For several decades, extensive research has endeavored to uncover the underlying mechanisms of type 1 diabetes (T1D) across various age groups, though the complexity of this autoimmune disorder continues to obscure full understanding. T1D, which involves the immune-mediated destruction of pancreatic beta cells and consequent disruption of insulin production and glucose metabolism, remains one of the most prevalent chronic conditions globally. Its incidence continues to increase, with Qatar currently ranking fourth worldwide in T1D prevalence. Recently, obesity, referred to as "diabesity" when occurring alongside T1D, has emerged with increasing prevalence among children with T1D, further complicating disease management. T1D is widely acknowledged as a multifactorial condition, influenced by genetic, epigenetic, environmental. Diet being one of the major factors contributing to the management of these two phenotypes. This study aims to elucidate biomarkers and dietary factors distinguishing T1D-Obese from T1D-Lean children in Qatar, leveraging multi-omics analyses including microbiome profiling, gene expression, DNA methylation, and metabolic profiling. We recruited 176 children from Sidra Medicine, categorized into T1D (n=98), Obese (n=30), T1D-Obese (n=28), and healthy controls (n=20), collecting blood, urine, stool samples, and 24-hour dietary recalls. Dietary intake was quantified using Nutritionist Pro software, gut microbiome taxonomy was assessed via 16S rRNA sequencing on Illumina Miseq, transcriptomics by RNA sequencing on the Illumina Novaseq 6000 system, DNA methylation through Illumina Infinium MethylationEPIC arrays, and urine metabolites with untargeted Gas Chromatography-Mass Spectrometry. Integrative analysis was conducted using the mixOmics package in R, followed by network analysis to elucidate nutrient-omics interactions. Our findings indicate outstanding differences in dietary consumption and gut microbiota diversity across groups, identifying unique bacterial species potentially serving as biomarkers for T1D and diabesity.
Epigenetic analysis demonstrated that hypermethylation of ZFP57 was common across T1D, T1D-Obese, and Obese groups, while hypermethylation of HLA-DBR1 and HOOK2 was specific to T1D and T1D-Obese, respectively suggesting a distinct role in two phenotypes. Differential gene expression analysis confirmed the affected expression (downregulation) of HLA-DQB, ZFP57 and several genes (e.g., C4BPA, MMP9, and FSTL1) associated with T1D pathogenesis and diabesity. Urine metabolomics revealed metabolic distinctions between diabetic and non-diabetic subjects (e.g., Neu5Ac), and between T1D-Obese and Obese or T1D groups (e.g., Saccharopine). The methylation patterns interacted with dietary intake, gut microbiota composition, gene expression, and urine metabolites. Epigenetic modifications, despite their heritable nature, remain reversible, positioning them as promising therapeutic targets. As this is the first comprehensive multi-omics investigation in this population, our study presents novel biomarkers that differentiate T1D and T1D-Obese in children. These findings support the potential of nutrition-based interventions tailored to Qatar's population, warranting further research for validation and broader application within clinical care pathways.
| Date of Award | 2024 |
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| Original language | American English |
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| Awarding Institution | - HBKU College of Health & Life Sciences
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