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Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes.

ABSTRACT: Better risk prediction and new molecular targets are key priorities in type 2 diabetes (T2D) research. Little is known about the role of the urine metabolome in predicting the risk of T2D. We aimed to use non-targeted urine metabolomics to discover biomarkers and improve risk prediction for T2D. Urine samples from two community cohorts of 1,424 adults were analyzed by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). In a discovery/replication design, three out of 62 annotated metabolites were associated with prevalent T2D, notably lower urine levels of 3-hydroxyundecanoyl-carnitine. In participants without diabetes at baseline, LASSO regression in the training set selected six metabolites that improved prediction of T2D beyond established risk factors risk over up to 12 years' follow-up in the test sample, from C-statistic 0.866 to 0.892. Our results in one of the largest non-targeted urinary metabolomics study to date demonstrate the role of the urine metabolome in identifying at-risk persons for T2D and suggest urine 3-hydroxyundecanoyl-carnitine as a biomarker candidate.

SUBMITTER: Salihovic S

PROVIDER: S-EPMC7536211 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes.

Salihovic Samira S Broeckling Corey D CD Ganna Andrea A Prenni Jessica E JE Sundström Johan J Berne Christian C Lind Lars L Ingelsson Erik E Fall Tove T Ärnlöv Johan J Nowak Christoph C

Scientific reports 20201005 1

Better risk prediction and new molecular targets are key priorities in type 2 diabetes (T2D) research. Little is known about the role of the urine metabolome in predicting the risk of T2D. We aimed to use non-targeted urine metabolomics to discover biomarkers and improve risk prediction for T2D. Urine samples from two community cohorts of 1,424 adults were analyzed by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). In a discovery/replication design, three out of 62 annotated ...[more]

PMID: 33020500

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Project description:Aims/hypothesisIdentification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction.MethodsIn this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies.ResultsOut of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes.Conclusions/interpretationWe found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes.Access to research materialsMetabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS).

Project description:Aims/hypothesisData on type 1 diabetes incidence and prevalence are limited, particularly for adults. This study aims to estimate global numbers of incident and prevalent cases of type 1 diabetes in 2017 for all age groups, by country and areas defined by income and region.MethodsIncidence rates of type 1 diabetes in children (available from 94 countries) from the IDF Atlas were used and extrapolated to countries without data. Age-specific incidence rates in adults (only known across full age range for fewer than ten countries) were obtained by applying scaling ratios for each adult age group relative to the incidence rate in children. Age-specific incidence rates were applied to population estimates to obtain incident case numbers. Duration of diabetes was estimated from available data and adjusted using differences in childhood mortality rate between countries from United Nations demographic data. Prevalent case numbers were derived by modelling the relationship between prevalence, incidence and disease duration. Sensitivity analyses were performed to quantify the impact of alternative assumptions and model inputs.ResultsGlobal numbers of incident and prevalent cases of type 1 diabetes were estimated to be 234,710 and 9,004,610, respectively, in 2017. High-income countries, with 17% of the global population, accounted for 49% of global incident cases and 52% of prevalent cases. Asia, which has the largest proportion of the world's population (60%), had the largest number of incident (32%) and prevalent (31%) cases of type 1 diabetes. Globally, 6%, 35%, 43% and 16% of prevalent cases were in the age groups 0-14, 15-39, 40-64 and 65+ years, respectively. Based on sensitivity analyses, the estimates could deviate by ±15%.Conclusions/interpretationGlobally, type 1 diabetes represents about 2% of the estimated total cases of diabetes, ranging from less than 1% in certain Pacific countries to more than 15% in Northern European populations in 2017. This study provides information for the development of healthcare and policy approaches to manage type 1 diabetes. The estimates need further validation due to limitations and assumptions related to data availability and estimation methods.

Project description:The mechanisms by which exercise benefits patients with non-alcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, remain poorly understood. A non-targeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics analysis was used to identify metabolic changes associated with NAFLD in humans upon exercise intervention (without diet change) across four different sample types-adipose tissue (AT), plasma, urine, and stool. Altogether, 46 subjects with NAFLD participated in this randomized controlled intervention study. The intervention group (n = 21) performed high-intensity interval training (HIIT) for 12 weeks while the control group (n = 25) kept their sedentary lifestyle. The participants' clinical parameters and metabolic profiles were compared between baseline and endpoint. HIIT significantly decreased fasting plasma glucose concentration (p = 0.027) and waist circumference (p = 0.028); and increased maximum oxygen consumption rate and maximum achieved workload (p < 0.001). HIIT resulted in sample-type-specific metabolite changes, including accumulation of amino acids and their derivatives in AT and plasma, while decreasing in urine and stool. Moreover, many of the metabolite level changes especially in the AT were correlated with the clinical parameters monitored during the intervention. In addition, certain lipids increased in plasma and decreased in the stool. Glyco-conjugated bile acids decreased in AT and urine. The 12-week HIIT exercise intervention has beneficial ameliorating effects in NAFLD subjects on a whole-body level, even without dietary changes and weight loss. The metabolomics analysis applied to the four different sample matrices provided an overall view on several metabolic pathways that had tissue-type specific changes after HIIT intervention in subjects with NAFLD. The results highlight especially the role of AT in responding to the HIIT challenge, and suggest that altered amino acid metabolism in AT might play a critical role in e.g. improving fasting plasma glucose concentration.Trial registration ClinicalTrials.gov (NCT03995056).

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Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes.

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Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes.

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