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  • 1
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    Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. 11 ( 2022-11-01), p. 2426-2437
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. 11 ( 2022-11-01), p. 2426-2437
    Abstract: Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or “known” and 2,342 nontargeted or “unknown” compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)—a community cohort of self-identified African Americans—who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of & lt;0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose. Of these, 144 and 68 associations, respectively, replicated in a multiethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ = 0.29), and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0033
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 2
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    Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. 12 ( 2019-12-01), p. 2337-2349
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. 12 ( 2019-12-01), p. 2337-2349
    Abstract: Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET] , or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-0236
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 3
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    Protein Markers of Diabetes Discovered in an African American Cohort
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. 4 ( 2023-04-01), p. 532-543
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. 4 ( 2023-04-01), p. 532-543
    Abstract: Proteomics has been used to study type 2 diabetes, but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans in the Jackson Heart Study (n = 1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and sample batch (false discovery rate q & lt; 0.05) measured using a single-stranded DNA aptamer affinity-based method on fasting plasma samples. A subset was independent of established markers of diabetes development pathways, such as adiposity, glycemia, and/or insulin resistance, suggesting potential novel biological processes associated with disease development. Thirty-six associations remained significant after additional adjustments for BMI, fasting plasma glucose, cholesterol levels, hypertension, statin use, and renal function. Twelve associations, including the top associations of complement factor H, formimidoyltransferase cyclodeaminase, serine/threonine–protein kinase 17B, and high-mobility group protein B1, were replicated in a meta-analysis of two self-identified White cohorts—the Framingham Heart Study and the Malmö Diet and Cancer Study—supporting the generalizability of these biomarkers. A selection of these diabetes-associated proteins also improved risk prediction. Thus, we uncovered both novel and broadly generalizable associations by studying a diverse population, providing a more complete understanding of the diabetes-associated proteome.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-0710
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 4
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    1994-LB: Metabolites Link Infections to Type 2 Diabetes in the Multiethnic Study of Atherosclerosis (MESA)
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: Introduction & Objective: Prior to T2D, patients experience increased infections, yet no pathways account for this immune/endocrine system cross-talk. We aimed to identify metabolites that link pathogens to T2D. Methods: Using plasma from 4,424 adults (61 ±9 y; 53% female), taxonomic classification was conducted on reads from sequencing that aligned with a microbial reference panel, and metabolites quantified. Incident T2D (ADA 2003 criteria) was assessed over ~18 y. A cox-proportional hazard model identified baseline microbes as ‘variables of importance’ to incident T2D, with a penalty function to minimize sparse data bias. Metabolome-wide associations identified metabolites shared between T2D-related microbes at baseline, and incident T2D. All models adjusted for age, gender, race/ethnicity, education, and AHA’s Life’s Simple 8 score. Results: Total microbes differed by race/ethnicity (X2= 30.4, df = 9, P= 3.8*10-4), but not any other covariates (all P & gt;.05). Incident T2D was associated with 2 microbes: Rahnella (HR=1.90 (1.09-3.30), P=.02) and Plasmodium falciparum (HR=1.34 (1.05-1.73), P=.02). 23 metabolites were associated with incident T2D (P & lt;.05 after an FDR-correction) and at least one of these microbes (P & lt;.05; Fig). Conclusions: These analyses indicate molecules linking exposure to, and / or continued presence in the plasma of, infectious microbes, and increased risk of T2D. Disclosure A. Wood: Research Support; Beef Checkoff. Consultant; Lundquist. M.O. Goodarzi: Advisory Panel; Nestlé Health Science, Organon. Z. Chen: None. X. Guo: None. S.S. Rich: None. C.B. Clish: None. R.E. Gerszten: None. J.I. Rotter: None. K. Taylor: None. Funding USDA/ARS cooperative agreement (#58-3092-5-001). Advancing Translational Sciences (UL1TR001420, UL1TR001881).
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-1994-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
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  • 5
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    1479-P: The Association between Race and Ethnicity and Type 2 Diabetes Is Partially Mediated by Circulating Proteins—A Meta-analysis of 2,339 Individuals from Two Multiethnic Cohorts of the TOPMed Program
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: It is critical to understand the molecular basis for well-recognized disparities in type 2 diabetes (T2D) risk. We aimed to examine plasma proteomic profile variations among self-identified racial and ethnic groups and assess the mediating impact of race- and ethnic-specific proteomic signatures on prevalent T2D. Methods: We used proteomic data from 2339 individuals who self-identified as Non-Hispanic-White, Hispanic, or Non-Hispanic Black in the Women’s Health Initiative (N=1,400) and Multi-Ethnic Study of Atherosclerosis (N=939). To identify race- and ethnicity-specific associations we used linear models adjusting by confounders; site of recruitment, age, BMI, and eGFR. We employed structural equation modeling to examine the mediation by race and ethnic-specific proteins of the relationship between self-reported race/ethnicity and prevalent T2D. Models were stratified by sex, results were meta-analyzed and corrected for multiple comparisons (P & lt;10-5). Results: We tested associations for 324 proteins. A total of 138 proteins (41.04%) were associated with self-reported race/ethnicity (P & lt;10-5). Seven proteins independently mediated the association between self-reported race/ethnicity and T2D (P & lt;10-6). Top significant proteins included Growth/differentiation factor 8, Insulin-like growth factor-binding protein 2, and Apolipoprotein M. We identified that 8-11% of the association between self-reported race and prevalent T2D can be attributed to the direct mediating effect of race-ethnic-specific proteomic signatures. Conclusion: More than 40% of protein levels tested varied significantly by race and ethnicity. Seven protein levels were found to significantly mediate the association between race and ethnicity and T2D prevalence. These results provide insights into the molecular pathways that contribute to racial and ethnic disparities in T2D prevalence. Disclosure M. Sevilla-Gonzalez: Research Support; Novo Nordisk Foundation. K.E. Westerman: None. N. Wang: None. S. Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies. Advisory Panel; Alexion Pharmaceuticals, Inc. Other Relationship; Wolters Kluwer Health. Z. Chen: None. J.I. Rotter: None. C.L. Kooperberg: None. J.B. Meigs: None. A. Manning: None. Funding American diabetes Association (9-22-PDFPM-04); National Institutes of Health (5U24DK132733-02)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-1479-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
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  • 6
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    165-LB: Circulating Metabolomic Biomarkers of Glycemic Control in Youth with Type 2 Diabetes (T2D)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: There are few biomarkers of glycemic response among youth with T2D, despite increasing disease prevalence and suboptimal response to approved therapies. We hypothesized that plasma metabolites may predict glycemic outcomes in youth-onset T2D. We measured 480 metabolites in fasting plasma samples in the Treatment options for T2D in Adolescents and Youth (TODAY) study (n=391), in which youth with T2D aged 10-17 years were randomized to metformin alone, metformin + rosiglitazone, or metformin + intensive lifestyle intervention. Metabolite associations with loss of glycemic control (defined as HbA1c ≥8% for 6 months or need for insulin therapy) were modeled using Cox proportional hazards regression adjusted for baseline age, sex, race/ethnicity, BMI, treatment group, and fasting glucose. Loss of glycemic control was observed in 150 of 391 youth (mean 2.6 years). Baseline levels of 11 metabolites were associated with loss of glycemic control (FDR & lt;0.05, Fig. 1A). Treatment group modified the association of hexose and xanthurenic acid levels with glycemic control. For both compounds, youth with higher baseline levels had a lower risk of treatment failure when randomized to metformin therapy alone (Fig. 1B). Thus, metabolomics provides insight into circulating analytes associated with loss of glycemic control, and may highlight different effects of specific treatments in youth with T2D. Disclosure Z. Chen: None. C. Lu: None. X. Shi: None. S. Zheng: None. D. Wolfs: None. P. Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. R. E. Gerszten: None. E. M. Isganaitis: None. Funding National Institutes of Health (K23DK127073)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-165-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 7
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    1507-P: Baseline Metabolite Profiles of Incident Type 2 Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program (DPP)
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Novel biomarkers of T2D and preventative treatment response could predict outcomes in high-risk individuals. We used Cox models to assess the association of 334 profiled metabolites in 2,019 baseline plasma samples with incident T2D after 3.2 years in a DPP substudy. We further assessed if associations out of the 334 metabolites differed by treatment (lifestyle (ILS), metformin (MET), and placebo (PLA)) and if, after stratification into concentration quartiles, the metabolite levels modified treatment effect in pair-wise treatment comparisons. We found 69 metabolites associated with incident T2D in the entire cohort (FDR-q & lt;0.05) including the novel association of cytosine, which had the lowest risk (HR of 0.77 per 1 SD, 95% CI 0.67-0.89, FDR-q 0.008). The associations of 35 metabolites differed across the three treatments (p for homogeneity & lt;0.05) and the quartiles of several of these metabolites modified treatment effects in pair-wise comparisons (Table 1). For example, individuals in higher quartiles of specific phospholipids had decreased T2D risk with ILS compared to PLA and MET, but not with MET when compared to PLA. In conclusion, we identified baseline metabolites associated with T2D risk prediction and efficacy of prevention interventions. This motivates further studies to validate interactions between biomarkers and diabetes prevention strategies. Disclosure Z. Chen: None. J. Liu: None. J. Morningstar: None. B.M. Heckman-Stoddard: None. C. Lee: None. S. Dagogo-Jack: Board Member; Self; Jana Care Inc. Consultant; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi-Aventis. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Stock/Shareholder; Self; Dance Biopharm Holdings Inc. J.F. Ferguson: None. R.F. Hamman: None. W.C. Knowler: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. J.C. Florez: None. T. Wang: None. C.B. Clish: None. M. Temprosa: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Other Relationship; Self; Merck KGaA. R.E. Gerszten: None. DPP Research Group: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-1507-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
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  • 8
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    170-LB: Obesity-Related Metabolites and Risk of Type 2 Diabetes in Chinese Adults
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: The mechanisms linking overall/central obesity with type 2 diabetes are not fully understood. In a nested case-control study of 1039 incident cases and 1039 matched controls from two prospective cohorts of Chinese adults, we measured 142 plasma metabolites using LCMS platforms. We identified and validated 28 metabolites associated with body mass index (BMI) and 34 metabolites with waist circumference (WC) in multivariable-adjusted linear models at false discovery rate & lt;0.05. Using LASSO regression, we selected 15 and 21 metabolites, respectively, to create BMI- and WC-related metabolite composite scores (MCSs), including glutamate, branched-chain amino acids, tyrosine, uric acid, dimethylguanidino valeric acid, C5-carnitine, cis-aconitic acid, and homogentisic acid (positive associations) and 1,5-anhydrosorbitol, pyruvic acid, serine, glycine, and asparagine (inverse associations). Both MCSs showed strong linear associations with diabetes risk: OR (95% CI) in the highest vs. lowest quartiles was 3.92 (1.88, 8.15) for BMI-related MCS and 7.87 (3.53, 17.53) for WC-related MCS after adjusting for diabetes risk factors including plasma glucose (both P-trend & lt;0.001). Strikingly, the MCSs showed even stronger associations with diabetes among participants with normal BMI or WC: OR (95% CI) across quartiles was 6.99 (3.97, 12.3) and 9.98 (6.11, 16.3), respectively. The MCSs mediated 50-70% of the BMI/WC-diabetes association. MCSs alone achieved similar prediction performance as traditional risk factors, including age, sex, lifestyles, diet, family history, and BMI/WC (all C-statistics~0.75). Adding MCSs to traditional risk factors and plasma glucose improved the C-statistics from 0.79 to 0.83 (P & lt;0.001). In conclusion, we identified multiple obesity-related circulating metabolites strongly associated with diabetes risk, even among individuals with normal BMI or WC. Those metabolites could explain up to 70% of obesity-related diabetes risk and further improve diabetes risk prediction. Disclosure X. Pan: None. Z. Chen: None. T. Wang: None. W. Zheng: None. R. E. Gerszten: None. X. Shu: None. D. Yu: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK108159 to T.W., X-O.S., R.E.G.), (R01DK126721 to D.Y.); National Cancer Institute (UM1CA173640 to X-O.S.), (UM1CA182910 to W.Z.)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-170-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 9
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    1476-P: Metabolomic and Genetic Diabetes Predictors in the Diabetes Prevention Program (DPP)
    American Diabetes Association ; 2024
    In:  Diabetes Vol. 73, No. Supplement_1 ( 2024-06-14)
    Details
    In: Diabetes, American Diabetes Association, Vol. 73, No. Supplement_1 ( 2024-06-14)
    Abstract: Objective: Type 2 diabetes (T2D) can be prevented, but the risk is heterogeneous even among high-risk individuals. We aimed to create a metabolite T2D risk model and evaluate its utility compared to a genetic risk score (GRS) and traditional clinical factors in 1,635 participants with available genomics and metabolomics. Methods: Predictors were picked using elastic net from 3,145 mass spectrometry measured metabolites in baseline fasting plasma. Predictive performance after 3.2 years follow-up was assessed using AUC and IDI of Cox models that included the metabolites, the 120-SNP GRS, and clinical factors. Results: The composite monosaccharide measurement of glucose/fructose/galactose and a 50 carbon:1 double bond triacylglycerol (TG 50:1) were selected and minimally increased the AUC beyond the clinical model (AUC=0.71 vs AUC=0.69, Fig1A). There was no change with the addition of the GRS (AUC=0.69). When added to FPG, TG 50:1 provided the same increase in the integrated discrimination index (IDI) as with clinical triglycerides (Fig1B), but glucose/fructose/galactose provided a significant increase in IDI beyond clinical FPG. Conclusion: Metabolites minimally improve DM prediction beyond clinical risk factors in a high-risk adult population. A glucose/fructose/galactose composite metabolite significantly improves IDI. Disclosure Z. Chen: None. R. Shu: None. M. Tripputi: None. X. Shi: None. J. Avila: None. W.C. Knowler: None. S.E. Kahn: Advisory Panel; AltPep, Boehringer-Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk A/S. B.M. Heckman-Stoddard: None. C.B. Clish: None. Q. Pan: None. J.C. Florez: Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, AstraZeneca. R.E. Gerszten: None. M. Temprosa: None. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db24-1476-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2024
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