Modulation of Insulin Resistance, Dyslipidemia and Serum Metabolome in iNOS Knockout Mice following Treatment with Nitrite, Metformin, Pioglitazone, and a Combination of Ampicillin and Neomycin

Aggarwal, Hobby; Pathak, Priya; Kumar, Yashwant; Jagavelu, Kumaravelu; Dikshit, Madhu

doi:10.3390/ijms23010195

Cited by 9 publications

(11 citation statements)

References 94 publications

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“…Pioglitazone is another highly effective antidiabetic agent for T2D that is widely used as an insulin sensitizer and acts by activating peroxisome proliferator-activated receptor gamma, leading to the activation of various pathways associated with glycemic homeostasis and lipid metabolism ( Ahmadian et al, 2013 ). A few experimental animal studies revealed that pioglitazone treatment slightly modified gut flora homeostasis ( Bai et al, 2016 ; Li et al, 2019 ; Aggarwal et al, 2021 ). Pioglitazone reversed the high abundance of Proteobacteria in high-fat diet (HFD)-induced obese rats ( Bai et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice

et al. 2022

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Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined administration of pioglitazone and metformin achieved superior protective effects on high-fat diet (HFD)-fed obese mice and elucidated its molecular mechanism via the gut microbiota and its metabolites. C57BL/6 males were randomly divided into five groups: the control group, fed a normal control diet; the HFD group, fed an HFD; the metformin monotherapy group, fed an HFD and treated with metformin; the pioglitazone monotherapy group, fed an HFD and treated with pioglitazone; and the combination therapy group, fed an HFD and treated with metformin and pioglitazone combination therapy. The cecal contents were collected for 16S rDNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the combination therapy of metformin and pioglitazone significantly improved insulin sensitivity and glucolipid metabolism in HFD-fed mice. Combination therapy markedly altered gut microbiota by increasing beneficial bacteria, such as Bifidobacterium, Christensenellaceae_R-7_group, Faecalibacterium and Roseburia, and decreasing harmful bacteria, such as Oscillibacter and Eubacterium_xylanophilum_group. Fecal metabolites were significantly changed in the combination therapy group, including a reduction in amino acid metabolism and augmentation of lipid metabolism, such as citrulline, sarcosine, D-glutamine, lipoxin A4, prostaglandin E2, stearidonic acid and lucidenic acid A. These results revealed that combined metformin and pioglitazone therapy had synergistic effects or at least have an additive effect on modifying gut microbiota and metabolites, closely associated with improved glucolipid metabolic parameters in HFD-fed mice, which provides novel evidence and promising targets for metformin and pioglitazone combination therapy in type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice

et al. 2022

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“…Most of these drugs have shown good vascular protection in preclinical and clinical studies. For instance, the common drugs used to treat diabetes, such as insulin and metformin, have been shown to be effective in stimulating the release of NO and maintaining vascular stability ( Tousoulis et al, 2008 ; Aggarwal et al, 2021 ). Moreover, metformin can regulate AMPK-related pathways to protect endothelial cells ( Ding et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The mechanisms of glycolipid metabolism disorder on vascular injury in type 2 diabetes

Chen

Shi²,

Wang

et al. 2022

Front. Physiol.

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Patients with diabetes have severe vascular complications, such as diabetic nephropathy, diabetic retinopathy, cardiovascular disease, and neuropathy. Devastating vascular complications lead to increased mortality, blindness, kidney failure, and decreased overall quality of life in people with type 2 diabetes (T2D). Glycolipid metabolism disorder plays a vital role in the vascular complications of T2D. However, the specific mechanism of action remains to be elucidated. In T2D patients, vascular damage begins to develop before insulin resistance and clinical diagnosis. Endothelial dysregulation is a significant cause of vascular complications and the early event of vascular injury. Hyperglycemia and hyperlipidemia can trigger inflammation and oxidative stress, which impair endothelial function. Furthermore, during the pathogenesis of T2D, epigenetic modifications are aberrant and activate various biological processes, resulting in endothelial dysregulation. In the present review, we provide an overview and discussion of the roles of hyperglycemia- and hyperlipidemia-induced endothelial dysfunction, inflammatory response, oxidative stress, and epigenetic modification in the pathogenesis of T2D. Understanding the connections of glucotoxicity and lipotoxicity with vascular injury may reveal a novel potential therapeutic target for diabetic vascular complications.

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“…Another experimental study discovered that microbial metabolites, for example, hippurate and indole-3-ethanol, were decreased by pioglitazone intervention in iNOS knockout mice (122). These experiment research suggested that TZDs might have mild protective effects on gut microbiota, mainly focused on lipid and carbohydrate metabolism and inflammation.…”

Section: Thiazolidinedione Insulin Sensitizersmentioning

confidence: 99%

“…The expression of PPAR-γ is abundant in the intestinal tract; thus, it is possible that PPAR-γ agonists straightly impact on gut microbiome homeostasis to improve energy metabolism ( 119 , 120 ). However, only a few experimental animal studies explored whether TZD treatment can modify gut microbiota homeostasis ( 119 , 121 , 122 ). In a high-fructose-fed mouse model, pioglitazone partly altered gut microbiota and relieved the intestinal inflammation and epithelial barrier impairment, such as preventing the increment of the pathogenic bacteria Deferribacteraceae ( Mucispirillum ) ( 121 ).…”

Section: The Effects Of Oral Antidiabetic Drugs On Gut Microbiota And...mentioning

confidence: 99%

“…In diabetic mice, treatment with rosiglitazone promoted insulin sensitivity without modifying the composition of gut flora but improved the gene expression related to lipid and carbohydrate metabolism as well as immune regulation in the ileum and colon ( 119 ). Another experimental study discovered that microbial metabolites, for example, hippurate and indole-3-ethanol, were decreased by pioglitazone intervention in iNOS knockout mice ( 122 ). These experiment research suggested that TZDs might have mild protective effects on gut microbiota, mainly focused on lipid and carbohydrate metabolism and inflammation.…”

Section: The Effects Of Oral Antidiabetic Drugs On Gut Microbiota And...mentioning

confidence: 99%

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Effects of Oral Glucose-Lowering Agents on Gut Microbiota and Microbial Metabolites

et al. 2022

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The current research and existing facts indicate that type 2 diabetes mellitus (T2DM) is characterized by gut microbiota dysbiosis and disturbed microbial metabolites. Oral glucose-lowering drugs are reported with pleiotropic beneficial effects, including not only a decrease in glucose level but also weight loss, antihypertension, anti-inflammation, and cardiovascular protection, but the underlying mechanisms are still not clear. Evidence can be found showing that oral glucose-lowering drugs might modify the gut microbiome and thereby alter gastrointestinal metabolites to improve host health. Although the connections among gut microbial communities, microbial metabolites, and T2DM are complex, figuring out how antidiabetic agents shape the gut microbiome is vital for optimizing the treatment, meaningful for the instruction for probiotic therapy and gut microbiota transplantation in T2DM. In this review, we focused on the literatures in gut microbiota and its metabolite profile alterations beneficial from oral antidiabetic drugs, trying to provide implications for future study in the developing field of these drugs, such as combination therapies, pre- and probiotics intervention in T2DM, and subjects with pregestational diabetes and gestational diabetes mellitus.

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Modulation of Insulin Resistance, Dyslipidemia and Serum Metabolome in iNOS Knockout Mice following Treatment with Nitrite, Metformin, Pioglitazone, and a Combination of Ampicillin and Neomycin

Cited by 9 publications

References 94 publications

Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice

Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice

The mechanisms of glycolipid metabolism disorder on vascular injury in type 2 diabetes

Effects of Oral Glucose-Lowering Agents on Gut Microbiota and Microbial Metabolites

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