Chronic effects of clozapine administration on insulin resistance in rats: Evidence for adverse metabolic effects

Elseweidy, Mohamed M.; Sadik, Nermin Abdel Hamid; Malek, Marwa M.; Amin, Rawia Sarhan

doi:10.1016/j.prp.2013.09.010

Cited by 9 publications

(11 citation statements)

References 49 publications

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“…Our results confirm previous studies, which found that hyperglycemia is more frequent in patients treated with clozapine [27]. Contrary to results of animal [28] and human [29] studies, we did not find that subjects with schizophrenia on clozapine monotherapy had higher fasting insulin levels comparing to age-and sex-matched healthy controls. On the other hand, this result is consistent with one reported by Howes et al [23].…”

Section: Discussionsupporting

confidence: 81%

Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy

Wysokiński

2014

Diabetes & Metabolic Syndrome: Clinical Research & Revi

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Section: Discussionsupporting

confidence: 81%

Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy

Wysokiński

2014

Diabetes & Metabolic Syndrome: Clinical Research & Revi

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“…For example, clozapine elevated serum lipid levels in Sprague-Dawley (S-D) rats, 48 increased serum triacylglycerol, total cholesterol, free fatty acids, progesterone, and corticoster-one levels in the S-D rats, 49 led to hepatic accumulation of lipids in female S-D rats, 50 and resulted in hyperglycemia, hyperinsulinemia, and insulin resistance in Wistar albino rats. 51 In the present study, daily intraperitoneal injection of clozapine for 6 weeks significantly increased plasma levels of triglycerides, led to hepatic steatosis and fibrosis along with increased activities of ALT and AST in male Wistar rats, but showed no effects on blood glucose, insulin levels, and total cholesterol. Some of the clozapine-induced metabolic adverse effects such as increased plasma levels of triglycerides and hepatic steatosis were same as those reported by the above-mentioned previous animal studies, 48 – 50 while the others including increased total cholesterol 49 and hyperglycemia 51 were not seen in the present study.…”

Section: Discussionsupporting

confidence: 43%

“… 51 In the present study, daily intraperitoneal injection of clozapine for 6 weeks significantly increased plasma levels of triglycerides, led to hepatic steatosis and fibrosis along with increased activities of ALT and AST in male Wistar rats, but showed no effects on blood glucose, insulin levels, and total cholesterol. Some of the clozapine-induced metabolic adverse effects such as increased plasma levels of triglycerides and hepatic steatosis were same as those reported by the above-mentioned previous animal studies, 48 – 50 while the others including increased total cholesterol 49 and hyperglycemia 51 were not seen in the present study.…”

Section: Discussionsupporting

confidence: 43%

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

Li¹,

Su²,

Xu³

et al. 2017

NDT

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Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects.

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“…A previous rat study reported that administration of a single dose of clozapine resulted in suppression of the serum level of GLP-1 and increase in glucagon level, thereby resulting in acute derangement of glucose metabolism [8] . Mechanisms such as the clozapine-induced activation of hepatic phosphorylase and G6Pase have been proposed to be involved in atypical antipsychotic-associated increases in the hepatic glucose output [14] . It also has been reported that clozapine is a potent acetylcholine muscarinic M3 receptor (M3R) antagonist and both pancreatic and hypothalamic and brainstem M3Rs regulate the insulin secretion and alter glucometabolic status of the body [15] .…”

Section: Discussionmentioning

confidence: 99%

GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

Hsu

2016

Toxicology Reports

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Background and aimsThe aim of this study was to investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), exenatide, on clozapine-associated glucose dysregulation in mice.Materials and methodsWe randomly separated B6 male mice into four groups (A to D). Mice in groups C and D received a daily oral dose of 13.5 mg/kg body weight of clozapine for 4 months. Mice in groups B and D received 1 μg of exenatide daily. The body weight and blood glucose before and 2 h after clozapine treatment were measured twice a week. Intraperitoneal glucose tolerance test (IPGTT) scores and the amount of daily food intake were recorded. The pancreases of the mice were removed for insulin content (PIC) measurement and histological examination after sacrifice.ResultsThe mean non-fasting blood glucose levels were not different, and the mean changes in blood glucose 2 h after oral clozapine were 0 ± 4, −40 ± 2, 25 ± 3, and −39 ± 2, in groups A to D, respectively. There was no significant difference in daily calorie intake or area under the curve of IPGTT among the four groups. At sacrifice, the PIC of mice treated with clozapine was significantly lower than that of the control mice, however the PIC was completely restored in the mice treated with exenatide. Histological examination of the pancreas revealed that exenatide treatment reversed the clozapine-induced apoptosis of islet cells.ConclusionOur results provide preclinical evidence of a pharmaceutical role of GLP-1RA in managing glucose dysregulation in schizophrenic patients under long-term atypical antipsychotic treatments.

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Chronic effects of clozapine administration on insulin resistance in rats: Evidence for adverse metabolic effects

Cited by 9 publications

References 49 publications

Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy

Blood levels of glucose and insulin and insulin resistance in patients with schizophrenia on clozapine monotherapy

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

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