Title: Therapeutic Targets in African-American Youth With Type 2 Diabetes

Type 2 Diabetes in youth is an emerging public health concern that disproportionately affects
minority children. Among minority youth, African-Americans have the highest complication
rates, yet the reasons underlying this health disparity are not fully understood.
Furthermore, current treatment options are limited and African-American youth have high
treatment failure rates. Metformin therapy is the only oral diabetes drug approved for use in
youth with type 2 diabetes. However, metformin works less than 50% of the time in
African-American youth and there is marked variability among individuals. Improving outcomes
in youth requires understanding the way that drugs such as metformin work in youth and why it
does not work in some individuals. New evidence suggests that the ability of metformin to
work effectively may be influenced by certain genes or differences in gut bacteria. However,
little is known about how genes or gut bacteria may affect youth, especially
African-Americans.

To treat this aggressive disease, it is also necessary to simultaneously evaluate new
therapeutic options, such as combination therapy of metformin with liraglutide in youth at
highest risk for complications. Liraglutide is approved to treat diabetes in adults but is
not yet approved in children. Liraglutide may be a useful early treatment in youth with type
2 diabetes because it may decrease glucose produced by the liver (an early prominent feature
of type 2 diabetes in youth). This study is designed to examine the mechanism of action in
the liver of these 2 agents and explore how genetic and gut factors may influence this
action.

The primary objective of this pilot study is to compare the ability of two anti-diabetic
regimens (metformin and liraglutide versus metformin alone) to lower gluconeogenesis (glucose
produced by the liver) in African-American youth with type 2 diabetes. The secondary
objectives are to evaluate the effect of these regimens on the following: (1) hepatic glucose
production, and insulin sensitivity and (2) insulin and gut hormones concentrations (e.g.
incretins). In addition, we will examine the relationship of known differences in genes
associated with metformin transport and action with changes in gluconeogenesis and begin to
explore the role of gut bacteria to metformin s glucose-lowering effect.

The study design is a parallel-randomized intervention trial of African-American youth with
type 2 diabetes who are not on insulin therapy and who are within 3 years of diagnosis.
Patients aged 12-21 years with type 2 diabetes will be enrolled. Participants will be
randomized into two intervention arms (16 in each group): metformin and liraglutide versus
metformin alone. The study will consist of 5 visits. At Visit 1, a medical history, physical
examination and screening labs will be done. Then the eligible participants will undergo a
one-week drug-free run-in. At Visit 2 there will be an overnight inpatient stay to perform
metabolic testing prior to starting the study drug(s). Participants will start the study
drug(s) immediately after Visit 2 and remain on the study drug(s) for 12 weeks. Follow-up
monitoring will be performed at 4 week intervals (Visit 3 and 4). The final visit (Visit 5)
will occur after 12 weeks.

The ultimate goal of this project is to begin to address diabetes disparities in
African-American youth by understanding the mechanism of action of these diabetes agents to
inform precision medicine initiatives. This project brings together the skills and expertise
of investigators within the National Institute of Diabetes and Digestive Disorders and Kidney
Diseases (NIDDK), the National Human Genome Research Institute (NHGRI) and the Children s
National Medical Center (CNMC).

- INCLUSION CRITERIA:

1. Youth must self-identify as African-American and identify both parents as
African-American

2. Age 12-21 years

3. Pubertal or post-pubertal: Girls Tanner stage IV-V breast; Boys Testicular volume
11-25cc

4. Diagnosis of type 2 diabetes of <3 years duration

5. Hemoglobin A1C <9% at study initiation

6. Negative to mild ketonuria without acidosis (negative or 1+ ketones on
urinalysis)

7. Negative test for diabetes-related autoantibodies (glutamic acid decarboxylase 65
and tyrosine phosphataserelated islet antigen 2 (IA-2))

8. Willing and able to take daily medications and check blood glucose levels at
least twice per day

EXCLUSION CRITERIA:

1. Pregnancy or breastfeeding

2. Allergy to study medications

3. Allergy to milk protein

4. Chronic insulin therapy

5. Treatment with other medications which are known to affect the parameters under study

6. Metabolic derangement such as metabolic acidosis, severe hyperglycemia (fasting blood
glucose greater than or equal to 200mg/dL), and/or liver enzymes > three times the
upper limit of normal.

7. Personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia
syndrome type 2

8. Any other condition that, in the opinion of the investigators, will increase risk to
the subject, or impede the accurate collection of study-related data.

9. Body weight greater than or equal to 450 lbs

10. Body weight less than or equal to 58kg

11. Serum triglyceride concentrations greater than or equal to 500mg/dl

12. Hemoglobin concentration <11g/dL