Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations

• Published in: npj vaccines Vol. 3; no. 1; p. 23
• Main Authors: Kühtreiber, Willem M., Tran, Lisa, Kim, Taesoo, Dybala, Michael, Nguyen, Brian, Plager, Sara, Huang, Daniel, Janes, Sophie, Defusco, Audrey, Baum, Danielle, Zheng, Hui, Faustman, Denise L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.06.2018; Nature Publishing Group
• Subjects: 631/326/590/1867; 692/699/249/1313/1418; 692/699/2743; Biomedical and Life Sciences; Biomedicine; Blood; Diabetes; Epigenetics; Glucose; Hyperglycemia; Immune system; Infectious Diseases; Medical Microbiology; Metabolism; Public Health; Sugar; Tuberculosis; Vaccine; Vaccines; Virology
• ISSN: 2059-0105; 2059-0105
• DOI: 10.1038/s41541-018-0062-8

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. Diabetes: Repurposing a classic tuberculosis vaccine In patients with long-term type 1 diabetes, the tuberculosis vaccine BCG lowers blood sugar levels to near-normal after three years. Denise Faustman and her team from Massachusetts General Hospital and Harvard Medical School investigated a cohort of type 1 diabetics that received two doses of BCG before being monitored over eight years. After three years, vaccine-treated patients lowered their HbA1c levels—a diabetes biomarker reflecting average blood sugar over 8–12 weeks—by over 10%. This reduction increased to 18% in the fourth year, after which HbA1c levels remained low up to the final year of monitoring. The researchers report that the BCG vaccine appeared to reset diabetes-implicated parts of the immune system and, through a novel mechanism, shift glucose metabolism to lower blood sugar to healthy levels. Future studies will further classify BCG’s benefits in diabetes.