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

Type I Diabetes Clinical Trial

— GABA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02002130
• Other study ID #: GABA-GAD
• Status: Completed
• Phase: Phase 1
• Start date: January 2015
• Est. completion date: April 15, 2022

Study information

• Verified date: May 2022
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 101
• Est. completion date: April 15, 2022
• Est. primary completion date: October 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 18 Years

Eligibility

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.)

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type I Diabetes

Intervention

Drug:
• Placebo GABA and Placebo GAD-alum
Maltodextrin as a placebo formulation for GABA Placebo GAD-alum injection
• GABA and Placebo GAD-alum
Oral Active GABA with Placebo GAD-alum
• Active Oral GABA and Active GAD-alum injection
Active Oral GABA and Active GAD-alum injection

Locations

Country	Name	City	State
United States	Children's of Alabama	Birmingham	Alabama

Sponsors (5)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	Diamyd Inc, Janssen Pharmaceuticals, Juvenile Diabetes Research Foundation, NOW Foods

Country where clinical trial is conducted

United States, 

References & Publications (2)

Ludvigsson J, Faresjö M, Hjorth M, Axelsson S, Chéramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1909-20. doi: 10.1056/NEJMoa0804328. Epub 2008 Oct 8. — View Citation

Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11692-7. doi: 10.1073/pnas.1102715108. Epub 2011 Jun 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Compare the effect of oral GABA or oral GABA/GAD combination administration on pancreatic beta cell function by quantitative C-peptide secretion	This will be assessed by meal stimulated c-peptide secretion in treatment cohorts compared to age matched placebo controls before and after 1 year of treatment.	12 months after baseline
Secondary	Compare the effect of oral GABA or GABA/GAD administration on fasting and meal stimulated glucagon and pro-insulin levels.	This will be assessed by meal stimulated glucagon and pro-insulin secretion in treatment cohorts compared with age matched placebo controls before and after 1 year of treatment.	12 months after baseline
Secondary	Compare the effect of oral GABA or GABA/GAD administration on total daily insulin usage by participants and corrected Hemoglobin A1C.	This will be assessed by measuring insulin usage and corrected Hemoglobin A1C linearly for each participant, in addition to comparison with age matched controls	12 months after baseline
Secondary	Compare the effect of oral GABA or oral GABA/GAD administration on indices of immune system function.	This will be assessed by measuring immunologic markers of inflammation linearly over the 12 month treatment course for each patient and comparing to age matched placebo controls.	12 months after baseline
Secondary	Compare the effect of oral GABA or oral GABA/GAD administration on diabetes related autoantibodies	This will be assessed by measuring GAD65, ICA512, and Zinc Transporter 8 antibodies throughout the treatment period.	12 months after baseline