Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus

Abstract

The mortality rate of patients with schizophrenia is high, and life expectancy is shorter by 10 to 20 years. Metabolic abnormalities including type 2 diabetes mellitus (T2DM) are among the main reasons. The prevalence of T2DM in patients with schizophrenia may be epidemiologically frequent because antipsychotics induce weight gain as a side effect and the cognitive dysfunction of patients with schizophrenia relates to a disordered lifestyle, poor diet, and low socioeconomic status. Apart from these common risk factors and risk factors unique to schizophrenia, accumulating evidence suggests the existence of common susceptibility genes between schizophrenia and T2DM. Functional proteins translated from common genetic susceptibility genes are known to regulate neuronal development in the brain and insulin in the pancreas through several common cascades. In this review, we discuss common susceptibility genes, functional cascades, and the relationship between schizophrenia and T2DM. Many genetic and epidemiological studies have reliably associated the comorbidity of schizophrenia and T2DM, and it is probably safe to think that common cascades and mechanisms suspected from common genes' functions are related to the onset of both schizophrenia and T2DM. On the other hand, even when genetic analyses are performed on a relatively large number of comorbid patients, the results are sometimes inconsistent, and susceptibility genes may carry only a low or moderate risk. We anticipate future directions in this field.

Keywords: ARHGEF11; Akt/GSK3β; DISC1; Wnt/β-catenin; kalirin.

Figure 1.

Summary of plausible shared mechanisms for the pathogenetic association between schizophrenia and type 2 diabetes mellitus (T2DM). (A) Schematic representation of Rho family of small GTPases (Rho GTPases) signaling cascades involved in synaptic plasticity. Rho guanine-nucleotide exchange factor 11 (ARHGEF11) interacts and colocalizes with synapse marker postsynaptic density protein 95 (PSD-95) at synapse sites and negatively regulated the formation of dendritic spines in cortical primary neurons (Mizuki et al., 2016). Disrupted-in-schizophrenia 1 (DISC1) directly interacts with PSD-95 and kalirin-7, a GEF for Rac1, and blocks access of kalirin-7 to Rac1. This binding is released by N-methyl-D-aspartate (NMDA) receptor activation, allowing free access of kalirin-7 to Rac1 and leading to the resultant activation of Rac1 and spine enlargement (Hayashi-Takagi et al., 2010). (B) The role of Rho GTPase in pancreatic β cells. Rac1 is particularly important for glucose-stimulated insulin secretion (Wang and Thurmond, 2009). In contrast, RhoA expression is increased in β-cells under diabetic conditions, and Rho/Rho-kinase activation is involved in the suppression of insulin biosynthesis (Nakamura et al., 2006). Insulin release from pancreatic islet β-cells could be determined by the resulting balance of Rho GTPase signaling. Illustrating this schematic figure, we referenced figures of Hayashi-Takagi et al., 2010 and Wang et al., 2009.

Figure 2.

Mechanisms that underlie the association between schizophrenia and type 2 diabetes mellitus (T2DM). The mechanisms of the increasing prevalence of T2DM in patients with schizophrenia are multifactorial. Poor diet and sedentary lifestyle are included in the traditional risk factors. Iatrogenic risk during treatment with antipsychotics is included in risk factors unique to schizophrenia (Ward and Druss, 2015). Accumulating evidence suggests shared genetic susceptibility and biological common pathway of both schizophrenia and T2DM.