A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human

Salek, Reza M.; Maguire, Mahon L.; Bentley, Elizabeth; Rubtsov, Denis V.; Hough, Tertius; Cheeseman, Michael; Nunez, Derek J.; Sweatman, Brian C.; Haselden, John N.; Cox, Roger D.; Connor, Susan C.; Griffin, Julian L.

doi:10.1152/physiolgenomics.00194.2006

Cited by 375 publications

(404 citation statements)

References 48 publications

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“…Although this model has shortcomings (Breyer et al 2005;Brosius et al 2009;Breyer 2012), these mice do recapitulate early renal consequences of systemic hyperglycemia, such as the development of glomerular hyperfiltration (elevated glomerular filtration rate (GFR) above the normal filtration rates), increased albuminuria and some histopathologic changes. Metabolomic comparisons of urinary metabolites show similarities between this mouse model and type 2 diabetic humans (Salek et al 2007). Similar to many cases of human type 2 diabetes mellitus, obesity drives this disease in db/db mice.…”

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confidence: 75%

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

Verma

Chopra

Giardina

et al. 2015

Cell Stress and Chaperones

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The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.

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confidence: 75%

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

Verma

Chopra

Giardina

et al. 2015

Cell Stress and Chaperones

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“…15 Urinary levels of hippurate have been shown to correlate with the obese phenotype in different animal models [16][17][18][19] and to associate with the fecal counting of several bacterial species in a rat model of obesity; 16 moreover, lower levels of hippurate were found in the urinary metabolic phenotypes of human type-2 diabetes mellitus patients. 17 Hippurate has also been inversely linked to blood pressure, suggesting a further connection with diet and obesity. 20 The changes in urinary excretion of trigonelline (N-methylnicotinate) indicate a class-specific metabolism of niacin, which is an essential vitamin involved in major Gut flora and human obese metabotype R Calvani et al physiological functions such as a coenzyme in tissue respiration, and carbohydrate and lipid metabolism.…”

Section: Resultsmentioning

confidence: 99%

Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype

et al. 2010

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Obesity is a complex multifactorial disease involving genetic and environmental factors and influencing several different metabolic pathways. In this regard, metabonomics, that is the study of complex metabolite profiles in biological samples, may provide a systems approach to understand the global metabolic regulation of the organism in relation to this peculiar pathology. In this pilot study, we have applied a nuclear magnetic resonance (NMR)-based metabolomic approach on urinary samples of morbidly obese subjects. Urine samples of 15 morbidly obese insulin-resistant (body mass index440; homeostasis assessment model of insulin resistance43) male patients and 10 age-matched controls were collected, frozen and analyzed by high-resolution 1 H-NMR spectroscopy combined with partial least squares-discriminant analysis. Furthermore, two obese patients who underwent bariatric surgery (biliopancreatic diversion and gastric bypass, respectively) were monitored during the first 3 months after surgery and their urinary metabolic profiles were characterized. NMR-based metabolomic analysis allowed us to identify an obesity-associated metabolic phenotype (metabotype) that differs from that of lean controls. Gut flora-derived metabolites such as hippuric acid, trigonelline, 2-hydroxyisobutyrate and xanthine contributed most to the classification model and were responsible for the discrimination. These preliminary results confirmed that in humans the gut microflora metabolism is strongly linked to the obesity phenotype. Moreover, the typical obese metabotype is lost after weight loss induced by bariatric surgery.

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“…10 Metabolomics is a rapidly advancing field that aims to characterize the concentration changes of all small molecules existing in a biofluid.11 Application of metabolomic technologies to the understanding of physiology, toxicology, and disease progression has led to appreciable advances by defining novel drug and carcinogen metabolites,12-15 as well as biomarkers of disease. 16,17 At the same time, the metabolomic technologies have contributed to a general understanding of how metabolites and their concentrations change under defined conditions.18 However, in contrast to transcriptomics and proteomics, broadbased metabolomic studies have not been used to analyze the cellular effects of IR. Smallscale, directed approaches using high-sensitivity nuclear magnetic resonance spectroscopy (NMR) [19][20][21][22][23] have been applied to estimate the relative concentration changes of a small subset of metabolites (e.g., reduced glutathione) following IR, but a global metabolomic approach has not yet been reported.…”

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UPLC-ESI-TOFMS-Based Metabolomics and Gene Expression Dynamics Inspector Self-Organizing Metabolomic Maps as Tools for Understanding the Cellular Response to Ionizing Radiation

et al. 2008

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Global transcriptomic and proteomic profiling platforms have yielded important insights into the complex response to ionizing radiation (IR). Nonetheless, little is known about the ways in which small cellular metabolite concentrations change in response to IR. Here, a metabolomics approach using ultraperformance liquid chromatography coupled with electrospray time-of-flight mass spectrometry was used to profile, over time, the hydrophilic metabolome of TK6 cells exposed to IR doses ranging from 0.5 to 8.0 Gy. Multivariate data analysis of the positive ions revealed doseand time-dependent clustering of the irradiated cells and identified certain constituents of the water-soluble metabolome as being significantly depleted as early as 1 h after IR. Tandem mass spectrometry was used to confirm metabolite identity. Many of the depleted metabolites are associated with oxidative stress and DNA repair pathways. Included are reduced glutathione, adenosine monophosphate, nicotinamide adenine dinucleotide, and spermine. Similar measurements were performed with a transformed fibroblast cell line, BJ, and it was found that a subset of the identified TK6 metabolites were effective in IR dose discrimination. The GEDI (Gene Expression Dynamics Inspector) algorithm, which is based on self-organizing maps, was used to visualize dynamic global changes in the TK6 metabolome that resulted from IR. It revealed dose-dependent clustering of ions sharing the same trends in concentration change across radiation doses. "Radiation metabolomics," the application of metabolomic analysis to the field of radiobiology, promises to increase our understanding of cellular responses to stressors such as radiation.High-throughput studies of the molecular and cellular effects of ionizing radiation (IR) have depended on "omic"1 profiling technologies, particularly genomic, transcriptomic, and proteomic platforms.2-6 Such efforts have discovered IR-induced perturbations of DNA, RNA, and protein molecules and have been successful in developing markers that provide information about IR-induced phenomena such as the threshold dose.4,7,8 Furthermore, integrating data from combinations of such platforms, in the spirit of emerging systems biology, has given investigators the ability to reconstruct and analyze IR-responsive For assessment of the potential application of metabolomics to radiobiology, a UPLC-ESI-TOFMS metabolomic assay was established to evaluate the changes in small-molecule concentration that occur after γ-irradiation of cells in culture. The high-resolution of ultraperformance liquid chromatography (UPLC) and the accurate mass measurement of electrospray ionization time-of-flight mass spectrometry (ESI-TOFMS) were combined to generate protonated molecular ion matrices consisting of peak areas identified by specific m/ z values and retention times. The hydrophilic metabolomes of the lymphoid TK6 cell line and the hTERT-transformed fibroblast BJ cell line were analyzed following different doses of IR over a period of 16 h. The overall...

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A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human

Cited by 375 publications

References 48 publications

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype

UPLC-ESI-TOFMS-Based Metabolomics and Gene Expression Dynamics Inspector Self-Organizing Metabolomic Maps as Tools for Understanding the Cellular Response to Ionizing Radiation

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