SCHRES-08639; No of Pages 5

Schizophrenia Research xxx (xxxx) xxx

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Schizophrenia Research

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The prevalence, risk factors and clinical correlates of diabetes mellitus in

Chinese patients with schizophrenia
Lijuan Huo a,b, Guangya Zhang c, Xiang-Dong Du c, Qiaqiufang Jia c, Zheng-Kang Qian c, Dachun Chen d,
Meihong Xiu d, Fengchun Wu a,b, Jair C. Soares e, Xingbing Huang a, Ryan M. Cassidy e,
Yuping Ning a,b,⁎, Xiang Yang Zhang a,b,f,⁎⁎
a
Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
b
Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
c
Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, Jiangsu Province, China
d
Beijing HuilongGuan Hosptial, Beijing, China
e
Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
f
CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China

a r t i c l e i n f o a b s t r a c t

Article history: Diabetes is one of the most common comorbid diseases in patients with schizophrenia. The present study exam-
Received 15 January 2019 ined the prevalence of diabetes and its clinical correlates in a large sample of Chinese patients with schizophrenia,
Accepted 21 December 2019 which has not been examined systemically. In this cross-sectional study, a total of 1189 patients (males/fe-
Available online xxxx
males = 938/251; average age: 48.51 ± 10.09 years) were recruited. Fasting blood samples were collected to di-
agnose diabetes. Psychiatric symptoms were measured with the Positive and Negative Syndrome Scale (PANSS).
Keywords:
Schizophrenia
The prevalence of diabetes was 12.53% with a significant gender difference (males: 10.87% versus females:
Diabetes 18.73%). Compared to patients without diabetes, those with diabetes were older, had a later age of onset, had a
Prevalence higher BMI, had higher positive symptom scores and had higher level of metabolic indices, including triglyceride,
Risk factor cholesterol and HDL cholesterol. After stepwise binary logistic regression analysis, age, BMI, and triglyceride level
remained significantly associated with diabetes. This study suggests that diabetes occur with high prevalence in
Chinese schizophrenia patients. In addition, age, BMI, and triglyceride level possibly are useful markers predicting
an increased risk for diabetes.
© 2020 Elsevier B.V. All rights reserved.

1. Introduction recent meta-analyses, the prevalence of diabetes in schizophrenia

Diabetes mellitus is a major metabolic disorder which, if not well-
controlled, leads to many medical sequela affecting nearly every organ
system. The substantial excess risks of death among persons with type
2 diabetes (Tancredi et al., 2015) make it a public health problem world-
wide; deaths attributable to diabetes account for more than five million
deaths per year (IDF Diabetes Atlas Group, 2015). According to Global
Report on Diabetes from WHO (2016), the prevalence of diabetes in
the general population is steadily increasing - most markedly, in the
world's middle-income countries. Special populations, such as patients
with schizophrenia, are at even greater risk. As confirmed by several
⁎ Correspondence to: Y. Ning, The Affiliated Brain Hospital of Guangzhou Medical
University (Guangzhou Huiai Hospital), 36 Mingxin Road, Liwan District, Guangzhou
510370, China
⁎⁎ Correspondence to: X.Y. Zhang, Institute of Psychology, Chinese Academy of Sciences;
16 Lincui Road, Chaoyang District, Beijing, 100101, China.
E-mail addresses: ningjeny@126.com (Y. Ning), zhangxy@psych.ac.cn (X.Y. Zhang).
ranges from 10% to 15%, two to three times higher than that in the gen-
eral population (Stubbs et al., 2015; Schoepf et al., 2012; Vancampfort
et al., 2016).
The underlying mechanisms for increased co-morbidity with diabe-
tes in schizophrenia are multifactorial. The clearest evidence demon-
strates that some of the increased risks for diabetes stem from the use
of antipsychotics, especially atypical antipsychotics (Smith et al., 2008;
Lin and Shuldiner 2010; De Hert et al., 2012). However, even first-
episode, drug-naïve patients with schizophrenia have impaired fasting
glucose, greater insulin resistance, and elevated fasting 2-h plasma glu-
cose levels (Zhang et al., 2015). The origins of this association are not
known, but one possible explanation arises from overlapping genetic
risk factors between diabetes and schizophrenia (Zhang et al., 2013).
Using genome-wide approaches, Hackinger et al. (2018) identified 29
genes associated with both disorders. As further evidence for this, one
recent study showed that dopamine dysfunction potentially contrib-
uted to the comorbidity of schizophrenia and diabetes (Gragnoli et al.,
2016). It also must be said that schizophrenia patients may engage in

https://doi.org/10.1016/j.schres.2019.12.029
0920-9964/© 2020 Elsevier B.V. All rights reserved.

Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese
patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
2 L. Huo et al. / Schizophrenia Research xxx (xxxx) xxx
lifestyle drivers of metabolic disease, such as sedentarism, poor diet, in-
creased food intake, and increased smoking behavior (Heald et al.,
2017).
There is significant variability in the prevalence and association of
diabetes with schizophrenia in different regions or ethnic popula-
tions (Stubbs et al., 2015; Vancampfort et al., 2016). In mainland
China, only one study has been conducted which found that, in
schizophrenia patients receiving long-term clozapine treatment,
there was a 22% prevalence of diabetes (Zhang et al., 2011). This
study focused on the influence of clozapine and found that it, at
least in part, increased the risk of diabetes. There are many other
risk factors that could also be predictive, which have yet to be ex-
plored in this population.
In this study, we investigated the prevalence of diabetes and its clin-
ical correlates in a large of sample (n = 1189) of chronic patients with
schizophrenia in a Chinese Han population. The preliminary purpose
of this study was to investigate whether diabetes was significantly
higher in schizophrenia patients in a Chinese Han population. A second-
ary aim of this study was to determine factors associated with increased
diabetes in individuals with schizophrenia.
2. Methods
2.1. Study setting and subjects
The cross-sectional study was conducted at Beijing Hui-Long-Guan
hospital and Hebei Rong-Jun hospital. Both of these are large public psy-
chiatric hospitals in China. In total, 1189 Chinese inpatients between 16
and 76 years old with a DSM-IV diagnosis of schizophrenia were re-
cruited. Diagnoses were made for each patient by two independent ex-
perienced psychiatrists, according to the Structured Clinical Interview
for DSM-IV (SCID). All subjects signed written informed consent before
participating in the study - this was approved by the ethics committee
of Beijing Hui-Long-Guan hospital.
2.2. Demographic data collection
A detailed questionnaire that recorded general information,
sociodemographic characteristics, medical and psychiatric conditions
were administered by research staff. Medical records and collateral re-
sources were also used to collect additional information. The following
data were collected on each patient: sex, age, education, age of onset,
age of the first hospitalization, number of hospitalizations, duration of
illness, antipsychotic medicines (type and dose), and smoking behavior.
2.3. Measurement of anthropometric variables, plasma glucose and lipid
profile
Body weight and height were measured to calculate body mass
index (BMI, weight in kg/square of height in meters). Body weight
was measured with an electronic scale calibrated to 0.1 kg with subjects
wearing light indoor clothes. Height was measured to the nearest milli-
meter when subjects stood barefoot and upright. Patients were defined
as obese with BMI ≥ 28, consistent with the criteria of Chinese Working
Group on Obesity in China (WGOC) (Ji and Chen, 2013).
Blood samples of all patients were collected between 7 and 9 a.m.
after an overnight fast. According to World Health Organization diag-
nostic criteria for diabetes mellitus, diabetes was diagnosed as fasting
hyperglycemia (≥126 mg/dL) or plasma glucose levels higher than
200 mg/dL after a 75-g Oral Glucose Tolerance Test (OGTT). Addition-
ally, triglycerides, HDL cholesterol, and LDL cholesterol levels, apolipo-
protein A1 (APOA1), and APOB were measured using in-hospital
laboratory facilities.
Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese
patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
2.4. Clinical measurement
The 30-item Positive and Negative Syndrome Scale (PANSS) was
assessed by four independent experienced psychiatrists, who simulta-
neously attended a training program prior to the study. The inter-rater
correlation coefficient was N0.8 for repeated assessments of the PANSS
total score.
2.5. Data analysis
The normality test was conducted for data of each variable using the
Kolmogorov–Smirnov one-sample test. Demographic and clinical vari-
ables of the diabetic and non-diabetic groups were compared with inde-
pendent t-tests for continuous variables and chi-squared test for
categorical variables. A binary logistic regression analysis was per-
formed to assess which factors were strongly associated with diabetes
mellitus. All statistical analyses were performed with SPSS version 21.0.
3. Results
3.1. Demographic characteristics of patients with schizophrenia
Since some patients did not fully complete the questionnaire or clin-
ical measures, numbers of patients varied slightly in different categories.
A total of 1189 patients, with 251 females and 938 males, were included
in our study. The average age of patients was 48.51 ± 10.09 years, rang-
ing from 16 to 76 years. The average years of education was 9.08 ±
2.71 years, ranging from 0 to 19 years. The average age of illness onset
was 23.88 ± 6.05 years, ranging from 1 to 19 years. Among all patients,
23.7% took typical antipsychotics, while 76.3% took atypical antipsy-
chotics. 63.5% patients were regular smokers, with the average number
of cigarettes/day being 12.31 ± 8.73.
3.2. Prevalence of diabetes mellitus and risk factors
The overall prevalence of diabetes mellitus was 12.53% (149/1189)
in patients with schizophrenia. 10.87% (102/938) of males and 18.73%
(47/251) of females were diabetic; this difference was significant
(X2 = 11.14, p = 0.001). In addition, the prevalence of obesity was
17.5% (146/834).
The demographic and clinical characteristics of patients with diabe-
tes vs. those without diabetes were compared and depicted in Table 1.
Significant differences between the diabetic and non-diabetic groups
were found in the following variables: age (t = 4.312, p b 0.001), sex
(X2 = 11.14, p = 0.001), age of onset (t = 4.312, p = 0.01), BMI (t =
−5.66, p b 0.001) and positive subscore of PANSS (t = 2.303, p =
0.021). Patients with diabetes were older, with a later onset of schizo-
phrenia, a higher BMI and more severe positive symptoms than patients
without diabetes. In addition, triglycerides (t = 6.92, p b 0.001), total
cholesterol (t = 0.251, p = 0.002) and LDL cholesterol (t = 3.54,
p b 0.001) levels were significantly higher in the diabetic group.
Furthermore, a stepwise forward binary logistic regression was per-
formed to identify the risk factors for diabetes, showing that older age
(odd ratio = 1. 04, 95% CI = 1.01–1.07, Wald x2 = 5.1, p = 0.02),
greater BMI (odd ratio = 1. 15, 95% CI = 1.07–1.23, Wald x2 = 15.52,
p ≤ 0.001) and higher triglyceride level (odd ratio = 1. 32, 95% CI =
1.05–1.67, Wald x2 = 5.73, p = 0.02) were important predictors for
diabetes.
4. Discussion
Diabetes and its complications are major drivers of increased mor-
tality in patients with schizophrenia. To the best of our knowledge,
this is the first study reporting the prevalence and risk factors of diabe-
tes in schizophrenia patients in a Chinese Han population. We found
that 12.53% of patients with schizophrenia had concomitant diabetes.
 L. Huo et al. / Schizophrenia Research xxx (xxxx) xxx 3

Table 1
Characteristics of patients with schizophrenia with or without diabetes mellitus.

Patient with diabetes Patient without diabetes t or x2 P value

Age (years) 52.14 ± 8.94 48 ± 10.14 4.312 b0.001

Gender
Male (%) 102/149 (68.46%) 836/1040 (80.38%) 11.14 0.001
Female (%) 47/149 (37.54%) 204/1040 (19.62%)
Education (years) 9.18 ± 2.72 9.06 ± 2.71 0.596 0.551
Age of onset (years) 24.66 ± 5.56 23.77 ± 6.11 2.584 0.01
Hospitalization numbers 4.29 ± 3.53 3.98 ± 2.62 0.606 0.544
BMI 26.95 ± 4.36 24.15 ± 4.06 −5.66 b0.001
Obesity 31/75 (41.3%) 115/759 (15.2%) 46.02 b0.001
Smoking behavior 84/142 (59.2%) 636/991 (64.1%) 1.35 0.245
Cigarettes/day 10.73 ± 7.15 12.52 ± 8.9 −1.477 0.140
Antipsychotic
Atypical 107/146 (73.3%) 780/1018 (76.7%) 0.819 0.365
Typical 39/146 (26.7%) 237/1018 (23.3%)
Antipsychotic dose (mg/day) (chlorpromazine equivalents) 479.93 ± 526.89 438.29 ± 384.01 0.360 0.719
PANSS
Total score 62.97 ± 19.04 61.66 ± 17.58 1.102 0.271
P subscore 13.55 ± 6.48 12.32 ± 5.62 2.303 0.021
N subscore 22.03 ± 8.27 22.79 ± 8.4 −0.759 0.448
G subscore 27.38 ± 8.35 26.51 ± 7.78 1.603 0.109
Cardo-metabolic
Triglyceride (mmol/L) 2.24 ± 1.31 1.58 ± 1 6.92 b0.001
Cholesterol (mmol/L) 4.67 ± 1.05 4.39 ± 0.96 0.251 0.002
HDL cholesterol (mmol/L) 1.27 ± 0.3 1.24 ± 0.35 0.983 0.326
LDL cholesterol (mmol/L) 2.96 ± 0.82 2.76 ± 0.95 3.544 b0.001
APOA1 (g/L) 1.61 ± 0.35 1.60 ± 0.49 1.1 0.272
APOB (g/L) 0.99 ± 0.34 0.98 ± 0.26 −0.581 0.561

Furthermore, some demographic and clinical variables were demon-
strated to be the risk factors for diabetes, including older age, being fe-
male, higher BMI, and higher triglyceride level.
The prevalence rate of diabetes was higher in our sample than that
reported in studies performed in high-income areas of Asia, i.e.
Taiwan and Japan (Chien et al., 2009; Hung et al., 2005; Okumura
et al., 2010), but slightly lower than in India (15%) (Subashini et al.,
2011). The differences between regions may be attributable to the dis-
crepancies in quality of health care, policies and environments
supporting healthy lifestyles, dietary habits, antipsychotics typically
prescribed, and genetic risk factors for diabetes that are independent
of those for schizophrenia. Differences in methodology and sample
size between studies may also contribute.
Given the global trend toward an obesogenic and diabetogenic life-
style, it is not surprising that the worldwide prevalence of diabetes is
on the rise (NCD Risk Factor Collaboration, 2016). In China, a large, na-
tionally representative survey in 2013 found that the estimated overall
prevalence of diabetes was about 11% (Wang et al., 2017; Xu et al.,
2013). As a result, the difference in the occurrence of diabetes between
the normal population and the schizophrenia may be getting smaller.
Dispute remains over whether gender contributes to the risk of dia-
betes. Even in the normal population, various studies have found that
diabetes is more common in females (Gu et al., 2003) and in males
(Yang et al., 2010). Markedly higher risk of diabetes in female schizo-
phrenia was found in the current study, which was consistent with
some previous studies (Dixon et al., 2000; Chen et al., 2011; Chien
et al., 2009; Vancampfort et al., 2016). There were chronic patients
with schizophrenia receiving long-term antipsychotics included in
these studies. We could speculate that poorer diabetes treatment and
more complications among women with schizophrenia may cause the
higher prevalence. Another study reported that in the first-episode
schizophrenia group, male gender was associated with higher metabolic
risk (Chen et al., 2016). Systematic research and cogent summary of the
available data are lacking to make any clear picture of the ultimate role
that gender plays in predicting the development of diabetes in
schizophrenia.
Agreeing with most previous literature (Annamalai et al., 2017; Li
et al., 2017; Vancampfort et al., 2015), we found that the prevalence of
diabetes in schizophrenia increased with high BMI, or obesity. Obesity
is a symptom of metabolic disease and is predictive of insulin resistance
and altered blood chemistry, which in turn drives the development car-
diovascular disease and diabetes. Unhealthy lifestyles (Heald et al.,
2017) and antipsychotic therapy (Manu et al., 2015) are likely to be
the prime drivers of obesity and then diabetes in schizophrenia. Shared
genetic risk factors for both schizophrenia and metabolic disease may
also contribute; for example, the fat mass and associated genes (FTO)
and leptin and leptin receptor genes (LEP, LEPR) are strongly related
to both metabolic syndrome and schizophrenia (Malan-Müller et al.,
2016).
Interestingly, our result showed that only positive symptomatology
on the PANSS, rather than greater symptom burden overall or negative
symptoms, was associated with diabetes in our patients. As far as we
know, only one previous study (Nuevo et al., 2011) provided evidence
for the direct relationship between positive symptoms and the preva-
lence of diabetes. Nuevo et al. (2011) found that the prevalence was in-
creased with the severity of positive symptoms. Why this may be the
case is not known; more research about the relation between symptom-
atology of schizophrenia and diabetes is needed.
Contrary to the literature, we did not find that the antipsychotic
therapy, including type and dosage, differed between the diabetic and
non-diabetic groups. Antipsychotic usage correlates with β-cell damage
and insulin resistance, likely driving diabetes through this mechanism
(though whether this is associated with altered eating habits or direct
damage is not yet known). (Chen et al., 2017; Whicher et al., 2018).
Zhang et al., 2011 found a 22% rate of diabetes among clozapine-
treated schizophrenia patients in mainland China; notably, this was
much higher than the present study. This result indirectly proved that
patients using clozapine were more likely to develop diabetes. In fact,
the most notable side effect of second-generation antipsychotic medica-
tions is metabolic syndrome (Rubin et al., 2015; Solmi et al., 2017).
However, a meta-analysis showed that compared to a drug-naïve condi-
tion, both first and second generation antipsychotics increase the risk of
metabolic abnormalities (Vancampfort et al., 2015).
Several limitations of this study should be noted. First, a major limi-
tation is the absence of healthy controls with matched age and gender.
Therefore, some bias possibly occurred when comparing patients of our

Please cite this article as: L. Huo, G. Zhang, X.-D. Du, et al., The prevalence, risk factors and clinical correlates of diabetes mellitus in Chinese
patients with s..., Schizophrenia Research, https://doi.org/10.1016/j.schres.2019.12.029
4 L. Huo et al. / Schizophrenia Research xxx (xxxx) xxx
study with the general population of other studies. Second, there is im-
balanced ratio of gender in our sample, with a much higher number of
male patients. It may partly explain the discrepancies in prevalence
rate between our results and those of other studies, as our data indi-
cated that being female increased the chance of diabetes. Third, as a
cross-sectional study, it does not prove a direct causal relationship be-
tween clinical variables and increased diabetes in patients with schizo-
phrenia. Fourth, there are many genetic and environmental factors that
may affect glycometabolism, such as genetic susceptibility, the level
of brain derived neurotrophic factor, physical activity, a family history
of diabetes and so on. However, these data were not collected in
our study. Further large controlled prospective studies should be con-
ducted to demonstrate the relationship between these factors and
glycometabolism.
In summary, the current study revealed a 12.5% prevalence of diabe-
tes in patients with schizophrenia, suggesting that metabolic dysfunc-
tion is common in schizophrenia in the Chinese Han population.
Furthermore, our study demonstrated a significantly higher rate of co-
morbid diabetes in female compared to male patients (10.87% vs.
18.73%), suggesting a sex difference in the rate of diabetes in schizo-
phrenia. Our study further showed that risk factors for diabetes were
old age, high BMI and triglyceride levels. Diabetes results in increased
mortality and decreased quality of life. Understanding the risk factors
of diabetes would provide important implications for prevention and
interventions, reducing the burden of diabetes in patients with
schizophrenia.
Contributors
Lijuan Huo and Xiang Yang Zhang were responsible for study design, statistical anal-
ysis, and manuscript preparation. Dachun Chen, Meihong Xiu, Guangya Zhang, Xiang-
Dong Du, and Fengchun Wu were responsible for recruiting the patients, performing the
clinical rating and collecting the samples. Qiufang Jia, Zheng-Kang Qian, Yu-Ping Ning,
Xing-Bing Huang and Jair C. Soares were involved in evolving the ideas and editing the
manuscript. Lijuan Huo, Ryan M. Cassidy and Xiang Yang Zhang were involved in writing
the protocol, and cowrote the paper. Fengchun Wu and Xiang-Dong Du were responsible
for providing the funding for the study. All authors have contributed to and have approved
the final manuscript.
Role of the funding source
This study was supported by the grants from the Science
and Technology Department, Guangdong Province (2016A020216004),
and Guangzhou Municipal Science and Technology Pro-
ject (201704020168, 201807010064), CAS Pioneer Hundred
Talents Program, Key Diagnosis and treatment Program of Suzhou
(LCZX201515), Suzhou Key Medical Center for Psychiatric Diseases
(Szzx201509), Suzhou Key Disciplines (Szxk201515), and Suzhou In-
troduced Project for Clinical Medical Expert Team (SZYJTD201715).
These sources had no further role in study design; in the collection,
analysis and interpretation of data; in the writing of the report; and in
the decision to submit the paper for publication.
Declaration of competing interest
No conflict of interest was disclosed for each author.
Acknowledgements
The authors would like to thank Drs. Yunlong Tan, Wu Fang Zhang, Zhi Ren Wang, Bao
Hua Zhang, Ling Yan Qi and Gui Gang Yang for all of their hard work and significant con-
tributions toward the study.
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