Mahtab Ordouei - Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran
Azam Golzar - Hematology and Oncology Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran
Zahra Nafei - Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Science, Yazd, Iran
Mahta Mazaheri - Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

Introduction: The bacillus Calmette–Guerin (BCG) vaccine is a microorganism developed as a vaccine for tuberculosis 100 years ago and used as therapy for bladder cancer 40 years ago. More recently, BCG has shown therapeutic promise for type 1 diabetes (T1D) and several other autoimmune diseases. This clinically important effect may be driven by resetting of the immune system and the shifting of glucose metabolism from overactive oxidative phosphorylation, a state of minimal sugar utilization, to aerobic glycolysis, a state of high glucose utilization, for energy production.Materials & Methods: A search was made on the relationship between BCG vaccine and type 1 diabetes. Results: We identified trials reporting the efficacy of BCG by reduction of HbA1c.The 4 year long followed and BCG-treated diabetes showed a reduction in HbA1c levels from7.3 to 5.9. The efficacy of BCG was also apparent with raw HbA1c values, which show the BCG-treated TIDs by year 8 declined to a HbA1c value of 6.65%. BCG treatment subjects with the improved and tight blood sugar control demonstrated blood sugar stability and lowered blood sugar persistently for 5 continuous years after the initial drop in values. Semi-annual surveys confirmed that during BCG vaccinations there were no reports of severe hypoglycemia, even with lowered HbA1Cs near the normal range, and no change in their care as it related to new insulin pumps or continuous glucose monitoring devices. Findings also suggest repeat BCG administration, but not single BCG vaccinations in childhood prevents diabetes onset.Conclusion & discussion: 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. 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. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes

BCG vaccine, Type 1 diabetes, HbA1c