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