Type 1 Diabetes and Current Research
Patients and families often alert me to interesting studies based on headlines from TV, health and diabetes related magazines, and word of mouth. A few studies have been brought to my attention that are worthy of mention: GABA therapy (Prud’homme and Wang, Toronto, Canada), application of the ATP/P2X7 R pathway (Fiorina, Boston Children’s Hospital Blog), and inverse vaccination for the treatment of Type 1 diabetes (Steinman, Stanford University).
In the, GABA therapy paper, researchers found that GABA exerts protective and regenerative effects on islet beta cells and reverses Type 1 diabetes (Senior authors Prud’homme and Wang in PNAS, 7.12.11, Vol 108, no. 28, pages 11692-11697). Researchers report that GABA "exerts anti-diabetic effects by acting on both the B-islet cells and the immune system." In B-islet cells, GABA produces membrane depolarization and Calcium influx, leading to the activation of P13-K/AkT- dependant growth and survival pathways. Administering GABA to severely diabetic mice resulted in reduced lymphocytic islet cell infiltration, restoration of B cell mass, and a complete reversal of hyperglycemia. This reversal was also associated with increased insulin and decreased glucagon levels in the circulation (glucagon increases blood sugar levels).
What does this mean for insulin production?
This finding provides a potential mechanism that supports the in vivo findings that GABA therapy does, indeed, preserve B cell mass and prevents the development of Type 1 diabetes in mice. And, because GABA does not cross the blood brain barrier and can be given orally to humans in large amounts, GABA or GABA-like medications may actually have therapeutic implications in the treatment of Type 1 Diabetes.
A recent blog circulating from Boston Children’s Hospital was brought to our attention noting that Paolo Fiorina (Nephrology division) found a pathway (ATP/P2X7R) that triggers T-cell attacks on the pancreas thereby preventing insulin production. Based on his finding that this pathway may be the early mechanism that "fires up the alloimmune response," Fiorina believes that he found the "root cause of diabetes."
I searched for a recent paper documenting Dr. Fiorina’s findings and found an article from Circulation: Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7 (Circulation. 2013; 127: 463-475). Dr. Fiorina developed a short-term and effective immunomodulatory protocol in which targeting the P2X7R pathway can halt the progression of heart transplant rejection. This potential form of immune therapy has immediate implications for Type 1 diabetes that also results from "attack of the B-islet cells." I await further evidence- based studies relating to trials on people with Type 1 diabetes.
Lastly, an interesting study at Stanford University involving "inverse vaccination" leading to reversal of diabetes was brought to my attention. Dr. Steinman, in the Journal of Internal Medicine (JInternMed 2010: 267:441-451-Inverse vaccination, the opposite of Jenner’s concept, for therapy of autoimmunity), notes that DNA vaccines for autoimmunity are now being tested in human clinical trials for relapsing multiple sclerosis and for Type 1 diabetes. In his paper, he indicates that specific inhibition of antigen-specific antibodies and T-cell responses are attainable in humans and trials are now under way. According to Steinman, this new "version of immunization termed ‘inverse vaccination’ when applied to autoimmune disease, may allow targeted reduction of unwanted antibody and T-cell responses to autoantigens, while leaving the remainder of the immune system intact."
Steinman and his group (Sci Transl Med 26 June 2013: Vol. 5, Issue 191, p. 191ra82
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006103 hypothesized that an engineered DNA plasmid encoding proinsulin (c-peptide + insulin) would preserve Î² cell function in T1D patients through reduction of insulin-specific CD8+ T cells. They studied 80 subjects over 18 years of age who were diagnosed with T1D within the past five years. They were randomly placed in one of five groups. Four groups received various doses of the vaccine and the fifth group received placebo injections. Shots were given weekly for 12 weeks. The results of the pilot study demonstrated that a plasmid encoding proinsulin (inverse vaccination) reduced the frequency of CD8+ T cells reactive to proinsulin (autoimmune response- Killer T cells) while preserving C-peptide over the course of dosing. No one in the study was able to stop using insulin.
In summary, these are just three of the interesting areas involving research in
Type 1 diabetes. A unifying link between these studies is that of signaling and pathways - presently an electrifying area in which many diabetes researchers are engaged.
Fran Cogen, M.D., C.D.E., is the director of the Childhood and Adolescent Diabetes Program at Children’s National Health System. She wrote about diabetes for HealthCentral.