The development of hyperglycemia induced by antipsychotics (APs) has been reported since the introduction of the first-generation APs, such as chlorpromazine and thioridazine.1 More recently, second-generation APs have been reported to be associated with the development of overt metabolic complications, such as diabetes mellitus (DM).2,3 Based on the World Health Organization criteria for diabetes, approximately 10.1% of patients treated with APs develop DM after only 6 weeks of treatment.4 Many studies have examined the safety and tolerability of APs. Some APs, mainly second-generation APs, show a greater risk of metabolic dysfunctions than other APs.5,6 On the other hand, other studies have found no differences in glucose tolerance between patients treated with different APs.7
Although obesity is a significant public health concern and is a well-documented risk factor for insulin resistance and ultimately type 2 diabetes and atherosclerosis,8,9 the diabetogenic risk associated with APs has been reported in the absence of significant weight gain.10,11 That AP treatment can lead to severe hyperglycemia and ketoacidosis in the absence of weight gain shortly after starting treatment suggests that some APs may rapidly and directly impair the glucose-insulin response.12,13 In fact, several in vitro studies and preclinical studies have shown that APs may alter insulin action and glucose uptake.14,15
It has been reported that the insulin secretory capacity, a marker for pancreatic β-cell function, in Japanese individuals is only one half that of whites. Because of these racial differences, it is difficult to translate the results of previous studies that examined the glucose-insulin response in whites to Japanese individuals.16
The 75-g oral glucose tolerance test (OGTT) is a standard method to screen for impaired glucose handling and DM and can detect glucose tolerance abnormalities that may not be apparent in fasting plasma glucose levels (FPG). The American Diabetes Association expert committee defines subjects with FPG of 125 mg/dL or more as having DM and those with FPG of 100 to 125 mg/dL as having impaired fasting glucose (IFG). Subjects with glucose levels of 140 to 199 mg/dL at 120 minutes after a glucose load are defined as having impaired glucose tolerance (IGT). Recent studies have shown that IFG and IGT are likely to progress into type 2 DM.17–19 However, most of the earlier studies that examined the relationship between AP treatment and glucose/insulin metabolism included subjects with IFG or IGT. In the present study we conducted 75-g OGTTs in Japanese subjects, including subjects with NFG, to further examine the effects of APs on the glucose-insulin response before and after glucose loading.
METHODS AND MATERIALS
Japanese inpatients with AP-treated schizophrenia (AP-treated patients) were recruited from the medical and dental hospitals affiliated to Niigata University and from 5 psychiatric hospitals in Niigata prefecture. Medical staff at these institutes who did not have DM, hyperlipidemia, or a history of these diseases were recruited as healthy controls. We obtained consent from all participants after describing the purpose of the study. Although 204 Japanese inpatients with schizophrenia and 148 healthy control subjects agreed to participate in the study, 45 patients treated with AP and 58 healthy control subjects dropped out before or during OGTTs. Therefore, OGTTs were successfully completed in 159 Japanese inpatients with AP-treated schizophrenia and in 90 healthy subjects without DM. The AP-treated patients were treated with atypical (n = 148) or typical APs (n = 11). Antipsychotic-treated patients and healthy subjects were matched for age, sex, and body mass index (BMI; weight in kilograms divided by the square of the height in meters). Patients aged 18 to 50 years were included in the present study if they fulfilled the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Participants were required to have been receiving some APs for at least 8 weeks, with no change in AP dose for 3 weeks before the study. Only benzodiazepine drugs were allowed as concomitant therapy. The study was approved by the Institutional Review Board of the Niigata University School of Medicine.
Patients were excluded for the following reasons: other Axis I disorders and medical conditions that could confound metabolic assessments, including history of DM, recognized cardiovascular and respiratory conditions with hemodynamic compromise or hypoxia, malignancy, epilepsy, endocrine disease, fever, dehydration, nausea, pregnancy or high-dose estrogen therapy; current narcotic, corticosteroid, or spironolactone therapy; or sedative hypnotic withdrawal. Patients treated with glucose- or lipid-lowering drugs were also excluded. Patients treated with psychotropic drugs other than antipsychotics that can increase weight or serum triglyceride levels (eg, lithium, valproate, and mirtazapine) were also excluded.
The day before assessment, the medical staff checked patients and reminded them not to ingest anything except water until after the OGTTs were completed. Oral glucose tolerance tests were performed in treatment rooms at each institute at 6:30 A.M. Blood samples were drawn before (0 minute) and at 30, 60, 90, and 120 minutes after the 75-g glucose load to measure plasma glucose and serum insulin concentrations. Body mass index was calculated as described above. Waist circumference was measured by snugly placing a tape measure around the abdomen at the level of the iliac crest without compressing the skin. Total cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), plasma glucose, serum insulin, and hemoglobin A1c were measured using blood samples obtained after an overnight fast of at least 8 hours. Plasma samples were centrifuged at 4°C and frozen at −80°C. All serum analyses were performed by standard methods by a central laboratory (SRL Inc, Japan). The homeostasis model assessment of insulin resistance (HOMA-IR), which is used to estimate insulin resistance, was calculated using the equation HOMA-IR = fasting plasma insulin (μIU/mL) × FPG (mg/dL)/405.
Statistical analyses were performed using SPSS software version 19.0 (SPSS Japan, Tokyo, Japan). Mixed-model analysis of variance (ANOVA) was used to compare the plasma glucose and serum insulin levels during the OGTTs between the AP-treated patients and the healthy subjects. Waist circumference was included in the analysis as a covariate. The clinical and demographic characteristics were compared between the AP-treated patients and the healthy subjects using χ2 and unpaired t tests, as appropriate. The clinical and demographic characteristics are presented as mean ± SD values or as proportions. Differences were considered to be statistically significant for P < 0.05.
The demographic and clinical characteristics of the subjects who underwent an OGTT are summarized in Table 1. There were no significant differences in age or BMI between the AP-treated patients and the healthy subjects. The distribution of sex, the number of family relatives with DM or lipid disorders, and the proportion of smokers were not significantly different between the 2 groups. Waist circumference was significantly greater in the AP-treated patients than in the healthy subjects (P = 0.001), whereas total cholesterol and HDL were significantly higher in the healthy subjects than in the AP-treated patients (both P < 0.001).
Mixed-model ANOVA with waist circumference as a covariate was performed including all subjects who underwent OGTTs. This analysis revealed significant differences in the time-course of plasma glucose levels (P = 0.006) and serum insulin (P < 0.001) levels during the OGTT between the 2 groups (Fig. 1, A and B). Although plasma glucose at 0 minute was significantly higher in the healthy subjects than in the AP-treated patients, the values at 60, 90, and 120 minutes after the glucose load were significantly higher in the AP-treated patients. The mean glucose levels at 0 minute were within the reference range in both groups. There were no significant differences in insulin levels at 0 minute, which were also within the reference range, or HOMA-IR between the 2 groups. Of note was that insulin levels at all times after the glucose load were significantly higher in the AP-treated patients than in healthy subjects.
In a mixed-model ANOVA of subjects with NFG, there were significant differences in the time-course of plasma glucose (P = 0.007) and serum insulin (P = 0.001) levels during the OGTT between the AP-treated patients and healthy subjects (Fig. 2, A and B). The serum insulin concentration was significantly higher in the AP-treated patients than in the healthy subjects at all times after the glucose load, despite similar levels at 0 minutes. The mean plasma glucose levels after the glucose load were also higher in the AP-treated patients than in the healthy subjects, although these differences only reached statistical significance at 60 minutes after the glucose load.
In the present study, we found that the AP-treated patients with schizophrenia had higher plasma glucose levels and serum insulin concentrations after a 75-g glucose load than did the healthy subjects matched for age, sex, and BMI, although fasting glucose levels were significantly higher in healthy subjects and there were no differences in fasting insulin concentrations or HOMA-IR. These findings were confirmed in an analysis of subjects with NFG.
One previous study using OGTT showed that although fasting glucose, fasting insulin, and HOMA-IR were not different among subjects treated with risperidone or olanzapine, and healthy control subjects, the areas under the concentration time curves for plasma glucose and serum insulin concentrations from 0 to 120 minutes in the patients treated with risperidone and olanzapine were significantly higher than those in healthy subjects.20 Another study performed intravenous glucose tolerance tests and showed that the mean fasting glucose level was higher and insulin sensitivity was lower in patients treated with olanzapine than in healthy control subjects, although there was no significant difference in the fasting insulin concentrations between the 2 groups.21 These results are not contradictory to our results. On the other hand, several animal studies have shown that insulin secretion was reduced by second-generation APs.15 This discrepancy might be due to differences in doses used between the animal or in vitro studies and clinical studies. It is also apparent that Japanese individuals have reduced β-cell function and are more prone to develop type 2 DM compared with whites.16 In fact, some patients have developed diabetic ketoacidosis during treatment with atypical APs. Therefore, olanzapine and quetiapine are contraindicated for use in patients with DM in Japan. Although racial differences may exist in the adverse effects of APs in impaired glucose tolerance, the results observed in whites and other races should not be applied to Japanese patients, or vice versa. Other factors that may cause the differences in the glucose-insulin responses detected in the studies include study design, differences in glucose loading methods, and the number of subjects involved.
The American Diabetes Association defines IFG as FPG of 100 to 125 mg/dL (110–125 mg/dL in Japan), and IFG is considered a preliminary step toward diabetes because the rate of transition into DM is significantly higher for individuals with FPG of 100 mg/dL or more compared with individuals with FPG of less than 100 mg/dL.19 Fasting plasma glucose increases in response to insulin resistance in the peripheral tissue and is positively correlated with insulin sensitivity.22 Even among people with NFG, pancreatic β-cell function has already decreased at FPG of 94 mg/dL or more.23 Based on these findings, it is believed that decreased insulin sensitivity appears along with mild insulin resistance in AP-treated patients, particularly once FPG exceeds 110 mg/dL. Impaired glucose tolerance is associated with inadequate insulin secretion, decreased acute-phase insulin responses, and peripheral insulin sensitivity.24 In the presence of insulin resistance, the secreted insulin is unable to stimulate sufficient cellular glucose uptake and may lead to IGT or DM.25 Although many previous studies have examined the effects of APs on dysfunction of the glucose-insulin response, most of the earlier studies included subjects with IFG or IGT. Therefore, in the present study, we repeated the analysis after excluding subjects with IFG or IGT. The results in this subset of subjects with NFG were similar to those in all subjects, including subjects with IFG or IGT. Thus, we confirmed that AP-treated patients with schizophrenia exhibit excessive insulin secretion compared with healthy subjects after a glucose load, regardless of the fasting glucose levels and fasting insulin concentrations. This was even true among subjects with normal glucose tolerance. Although it is unknown what causes the decrease in insulin-stimulated glucose uptake, this phenomenon is clinically important and results in IGT and hyperinsulinemia and may ultimately lead to arteriosclerosis as a result of insulin resistance.26 The earlier studies included patients with IFG; however, as described earlier, IFG represents a transitional stage of DM. Furthermore, the dynamics of the glucose-insulin response are predicted to be more complicated in this stage than in later stages. Therefore, these problems in selecting subjects might have led to the discrepancies between the earlier studies.
High-density lipoprotein level and waist circumference are both associated with insulin resistance.27,28 In the present study, the AP-treated patients had significantly lower HDL levels and greater waist circumference compared with the healthy subjects. Therefore, when interpreting the results of the OGTTs, it may be necessary to consider the possible effects of HDL and waist circumference, as well as the effects of APs. Although waist circumference, which represents central adiposity, is associated with abnormal lipid metabolism, some studies have found no association between these factors.29,30 Moreover, it has been demonstrated that human genetic defects in HDL-C synthesis may affect β-cell function.31 Therefore, future studies should take into account these factors, including molecular genetic information.
Our results should be interpreted with care considering the possible limitations of the study. First, this was a cross-sectional study, and we could not compare the effects of using APs on the glucose-insulin response in individual patients relative to that before starting AP therapy. Some of the AP-treated patients had a history of using other antipsychotics before starting their current AP. Therefore, we could not fully account for the effect of previous drugs, which would need to be examined in a prospective study. Second, we did not compare the effects of specific APs. However, there was a large difference in the number of patients treated with atypical and typical APs. We could not detect the effect of each drug on serum insulin levels because of the small sample size. In future studies, we hope to enroll a larger number of patients to compare the effects of each drug on plasma glucose and serum insulin levels. Third, we recruited inpatients treated with APs, and these patients were under restricted dietary intake and exercise regimens. Therefore, our results cannot be directly compared with those of other studies that included outpatients. Fourth, we did not evaluate other disease states that can affect glucose/lipid metabolism, such as hypothyroidism. Fifth, because patients with confirmed DM were excluded at the start of the study, our results may not apply to subjects whose glucose levels are controlled by antidiabetic drugs. Finally, we did not assess pharmacokinetic factors such as drug dosage or blood drug concentrations, which may influence the results in individual patients.
In conclusion, we found that serum insulin concentrations after a glucose load were significantly higher in patients with schizophrenia treated with APs than in healthy subjects, although the healthy subjects had higher fasting glucose levels and there were no differences in fasting insulin concentrations or HOMA-IR. These findings were also apparent in analyses of NFG subjects. The results of the present study suggest that APs directly or indirectly affect the glucose-stimulated insulin responses, which may lead to subclinical insulin resistance before the onset of overt glucose intolerance. Therefore, we believe it is not sufficient to assess dysfunction in the glucose-insulin response using fasting plasma glucose levels or fasting insulin concentrations alone, both of which are widely used in clinical practice. If schizophrenia itself, regardless of AP treatment, is related to glucose intolerance, further studies are needed to examine the “health/harm” of APs. Taken together, the results of this study provide an important insight into the possible mechanism by which APs cause glucose intolerance, a problem that urgently needs further investigation.
The authors thank all the study participants. The authors also thank Koue Asama (Oojima Hospital), Yuji Suzuki (Suehirobashi Hospital), Manabu Wachi (Niigata Psychiatric Center), Hiroshi Tochikura (Sagata Mental Hospital), Hisashi Ishida (Itsukamachi Hospital), Yoshifumi Suzuki (Minamihama Hospital), Ryoichi Suga (Nakajo Daini Hospital), Shigeo Murata (Iizuka Hospital), and Kiyosi Nagashima (Manomizuho Hospital) for their help with data collection; and Hiroshi Kusano and Nanako Yamazaki for technical assistance.
AUTHOR DISCLOSURE INFORMATION
Dr Someya has received research support and honoraria from Asahi Kasei, Astellas Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Shionogi, Takeda Pharmaceutical, and Yoshitomiyakuhin. The other authors declare no conflicts of interest.
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