Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis

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Patients with psychotic disorders are at high risk for type 2 diabetes mellitus, and there is increasing evidence that patients display glucose metabolism abnormalities before significant antipsychotic medication exposure. In the present study, we examined insulin action by quantifying insulin sensitivity in first-episode psychosis (FEP) patients and unaffected siblings, compared to healthy individuals, using a physiological-based model and comprehensive assessment battery. Twenty-two unaffected siblings, 18 FEP patients, and 15 healthy unrelated controls were evaluated using a 2-h oral glucose tolerance test (OGTT), with 7 samples of plasma glucose and serum insulin concentration measurements. Insulin sensitivity was quantified using the oral minimal model method. Lipid, leptin, free fatty acids, and inflammatory marker levels were also measured. Anthropometric, nutrient, and activity assessments were conducted; total body composition and fat distribution were determined using whole-body dual-energy X-ray absorptiometry. Insulin sensitivity significantly differed among groups (F = 6.01 and 0.004), with patients and siblings showing lower insulin sensitivity, compared to controls (P = 0.006 and 0.002, respectively). Body mass index, visceral adipose tissue area (cm2), lipids, leptin, free fatty acids, inflammatory markers, and activity ratings were not significantly different among groups. There was a significant difference in nutrient intake with lower total kilocalories/kilogram body weight in patients, compared to siblings and controls. Overall, the findings suggest that familial abnormal glucose metabolism or a primary insulin signaling pathway abnormality is related to risk for psychosis, independent of disease expression and treatment effects. Future studies should examine underlying biological mechanisms of insulin signaling abnormalities in psychotic disorders.

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The authors would like to gratefully acknowledge patients and their families who participated in this study. This research was supported by NIMH to Dost Öngür (R01MH094594 and K24MH104449) and Virginie-Anne Chouinard (5T32MH016259), and the Dupont-Warren and Livingston Fellowships and Maria Lorenz Pope Fellowship to Virginie-Anne Chouinard. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102), financial contributions from Harvard University and its affiliated academic healthcare centers and the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and DK-075116. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

Author information


  1. Psychotic Disorders Division, McLean Hospital, Belmont, MA, USA

    • Virginie-Anne Chouinard
    • , Kyle P. Ryan
    • , Bruce M. Cohen
    •  & Dost Öngür
  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    • Virginie-Anne Chouinard
    • , Linda Valeri
    • , Bruce M. Cohen
    •  & Dost Öngür
  3. Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA

    • David C. Henderson
  4. Division of Psychiatry, Boston Medical Center, Boston, MA, USA

    • David C. Henderson
  5. Department of Information Engineering, University of Padova, Padova, Italy

    • Chiara Dalla Man
    •  & Claudio Cobelli
  6. Laboratory for Psychiatric Biostatistics, McLean Hospital, Belmont, MA, USA

    • Linda Valeri
  7. Translational and Clinical Research Centers, Massachusetts General Hospital, Boston, MA, USA

    • Brianna E. Gray
  8. Translational Physiology Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA

    • Aaron M. Cypess


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Conflict of interest

DH has received research grants from Otsuka Pharmaceuticals and Reckitt Benckiser. AMC is a recipient of sponsored research grants from Chugai Pharmaceutical Co., Ltd, and Molecular Metabolism, LLC, both through Joslin Diabetes Center; an honorarium for lecturing about brown fat to Pfizer, Inc.; and he has received payment for lecturing about clinical diabetes on behalf of Joslin Diabetes Center to employees of Sanofi, Genentech, Eli Lilly, Janssen, and Regeneron. DÖ was on Scientific Advisory Board for Neurocrine Inc. in 2017. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Virginie-Anne Chouinard.

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