Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes- NYU Clinical Center

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Abstract: Youth-onset type 2 diabetes (T2D) in the United States is increasing in prevalence (e.g. 4.8% per year between 2002 and 2015, and its phenotype is distinct from adult-onset T2DM in that it is accompanied by a greater degree of insulin resistance, more rapid deterioration of β-cell function, and earlier onset of life- threatening complications. These findings suggest the personal and societal costs of youth-onset T2D will be substantially greater than in adult-onset disease. The reasons for the more severe phenotype of youth-onset T2D are unclear and require further investigation. In order to develop therapeutic targets to delay, decrease the severity of, or prevent T2DM in youth, a more accurate predictive model is needed. This can only be determined through a prospective cohort study of youth at high risk for T2DM to identify characteristics or biomarkers of who progresses most rapidly. This will allow us to evaluate putative risk factors including: genetic factors, psychosocial and environmental factors, inflammation, and other sources of beta cell failure. Soluble receptors of Advanced Glycation End Products (sRAGE) have been associated with insulin resistance and β-cell dysfunction in adults with T2D. However, the AGE/RAGE axis has not been well researched in youth-onset T2D. Its potential role in the more rapid β-cell failure and increased rate of complications characteristic of youth-onset T2D warrants investigation. There is also mounting evidence of an association between exposure to metabolism disrupting chemicals (MDC) and obesity, insulin resistance, and β-cell dysfunction. Of note, MDC exposures disproportionately affect certain populations, including Black, Latinx, and low-income communities, mirroring the populations most affected by T2D. Non-chemical environmental exposures and psychosocial functioning also modify disease risk, including the built environment, social environment, and lifestyle/food environment. We propose to use remote data collection and ecological assessments as novel ways to track environmental exposures. We propose that the interaction of these internal and external exposures is responsible for the development of youth-onset T2D.The NYU Clinical Center team brings considerable expertise in engaging children and their families in longitudinal studies, scientific and clinical expertise to develop the final protocol, and a process for stakeholder engagement, used to develop our proposal, and which can be utilized in finalizing the study protocol. NYU Langone Health is an integrated system that will use its main hospitals and practices with a diverse group of over 11,500 youth with a BMI >95th %ile between the ages of 7-14 in our care to screen for this study. We will collaborate with the Consortium and key stakeholders to design and implement the study protocol; and suggest novel targets for evaluation, such as the AGE/RAGE axis, in the context of other factors including: social determinants of health, physical activity, food choices, depression, and MDC exposures on the progression of insulin resistance, β-cell failure, and the development of youth-onset T2D.