Dataset Information

Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.

ABSTRACT: Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39-1.95], P = 8.46 × 10(-9)) and was moderately heritable (h(2) = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34-2.11], P = 6.52 × 10(-6)) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27-2.75], P = 1 × 10(-3)). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.

SUBMITTER: Menni C

PROVIDER: S-EPMC3837024 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.

Menni Cristina C Fauman Eric E Erte Idil I Perry John R B JR Kastenmüller Gabi G Shin So-Youn SY Petersen Ann-Kristin AK Hyde Craig C Psatha Maria M Ward Kirsten J KJ Yuan Wei W Milburn Mike M Palmer Colin N A CN Frayling Timothy M TM Trimmer Jeff J Bell Jordana T JT Gieger Christian C Mohney Rob P RP Brosnan Mary Julia MJ Suhre Karsten K Soranzo Nicole N Spector Tim D TD

Diabetes 20130724 12

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting ...[more]

PMID: 23884885

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Project description:AIMS/HYPOTHESIS:Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection. METHODS:We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40-65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset). RESULTS:Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 × 10-4). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]). CONCLUSIONS/INTERPRETATION:In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology.

Project description:The worldwide prevalence and incidence of diabetes and obesity are increasing in pandemic proportions. This is particularly relevant for China, where an extremely large population is growing, aging, and urbanizing. We thus conducted a prospective study to examine the prevalence and incidence of impaired fasting glucose (IFG) and diabetes, the rate at which fasting blood glucose rises, and the major modifiable risk factors associated with these outcomes in a large Chinese population from the Kailuan prospective study.A prospective cohort included 100,279 Chinese participants, aged 18 years or more, who had available information on fasting blood glucose concentrations at the start of the study (2006). Examination surveys were conducted every 2 years in 2008 and 2010. For the analyses of incident diabetes, we included 76,869 participants who were free of diabetes, cardiovascular disease, and cancer at the baseline and participants in the 2008 and/or 2010 follow-up. Diabetes was defined by a fasting blood glucose concentration ≥7 mmol/L, self-reported history, or active treatment with insulin or any oral hypoglycemic agent. IFG was defined by a fasting blood glucose concentration between 5.6 and 6.9 mmol/L.During the 4-year study, the prevalence of diabetes and IFG rose from 6.6% to 7.7%, and 17.3% to 22.6%, respectively. There were 17,811 incident cases of IFG and 4867 incident cases of diabetes. The age-standardized incident rate of IFG and diabetes were 62.6/1000 person-years (51.2/1000 person-years in women and 73.8/1000 person-years in men) and 10.0/1000 person-years (7.8/1000 person-years in women and 12.1/1000 person-years in men), respectively. We observed steady increases in fasting blood glucose with body anthropometrics and in every defined category of body mass index, including in those traditionally considered to be well within the "normal" range.In this large longitudinal study of Chinese adults, we observed a high prevalence and incidence of IFG and diabetes over 4 years of follow-up. Our findings are alarming for Chinese public health since steady rises in fasting blood glucose were seen across all permutations of body habitus, even apparently very lean individuals.

Project description:BackgroundDiabetes is associated with higher fracture risk despite higher bone mineral density (BMD), with FRAX® underestimating risk. This study aimed to investigate FRAX score with and without BMD for women with normoglycaemia, impaired fasting glucose (IFG) and diabetes.MethodsAmong 566 women, aged 40-90?years, enrolled in the Geelong Osteoporosis Study, IFG was defined as fasting plasma glucose (FPG) ?5.5?mmol/L and diabetes as FPG???7.0?mmol/L, use of antihyperglycaemic medication and/or self-report. FRAX (Australia) 10-year probabilities of major osteoporotic (MOF) and hip fracture were calculated, with and without BMD, producing four FRAX scores per participant. Kruskal-Wallis test for non-parametric data was used to examine differences between the three glycaemia groups. Fractures over 10?years were ascertained using radiological reports. The number of fractures predicted by FRAX was compared with the number of fractures observed using Chi-square tests.ResultsFor MOF FRAX calculated without BMD, women with diabetes (n?=?67) tended to have a higher median score 7.1 (IQR 2.7-12.0) than normoglycaemia (n?=?252) (4.3 (IQR 1.9-9.9) and IFG (n?=?247) (5.1 (IQR 2.2-9.6)). For hip FRAX without BMD, diabetes tended to have a higher score (2.5 (IQR 06-4.3)) than normoglycaemia (1.2 (IQR 0.3-4.1)) and IFG (1.3 (IQR 0.3-4.1)). In the normoglycaemia and IFG groups, MOFs were underestimated; 15 predicted vs 28 observed, p?=?0.038; and 16 predicted vs 31 observed, p?=?0.021, respectively. Fractures were accurately estimated in all other groups.When including BMD, the association with diabetes was non-significant for both MOF FRAX (normoglycaemia 3.7 (IQR 1.9-8.0), IFG 4.3 (IQR 2.2-8.1) and diabetes 5.3 (IQR 2.7-9.4)) and hip FRAX scores (normoglycaemia 0.6 (IQR 0.2-2.5), IFG 0.8 (IQR 0.2-2.7) and diabetes 1.0 (IQR 0.3-3.0)). For normoglycaemia and IFG, MOFs were underestimated (normoglycaemia: 13 predicted vs 28 observed and IFG: 13 vs 31). For diabetes, both MOFs and hip fractures tended to be underestimated by FRAX with BMD (MOF: 4 predicted vs 11 observed, p?=?0.055, hip: 1 predicted vs 6 observed, p?=?0.052). Hip fractures were accurately estimated in the normoglycaemia and IFG groups.ConclusionsCompared with women who had normoglycaemia or IFG, women with diabetes tended to have a higher FRAX score for both MOF and hip fractures when BMD was not included. When BMD was included, there was no difference. Fractures in diabetes tended to be underestimated by FRAX with BMD. This suggests that FRAX calculations including BMD may not be accurate for estimating fractures in those with diabetes.

Dataset Information

Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.

Publications

Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.

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