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 type 2 diabetes in patient 10 years and older as an adjunct to diet and exercise. 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 5 years of diagnosis. Patients aged 12- 25 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 multi-site 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). Patient recruitment and data collection will occur at NIH Clinical Center. Eligible patients may be identified through CNMC but no enrollment, informed consent or study visits will occur at CNMC.

• INCLUSION CRITERIA:

• Youth must self-identify as African-American and identify both parents as African-American
• Age 12-25 years
• Pubertal or post-pubertal: Girls Tanner stage IV-V breast; Boys Testicular volume 11-25cc
• Diagnosis of type 2 diabetes of less than or equal to 5 years duration, as per American Diabetes Association Criteria
• Hemoglobin A1C <9% at study initiation
• Negative to mild ketonuria without acidosis (negative or 1+ ketones on urinalysis)
• Negative test for diabetes-related autoantibodies (glutamic acid decarboxylase 65 and tyrosine phosphatase-related islet antigen 2 (IA-2))
• Willing and able to take daily medications and check blood glucose levels at least twice per day or wear a continuous glucose monitoring device (CGM).

Exclusion criteria

• Pregnancy or breastfeeding
• Allergy to study medications
• Allergy to milk protein
• Chronic insulin therapy
• Treatment with other medications which are known to affect the parameters under study (for example sodium glucose transporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-IV) inhibitors, non-selective beta blockers).
• 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.
• Personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2
• 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.
• Body weight greater than or equal to 450 lbs
• Body weight less than or equal to 58kg
• Serum triglyceride concentrations greater than or equal to 500mg/dl
• Hemoglobin concentration <10g/dL