Understanding and Targeting the Pathophysiology of Youth-onset Type2 Diabetes

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Type 2 diabetes (T2D) in childhood has an aggressive etiology, with substantial short- and long-term health complications and medical costs. There is an urgent need to: 1) identify children and adolescents at highest risk; 2) identify modifiable contributing factors; 3) understand the underlying pathophysiology; and, 4) determine how these factors vary across sex and race/ethnicity. A comprehensive and holistic understanding of these issues is required to develop models that can identify individual factors and susceptible time windows for T2D conversion and requires a nationwide effort and multidisciplinary consortium. We propose to serve as 1 of the 15 Clinical Centers operating within the proposed NIDDK consortium that will recruit and track a national cohort of children (estimate = 3,750) representing the diversity of the pediatric population at risk for T2D. Our multidisciplinary team has extensive expertise in longitudinal studies of obesity and diabetes in children, including an NIDDK-funded 15-year longitudinal study (R01 DK 59211; PI: Goran) that followed a cohort of 300 Latino children at risk for T2D, resulting in almost 100 publications. From this and other prior studies, we have identified the need for a larger and more diverse cohort, incorporation of environmental exposures, and inclusion of comprehensive nutritional, metabolic, and social determinants. At our site, we will recruit 250 participants with obesity and family history of T2D with bi-annual assessments. We will work with stakeholders and other consortium sites to optimize recruitment and retention. We propose three complementary approaches to assess the metabolic basis of T2D: insulin secretion, clearance, and β-cell function from an oral glucose tolerance test with frequent sampling; hemoglobin A1c, and percent time in range from continuous glucose monitoring. We will monitor metabolic and environmental factors by measuring: 1) total body fat, visceral and subcutaneous abdominal adipose tissue, and liver and pancreatic fat by DEXA and MRI; 2) biochemical markers (free fatty acids, sex steroids, lipids, inflammatory profiles, incretins, and liver enzymes); 3) lifestyle (diet, sleep, and physical activity); 4) exposure to endocrine-disrupting chemicals and air pollution; 5) social determinants of health. In addition, we propose collection of biological samples (eg DNA, stool, saliva) to create a biobank for future investigation. We will work with the consortium to develop a unified protocol and harmonized outcome measures. We hypothesize: 1) Children who develop T2D will have a greater pubertal decline in β-cell function, and decreased glucose time-in-range, which will be associated with greater increase in overall adiposity and liver fat, compared to children who do not develop T2D, and that these relationships will differ across sex and ethnicity; and, 2) High dietary sugar, limited access to healthy foods, and higher exposure to perfluoroalkyl substances and/or air pollutants will also be associated with risk of T2D. Through harnessing the power of this consortium, we also propose development of a structured risk score analysis to characterize different endotypes, exposures and risk factors that predict progression to T2D during pubertal development.