Abstract
Mycobacterium 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.
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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