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.

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

“…Accumulating studies have attracted profound scientific and public attention to the greater metabolic comorbidity of T2DM in schizophrenia patients( Mizuki et al, 2020 ), which is partly owing to overlapping genetic risk factors, environmental susceptibility and antipsychotic drugs-related mechanisms( Suvisaari et al, 2016 ; Hackinger et al, 2018 ). Even first-episode drug-naïve patients with schizophrenia exhibited greater insulin resistance compared with normal subjects( Pillinger et al, 2017 ).…”

The Etiology of Metabolic Disturbances in Schizophrenia: Drugs, Genes, and Environment

“… Mizuki et al (2021) have provided an extensive analysis of the relationship between type 2 diabetes (T2D) and schizophrenia in which they have focused on a possible commonality of genetic risk as well as reviewing in depth some molecular mechanisms that may underlie the relationship between these 2 diseases. There is much to elucidate in this important yet complex topic, which, as these authors acknowledge, remains far from fully understood.…”

“…The extent of this increased incidence depends strongly on the particular drugs being taken ( Koro et al, 2002 ), indicating that antipsychotic medication, particularly with drugs that also induce weight gain, makes a substantial contribution to this relationship. Other consequences or correlates of schizophrenia, such as higher prevalence of smoking, less exercise, and poor diet, may also contribute to T2D risk, leading to the suggestion from Mizuki et al (2021) that “schizophrenia itself is a risk for increased onset of diabetes.” More difficult is determining whether there is an inherent association between schizophrenia and T2D independent of the consequences of psychotic symptoms and their treatment. The main approach is to search for T2D risk factors in early-stage, drug-naïve schizophrenia patients.…”

“…Unsurprisingly, there is really no evidence for an increased prevalence of T2D in such patients, given that it typically takes many years to develop. Several groups fail to identify any significant metabolic abnormalities at this early stage of psychotic illness, although some reports cited by Mizuki et al (2021) , including the meta-analysis of Pillinger et al (2017) , have identified increases in markers of glucose intolerance and insulin resistance. However, these findings still question whether the effect is truly trait, rather than state, related.…”

“…Incidentally, the findings of Zhang et al (2015) contrast profoundly with an earlier report from the same group in which no elevation compared with controls was found ( Chen et al, 2013 ); this inconsistency reflects a substantial difference in fasting glucose not between the patient groups but between the controls! While Mizuki et al (2021) identify other evidence for subtle differences in indicators of relative glucose intolerance or insulin resistance in first episode patients, it is important to bear in mind that these measures are not inevitable precursors of T2D.…”