ADA: A Vaccine Can Improve Blood Glucose Management

A single dose of BCG vaccine appears to decrease progression of new onset diabetes.

The bacillus Calmette-Guerin (BCG) vaccine has been used for years for the protection against tuberculosis and bladder cancer. Within recent years, the BCG vaccine has been studied for use against many autoimmune diseases such as multiple sclerosis, allergic reactions, and now type 1 diabetes (T1D).

A double-blinded study was conducted on 282 human research participants where 211 of these subjects had type 1 diabetes and 71 people without diabetes were control subjects. These participants were also compared to people with type 1 diabetes receiving standard care at Massachusetts General Hospital, where they served as the placebo group after 20 weeks. The trial was extended for eight years to monitor HbA1c values and glucose management in individuals with BCG-treated T1D to then compare to the placebo group and the group without diabetes.

The Connaught strain of BCG was administered intradermally in the right and left upper arm twice, four weeks apart. The same study was previously conducted in mice and the effects of the BCG vaccine observed included pancreas recovery or regeneration of the insulin-secreting islets of the pancreas, elevations of tissue necrosis factor (TNF), and beneficial T regulatory cell (T-reg) expansion. Stimulated C-peptide was measured with a glucagon challenge test that was done on three separate occasions: pre-BCG, 12 weeks post-BCG, and 208 weeks post-BCG. This involved asking the subjects to consume 150 grams of carbohydrates for three days and then fast for eight hours the night before the glucagon challenge test. After the fast, 5 ml of blood was drawn to be used as a glucose baseline comparison, then six minutes later, 1 mg of glucagon was administered intravenously. Another sIx minutes later, an additional 5 ml of blood was drawn. Blood samples were prepared and frozen to later be evaluated for HbA1c values and C-peptide levels using the C-peptide ELISA kits.

When compared to the mice who showed clinically significant C-peptide levels and therefore significant pancreatic recovery and regeneration, the C-peptide levels of the human subjects after the glucagon challenge were negligible to non-existent. T-reg cell de-methylation is critical in the T-reg function. T regulatory cells function to modulate the immune system to maintain tolerance to self-antigens and prevent autoimmune diseases. After administration of the BCG vaccine, de-methylation of T-reg genes was confirmed by using transcription profiling of cultured peripheral blood T lymphocytes.

It was observed that mRNA expression was increased with de-methylation induction with the BCG vaccine. Methylation trends were inversely correlated with mRNA levels. Insulin resistance was then studied after four years post BCG treatment with the Quantose IR test, which quantified four metabolites, which are resistance markers. Comparing values from baseline to post-BCG treatment was not significant and therefore could not be indicative of lowered insulin resistance and HbA1c reduction.

Purine biosynthesis was augmented and glucose metabolism was improved with BCG treatment. BCG downregulates enzymes in late glycolysis and upregulates the enzymes and glucose transporters in early glycolysis. Thus, a switch from oxidative phosphorylation to high aerobic glycolysis. When compared to the untreated group with TID and the control group without diabetes, purine and pyrimidine metabolites were higher in the group treated with BCG. Low amounts of purine and pyrimidine metabolites suggests underutilization of early aerobic glycolysis.

In conclusion, re-introduction of the avirulent mycobacterium bovis in the form of the BCG vaccine proves to be beneficial to patients with diabetes in that it helps with glucose control and re-establishes self-tolerance with T-reg cells.

Practice Pearls:

• The BCG vaccine may be beneficial in patients with type 1 diabetes.
• In murine studies, the BCG vaccine showed to increase C-peptide levels, which suggested pancreas regeneration and recovery.
• The BCG vaccine was also shown to improve glucose metabolism and purine and pyrimidine synthesis

References:

Kuhtreiber, Willem, et al. “Long-Term Reduction in Hyperglycemia in Advanced Type 1 Diabetes—The Value of Induced Aerobic Glycolysis by BCG Vaccinations.” Diabetes, vol. 67, no. Supplement 1, 21 June 2018, doi:10.2337/db18-2339-pub.

Amanda Cortes, PharmD Candidate, LECOM School of Pharmacy