Diabetes associated metabolomic perturbations in NOD mice

Grapov, Dmitry; Fahrmann, Johannes F.; Hwang, Jessica L.; Poudel, Ananta; Jo, Junghyo; Periwal, Vipul; Fiehn, Oliver; Hara, Manami

doi:10.1007/s11306-014-0706-2

Cited by 32 publications

(43 citation statements)

References 59 publications

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“…Increased representation of BCAA metabolism genes in the PAT metagenome as well as increased serum levels of leucine and isoleucine is consistent with higher BCAA serum levels in mice 43 and in humans who progress T1D 44 . The choline metabolites, TMAO and betaine, derived from gut microbiota, have associations with atherosclerosis 45 .…”

Section: Discussionmentioning

confidence: 52%

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice

et al. 2016

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The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.

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Section: Discussionmentioning

confidence: 52%

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice

et al. 2016

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“…Importantly, we found that chronic hyperglycemia (Ն250 mg/dl) and overt T1D manifested only in mice that lost ϳ70% of their total ␤-cell mass (23). Using an untargeted metabolomics approach, we performed an initial evaluation of primary metabolites in plasma of young (Ͻ25 wk) and old (Ն25 wk) nonprogressors (nondiabetic) vs. progressors (diabetic) to reveal distinct metabolomic pathways involved in disease progression (23). In the present study, we largely extended these investigations to capture alterations in primary metabolism, complex lipids, and lipid signaling mediators in the plasma of nonprogressors and progressors with the overall aim(s) of identifying circulating factors linked to disease progression and, potentially, ␤-cell destruction and dysfunction.…”

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confidence: 76%

“…T1D and performed an initial screening of primary metabolites in the plasma of these mice with the aims of identifying circulating factors linked with ␤-cell viability and/or T1D progression (23). In the current study, we aimed to expand upon our initial observations by using a multiplatform approach to recapitulate our initial metabolomic findings in addition to capturing perturbations in the lipidome and lipid signaling mediators.…”

Section: Legend)mentioning

confidence: 99%

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confidence: 99%

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Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia

Fahrmann

Grapov

Yang

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Hara M. Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia. Am J Physiol Endocrinol Metab 308: E978-E989, 2015. First published April 8, 2015; doi:10.1152/ajpendo.00019.2015.-Nonobese diabetic (NOD) mice are a commonly used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-highperformance liquid chromatography-accurate mass quadruple time-offlight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified Ͼ1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n ϭ 71). Statistical and multivariate analyses were used to identify age-and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-␦-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AAderived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D. diabetic mice; metabolomics; inflammation; oxidative stress TYPE 1 DIABETES (T1D) is an autoimmune disease characterized by the selective destruction of pancreatic ␤-cells. Currently, it is considered that the autoimmune insult is the primary driver of ␤-cell destruction that leads to development of T1D. However, it is becoming increasingly evident that early metabolic perturbations are inherently involved in the development and progression of T1D (39,40,53). These metabolic alterations may potentiate or attenuate ␤-cell loss and dysfunction. Oresic et al. (40) reported that alterations in branched-chain amino acids (BCAA) and lipid metabolism preceded the appearance of autoantibodies in children who later progressed to T1D. Pflueger et al. (44) found that, independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid (PUFA)-containing phospholipids than autoantibody-negative children. Furthermore, it was found that children who developed autoantibodies by age 2 yr had a signific...

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“…The top 10% feature model was evaluated using Monte Carlo training and testing cross-validation and permutation testing (18). Internal training and testing was done by further splitting the training set into 2/3 pseudo-training and 1/3 pseudo-test sets, while preserving individual patients’ tumor and control tissue pairs.…”

Section: Methodsmentioning

confidence: 99%

Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Wikoff

Grapov

Fahrmann

et al. 2015

Cancer Prevention Research

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109

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Adenocarcinoma, a type of non-small-cell lung cancer (NSCLC), is the most frequently diagnosed lung cancer and the leading cause of lung cancer mortality in the United States. It is well documented that biochemical changes occur early in the transition from normal to cancer cells, but the extent to which these alterations affect tumorigenesis in adenocarcinoma remains largely unknown. Herein we describe the application of mass spectrometry and multivariate statistical analysis in one of the largest biomarker research studies to date aimed at distinguishing metabolic differences between malignant and non-malignant lung tissue. Gas chromatography time-of-flight mass spectrometry was used to measure 462 metabolites in 39 malignant and non-malignant lung tissue pairs from current or former smokers with early stage (Stage IA–IB) adenocarcinoma. Statistical mixed effects models, orthogonal partial least squares discriminant analysis and network integration, were used to identify key cancer-associated metabolic perturbations in adenocarcinoma compared to non-malignant tissue. Cancer-associated biochemical alterations were characterized by: 1) decreased glucose levels, consistent with the Warburg effect, 2) changes in cellular redox status highlighted by elevations in cysteine and antioxidants, alpha- and gamma-tocopherol, 3) elevations in nucleotide metabolites 5,6-dihydrouracil and xanthine suggestive of increased dihydropyrimidine dehydrogenase and xanthine oxidoreductase activity, 4) increased 5'-deoxy-5'-methylthioadenosine levels indicative of reduced purine salvage and increased de novo purine synthesis and 5) coordinated elevations in glutamate and UDP-N-acetylglucosamine suggesting increased protein glycosylation. The present study revealed distinct metabolic perturbations associated with early stage lung adenocarcinoma which may provide candidate molecular targets for personalizing therapeutic interventions and treatment efficacy monitoring.

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Diabetes associated metabolomic perturbations in NOD mice

Cited by 32 publications

References 59 publications

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice

Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia

Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

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