Novel Biomarker for Development of T2D

The overarching hypothesis is that increases in whole body 11β-HSD1 activity precede and presage the development of type 2 diabetes (T2D) in high-risk obese adolescents, serving as a critical determinant of insulin resistance and glucose intolerance. The increase in 11β-HSD1 activity, in combination with decreases in 5α-reductase activity, will increase tissue cortisol production, promoting the development of insulin resistance and the metabolic syndrome and predisposing to T2D. The investigators predict that increases in 11β-HSD1 activity will be detected in obese children prior to the development of insulin resistance and glucose intolerance and that the progressive increases in 11β-HSD1 will correlate with progressive decreases in insulin sensitivity and glucose tolerance. Given preliminary findings, the investigators also predict that increases in 11β-HSD1 will be greater and occur earlier in development in males than females. This could establish 11β-HSD1 activity as a novel, non-invasive biomarker for progression to, or for development of, glucose intolerance and T2D.

The identification of 11β-HSD1 as a biomarker that predicts T2D would have critical clinical import, allowing us to identify obese children and adults at highest risk of metabolic decompensation. Studies of 11β-HSD1 in obese subjects with varying degrees of IR and glucose intolerance will also narrow critical gaps in the understanding of the pathogenesis of T2D.

The investigators would like to also validate if urine metabolomic profiling can be used for identifying key metabolomic signatures associated with insulin resistance. To that end the investigators would like to examine detailed metabolomic profiles in 24 hour and spot urine samples.

The study population will include 50 obese adolescents with T2D, 50 obese adolescents without T2D and 50 age, gender, race and pubertal status-matched normal weight controls. The subjects will be recruited at the Healthy Lifestyle Program at Duke, Diabetes Clinics at Lenox Baker Children's Hospital and Roxboro Clinics.

Study activities include physical exam and medical history, vitals, laboratory tests (only for obese adolescents), urine testing for sugar (only for normal weight adolescents), 24 hour urine collection, spot urine collection, body fat content measurement, and food and activity questionnaire.

Inclusion criteria

• Obese/Overweight adolescents/young adults without T2D who are having their first visit to the Healthy Lifestyle Program at Duke or Obese/Overweight adolescents/young adults without T2D recruited from the community at PBRC
• Obese/Overweight adolescents/young adults with prediabetes (HbA1c between 5.7-6.4%) and T2D (HbA1c≥6.5%)followed at Diabetes Clinics or recruited from the community at PBRC
• Age, gender, race and pubertal status matched normal weight adolescents presenting for "well child check" at Roxboro Clinics
• ≥12 to 21 (inclusive) years of age for urine studies
• 18-21 years of age obese adolescents/young adults without T2D and age, gender, race and pubertal status matched normal weight controls for OGTT sub-study
• Both the subject and one parent/guardian present will need to be able to speak and read English

Exclusion criteria

• Currently or within the past month taken systemic or inhaled corticosteroids, antipsychotics, medications for weight loss, topiramate, acute use of contraceptives (less than 3 months) or medroxy-progesterone acetate, medications to treat ADHD
• Children with any genetic syndrome
• Children with decompensated hypothyroidism (treated with levothyroxine and a TSH >10 µIU/mL )
• Normal weight children (BMI percentile 5%-<85%) with glucosuria, as defined by a positive urine glucose dip stick test
• Children and young adults who self report that they are pregnant (pregnancy is excluded in both the main and sub-study)
• Proteinuria, as defined by protein level equal to or above 300 mg/dl (+++) on a urine dip stick test.