Youth-Onset Type 2 Diabetes and Heart Disease: The Young at Heart Prospective Cohort Study

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet the following criteria according to their group:

Four categories of participants will be included in this study and the inclusion criteria for each group are given below:

• Participants with Y-T2DM

1a.Age 12-25 years

1b.Type 2 diabetes mellitus as defined by fasting blood glucose >= 126 mg/dL OR postprandial blood sugar >= 200 mg/dL OR Hemoglobin A1c >= 6.5% per American Diabetes Association Criteria and one element from the medical history consistent with ADA or AAP guidelines including: family history of diabetes and obesity, maternal or personal history of gestational diabetes, high-risk race and ethnicity, history of cardiovascular disease, hypertension, dyslipidemia, polycystic ovary syndrome, physical inactivity, other clinical conditions associated with insulin resistance (e.g. severe obesity, acanthosis nigricans, prediabetes), small or large for gestational age birth weight, history of breastfeeding, gestational history of illicit drugs including alcohol, smoking OR documentation of type 2 diabetes diagnosed at \<=25 years of age with verified medical history (as above).

• Youth with overweight/ obesity (Y-OW)

2a. Age 12-25 years

2b. For participants \< 18 years of age, BMI >= 85th percentile (overweight) and >= 95th percentile (obesity) for age and sex OR

2c. For participants >= 18 years of age, BMI >=25\<30 kg/m\^2 (overweight) or >=30 kg/m\^2 (obesity)

2d. Participants with obesity may have a diagnosis of prediabetes, defined as fasting blood glucose 100-125 mg/dL OR postprandial blood sugar 140-199 mg/dL OR HbA1c 5.7-6.4 percent (either during testing at NIH or as previously documented on outside medical record).

• Healthy control lean participants (Y-Lean)

3a. Age 12-25 years

3b. For participants \< 18 years of age, BMI \<= 85th percentile for age and sex OR

3c. For participants >=18 years of age, BMI 18-24.99 kg/m\^2.

3d. HbA1c \<5.7 percent (either during testing at NIH or as previously documented on outside medical record).

• Biological parents of Y-T2DM, Y-OW and Y-Lean participants

4a. Biological parent of enrolled Y-T2DM, Y-OW and Y-Lean by self-report.

EXCLUSION CRITERIA

An individual who meets any of the following criteria for their specific group will be excluded from participation in this study:

• Y-T2DM, Y-OW and Y-Lean Participants:

1a. Type 1 diabetes or the presence of >2 diabetes auto-antibodies (e.g., GAD-65, IA-2 antigen, Zinc transporter 8 autoantibodies).

• b. Medical, psychiatric or cognitive disorders that will, in the opinion of the investigators, limit the subject s ability to comply with study procedures (specific obesity-related comorbidities are explicitly permitted, including hypertension, hyperlipidemia, obstructive sleep apnea and non-alcoholic steatohepatitis).

1c. Serious medical illnesses or diseases thought to alter metabolism (including moderate to severe renal disease (\< 30 mL/min/1.73m\^2), congenital heart disease, Cushing s syndrome, cancer, or other metabolic diseases associated with diabetes or excess weight).

1d. For participants enrolled at the NIH, dietary allergies, intolerances or eating patterns that would preclude them from consuming metabolic meals.

1e. Unwilling to comply with all study procedures or to adhere to Lifestyle Considerations throughout study duration.

1f. Pregnancy at the time of the screening visit.

1g. Clinically significant anemia OR Hematocrit below the lower limit of normal for age and sex cutoffs.

• h. For Y-OW Participants- Meet lab and medical history criteria for Y-T2DM as described in inclusion criterion 1b above.

• Y-Lean participants:

In addition to the above exclusion criteria, any Y-Lean participant who meets any of the following additional criteria will be excluded from the study:

2a. Current use of prescription or non-prescription medication. Certain exceptions are permitted, including topical medications, vitamins, and hormonal contraceptives. Other medications may be permitted at the discretion of the investigators.

2b. Recent (past 2 months) use of drugs or supplements that alter glucose or lipid metabolism (e.g., niacin, fish oil, red yeast rice)

2c. History of diabetes or abnormal glucose tolerance

2d.. Abnormal screening labs, including the following:

i) ALT or AST >2 times the upper limit of normal

ii) Glycosuria

iii) Low eGFR (\<90 mL/min/1.73m\^2)Any other abnormality that, in the opinion of the investigator, will increase risk to the subject from participation, or interfere with interpretation of study data

2e. Meet lab and medical history criteria for Y-T2DM as described in inclusion criterion 1b above.

• Biological Parents

-No Exclusion Criteria