Type 2 diabetes mellitus decreases systemic exposure of clopidogrel active metabolite through upregulation of P-glycoprotein in rats

Yao, Hongwei; Gu, Jingkai; Shan, Yuqin; Wang, Yani; Xue, Chen; Sun, Dawei; Guo, Yingjie

doi:10.1016/j.bcp.2020.114142

Cited by 10 publications

(11 citation statements)

References 44 publications

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“…Recent two clinical studies demonstrates that Clop resistance in diabetic patients is mainly attributed to the decreased Clop-AM generation (Erlinge et al, 2008;Angiolillo et al, 2014). Similarly, our previous study found that T2DM rats had lower systemic exposure of Clop-AM than control rats, due 6 to P-gp upregulation-caused reduction of Clop absorption (Yao et al, 2020).…”

Section: Introductionsupporting

confidence: 51%

Antibiotics-Induced Disruption of Gut Microbiota Increases Systemic Exposure of Clopidogrel Active Metabolite in Type 2 Diabetic Rats

et al. 2022

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Gut microbiota play an important role in the pathophysiology of type 2 diabetic mellitus (T2DM) and biodisposition of drugs. Our previous study demonstrated that T2DM rats had the decreased plasma exposure of clopidogrel active metabolite (Clop-AM) due to upregulation of P-glycoprotein (P-gp). However, whether the change to clopidogrel (Clop) disposition under T2DM condition is associated with gut microbiota needs to be elucidated. In the study, we used an antibiotic cocktail consisting of ampicillin, vancomycin, metronidazole, and neomycin to disrupt gut microbiota and observed their influence on pharmacokinetic profiles of Clop-AM. Antibiotic administration markedly alleviated T2DM rats' phenotype including hyperglycemia, insulin resistance, oxidative stress, inflammation, hyperlipidemia, and liver dysfunction. Meanwhile, treatment with antibiotics significantly reversed the reduced systemic exposure of Clop-AM in T2DM rats relative to control rats, which was associated with the decreased intestinal P-gp level that might promote Clop absorption, resulting in more Clop transformation to Clop-AM.Fecal microbiome analysis exhibited a serious disruption of gut microbiota after antibiotic treatment with the sharply reduced microbial load and the altered microbial composition. Interestingly, an in vitro study showed that antibiotics had no influence on P-gp mRNA leve in SW480 cells, suggesting the microbiome disruption, not the direct role of antibiotics on P-gp expression, contributes to the altered P-gp level and Clop disposition in T2DM rats. The

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Section: Introductionsupporting

confidence: 51%

Antibiotics-Induced Disruption of Gut Microbiota Increases Systemic Exposure of Clopidogrel Active Metabolite in Type 2 Diabetic Rats

et al. 2022

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“…With reference to the method widely used in an abundance of literatures [16][17][18] , rats were fed on a high-fat diet for 8 weeks and then received a single low dose of streptozotocin (STZ, 30 mg/kg) injection to induce T2DM model. Speci cally, rats were randomly allocated to the blank control group (N = 20) and the model group (N = 40) according to body mass.…”

Section: Induction Of Diabetesmentioning

confidence: 99%

Protective effects of calorie restriction on insulin resistance and islets function in STZ-induced type 2 diabetes rats

Zhang

Huang

Sun

et al. 2021

Preprint

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Background Caloric restriction (CR) has become increasingly attractive in the treatment of type 2 diabetes mellitus (T2DM) because of the increasingly common high-calorie diet and sedentary lifestyle. This study aimed to evaluate the role of CR in T2DM treatment and further explore its potential molecular mechanisms.Methods Sixty male Sprague-Dawley rats were used in this study. The diabetes model was induced by 8 weeks of high-fat diet (HFD) followed by a single dose of streptozotocin injection (30 mg/kg). Subsequently, the diabetic rats were fed HFD at 28 g/day (diabetic control) or 20 g/day (30% CR regimen) for 20 weeks. Meanwhile, normal rats fed a free standard chow diet served as the vehicle control. Body mass, plasma glucose levels, and lipid profiles were monitored. After diabetes-related functional tests were performed, the rats were sacrificed at 10 and 20 weeks, and glucose uptake in fresh muscle was determined. In addition, western blotting and immunofluorescence were used to detect alterations in AKT/AS160/GLUT4 signaling. Results We found that 30% CR significantly attenuated hyperglycemia and dyslipidemia, leading to alleviation of glucolipotoxicity and thus protection of islet function. Insulin resistance was also markedly ameliorated, as indicated by notably improved insulin tolerance and homeostatic model assessment for insulin resistance (HOMA-IR). However, the improvement in glucose uptake in skeletal muscle was not significant. The upregulation of AKT/AS160/GLUT4 signaling in muscle induced by 30% CR also attenuated gradually over time. Interestingly, the consecutive decrease in AKT/AS160/GLUT4 signaling in white adipose tissue was significantly reversed by 30% CR. Conclusion CR (30%) could protect islet function from hyperglycemia and dyslipidemia, and improve insulin resistance. The mechanism by which these effects occurred is likely related to the upregulation of AKT/AS160/GLUT4 signaling.

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“…The intestinal and renal expression of Pxr also is affected by obesity and diabetes. PXR mRNA and protein levels were significantly increased in duodenum and jejunum, but not ileum, in a rat model of type 2 diabetic mellitus (HFD and streptozotocin treatment) [217]. Gut microbiota metabolites, such as the secondary bile acid lithocholic acid that activates PXR and is elevated in the presence of type 2 diabetic mellitus, could be involved in this upregulation [217].…”

Section: Diabetes and Obesitymentioning

confidence: 99%

“…PXR mRNA and protein levels were significantly increased in duodenum and jejunum, but not ileum, in a rat model of type 2 diabetic mellitus (HFD and streptozotocin treatment) [217]. Gut microbiota metabolites, such as the secondary bile acid lithocholic acid that activates PXR and is elevated in the presence of type 2 diabetic mellitus, could be involved in this upregulation [217]. In normal mouse kidney, Pxr is selectively expressed in proximal tubular cells and the promoter is demethylated.…”

Section: Diabetes and Obesitymentioning

confidence: 99%

Regulation of CAR and PXR Expression in Health and Disease

Daujat-Chavanieu

Gerbal‐Chaloin

2020

Cells

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Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on CAR and PXR expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.

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Type 2 diabetes mellitus decreases systemic exposure of clopidogrel active metabolite through upregulation of P-glycoprotein in rats

Cited by 10 publications

References 44 publications

Antibiotics-Induced Disruption of Gut Microbiota Increases Systemic Exposure of Clopidogrel Active Metabolite in Type 2 Diabetic Rats

Antibiotics-Induced Disruption of Gut Microbiota Increases Systemic Exposure of Clopidogrel Active Metabolite in Type 2 Diabetic Rats

Protective effects of calorie restriction on insulin resistance and islets function in STZ-induced type 2 diabetes rats

Regulation of CAR and PXR Expression in Health and Disease

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