Abstract
Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three-period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease, characterized by progressive loss of functional β-cell mass, resulting from insulitis, which leads to insulin deficiency, elevation of blood glucose, and various complications associated with this disease (Atkinson et al, 2014)
When the concentration-time profiles of gamma aminobutyric acid (GABA) were presented as area under the curve (AUC), the AUC0–4h and AUC0–24h of a single dose and repeated doses were statistically significant compared to the placebo control
AUC0–24h: single dose vs. control = 1451.68 ± 243.12 vs. 272.85 ± 14.28 h·ng/ml, p < 0.001; repeated dose vs. control = 1778.69 ± 433.21 vs. 272.85 ± 14.28 h·ng/ml, p < 0.001). This indicates that GABA was rapidly absorbed, with maximum plasma concentrations achieved approximately 1–1.5 h after an oral dose, and subsequent mean elimination half-life in a range of 5–5.2 h
Summary
Type 1 diabetes (T1D) is an autoimmune disease, characterized by progressive loss of functional β-cell mass, resulting from insulitis, which leads to insulin deficiency, elevation of blood glucose, and various complications associated with this disease (Atkinson et al, 2014). GABA stimulates βcell replication, protects β-cells against apoptosis, and attenuates insulitis (Soltani et al, 2011; Tian et al, 2013; Prud’homme et al, 2014; Purwana et al, 2014). These effects result in an enhanced functional β-cell mass and, in mice, this can reverse disease (Soltani et al, 2011). The following oral treatments were applied: placebo, single dose of 2 g GABA, or repeated dose of 2 g GABA three times daily for 7 days, with a 7-day washout between each period to evaluate the PK, PD, and safety profile
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