Project Summary / Abstract
Rising obesity has led to an unprecedented increase in pre-diabetes (preD) and type 2 diabetes (T2D) incidence
in children and adolescents, a worrisome trend amplified by the COVID 19 pandemic. Based on current evidence,
it remains difficult to predict whether children and adolescents with preD will progress to T2D. Our proposal aims
to address key questions in the pathogenesis of T2D, focusing on modifiable risk factors. Leveraging a
collaboration between Boston Children’s Hospital, Joslin Diabetes Center, and Massachusetts General Hospital,
in partnership with community health centers in the Greater Boston area, we propose to recruit a diverse cohort
of early pubertal youth (ages 7-15, n=300) with preD, elevated BMI (=95th percentile), a positive family history of
diabetes, and one or more additional risk factors. We propose to combine rigorous annual clinical studies with
convenient remote assessments, to gain a granular understanding of metabolic, hormonal and environmental
factors contributing to T2D pathogenesis. In Aim 1, we will test whether measures of glucose homeostasis and
beta cell function differ between youth with preD who progress to T2D versus those who revert to normoglycemia
or remain preD. We propose to analyze glycemia and beta cell function using oral GTT and incretin hormone
levels, and assessments adaptable to community settings, e.g., continuous glucose monitors and home A1c kits.
In Aim 2, we will test whether fitness level and amount of physical activity differ between youth with preD who
progress to T2D versus those who revert to normoglycemia or remain preD. We propose to evaluate fitness level
using detailed clinical assessments, including VO2 max, assessments adaptable to community settings including
grip strength, and free-living assessments using wearables and app-based activity tracking. In Aim 3, we will test
whether evolution of body composition during growth and puberty predicts progression to T2D. We propose to
analyze body composition (total and visceral fat) using DXA, and hepatic fat using echography-based
assessments, gonadal hormones, adrenal androgens, and mediators of growth hormone action, as well as
assessments adaptable to community settings, e.g., BMI and app-based dietary surveys. As secondary aims,
we propose to create a data repository to allow evaluation of social and environmental factors contributing to
T2D onset at a consortium level, with measures including social determinants of health, neighborhood and
geographic characteristics (using geocoding techniques), and the environmental exposome. We also propose
the creation of a biological repository to allow multi-omics studies to identify genomic, epigenetic, and/or
metabolomic markers for progression from preD to T2D in youth at a consortium level. We propose to collect a
rich biorepository of longitudinal samples (i.e., plasma, PBMCs, urine, stool, hair) from all participants that will
set the stage for future systems biology-driven studies. Together, these studies will permit development of a
predictive model based on variables easily measurable at the community level, which can then be applied to the
detection and treatment of youth at highest risk of T2D.
