals treated with clozapine (N=73), olanzapine (N=190), quetiapine (N=91) or risperidone (N=166) in a consecutive, single-site cohort of 783 adult psychiatric inpatients who underwent a comprehensive metabolic assessment. Insulin secretion was measured as the area under the curve (AUC(insulin)) generated by levels recorded at baseline, 30, 60 and 120 min after the intake of 75 g of glucose. The independent predictors of insulin secretion were determined with regression analysis in the entire sample and separately in patients with normal glucose tolerance (NGT) and prediabetes.
  
  
  RESULTS
  The post-challenge AUC(insulin) was independently predicted by AUC(glucose), waist circumference, triglyceride levels and younger age (p<0.0001); non-smoking status (p=0.0012); and treatment with clozapine (p=0.021). The model explained 33.5% of the variance in insulin secretion (p<0.0001). The clozapine effect was present in the NGT group, but not in prediabetics.
  
  
  CONCLUSIONS
  Clozapine, but not olanzapine, quetiapine and risperidone, is an independent predictor of post-challenge insulin secretion in non-diabetics, particularly in those with normal glucose tolerance. The findings suggest that the diabetogenic risk of clozapine may persist even after weight reduction.
authors.affiliation: Zucker Hillside Hospital, Glen Oaks, NY, United States. pmanu@nshs.edu
authors.forename: Peter
authors.initials: P
authors.lastname: Manu
authors.forename: Christoph U
authors.initials: CU
authors.lastname: Correll
authors.forename: Martien
authors.initials: M
authors.lastname: Wampers
authors.forename: Ruud
authors.initials: R
authors.lastname: van Winkel
authors.forename: Weiping
authors.initials: W
authors.lastname: Yu
authors.forename: Daphna
authors.initials: D
authors.lastname: Shiffeldrim
authors.forename: John M
authors.initials: JM
authors.lastname: Kane
authors.forename: Marc
authors.initials: M
authors.lastname: De Hert
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology; D019540:Area Under Curve; D001569:Benzodiazepines / Q000009:adverse effects* / Q000494:pharmacology; D003024:Clozapine / Q000009:adverse effects* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced* / Q000175:diagnosis; D003987:Dibenzothiazepines / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011237:Predictive Value of Tests; D000069348:Quetiapine Fumarate; D012044:Regression Analysis; D018967:Risperidone / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D007328:Insulin; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine