Diabetes & Metabolic Syndrome: Clinical Research & Reviews 9 (2015) 163–167
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Association of adipokines with metabolic disorders in patients with schizophrenia: Results of comparative study with mental healthy cohort Dmitry A. Tanyanskiy a,*, Ivan A. Martynikhin b, Oxana P. Rotar c, Alexandra O. Konradi c, Nina A. Sokolian d, Nikolay G. Neznanov b,d, Alexander D. Denisenko a a
Institute of Experimental Medicine, Russian Academy of Medical Sciences, Department of Biochemistry, St. Petersburg, Russia Pavlov First Saint Petersburg State Medical University, Department of Psychiatry and Narcology, St. Petersburg, Russia c Federal Almazov Medical Research Center, St. Petersburg, Russia d St. Petersburg V.M. Bekhterev Psychoneurological Research Institute, St. Petersburg, Russia b
A R T I C L E I N F O
A B S T R A C T
Keywords: Schizophrenia Antipsychotics Adipokines Insulin resistance Metabolic syndrome
Aim: The role of adipose tissue hormones, adipokines, in formation of metabolic disorders in schizophrenia is not fully understood. The aim was to investigate the association of leptin and adiponectin plasma levels with metabolic parameters in antipsychotic treated patients with schizophrenia and in the group of age, gender and body mass index matched mental healthy persons. Methods: One hundred patients with diagnosis of schizophrenia, who took antipsychotic medication, and equal number of control subjects, were enrolled for cross-sectional evaluation. Fasting blood plasma levels of glucose, lipids, insulin, adiponectin, leptin concentrations and insulin resistance HOMA index were determined. Results: In both groups plasma leptin concentration positively correlated with body mass index, insulin plasma level and HOMA index, while adiponectin level had negative correlations with adiposity measures and positive associations with high density lipoprotein cholesterol content. At the same time, in schizophrenia group, but not in control subjects, leptin level positively associated with cholesterol and triglycerides concentrations and adiponectin negatively correlated with plasma insulin content, HOMA index and triglycerides levels. After controlling for confounders significant correlations remained for leptin concentration with HOMA index and plasma triglycerides level in schizophrenic patients and for adiponectin concentration with plasma high density lipoprotein cholesterol concentrations in both studied groups. Conclusions: Both adipokines associate with metabolic parameters in antipsychotic treated patients with schizophrenia. Leptin can play more specific role in pathogenesis of metabolic syndrome in schizophrenic persons than in mental healthy subjects. ß 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction
schizophrenic patients is 1.5–2 times higher in comparison with general population or mental healthy cohort [3–5]. Metabolic disorders are largely explained by treatment of such persons with ‘‘atypical’’ or second generation antipshychotics (SGA), especially clozapine and olanzapine [6–8]. Our recent study of age, gender and body mass index (BMI) matched pairs also revealed higher prevalence of MS in patients with schizophrenia who took antipsychotic medication [9]. In spite of the same BMI, schizophrenic patients were more insulin resistant, dislipidemic and had more abdominal fat content in comparison with controls [9]. It is well known, that expansion of abdominal fat, especially in the omental area, plays an important role in development of lipid
Type 2 diabetes and cardiovascular disease are main somatic abnormalities, which lead to high mortality rates among patients with schizophrenia [1,2]. These disorders usually represent as clinical manifestations of metabolic syndrome (MS). According to studies in USA, Canada and Western Europe, frequency of MS in
* Corresponding author at: Acad. Pavlov str., 12, 197376 St. Petersburg, Russia. Tel.: +7 812 234 93 41. E-mail address: [email protected] (D.A. Tanyanskiy). http://dx.doi.org/10.1016/j.dsx.2015.04.009 1871-4021/ß 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.
164
D.A. Tanyanskiy et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 9 (2015) 163–167
and carbohydrate disorders [10]. The main players in this MS scenario are secreted adipose tissue proteins, named ‘‘adipokines’’ [11]. One of the adipokines, leptin, elevates in obesity and insulin resistance, and the other, adiponectin, reversibly associates with these features of MS [12]. Studies in animals and human cell cultures have shown that leptin and adiponectin both improve hepatic and skeletal muscle insulin sensitivity [13–15]. Moreover, adiponectin stimulates catabolism of serum triglycerides [16], declines hepatic production of apolipoprotein B (apoB), core atherogenic low density lipoprotein (LDL) apolipoprotein [17], and increases hepatic production of apolipoprotein A-1 (apoA-1), the main protein constituent of antiatherogenic high density lipoproteins (HDL) [17]. It was demonstrated that plasma leptin level increased while adiponectin content decreased in SGA treated patients [18,19]. Obviously, the observed ‘‘disadipokinemia’’ can be a result of weight gain – the main side effect of blocking hypothalamic serotonin and H1-histamine receptors by SGA [8]. Thereby, adipokines consider to be a hormonal link between weight gain and metabolic disorders in SGA treated patients with schizophrenia. On the other hand, results of cell culture experiments have shown that SGA have direct metabolic effects, such as decrease of glucose uptake in skeletal myocytes and adipocytes [20,21], stimulation of hepatic glycogenolysis and hepatic lipogenesis [22,23]. Interestingly, the influence of SGA on lipogenesis in hepatocytes was mediated through inhibition of AMPK – the main signal messenger of metabolic effects of adiponectin and leptin [23,24]. Moreover, it was shown that SGA selectively activate AMPK in arcuate and paraventricular hypothalamic nuclei, while leptin decreases AMPK activity in those areas inducing the satiety signal [25]. Thus, SGA can modulate the metabolic effects of adipokines, and as a result these drugs can change the impact of adipose tissue protein mediators on MS formation in SGA treated patients. To examine this possibility we applied the comparative association approach. The aim of this study was to compare correlations of adipokines plasma levels (leptin and adiponectin) with metabolic parameters between two groups: the group of antipsychotic-treated patients with schizophrenia and the group of age, gender and BMI-matched mental healthy persons. Results of this study show that both adipokines can be involved in formation of metabolic disorders in either group, with more pronounced impact of leptin in antipsychotic-treated patients with schizophrenia.
further determinations of glucose, triglycerides, total and HDL cholesterol parameters after 12 h fast [9]. The level of low density lipoprotein cholesterol (LDL-C, mmol/l) was calculated using the Friedewald formula: LDL-C = Total cholesterol (triglycerides/ 2.2 + HDL-C). After measurement of glucose and lipid parameters plasma samples of both groups stored at 20 8C and then used for ELISA determination of insulin, leptin (‘‘DRG Diagnostics’’, Germany’’) and adiponectin concentrations (‘‘Biovendor’’, Chezh Republic). Insulin resistance HOMA index was assessed as follows: HOMA index = insulin (mIU/ml) glucose (mmol/l)/22.5. Metabolic syndrome was diagnosed according to Alberti et al. definition [27]. 2.3. Statistics Statistical treatment of the data obtained was performed using the Statistica 6.0 software package (StatSoft, USA). Results are expressed as means standard deviations (SD). In order to normalize data distribution of the skewed variables, they were log transformed (see Section 3). Differences of metabolic parameters between two groups (control and schizophrenia) were analyzed using Student’s t-test for dependent groups, and between more than two groups – by one-way ANOVA test with Fisher LSD post hoc estimation. Differences of MS frequency and gender distribution were estimated by McNemar’s test for dependent variables. Group differences were assumed to be statistically significant at p value less than 0.05. Associations between various parameters were investigated by Pearson’s correlation analysis and also by multiple regression analysis.
3. Results 3.1. Demographic and metabolic characteristics Demographic and metabolic characteristics of study groups are presented in Table 1. In comparison with controls, schizophrenic patients had higher waist circumference, insulin resistance index HOMA, insulin and triglycerides concentration and decreased HDL cholesterol content. In spite of slightly lower levels of plasma glucose and total cholesterol concentration in schizophrenia group, these data as a whole indicate that patients with schizophrenia are prone to development of MS. Indeed, frequency of MS in patients with schizophrenia was 31% and in control subjects – 13% (p < 0.0001).
2. Materials and methods 2.1. Patients and control group One hundred patients with diagnosis of schizophrenia (ICD-10) and equal number of control subjects were enrolled from our previous study [9]. Briefly, patients and controls were matched by gender, age (1 year) and BMI (0.5 kg/m2). All patients with schizophrenia received antipsychotic drugs, and 51.3% of them – SGA (clozapine, olanzapine, risperidone). Controls were obtained from bank employee’s cohort, which included 1561 subjects [26]. All patients and controls were residents of the same region, St. Petersburg, Russia. Written informed consent was obtained from all patients, and the Institutional Review Board of the St. Petersburg V.M. Bekhterev Psychoneurological Research Institute approved this study. 2.2. Laboratory measurements BMI was calculated according Kettle’s formula: BMI (kg/ m ) = weight (kg)/height2 (m2). Venous blood was obtained for 2
Table 1 Demographic and metabolic characteristics of control subjects and patients with schizophrenia matched for sex, age and BMI (mean SD). Parameters
Control
Schizophrenia
p
Sex (males/females) Age (years) BMI (kg/m2) Waist circumference (cm) Glucose (mmol/l)a Insulin (mIU/ml)a HOMA indexa Total cholesterol (mmol/l) LDL cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l)a Adiponectin (mkg/ml)a Leptin (ng/ml)a
46/54 41.1 11.7 24.6 3.8 84.0 10.5 5.4 1.9 9.3 7.9 2.2 2.1 5.3 1.2 3.2 1.0 1.5 0.5 1.2 1.1 10.8 6.6 15.9 19.6
46/54 41.3 11.7 24.5 3.9 90.0 10.2 4.9 0.8 13.8 12.1 3.2 3.7 4.7 1.2 3.0 1.0 1.0 0.2 1.6 0.8 10.7 5.7 22.9 32.2
N.S. N.S. N.S.
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Association of adipokines with metabolic disorders in patients with schizophrenia: Results of comparative study with mental healthy cohort Dmitry A. Tanyanskiy a,*, Ivan A. Martynikhin b, Oxana P. Rotar c, Alexandra O. Konradi c, Nina A. Sokolian d, Nikolay G. Neznanov b,d, Alexander D. Denisenko a a
Institute of Experimental Medicine, Russian Academy of Medical Sciences, Department of Biochemistry, St. Petersburg, Russia Pavlov First Saint Petersburg State Medical University, Department of Psychiatry and Narcology, St. Petersburg, Russia c Federal Almazov Medical Research Center, St. Petersburg, Russia d St. Petersburg V.M. Bekhterev Psychoneurological Research Institute, St. Petersburg, Russia b
A R T I C L E I N F O
A B S T R A C T
Keywords: Schizophrenia Antipsychotics Adipokines Insulin resistance Metabolic syndrome
Aim: The role of adipose tissue hormones, adipokines, in formation of metabolic disorders in schizophrenia is not fully understood. The aim was to investigate the association of leptin and adiponectin plasma levels with metabolic parameters in antipsychotic treated patients with schizophrenia and in the group of age, gender and body mass index matched mental healthy persons. Methods: One hundred patients with diagnosis of schizophrenia, who took antipsychotic medication, and equal number of control subjects, were enrolled for cross-sectional evaluation. Fasting blood plasma levels of glucose, lipids, insulin, adiponectin, leptin concentrations and insulin resistance HOMA index were determined. Results: In both groups plasma leptin concentration positively correlated with body mass index, insulin plasma level and HOMA index, while adiponectin level had negative correlations with adiposity measures and positive associations with high density lipoprotein cholesterol content. At the same time, in schizophrenia group, but not in control subjects, leptin level positively associated with cholesterol and triglycerides concentrations and adiponectin negatively correlated with plasma insulin content, HOMA index and triglycerides levels. After controlling for confounders significant correlations remained for leptin concentration with HOMA index and plasma triglycerides level in schizophrenic patients and for adiponectin concentration with plasma high density lipoprotein cholesterol concentrations in both studied groups. Conclusions: Both adipokines associate with metabolic parameters in antipsychotic treated patients with schizophrenia. Leptin can play more specific role in pathogenesis of metabolic syndrome in schizophrenic persons than in mental healthy subjects. ß 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction
schizophrenic patients is 1.5–2 times higher in comparison with general population or mental healthy cohort [3–5]. Metabolic disorders are largely explained by treatment of such persons with ‘‘atypical’’ or second generation antipshychotics (SGA), especially clozapine and olanzapine [6–8]. Our recent study of age, gender and body mass index (BMI) matched pairs also revealed higher prevalence of MS in patients with schizophrenia who took antipsychotic medication [9]. In spite of the same BMI, schizophrenic patients were more insulin resistant, dislipidemic and had more abdominal fat content in comparison with controls [9]. It is well known, that expansion of abdominal fat, especially in the omental area, plays an important role in development of lipid
Type 2 diabetes and cardiovascular disease are main somatic abnormalities, which lead to high mortality rates among patients with schizophrenia [1,2]. These disorders usually represent as clinical manifestations of metabolic syndrome (MS). According to studies in USA, Canada and Western Europe, frequency of MS in
* Corresponding author at: Acad. Pavlov str., 12, 197376 St. Petersburg, Russia. Tel.: +7 812 234 93 41. E-mail address: [email protected] (D.A. Tanyanskiy). http://dx.doi.org/10.1016/j.dsx.2015.04.009 1871-4021/ß 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.
164
D.A. Tanyanskiy et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 9 (2015) 163–167
and carbohydrate disorders [10]. The main players in this MS scenario are secreted adipose tissue proteins, named ‘‘adipokines’’ [11]. One of the adipokines, leptin, elevates in obesity and insulin resistance, and the other, adiponectin, reversibly associates with these features of MS [12]. Studies in animals and human cell cultures have shown that leptin and adiponectin both improve hepatic and skeletal muscle insulin sensitivity [13–15]. Moreover, adiponectin stimulates catabolism of serum triglycerides [16], declines hepatic production of apolipoprotein B (apoB), core atherogenic low density lipoprotein (LDL) apolipoprotein [17], and increases hepatic production of apolipoprotein A-1 (apoA-1), the main protein constituent of antiatherogenic high density lipoproteins (HDL) [17]. It was demonstrated that plasma leptin level increased while adiponectin content decreased in SGA treated patients [18,19]. Obviously, the observed ‘‘disadipokinemia’’ can be a result of weight gain – the main side effect of blocking hypothalamic serotonin and H1-histamine receptors by SGA [8]. Thereby, adipokines consider to be a hormonal link between weight gain and metabolic disorders in SGA treated patients with schizophrenia. On the other hand, results of cell culture experiments have shown that SGA have direct metabolic effects, such as decrease of glucose uptake in skeletal myocytes and adipocytes [20,21], stimulation of hepatic glycogenolysis and hepatic lipogenesis [22,23]. Interestingly, the influence of SGA on lipogenesis in hepatocytes was mediated through inhibition of AMPK – the main signal messenger of metabolic effects of adiponectin and leptin [23,24]. Moreover, it was shown that SGA selectively activate AMPK in arcuate and paraventricular hypothalamic nuclei, while leptin decreases AMPK activity in those areas inducing the satiety signal [25]. Thus, SGA can modulate the metabolic effects of adipokines, and as a result these drugs can change the impact of adipose tissue protein mediators on MS formation in SGA treated patients. To examine this possibility we applied the comparative association approach. The aim of this study was to compare correlations of adipokines plasma levels (leptin and adiponectin) with metabolic parameters between two groups: the group of antipsychotic-treated patients with schizophrenia and the group of age, gender and BMI-matched mental healthy persons. Results of this study show that both adipokines can be involved in formation of metabolic disorders in either group, with more pronounced impact of leptin in antipsychotic-treated patients with schizophrenia.
further determinations of glucose, triglycerides, total and HDL cholesterol parameters after 12 h fast [9]. The level of low density lipoprotein cholesterol (LDL-C, mmol/l) was calculated using the Friedewald formula: LDL-C = Total cholesterol (triglycerides/ 2.2 + HDL-C). After measurement of glucose and lipid parameters plasma samples of both groups stored at 20 8C and then used for ELISA determination of insulin, leptin (‘‘DRG Diagnostics’’, Germany’’) and adiponectin concentrations (‘‘Biovendor’’, Chezh Republic). Insulin resistance HOMA index was assessed as follows: HOMA index = insulin (mIU/ml) glucose (mmol/l)/22.5. Metabolic syndrome was diagnosed according to Alberti et al. definition [27]. 2.3. Statistics Statistical treatment of the data obtained was performed using the Statistica 6.0 software package (StatSoft, USA). Results are expressed as means standard deviations (SD). In order to normalize data distribution of the skewed variables, they were log transformed (see Section 3). Differences of metabolic parameters between two groups (control and schizophrenia) were analyzed using Student’s t-test for dependent groups, and between more than two groups – by one-way ANOVA test with Fisher LSD post hoc estimation. Differences of MS frequency and gender distribution were estimated by McNemar’s test for dependent variables. Group differences were assumed to be statistically significant at p value less than 0.05. Associations between various parameters were investigated by Pearson’s correlation analysis and also by multiple regression analysis.
3. Results 3.1. Demographic and metabolic characteristics Demographic and metabolic characteristics of study groups are presented in Table 1. In comparison with controls, schizophrenic patients had higher waist circumference, insulin resistance index HOMA, insulin and triglycerides concentration and decreased HDL cholesterol content. In spite of slightly lower levels of plasma glucose and total cholesterol concentration in schizophrenia group, these data as a whole indicate that patients with schizophrenia are prone to development of MS. Indeed, frequency of MS in patients with schizophrenia was 31% and in control subjects – 13% (p < 0.0001).
2. Materials and methods 2.1. Patients and control group One hundred patients with diagnosis of schizophrenia (ICD-10) and equal number of control subjects were enrolled from our previous study [9]. Briefly, patients and controls were matched by gender, age (1 year) and BMI (0.5 kg/m2). All patients with schizophrenia received antipsychotic drugs, and 51.3% of them – SGA (clozapine, olanzapine, risperidone). Controls were obtained from bank employee’s cohort, which included 1561 subjects [26]. All patients and controls were residents of the same region, St. Petersburg, Russia. Written informed consent was obtained from all patients, and the Institutional Review Board of the St. Petersburg V.M. Bekhterev Psychoneurological Research Institute approved this study. 2.2. Laboratory measurements BMI was calculated according Kettle’s formula: BMI (kg/ m ) = weight (kg)/height2 (m2). Venous blood was obtained for 2
Table 1 Demographic and metabolic characteristics of control subjects and patients with schizophrenia matched for sex, age and BMI (mean SD). Parameters
Control
Schizophrenia
p
Sex (males/females) Age (years) BMI (kg/m2) Waist circumference (cm) Glucose (mmol/l)a Insulin (mIU/ml)a HOMA indexa Total cholesterol (mmol/l) LDL cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l)a Adiponectin (mkg/ml)a Leptin (ng/ml)a
46/54 41.1 11.7 24.6 3.8 84.0 10.5 5.4 1.9 9.3 7.9 2.2 2.1 5.3 1.2 3.2 1.0 1.5 0.5 1.2 1.1 10.8 6.6 15.9 19.6
46/54 41.3 11.7 24.5 3.9 90.0 10.2 4.9 0.8 13.8 12.1 3.2 3.7 4.7 1.2 3.0 1.0 1.0 0.2 1.6 0.8 10.7 5.7 22.9 32.2
N.S. N.S. N.S.
