This is a 3-month randomized trial in youth with type 2 diabetes with 2 intervention arms (metformin alone and metformin and liraglutide). Our project has successfully recruited participants but have experienced multiple delays in protocol initiation and recruitment that were related to interruptions in stable isotope supply at the NIH Clinical center. During Fiscal Year 2018, we continued enrollment and at the end of Fiscal Year 2018 we have a total of 23 participants in the study. Study implementation has progressed without procedural issues and no participants have experienced any serious adverse events. The data safety and monitoring board continues to meet twice per year and no safety or regulatory issues identified. However, recruitment efforts for the study were abruptly halted in November 2018 because of an interruption in intravenous stable isotopes available for human use at the NIH Clinical Center. This supply interruption directly impacted our study because the primary and some secondary outcomes can only be gathered with the use of IV stable isotope experiments. The delay in isotope production was directly related to new requirements set by the NIH Sterile Products for Human Administration and Office of Research Services Compliance Committee in June 2018. The committee instructed the NIH Clinical Center Pharmacy to discontinue intravenous (IV) stable isotope products with Pine Pharmaceuticals pending an audit and execution of a Quality Agreement between Pine and NIH. Although the above decision was made in June 2018, the signed Quality Agreement between NIDDK, NIH Pharmacy and Pine Pharmaceuticals was fully executed February 2019. Pine Pharmaceuticals validated procedures and isotope compounding and recruitment and study procedures will resume in September 2019. Our randomized study should be allowed to continue because our findings will provide novel insight into pathophysiology of diabetes in youth, the drugs used to treat this chronic disease and pharmacogenomic targets. Despite these delays, the exploratory outcomes and findings are intriguing. Our manuscript entitled Metformin Increases GLP-1 Concentrations and Improves Glycemia in Youth with Type 2 Diabetes will be presented at the American Diabetes Association Scientific Sessions Meeting in June 2019 and will be submitted to Diabetes Care September 2019. To test our hypotheses generated by the microbiome exploratory outcome, we developed a new sub-study to expand the scope of the current protocol. The sub-study was based on preliminary data from the primary study showing a change in stool metabolite concentrations with metformin and the observational case-control sub-study will test the hypothesis that metformin changes gut microbiota and stool metabolites in youth with type 2 diabetes.
| Hall, Kevin D; Chung, Stephanie T (2018) Low-carbohydrate diets for the treatment of obesity and type 2 diabetes. Curr Opin Clin Nutr Metab Care 21:308-312 |
| Chung, Stephanie T; Hsia, Daniel S; Chacko, Shaji K et al. (2015) Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes. Diabetologia 58:596-603 |
