The goal of the DISCOVERY study is to provide innovative critical information regarding the unique natural history of glycemic control, insulin sensitivity, and β-cell function, and their mechanistic determinates, in obese adolescents at risk for developing type 2 diabetes.

The DISCOVERY study will extensively phenotype a large cohort of youth at-risk for type 2 diabetes, as they transition through puberty, and characterize the course of dysfunction in pathophysiological indicators that lead to type 2 diabetes. The knowledge gained from this study of the pathophysiology and epidemiology of youth-onset type 2 diabetes with deep biochemical, clinical, and psychosocial phenotyping will critically inform the design and testing of future treatment and prevention approaches.

Inclusion Criteria:

Screening will occur to enrich the yield of individuals who are highly predisposed to develop youth-onset T2D and include those with all of the following criteria:

• Overweight or obesity with BMI ≥85th percentile
• Age 8-13 year for girls, 9-15 year for boys (inclusion younger for girls as puberty tends to start a year earlier in girls)
• Tanner Stage 2, 3, or 4
• Elevated HbA1c 5.5-6.4%

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation:

• Diabetes based on history, or HbA1c ≥6.5% in the medical record or at screening
• Unable/unwilling to provide consent/participate fully
• Conditions predisposing to diabetes or altering the trajectory of puberty
• Medications affecting glucose dynamics during the screening and enrollment period
• Prior treatment with insulin
• Use of glucagon-like peptide-1 (GLP-1) receptor agonist or any weight loss medications in the 6 weeks prior to enrollment
• Planning treatment with glucagon-like peptide-1 (GLP-1) receptor agonist or any weight loss medications
• Use of metformin or any glucose lowering medication for a reason other than treatment of diabetes (e.g., for PCOS) in the 6 weeks prior to enrollment
• Planning treatment with metformin or any glucose lowering medication or planning to use such medications for a reason other than treatment of diabetes (e.g., for PCOS)
• Known syndromic/monogenic obesity
• Blood disorders impacting HbA1c (e.g., anemia, hemoglobin variants)
• Major systemic organ disease
• History of bariatric surgery or currently planning bariatric surgery
• Current pregnancy or currently planning pregnancy
• Use of GnRH agonist, estrogen, or testosterone
• Individuals who do not speak English or Spanish, given validation of the questionnaires to be utilized

3,600 youth, aged 8-15 years at enrollment, of all genders and race/ethnic groups from 15 clinical centers in the United States will be included. Youth will be overweight or obese (BMI ≥85th percentile for age) and have evidence of dysglycemia with an HbA1c range from 5.5-6.4% at screening.