Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats

Li, Dejuan; Qin, Ya‐Zhen; Liu, Lu; Ke-ke, Che; Liu, Xuemei; Hu, Changhua

doi:10.1038/s41401-021-00680-x

Cited by 9 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taken together with the previous findings that both clozapine (high-risk of weight gain) and brexpiprazole (relatively low-risk of weight gain) suppress AMPK signalling in the peripheral organs 7 , 8 , assuming that BAIBA enantiomers contribute to the pathophysiology of clinical actions and adverse reactionsof clozapine, clozapine (but not brexpiprazole) may enhance hypothalamic AMPK signalling via BAIBA enantiomer, leading to metabolic disorders. According to our hypothesis, this study determined the distribution of BAIBA enantiomers, their intracellular and extracellular functions, and their release mechanisms in the brain.…”

Section: Introductionsupporting

confidence: 80%

“…Indeed, the most widely used agent for the treatment of type-2 diabetes, metformin, activates AMPK 6 . Conversely, several antipsychotics, including clozapine and brexpiprazole, suppress AMPK signalling in the liver, thereby altering glucose metabolism 7 , 8 . A meta-analysis also demonstrated that metformin led to clinically meaningful prevention of clozapine-induced weight-gain 9 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

2023

View full text Add to dashboard Cite

Clozapine is one of the most effective antipsychotics and has the highest risk of weight gain and metabolic complications; however, the detailed pathophysiology of its clinical action and adverse reactions remains to be clarified. Therefore, the present study determined the chronic effects of clozapine (high risk of weight gain) and brexpiprazole (relatively low risk of weight gain) on intracellular and extracellular levels of β-aminoisobutyric acid (BAIBA) enantiomers, which are endogenous activators of AMP-activated protein kinase (AMPK). L-BAIBA is the dominant BAIBA enantiomer in the rat hypothalamus and cultured astrocytes, whereas L-BAIBA accounts for only approximately 5% of the total plasma BAIBA enantiomers. L-BAIBA displayed GABAB receptor agonistic action in the extracellular space and was released through activated astroglial hemichannels, whereas in the intracellular space, L-BAIBA activated AMPK signalling. Chronic administration of the effective doses of clozapine increased intracellular and extracellular levels of L-BAIBA in the hypothalamus and cultured astrocytes, whereas that of brexpiprazole decreased them. These results suggest that enhancing hypothalamic AMPK signalling by increasing intracellular L-BAIBA levels is, at least partially, involved in the pathophysiology of clozapine-induced weight gain and metabolic complications.

show abstract

Section: Introductionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

2023

View full text Add to dashboard Cite

show abstract

“…Another finding showed integrin-linked kinase (ILK) blockade chronically inactivates AKT and shares with the exposed models some of the mechanisms that lead to reduced GLUT4 gene transcription [ 46 ]. Study showed olaznpine inhibited GLP1/GLP1R expressions in small intestine and pancreas, consequently lead to decreased insulin gene, including GLUT4, and ultimately dyslipidemia and glucose excursions [ 47 ]. Considering the complex mechanisms that affect GLUT4 expression and olanzapine may acted through a systemic action to influence glut4 expression in adipose tissue, we hypothesized olanzapine may be unable to influence intracellular GLUT4 expression in vitro, so the co-incubation of adipocyte with olanzapine didn’t change the intracellular GLUT4 expression significantly.…”

Section: Discussionmentioning

confidence: 99%

The mechanisms underlying olanzapine-induced insulin resistance via the brown adipose tissue and the therapy in rats

Wang

Zhou³

et al. 2022

Adipocyte

View full text Add to dashboard Cite

A rapid increase has been observed in insulin resistance (IR) incidence induced by a long-term olanzapine treatment with no better ways to avoid it. Our study aimed to demonstrate the mechanism underlying the olanzapine-induced insulin resistance and find appropriate drug interventions. In this study, firstly, we constructed rat insulin resistance model using a two-month gavage of olanzapine and used the main active ingredient mixture of Gegen Qinlian Decoction for the treatment. The activity of brown adipose tissue (BAT) was measured using the PET/CT scan, whereas Western blot and quantitative real-time PCR were used to detect the expression of GLUT4 and UCP1. The results showed that the long-term administration of olanzapine impaired glucose tolerance and produced insulin resistance in rats, while Gegen Qinlian Decoction could improve this side effect. The results of the PET/CT scan showed that the BAT activity in the insulin-resistant rats was significantly lower than that of the Gegen Qinlian Decoction treated rats. Also, the expression of GLUT4 and UCP1 in the insulin resistance group showed a significant decrease, which could be up-regulated by Gegen Qinliane Decoction treatment. The results of both in vivo and in vitro experiments were consistent. we demonstrated that the olanzapine could induce IR in vitro and in vivo by decreasing the expression of UCP1; thus, suppressing the thermogenesis of BAT and impairing glucose uptake. More importantly, we demonstrated a possible novel strategy to improve the olanzapine-induced IR by Gegen Qinlian Decoction.

show abstract

“…The oral glucose tolerance test (OGTT) is an important indicator of diabetes; so, it was performed on the experimental animals in this study [ 18 ]. One day before the end of the experiment, the rats in all groups fasted for 6 h; then, they were gavage-fed with 50% glucose solution at the dose of 1 mL/100 g body weight (equivalent to 5 g of glucose per 1 kg body weight).…”

Section: Methodsmentioning

confidence: 99%

Study of Water- and Organic-Soluble Extracts from Trichosanthes on Type 1 Diabetes Mellitus

Zhang

Yuan

Xiao

et al. 2022

Journal of Diabetes Research

View full text Add to dashboard Cite

This study investigates the effects of the water-soluble and organic-soluble Trichosanthes extracts on the hyperglycemic condition in streptozotocin- (STZ-) induced diabetic rats. The blood glucose levels, body weights, water intake, and urine volumes of rats in different experimental groups were monitored throughout the experiment, and the results obtained indicate that the two extracts can effectively reduce blood sugar levels, increase body weights, and improve water intake and urine volumes in diabetic rats. Based on blood biochemical analyses, the two extracts play an important role in regulating the diabetes-induced lipid metabolism disorder, increasing the levels of insulin and C-peptide, and alleviating the symptoms of diabetes. The variation in the liver glycogen contents of the water-soluble fraction and ethanol fraction groups suggests that the mechanisms underlying the hypoglycemic effects of the two extracts are different. Indeed, the water-soluble fraction alleviates diabetes symptoms in rats mainly by antioxidative activity, unlike the ethanol fraction.

show abstract

Brexpiprazole caused glycolipid metabolic disorder by inhibiting GLP1/GLP1R signaling in rats

Cited by 9 publications

References 50 publications

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

Opposing effects of clozapine and brexpiprazole on β-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain

The mechanisms underlying olanzapine-induced insulin resistance via the brown adipose tissue and the therapy in rats

Study of Water- and Organic-Soluble Extracts from Trichosanthes on Type 1 Diabetes Mellitus

Contact Info

Product

Resources

About