The Use of Glutamic Acid Decarboxylase (GAD) and Gamma-Amino Butyric Acid (GABA) in the Treatment of Type I Diabetes

The Use of Glutamic Acid Decarboxylase (GAD)and Gamma-Amino Butyric Acid(GABA)in the Treatment of Type I Diabetes.

Type I Diabetes is an auto immune disease in which the body's immune system attacks and destroys the insulin-producing beta cells of the pancreas. Therefore, children affected by this condition present with high blood sugars. This condition affects 1:400/500 persons worldwide.Type I Diabetes, previously known as Juvenile Diabetes,usually strikes in childhood, adolescence, or young adulthood, but lasts for a lifetime. To date, there has been no treatments that can arrest, or reverse the ongoing beta cell destruction. We hypothesize that GABA, a naturally occurring substance, has the potential to reduce the inflammation and protect the pancreatic beta cells from autoimmune destruction. GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent onset, Type I Diabetes.

The primary defect in autoimmune Type I Diabetes Mellitus (T1DM) involves the infiltration of the pancreatic islet cells by T-lymphocytes, macrophages, and other immune cells, and consequent loss of beta cells. At the onset of T1DM more than 70% of the beta cells are destroyed, whereas the residual beta cells most likely represent the only reservoir for the potential regeneration of the islet beta cell mass. A series of immunological abnormalities have been reported in those with T1DM including, but not limited to, the production of autoantibodies (i.e., glutamic acid decarboxylase (GAD-65), tyrosine phosphatase-related islet antigen 2 (IA2), Zinc Transporter 8 (ZnT8A), or insulin (IAA) as well as alterations in the capacity of regulatory T cells (Treg) to suppress the action of effector T cells (Teff); the latter population thought as playing a key role in the immune destructive process. Therefore, a vast majority of studies attempting to prevent or reverse the disease have focused on immune suppression. While some of these studies have shown limited promise, many has side effects which were significant enough that one must question the value of short term benefits associated with utilizing these drugs.

GABA is a naturally occurring substance in physiology and has the potential to locally reduce inflammation and protect pancreatic beta cells from auto-immune destruction. GABA, synthesized from glutamate by GAD, is a well known neurotransmitter in the CNS and acts mainly through the GABAA receptor (GABAAR). GABA is locally produced by the pancreatic beta cells. GABAARs are also expressed in various immune cells, including T-cells, peripheral blood mononuclear cells, and are known to exert immune-inhibitory effects. BABA appears to play multiple roles in the pancreas. GABA promotes beta-cell growth and survival, and GABA can also act on the GABA(A) receptors in the pancreatic alpha cells, in so doing suppressing glucagon secretion, and GABA suppresses inflammation and increases regulatory T-cell numbers. Based on the aforementioned information, we envisage that administering GABA to those with new onset T1DM may preserve or increase residual insulin production, suppress glucagon release, and decrease inflammation surrounding the pancreas. With this, GABA may prolong the beta-cell life after diagnosis. Combining with GAD-alum injections, which aim to halt the autoimmune attack by inducing tolerance thereby saving residual insulin production, may improve glycemic control even more and significantly decrease the risk of hypoglycemia and long-term complications in the future.

Inclusion Criteria:

• Patients must be positive for GAD-65 antibody.
• They must meet ADA criteria for diabetes: classic symptoms, plus blood sugar > 200mg/dL or fasting blood sugar > 126 mg/dL.
• Must be enrolled with 5 weeks of diagnosis
• Females who are post-menarchal must use 2 forms of contraception if not abstinent. The types of contraception deemed acceptable would be oral contraceptives, intrauterine devices, and barrier methods.
• Signed informed consent form.

Exclusion Criteria:

• Chronic systemic steroid use, including inhaled compounds, or any medication which can alter glucose metabolism
• Obesity, defined as BMI > 95% or BMI > 27 in adolescents with acanthosis score between 1-1.5.
• Pregnant and/or breast feeding
• History of seizure disorder
• Patients on medications that may disturb GABA action, such as Baclofen, Valium, Acamprosate, Neurontin, or Lyrica
• history of any alcoholism or substance abuse.
• Chronic Disease (such as liver, cancer, cystic fibrosis, or renal failure)
• Chromosome abnormality (such as Trisomy 21, Turner Syndrome, etc.)