Kuhtreiber, WillemTran, LisaKim, TaesooDybala, MichaelNguyen, BrianPlager, SaraHuang, DanielJanes, SophieDefusco, AudreyBaum, DanielleZheng, HuiFaustman, Denise2018-07-252018Kühtreiber, W. M., L. Tran, T. Kim, M. Dybala, B. Nguyen, S. Plager, D. Huang, et al. 2018. “Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations.” NPJ Vaccines 3 (1): 23. doi:10.1038/s41541-018-0062-8. http://dx.doi.org/10.1038/s41541-018-0062-8.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298257Mycobacterium are among the oldest co-evolutionary partners of humans. The attenuated Mycobacterium bovis Bacillus Calmette Guérin (BCG) strain has been administered globally for 100 years as a vaccine against tuberculosis. BCG also shows promise as treatment for numerous inflammatory and autoimmune diseases. Here, we report on a randomized 8-year long prospective examination of type 1 diabetic subjects with long-term disease who received two doses of the BCG vaccine. After year 3, BCG lowered hemoglobin A1c to near normal levels for the next 5 years. The BCG impact on blood sugars appeared to be driven by a novel systemic and blood sugar lowering mechanism in diabetes. We observe a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization. Confirmation is gained by metabolomics, mRNAseq, and functional assays of cellular glucose uptake after BCG vaccinations. To prove BCG could induce a systemic change to promote accelerated glucose utilization and impact blood sugars, murine data demonstrated reduced blood sugars and aerobic induction in non-autoimmune mice made chemically diabetic. BCG via epigenetics also resets six central T-regulatory genes for genetic re-programming of tolerance. These findings set the stage for further testing of a known safe vaccine therapy for improved blood sugar control through changes in metabolism and durability with epigenetic changes even in advanced Type 1 diabetes.en-USJournal Article2018-07-2510.1038/s41541-018-0062-8