|Year : 2017 | Volume
| Issue : 1 | Page : 28-32
Antipsychotics-induced diabetes mellitus in rats: it is time to change
Shimaa M Motawei
Department of Forensic Medicine & Clinical Toxicology, Faculty of Medicine; Lecturer of Forensic Medicine & Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||22-Jul-2016|
|Date of Acceptance||09-Jan-2017|
|Date of Web Publication||24-May-2017|
Shimaa M Motawei
Faculty of Medicine, El-Gomhoria street, Mansoura city, P.O. 35516
Source of Support: None, Conflict of Interest: None
The use of antipsychotics has progressively increased in the last 50 years. Despite the fact that second-generation antipsychotics have shown marked therapeutic benefits in treatment of psychosis than earlier typical ones, they produce many metabolic side-effects.
This study aimed to measure the metabolic effects of three classes of atypical antipsychotics on albino rats.
Materials and methods
A total of 40 albino rats including 16 males and 24 females were grouped into four groups: group I (control group) received the control diet and tap water ad libitum; group II received olanzapine 10 mg/kg intraperitoneally, group III received respiridone 0.2 mg/kg intraperitoneally; and group IV received aripiprazole 20 mg/day intraperitoneally. Blood glucose and insulin as well as serum cholesterol, triglycerides, malondialdehyde, high-density lipoprotein, and low-density lipoprotein were measured before treatment and 60 days after continuation of treatment.
Significant elevation in blood glucose levels, disturbance in insulin levels, and elevation in malondialdehyde, low-density lipoprotein, and total serum cholesterol levels in atypical antipsychotics-treated animals, as compared with vehicle-treated rats, were found. These effects were more prominent with olanzapine, which is a very commonly used antipsychotic, followed by respiridone. Aripiprazole produced the least disturbance in these parameters.
Individual second-generation antipsychotics disturb blood glucose and insulin levels and produce different degrees of other metabolic derangements. There is a need to introduce safer agents for clinical use.
Keywords: hyperglycemia, metabolic derangements, rats, second-generation antipsychotics
|How to cite this article:|
Motawei SM. Antipsychotics-induced diabetes mellitus in rats: it is time to change. Benha Med J 2017;34:28-32
| Introduction|| |
Antipsychotics are widely used to treat several psychiatric disorders in pediatric and adult populations. Antipsychotics are categorized into two drug classes – first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). Although FGAs provide treatment for psychotic symptoms, they can cause extrapyramidal symptoms, dry mouth, and sedation .
Although SGAs are thought to be safer, they are associated with significant weight gain, hyperglycemia, and lipid and prolactin elevation. Other adverse effects are neuroleptic malignant syndrome, sudden cardiac death, and coagulopathies. These side-effects vary and are medication specific. In addition, certain evidences show that SGAs are not identical in their effects on weight and insulin sensitivity .
| Aim|| |
This study aimed to investigate the metabolic side-effects of three SGAs in rats as inducers of secondary diabetes mellitus and other metabolic derangements.
| Materials and methods|| |
After approval of local ethics committee, the study was conducted. The effects of three distinct classes of SGA drugs on glucose tolerance, insulin sensitivity, and lipid metabolism were compared in rats .
- Olanzapine (originally branded Zyprexa): Product of Lilly Pharmaceutical Company (USA, Office in Misr Elgadida, Cairo, Egypt). It was administered at a dose of 10 mg/kg intraperitoneally for 60 days.
- Respiridone (trade name Risperdal): Product of Janssen of Johnson & Johnson Pharmaceutical Company (Multinational, Office Mohamed Tawfiq Diab St. Off Makram Ebaid St, Nasr City, Cairo, Egypt). It was administered at a dose of 0.2 mg/kg for 60 days.
- Aripiprazole (trade name Abilify): Product of Bristol–Myers Squibb Company (USA, Office in Studio Misr street, ElHaram, Giza, Egypt). It was administered at a dose of 20 mg/day intraperitoneally for 60 days.
Forty albino rats of both sexes were used in this study (16 male and 24 female). Their weight ranged from 170–190 g. They were maintained in the same housing and feeding conditions and were divided into four groups of 10 rats each.
Group I (control group) received the control diet and tap water ad libitum.
Group II received olanzapine 10 mg/kg intraperitoneally.
Group III received respiridone 0.2 mg/kg intraperitoneally.
Group IV received aripiprazole 20 mg/day intraperitoneally.
This was continued for 60 days, and then the animals were killed by cervical decapitation. Blood samples were collected, were allowed to clot, and then centrifuged. Serum was separated and preserved at −20°C until assay of the study parameters. An oral glucose tolerance test was carried out 2 days before the animals were killed. The rats were fasted overnight and 30% glucose was administered (2 g/kg body weight). Blood samples were collected before glucose supplementation and every half an hour after glucose supplementation for 90 min. Blood glucose levels were immediately measured.
- Serum glucose was measured according to the enzymatic glucose oxidase method of Trinder .
- Fasting serum insulin was measured using enzyme-linked immunosorbent assay kits and human insulin as standard.
- Insulin resistance was measured by the Homeostasis Model Assessment of Insulin Resistance using the formula [insulin (µU/ml)×glucose (mmol/l)/22.5] .
- Total serum cholesterol was measured using kits from Biomerieux Company (Multinational, bioMérieux Egypt Office in Aly Rashed Street, Star Capital Tower A2, Heliopolis West, Cairo, Egypt) according to Richmond ; serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were measured according to Burstein et al.  using kits from Biomerieux Company. Triglycerides were measured according to Fossati and Prencipe .
- Determination of thiobarbituric acid-reactive substances: malondialdehyde was assayed by kits purchased from Biodiagnostic Chemical Company (Egyptian, 29 El-Tahrer Street, Dokki, Giza, Egypt) according to Walker and Shah .
All data were tabulated, coded, and then analyzed using the computer program statistical package for social science, version 17.0 (SPSS Inc. 233 S. Wacker Drive, Chicago, IL 60606-6307, USA). Descriptive statistics were calculated as mean±SD. For statistical comparison between the different groups, the significance of difference was tested using one of the following tests.
- Student’s t-test (paired) was used to compare the mean values of two related groups of numerical (parametric) data. It is known that this test is very sensitive to minimal changes.
- Analysis of variance was used to compare more than two groups of numerical (parametric) data followed by post-hoc test.
A P-value less than 0.05 was considered statistically significant.
| Results|| |
Results are shown in [Table 1] and [Table 2].
|Table 1 Levels of serum glucose, serum insulin, insulin sensitivity index, and other tested biomarkers in all groups of the studied animals before and after drug treatment|
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|Table 2 Fasting blood glucose and other measured parameters before and after treatment in all groups|
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| Discussion|| |
Antipsychotics are well-known for their harmful effects. Although SGAs, which emerged in the 1980s, have lower risk of motor side-effects that are prominent features of FGAs, they are associated with significant weight gain, disruption of lipid metabolism, and the development of type 2 diabetes .
In the present study, the metabolic effects of three distinct classes of SGA drugs were studied and compared in rats. The drugs used were olanzapine, respiridone, and aripiprazole.
Rats are often used experimentally draw conclusions on what occurs in humans − for example, reaction to poisonous substances. Rats are often considered to be a ‘closer’ model for human drug response and behavior than mice. The collective effect of many experiments on rats makes more data available about the validity of the animal model, thus making further experiments − for example, development of a less-toxic drug − easier to interpret, as scientists know more about how good a model a rat is for particular biological processes in humans .
To assess the metabolic effects of the three tested antipsychotics, the following parameters were measured: fasting blood glucose, fasting blood insulin, insulin resistance index, total serum cholesterol, HDL, LDL, triglycerides, and thiobarbituric acid-reactive substance. There were no significant differences between the four groups at the beginning of the study ([Table 1]).
Sixty days after treatment with specific antipsychotic drugs, there were highly significant within-group differences in levels of the measured biomarkers compared with baseline ([Table 2]), as well as between the four groups ([Table 1]).
The highest significance as compared with the control group (which was fed normal diet and no drug) was found for group II (which was given olanzapine). The difference was less when compared with group III (given respiridone), and the least significant difference was found for group IV (which was given aripiprazole).
Therefore, olanzapine was found to be highly associated with elevation of blood glucose levels, decrease in insulin sensitivity, and disturbance in lipid metabolism, followed by risperidone. Aripiprazole is thought to have the smallest effects on weight and insulin resistance.
These results are in agreement with the results of van der Zwaal et al.  who found an association between olanzapine and risk of induced diabetes mellitus and weight gain in rats, and that these findings can be used to predict the risk of these drugs in clinical settings. Boyda et al.  and Weston-Green et al.  agree to the same findings and state that benzepines (like olanzapine) can cause fatal diabetic complications such as diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma.
Chintoh et al.  who tested the metabolic effects of different antipsychotics in an animal model found that risperidone disturbs insulin secretion and induces hyperglycemia and metabolic disturbances.
Kalinichev et al.  found that aripiprazole disturbs fat metabolism and causes obesity, although to a lesser degree compared with olanzapine, but these harmful effects can cause patient noncompliance to the drug therapy and risk of relapse and medical complications.
Bogdan et al.  agree with the above findings, and furthermore they found that aripiprazole causes less disturbance of total cholesterol, LDL and HDL, and triglycerides.
Time has come to abandon the terms FGAs and SGAs, as they do not merit this distinction. Identification of genes that are involved in psychotic disorders and in antipsychotic action, which cause glucose and cellular metabolic disturbances, opens insights for drug discovery and patient biomarker development to provide safer drugs than current SGA .
- Time has come to abandon the use of SGAs because of their many harmful metabolic side-effects.
- Olanzapine caused a large and highly significant glucose intolerance compared with vehicle-treated rats and both resperidone and aripiprazole.
- Studies have shown that prescriptions for psychotropics including antipsychotics have increased during the last 20 years in children and youth.
- Newer drug classes can be developed in the future (i.e. third-generation antipsychotics) to avoid all these drawbacks of currently available drugs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]