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      Metabolomics in Prediabetes and Diabetes: A Systematic Review and Meta-analysis

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          Abstract

          OBJECTIVE

          To conduct a systematic review of cross-sectional and prospective human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on prediabetes and type 2 diabetes.

          RESEARCH DESIGN AND METHODS

          We searched MEDLINE and EMBASE databases through August 2015. We conducted a qualitative review of cross-sectional and prospective studies. Additionally, meta-analyses of metabolite markers, with data estimates from at least three prospective studies, and type 2 diabetes risk were conducted, and multivariable-adjusted relative risks of type 2 diabetes were calculated per study-specific SD difference in a given metabolite.

          RESULTS

          We identified 27 cross-sectional and 19 prospective publications reporting associations of metabolites and prediabetes and/or type 2 diabetes. Carbohydrate (glucose and fructose), lipid (phospholipids, sphingomyelins, and triglycerides), and amino acid (branched-chain amino acids, aromatic amino acids, glycine, and glutamine) metabolites were higher in individuals with type 2 diabetes compared with control subjects. Prospective studies provided evidence that blood concentrations of several metabolites, including hexoses, branched-chain amino acids, aromatic amino acids, phospholipids, and triglycerides, were associated with the incidence of prediabetes and type 2 diabetes. We meta-analyzed results from eight prospective studies that reported risk estimates for metabolites and type 2 diabetes, including 8,000 individuals of whom 1,940 had type 2 diabetes. We found 36% higher risk of type 2 diabetes per study-specific SD difference for isoleucine (pooled relative risk 1.36 [1.24–1.48]; I 2 = 9.5%), 36% for leucine (1.36 [1.17–1.58]; I 2 = 37.4%), 35% for valine (1.35 [1.19–1.53]; I 2 = 45.8%), 36% for tyrosine (1.36 [1.19–1.55]; I 2 = 51.6%), and 26% for phenylalanine (1.26 [1.10–1.44]; I 2 = 56%). Glycine and glutamine were inversely associated with type 2 diabetes risk (0.89 [0.81–0.96] and 0.85 [0.82–0.89], respectively; both I 2 = 0.0%).

          CONCLUSIONS

          In studies using high-throughput metabolomics, several blood amino acids appear to be consistently associated with the risk of developing type 2 diabetes.

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          Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity.

          Stephanie Mihalik, Bret Goodpaster, David Kelley … (2010)
          Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
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            Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults

            Peter Würtz, Pasi Soininen, Antti Kangas … (2013)
            OBJECTIVE Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.
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              2-Aminoadipic acid is a biomarker for diabetes risk.

              NIKOLAOS PSYCHOGIOS, Anh D. Ngo, Robert Gerszten … (2013)
              Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Care
                Journal ID (iso-abbrev): Diabetes Care
                Journal ID (hwp): diacare
                Journal ID (pmc): dcare
                Journal ID (publisher-id): Diabetes Care
                Title: Diabetes Care
                Publisher: American Diabetes Association
                ISSN (Print): 0149-5992
                ISSN (Electronic): 1935-5548
                Publication date (Print): May 2016
                Publication date (Electronic): 14 April 2016
                Volume: 39
                Issue: 5
                Pages: 833-846
                Affiliations
                [1] 1Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
                [2] 2Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Institute for Health Research, Rovira i Virgili University, Reus, Spain
                [3] 3CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
                [4] 4Department of Preventive Medicine and Public Health, University of Navarra, Health Research Institute of Navarra, Pamplona, Spain
                [5] 5Broad Institute, Cambridge, MA
                [6] 6Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
                [7] 7Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
                Author notes
                Corresponding author: Frank B. Hu, nhbfh@ 123456channing.harvard.edu .
                Author information
                http://orcid.org/0000-0001-8525-1404
                http://orcid.org/0000-0003-2700-7459
                Article
                Publisher ID: 2251
                DOI: 10.2337/dc15-2251
                PMC ID: 4839172
                PubMed ID: 27208380
                SO-VID: dedbc7f1-7d45-427b-b474-bd0ad47eb6a5
                Copyright © © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                History
                Date received : 14 October 2015
                Date accepted : 6 February 2016
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 65, Pages: 14
                Funding
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Award ID: R01-DK-102896
                Award ID: R01-HL-118264
                Award ID: P30-DK-46200
                Award ID: HL-60712
                Categories
                Subject: Meta-Analysis

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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