Proteomic signatures for identification of impaired glucose tolerance

Carrasco-Zanini, Julia; Pietzner, Maik; Lindbohm, Joni V; Wheeler, Eleanor; Oerton, Erin; Kerrison, Nicola D.; Simpson, Missy; Westacott, Matthew J.; Drolet, D.; Kivimäki, Mika; Ostroff, Rachel; Williams, Stephen; Wareham, Nick; Langenberg, Claudia

doi:10.1038/s41591-022-02055-z

Cited by 25 publications

(14 citation statements)

References 62 publications

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“…However, little is known about the association of plasma GHR levels with systemic metabolism. Plasma GHR levels were recently reported to be associated with incident T2D in a large cohort study, and reductions in GHR levels were identified as a causal mediator of improvements in glycemia after bariatric surgery in adults with T2D . Prior studies showed that circulating GHR positively correlates with hepatosteatosis and adiposity in children with obesity, and we did find in our exploratory analyses that GHR level is positively associated with both BMI z score and fat mass in both sexes.…”

Section: Discussionsupporting

confidence: 62%

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Lu,

Wolfs,

El ghormli

et al. 2024

JAMA Netw Open

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ImportanceYouth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk.ObjectiveTo identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D.Design, Setting, and ParticipantsThis post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023.ExposurePlasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1).Main Outcomes and MeasuresMain outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index).ResultsThis analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P &lt; .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (β [SE], 0.015 [0.003]; P &lt; .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (β [SE], −0.02 [0.006]; P &lt; .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (β [SE], 431 [156]; P = .007).Conclusions and RelevanceThis study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk.Trial RegistrationClinicalTrials.gov Identifier: NCT00081328

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Section: Discussionsupporting

confidence: 62%

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Lu,

Wolfs,

El ghormli

et al. 2024

JAMA Netw Open

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“…Finally, the proteomic profiles of our cohort suggest our IUGR subjects are at increased risk of cardiometabolic disease. We identified some metabolic risk proteins associated with obesity (EFEMP1, TIMP1, S100A8, ITIH1, and ITIH3), type-2 diabetes/metabolic syndrome (IGFB2, FCN3, and TGFBR3), increased BMI (SERPINC1, IGFBP2, and SHBG), and glucose tolerance (GLRX and PCSK9), with a significant interaction of the growth and sex variables identified for EFEMP1, TGFBR3, and PSK9 in our significantly differentially abundant proteins in IUGR cord plasma [33][34][35][36][37][38].…”

Section: Discussionmentioning

confidence: 87%

“…Carrasco‐Zanini et al. found GLRX, SHBG, F9, and C3 to be associated with risk of impaired glucose intolerance [38].…”

Section: Discussionmentioning

confidence: 99%

Human cord plasma proteomic analysis reveals sexually dimorphic proteins associated with intrauterine growth restriction

Akinyemi,

Du,

Aguilan

et al. 2023

Proteomics

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Intrauterine growth restriction (IUGR) is associated with increased risk of cardiometabolic disease later in life and has been shown to affect female and male offspring differently, but the mechanisms remain unclear. The purpose of this study was to identify proteomic differences and metabolic risk markers in IUGR male and female neonates when compared to appropriate for gestational age (AGA) babies that will provide a better understanding of IUGR pathogenesis and its associated risks. Our results revealed alterations in IUGR cord plasma proteomes with most of the differentially abundant proteins implicated in peroxisome pathways. This effect was evident in females but not in males. Furthermore, we observed that catalase activity, a peroxisomal enzyme, was significantly increased in females (p < 0.05) but unchanged in males. Finally, we identified risk proteins associated with obesity, type‐2 diabetes, and glucose intolerance such as EGF containing fibulin extracellular matrix protein 1 (EFEMP1), proprotein convertase subtilisin/kexin type 9 (PCSK9) and transforming growth factor beta receptor 3 (TGFBR3) proteins unique to females while coagulation factor IX (C9) and retinol binding protein 4 (RBP4) are unique in males. In conclusion, IUGR may display sexual dimorphism which may be associated with differences in lifelong risk for cardiometabolic disease between males and females.

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“…Genes exhibiting an FDR-corrected MAGMA P < 0.05 were considered to be significant. Finally, for genomic loci reaching at least a suggestive level of significance in the GWAS ( P < 5 × 10 −5 ), we performed SMR and HEIDI tests (v.1.02) 63 using blood gene expression level data from the eQTLGen study 64 and blood protein level data from the Fenland study 65 . For both datasets, we considered expression of a gene to be influenced by the same genomic variation as that seen in the LOY GWAS if the FDR-corrected P value for the SMR test was P < 0.05 and the P value for the HEIDI test was P > 0.01.…”

Section: Methodsmentioning

confidence: 99%

Genetic determinants of micronucleus formation in vivo

Adams,

Barlas,

McIntyre

et al. 2024

Nature

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Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR–Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

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Proteomic signatures for identification of impaired glucose tolerance

Cited by 25 publications

References 62 publications

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Human cord plasma proteomic analysis reveals sexually dimorphic proteins associated with intrauterine growth restriction

Genetic determinants of micronucleus formation in vivo

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