The Use of Glutamic Acid Decarboxylase (GAD) and Gamma-Amino Butyric Acid (GABA) in the Treatment of Type I Diabetes
Condition: Type I Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Placebo GABA and Placebo GAD-alum; GABA and Placebo GAD-alum; Active Oral GABA and Active GAD-alum injection
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Maltodextrin as a placebo formulation for GABA Placebo GAD-alum injection; Oral Active GABA with Placebo GAD-alum; Active Oral GABA and Active GAD-alum injection
Other intervention name(s): Placebo for Gamma-Amino Butyric Acid
Intervention MeSH terms: Aluminum sulfate; gamma-Aminobutyric Acid; Butyric Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetes