Novel protein biomarkers of youth-onset type 2 diabetes

The effective treatment of youth-onset type 2 diabetes (YOT2D), with rising rates and an aggressive disease course that causes morbidity and mortality in young adulthood, is a healthcare priority. Our ability to develop treatments, however, is limited by our incomplete understanding of what drives this rapid progression. Proteomics has emerged as an innovative method for adult-onset type 2 diabetes (T2D) biomarker identification that can elucidate biological pathways contributing to disease or that can be affected by it, but it has not been widely used to study youths. We propose to complete comprehensive proteomics profiling on plasma obtained at multiple timepoints from a cohort of youths with T2D and integrative analyses with existing genetic data to identify novel circulating biomarkers of YOT2D. We will compare these to findings in adults with T2D to identify age-specific determinants of disease progression. Identified proteins have the potential to serve as prognostic markers and therapeutic targets to improve YOT2D outcomes. We will conduct proteomics profiling using a multi-plex oligonucleotide-conjugated antibody-based platform that measures >5,000 proteins. Samples will be from multi-ethnic participants of the Treatment Options for T2D in Adolescents and Youths (TODAY) which was a randomized control trial of YOT2D treatments, and its follow-up observational study (TODAY2); one of two seminal YOT2D cohorts. Participants were aged 10-17 at enrollment; had a mean 10 years of follow-up; and were deeply phenotyped including with repeated oral glucose tolerance tests (OGTTs) and genotyping. We will compare our findings to adults with T2D (mean baseline age 59 and mean 18 years follow-up) from the Multi-ethnic Study of Atherosclerosis (MESA) with T2D complication, genotyping, and similarly profiled proteomics data at multiple timepoints. We will identify novel proteomic biomarkers of beta-cell function (using measures derived from the OGTT) and YOT2D progression (defined by sustained elevations in glycemia and the development of micro- and macrovascular complications) that were measured at a single timepoint (Aim 1) and longitudinally (Aim 2) using regression and survival models in TODAY. We will then compare with results in adults with T2D from MESA. We hypothesize that differences will be enriched for biomarkers of beta-cell function in youths since rapid beta-cell loss appears to be a unique feature of YOT2D. We will also assess the predictive potential of these protein biomarkers. In Aim 3 we will identify protein-associated genetic loci and use Mendelian Randomization and colocalization experiments to determine if these protein associations may be causal. We will also compare the predictive performance of polygenic and proteomic risk scores (derived in both youths and adults) of T2D progression in TODAY. This proposal will identify youth-specific protein biomarkers of T2D that have the potential to catalyze our understanding of the drivers of this unique T2D phenotype and inform future studies targeting these biomarkers and pathways as effective treatment strategies. Project Number: 1R01HL181500-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Zsu-Zsu Chen | Institution: BETH ISRAEL DEACONESS MEDICAL CENTER, BOSTON, MA | Award Amount: $693,964 | Activity Code: R01 | Study Section: Kidney Endocrine and Digestive Disorders Study Section[KEDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18150001