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:

1. Obese/Overweight adolescents without T2D who are having their first visit to the
Healthy Lifestyle Program at Duke

2. Obese/Overweight adolescents with T2D followed at Diabetes Clinics at Lenox Baker
Children's Hospital

3. Age, gender, race and pubertal status matched normal weight adolescents presenting for
"well child check" at Roxboro Clinics

4. ≥12 to 18 (inclusive) years of age

5. Both the subject and one parent/guardian present will need to be able to speak and
read English

Exclusion Criteria:

1. Currently or within the past month taken systemic corticosteroids, antipsychotics,
medications for weight loss, topiramate, oral contraceptives or medroxy-progesterone
acetate

2. Children with genetic syndrome causing obesity

3. Children with decompensated hypothyroidism

4. Normal weight children with glucosuria as this might indicate undiagnosed diabetes

5. Children that are pregnant