Long-Term Reduction in Hyperglycemia in Advanced Type 1 Diabetes—The Value of Induced Aerobic Glycolysis by BCG Vaccinations

Mycobacteria are among the oldest co-evolutionary partners of humans. Attenuated Mycobacterium bovis, known as the Bacillus Calmette Guérin (BCG) vaccine, has been administered globally for 100 years for TB prevention. BCG vaccination shows clinical promise in numerous autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes (T1D). In published Phase II clinical trials in MS, BCG shows benefit starting 2 years after administration with continuing effectiveness at year 5. Here we report on the long-term stabilizing effect of BCG vaccination on blood sugar control in advanced T1D with 8 years of follow-up data. The data examines T1D subjects with long-term disease (>10 years duration) who received 2 doses of BCG 4 weeks apart. Starting after year 3, only BCG vaccinated T1D subjects had lowered HbA1c near normal (BCG treated 6.18+/-.34, placebo 7.07+/-.41, reference diabetic 7.22+/-.17, p=0.02; year 5 data with n=46 total subjects). Continued follow-up of 6 subjects for 8 years total confirmed the ability of BCG vaccinations to maintain lowered HbA1c levels without hypoglycemia (BCG treated 6.65+/-.26 vs. 7.22+/-.38, p=0.0002). Glucagon challenge tests were performed once HbA1cs were lowered but did not confirm a therapeutic return of C-peptide levels for improved blood sugar control. Pre-clinical NOD mouse data had shown in mice that BCG induces massive islet regeneration for restore murine blood sugars. In humans, BCG’s impact on blood sugars appears to be driven by a novel mechanism—a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization as measured by metabolomics, RNAseq and cellular glucose uptake, in subjects receiving a long-term benefit with BCG vaccinations. These clinical and novel mechanistic findings, buttressed with further murine testing, set the stage for a safe and cost effective way to possibly improve blood sugars in humans with diabetes.