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

Abstract

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.

The benefits of the Mediterranean diet in first episode psychosis patients taking antipsychotics

“…The higher glucose levels in the FEP AP2 subgroup may be indicative of a sub-clinical oxidative stress response of the pancreatic cells, also related to the reduced adherence to the MedDiet. In a study of Hsu et al, clozapine categorized here in the AP2, was associated with glucose dysregulation in a mouse model [ 33 ]. In FEP treated with AP2, MedDiet appeared to be beneficial in regulating glucose levels [ 34 ].…”

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain

“…This increase in glucagon levels can directly increase HGO, as mentioned previously. In this line, it was reported that the GLP-1 receptor agonist exenatide reversed the damage to pancreatic islets in male C57BL/6 mice treated for 4 months with clozapine (13.5 mg/kg, orally), suggesting a dysregulation of GLP-1-mediated signaling and the subsequent impairment of pancreatic hormone secretion [147]. An increase in glucagon levels after clozapine treatment (5 mg/kg, i.v.)…”

“…For example, the rs10423928 polymorphism (A/T) in the β-cell glucose-dependent insulinotropic polypeptide receptor ( GIPR ), which stimulates insulin secretion upon binding of the incretin GIP, was associated with increased insulin levels in an oral glucose tolerance test in patients with schizophrenia treated with olanzapine [158]. As discussed earlier, long-term treatment with high-risk diabetogenic SGAs has been also linked to decreased GLP-1 levels in rats [146], and the positive effects of GLP-1 analogs have been proved in animals [147] and humans [159,160]. Correspondingly, GCG (encoding for a preprotein cleaved into four different proteins, including GLP-1 and glucagon) and GLP1R have been assessed as potential pharmacogenetic markers of antipsychotic response.…”

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

“…The majority of rodent studies demonstrated evidence of apoptosis (e.g., increased terminal deoxynucleotide transferase dUTP nick-end labeling staining or caspase-3 activation) between weeks 1 and 4 of treatment (Wasti et al, 2006;Jarskog et al, 2007;Huang et al, 2012;Jia et al, 2014;Zlatkovi c et al, 2014;Hsu and Fu, 2016;Khalaf et al, 2019) using doses that would approximate therapeutic concentrations in patients (Lobach and Uetrecht, 2014a). One study also noted that clozapine induced autophagy within hours of administration (Kim et al, 2018), and others noted decreased proliferation within the first few weeks of treatment (Huang et al, 2012;Hsu and Fu, 2016;Khalaf et al, 2019) as well. Translocation of apoptosis-inducing factor was not observed in the striatum of clozapine-treated patients or in rodents after 1 month of treatment (Skoblenick et al, 2006), suggesting against the involvement of caspase-independent cell death with clozapine.…”