GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes

Daniel Espes, Hanna Liljebäck, Henrik Hill, Andris Elksnis, José Caballero-Corbalan, Per-Ola Carlsson, Daniel Espes, Hanna Liljebäck, Henrik Hill, Andris Elksnis, José Caballero-Corbalan, Per-Ola Carlsson

Abstract

Introduction: Experimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical).

Research design and methods: Six adult male subjects with long-standing T1D (age 24.8±1.5 years, disease duration 14.7±2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic clamps were evaluated at every dose increase (200 mg, 600 mg and 1200 mg).

Results: During the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia.

Conclusions: We find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted.

Trail registration number: NCT03635437 and EudraCT2018-001115-73.

Keywords: GABA-A; diabetes mellitus; hypoglycemia; receptors; type 1.

Conflict of interest statement

Competing interests: DE and P-OC are listed as coinventors for a patent application submitted by Diamyd Medical, but do not have any financial interests in Diamyd Medical. None of the other authors have any conflicts of interest to declare.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
GABA treatment improves the counter-regulatory hormone response to hypoglycemia in type 1 diabetes. (A) Flash glucose monitoring for all subjects (n=6) at baseline and during short-term oral treatment with GABA in increasing doses. (B–F) Hormonal counter-regulatory response during hyperinsulinemic hypoglycemic clamps. Glucose levels were regulated by an intravenous continuous rate of insulin and a variable rate of glucose in order to reach first a 30 min plateau with glucose levels of 5.5 mmol/L, followed by a 30 min plateau at 2.5 mmol/L. Blood samples were collected at the end of each plateau. The analysis contains data from the five subjects without detectable C peptide (

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