Abstract
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. Disclosure W. Kuhtreiber: None. L. Tran: None. B. Nguyen: None. S.E. Janes: None. A.A. DeFusco: None. D.L. Faustman: None.
Highlights
The bacillus Calmette-Guérin (BCG) vaccine is one of the oldest vaccines in the world, developed for tuberculosis (TB) protection and for early stage bladder cancer therapy
The same trends were glycolysis, Krebs cycle enzymes were down-regulated (DLST, IDH3B, IDH3G, MDH2, OGDH) (Fig. 4a). This data supports a BCG-driven process of a shift in energy metabolism. To further confirm this shift to accelerated glucose utilization through aerobic glycolysis, we studied in vivo observed for two additional purine synthesis intermediates: N6carbamoylthreonyladenosine (p = 0.003, q = 0.0005) and methylguanine (p < 0.001, q = 0.0006) that were both lower in untreated serum lactate production and in vitro cellular lactate production and glucose uptake rates after BCG exposures to cultured lymphocytes
The results indicate that glucose metabolism is shifted towards aerobic glycolysis in the BCG treated type 1 diabetes (T1D)
Summary
The bacillus Calmette-Guérin (BCG) vaccine is one of the oldest vaccines in the world, developed for tuberculosis (TB) protection and for early stage bladder cancer therapy. The placebo group of humans and in culture experiments has weakened efficacy for TNF and NFkB induction.[27] This published data illustrates the subjects continued to show hypoglycemia events during the same time periods of monitoring We presumed at this point that the return of near normoglyadministration as critical for murine autoimmune disease reversal cemia in the BCG treated human T1D (8 year long followed and maybe even early signs of efficacy or failed efficacy in human subjects) was by the same mechanism as was observed in the type 1 diabetes. Stimulated C-peptide was measured with a glucagon challenge phosphorylation to augmented early aerobic glycolysis, a systemic in the BCG and placebo type 1 diabetic subject groups at three metabolic shift that occurs gradually and allows cells to consume time points (pre-BCG, post-BCG 12 weeks, and 208 weeks) to look in a regulated fashion large amounts of glucose to safely lower for pancreas recovery or regeneration The details of The mechanism for lowered HbA1c values was not equivalent to all subjects and corresponding clinical subject data are depicted in the NOD diabetic mouse pancreas regeneration after BCG
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