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

Abstract

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-hour 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, P=0.004), with patients and siblings showing lower insulin sensitivity, compared to controls (P=0.006, and P=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.

Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia

“…While it is unknown how antipsychotic medications impact brain IR, studies suggest that adults with SZ have an increased risk for diabetes or impaired glucose metabolism regardless of medication status (Rajkumar et al, 2017), glucose homeostasis is altered from illness onset of SZ (Pillinger et al, 2017), and glycemic abnormalities are likely intrinsic to the illness beyond the known effects of medication, lifestyle, and health care access (Perry et al, 2016). Finally, a study in patients with first episode psychosis, unaffected patient siblings, and HC found that patients and their siblings had lower sensitivity to insulin than HC (Chouinard et al, 2018). Abnormal peripheral glucose metabolism or insulin signaling may be an increased risk factor for psychosis and independent of treatment effects.…”

Common mechanisms for type 2 diabetes and psychosis: Findings from a prospective birth cohort

“…One contributor to comorbidity between cardiometabolic disorders and schizophrenia could be shared genetic susceptibility ( Lin and Shuldiner, 2010 ). Risk of insulin resistance (IR) ( Chouinard et al, 2019 ) and impaired glucose tolerance ( Ferentinos and Dikeos, 2012 ), two key precursors of T2DM, are higher in unaffected relatives of patients with psychosis compared with controls. People with comorbid schizophrenia and T2DM have a higher genetic predisposition for both disorders compared to controls ( Hackinger et al, 2018 ), and an association between genetic predisposition for schizophrenia and IR has been reported in a clinical sample ( Tomasik et al, 2019 ).…”

Metabolic-inflammatory status as predictor of clinical outcome at 1-year follow-up in patients with first episode psychosis

“…A further aspect to consider is that, due to the relationship between the immune and the metabolic system, high levels of peripheral inflammation are generally associated with metabolic abnormalities in both the general population and in FEP patients (Russell et al, 2015) (Petrikis et al, 2015;Pillinger et al, 2017a;Pillinger et al, 2017b;S et al, 2013). More interestingly, weight gain, increased visceral fat and impaired glucose metabolism have been detected also in drug naïve patients (Correll et al, 2014), with altered insulin signaling being present also in unaffected siblings (Chouinard et al, 2018).…”