Wednesday, January 15, 2025
1/15/2025
ABSTRACT While obesity, ancestry, family history of diabetes, insulin resistance, and puberty are all risk factors for pediatric-onset type 2 diabetes (T2D), identifying the subset of youth at greatest risk of advancing from “prediabetes” to T2D and the mechanisms underlying the deterioration remain elusive. This lack of specificity defies the medical community's ability to 1) direct care to the youth at greatest risk of pediatric onset T2D and 2) develop targeted interventions. The particularly aggressive nature of pediatric T2D and the unique hormonal milieu of the adolescent suggest while the mechanisms underlying adult-onset T2D in adults resonate in pediatric T2D, additional perturbances are operative. Our team proposes to collaborate in a multi-center study, informed by partnerships with family and community members, to define clinically accessible metrics of increased diabetes risk as well as potential mechanisms that compromise the normal adaptations to insulin resistance during adolescence. We propose a longitudinal study leveraging a 3-hour, multi-sample oral glucose tolerance test performed at baseline, 18-months, and 36-months in obese pubertal youth with pre-diabetes to 1) test the utility of the one-hour glucose in predicting T2D and deterioration in insulin secretion, 2) perform extensive phenotyping for testing the relationships of changes in insulin secretion (early phase and second phase), insulin sensitivity, incretin secretion, glucagon suppression, hepatic glucose clearance, and free fatty flux with emergence of T2D. The contributions of genetic variants, in utero environment, visceral adipose accumulation, eating behaviors, mental health issues, social determinants of health, diet, physical activity, sleep and COVID infection to perturbances in insulin secretion and sensitivity will be tested. Home health care workers will provide additional critical insight into the home environment. Glucose-potentiated arginine stimulation tests will be conducted in subsets of participants in whom glucose homeostasis is preserved, worsens, or advances to T2D. This study is anticipated to specify useful indicators of T2D risk and advance our understanding of the underpinnings of progressive defects in insulin secretion and sensitivity to inform individualized programs aimed at interrupting emergence of T2D.
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