DISCOVERY of Risk Factors for Type 2 Diabetes in Youth

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.

Eligibility Criteria:
Inclusion Criteria:

Screening will occur to enrich the yield of individuals who are highly predisposed to develop youth-onset type 2 diabetes and include those with all of the criteria in Category A:

* Overweight or obesity with BMI ≥85th percentile
* Age 9-13 year for girls, 10-14 year for boys (inclusion younger for girls as puberty tends to start a year earlier in girls)
* Tanner Stage 2 or 3 or Tanner Stage 4 (without initiation of menses for Tanner 4 girls)
* Elevated HbA1c 5.5-6.4%

Participants who meet all of these categories will further need to meet at least one criterion in Category B:

* Family history of type 2 diabetes in 1st or 2nd degree relative
* Personal exposure to maternal diabetes (i.e., gestational diabetes mellitus (GDM) or mother with type 1 or type 2 diabetes while pregnant with participant)
* HbA1c \>6.0%
* Severe obesity (BMI \>99th percentile)
* Personal history of intrauterine growth restriction (IUGR), small for gestational age (SGA), or low birth weight

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 (transplant, cancer, Down Syndrome, Turner Syndrome, Klinefelter Syndrome, ovarian/testicular failure, etc.)
* Medications affecting glucose dynamics during the screening and enrollment period (oral steroids, inhaled steroids \>1,000mcg/day past month, atypical antipsychotics, topiramate)
* 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
* 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