Prebiotics and Metformin Improve Gut and Hormones in Type 2 Diabetes in Youth (MIGHTY-fiber)

Metformin is the most widely prescribed anti-diabetes medication in the world and the first-line therapy for treating type 2 diabetes (T2D) in youth and adults. However, metformin s glucose-lowering ability is variable in clinical practice, and efficacy is further limited by poor medication adherence because of metformin-associated adverse effects. Gastrointestinal (GI) symptoms such as bloating, abdominal discomfort, cramping, and diarrhea are the most common side effects associated with metformin use occurring in up to 80% of individuals at drug initiation and up to 30% in individuals on chronic treatment. In youth with type 2 diabetes, the burden of metformin-associated side effects is high because metformin is the only oral FDA-approved for treatment and there are no other oral alternatives. Therefore, identifying ways to mitigate these GI side effects, especially in youth with type 2 diabetes, is of high clinical significance. New data suggest that metformin-induced changes in the gut and/ or the microbiome may be related to both its beneficial (glucose-lowering) and adverse effects. To address this clinical challenge, prebiotic fibers that are non-digestible food ingredients, may help to improve metformin tolerability by increasing beneficial bacteria and stool metabolites, such as short chain fatty acid (SCFA) stool concentrations. This pilot study will test the hypothesis that a prebiotic microbiome modulator (MM) - containing prebiotic fibers and polyphenols - will reduce GI side effects of metformin at time of initiation and change the stool metabolite profile in youth and young adults with T2D treated with metformin, age 10-25 years who are not on insulin therapy. The 9-week study will have 2 phases and 6 outpatient visits at the NIH Clinical Center. Phase 1 is a 5-week randomized double blind cross-over trial with two 1-week intervention periods (metformin + prebiotic and metformin + placebo) during which subjects will eat a standardized diet. Phase 2 will occur immediately following phase 1 in which participants will start an open-label 4-week intervention with metformin and the prebiotic MM.

• INCLUSION CRITERIA:

• Age 10-25 years
• Pubertal or post-pubertal: Girls - Tanner stage IV-V breast; Boys - Testicular volume >10cc
• Diagnosis of type 2 diabetes by American Diabetes Association (ADA) guidelines [36] or with established diagnosis previously treated with metformin.
• Negative test for diabetes-related autoantibodies (glutamic acid decarboxylase 65 and tyrosine phosphatase-related islet antigen 2 (IA-2)) documented in NIH CRIS chart or via outside laboratory assessment within the last 10 years.
• Hemoglobin A1C <8% at study initiation

Exclusion criteria

• Pregnancy or breastfeeding
• Allergy to study medications
• Allergy or self-reported intolerance to blueberry, pomegranate, or oats, soy, gluten or dairy products.
• Chronic insulin therapy or insulin use within the last 3 months
• Treatment with other medications which are known to affect the parameters under study, including antibiotics within the last month, immunosuppressants, proton-pump inhibitors, supraphysiologic systemic steroids, probiotic or prebiotic supplements
• Heavy yogurt consumption (2 or more servings of >=6 oz per day)
• Chronic GI disease, gastric bypass surgery, cancer diagnosis or autoimmune disease
• Metabolic derangement such as metabolic acidosis, severe hyperglycemia (fasting blood glucose >= 200mg/dL), and/or liver enzymes > three times the upper limit of normal.
• 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 >= 450lbs
• Body weight <=58kg
• Hemoglobin concentration <10g/dL