Scientists claim GABA administration preserves islet β-cell mass, stimulates β-cell regeneration, and blocks autoimmune response.
Treating type 1 diabetes (T1D) with gamma-aminobutiric acid (GABA) attenuates insulitis, preserves islet β-cell mass, and can even lead to β-cell regeneration and reverse established disease in experimental mice, researchers claim. Studies by a team at St. Michael’s Hospital in Toronto in different mouse models of type 1 diabetes, have found that GABA promotes β-cell growth and survival, and exerts immunoinhibitory effects that may protect them against autoimmune destruction.
Writing in PNAS, Qinghua Wang, M.D., Gerald J. Prud’homme, M.D., and colleagues conclude that because GABA does not cross the blood brain barrier and can be administered orally in humans in large amounts, GABA or GABA-mimicking drugs may have therapeutic utility in the prevention and treatment of T1D. The researchers report their findings in a paper titled “GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes.”
T1D is an autoimmune disease characterized by insulitis and islet β-cell loss, but there are currently no effective therapies capable of restoring β-cells from the surviving islet cell population, or suppressing the autoimmune response, the St. Michael’s team reports. GABA is a major neurotransmitter in the CNS, and is also produced by pancreatic β-cells, where it acts on the GABAA receptor in alpha cells to suppress glucagon secretion. However, studies by both the St. Michael’s team and independent researchers have shown that β-cells also express GABAA receptors, forming an autocrine GABA signalling pathway, the functions of which are unknown.
In view of the critical role of GABA–GABAA receptor signaling in neuronal cell proliferation and maturation, the authors hypothesized that activation of GABA–GABAAR signaling in pancreatic β-cells may also have trophic effects and potentially exert therapeutic effects in diabetic patients.
Initial tests on β-cells in vitro confirmed that GABA treatment increased DNA synthesis, while in vivo studies in experimental mice showed that injections of GABA led to increased numbers of β-cells, indicating cell proliferation. Treatment of β-cells in isolate mouse islets also prevented cell death after challenge with cytotoxic drugs.
Electrophysiological studies threw up the surprising finding that in contrast with GABA’s hyperpolarizing effects on α-cells, administering GABA to β-cells induces membrane depolarization, and in isolated mouse islet β-cells administration of either GABA or a GABAAR agonist stimulated calcium ion influx. “These observations suggested that GABA induced membrane depolarization, subsequent Ca2+ entry, and activation of the PI3K/Akt pathway, which may represent a mechanism underlying its in vivo effects in promoting β-cell growth and survival,” the authors note.
The researchers then moved on to evaluate the effects of GABA on different mouse models of diabetes, including MDSD mice, which can be induced chemically to develop diabetes and display severe loss of islet β-cells. Administering GABA injections to these animals prior to the chemical induction of diabetes prevented β-cell loss, and led to higher circulating insulin, lower glucagon, nearly normal glycemia and improved metabolic features, with close to normal glucose tolerance. While insulin sensitivity wasn’t altered, glucagon tolerance was significantly improved, “indicating that GABA prevented diabetic hyperglycemia in MDSD mice through the preservation of β-cell mass and function,” the researchers state.
The effects of GABA administration were tested on nonobese diabetic mice (NOD), a spontaneous autoimmune mouse model of T1D. NOD animals typically develop severe insulitis, β-cell depletion, and hyperglycemia by 13 weeks of age. However, NOD animals started on GABA injection therapy prior to the onset of diabetic features demonstrated mostly normal islets (only about 15% of islets demonstrated mild insulitis), reduced β-cell death and increased β-cell proliferation, and relatively constant glucose levels. By 18 weeks of age and onward, untreated NOD animals progressed to severe diabetes and a complete depletion of islet β-cells, and required insulin injections to survive. In contrast, GABA-treated NOD mice had preserved β-cell mass, no signs of diabetes, and nearly normal glucose tolerance. Significantly, GABA therapy partially suppressed the proliferation of diabetogenic islet cell-reactive CD8+ cytotoxic lymphocytes (CTLs), which are integral to the disease process.
Encouragingly, studies using the diabetic mouse models suggested that GABA therapy could not only prevent the onset of diabetes, but reverse established disease. Administering GABA to severely diabetic MDSD mice resulted in reduced lymphocytic islet infiltration, restoration of β-cell mass, and a complete reversal of hyperglycemia. This was associated with increased insulin, decreased glucagon levels in the circulation, and improved metabolic conditions. Similarly, GABA therapy ameliorated diabetes in established hyperglycemic NOD mice, and resulted in significant β-cell mass recovery and improved metabolic conditions, suggesting that GABA exerts stimulatory effects on the regeneration of islet β-cells. Importantly, β-cell restoration in NOD mice was dependent on GABA treatment being initiated early after the onset of disease, when there are still some β-cells remaining to allow regeneration.
Treating diabetic MDSD mice with GABA led to markedly lower levels of the circulating inflammatory cytokines IL-1β, TNF-α, IFN-γ, and IL-12, which are otherwise highly elevated in this mouse model of diabetes, but had no effect on the anti-inflammatory cytokine IL-10. Further evaluation of the anti-inflammatory effects of GABA showed that the treatment suppressed the production of IL-12 by macrophages, and of IFN-γ by CD4+ and CD8+ T cells.
Conversely, examination of the splenocytes of NOD mice showed that GABA therapy increased the numbers of regulatory T cells (Tregs) that exert inhibitory effects on immunological responses and are involved in the control of T1D. “Our data suggest that GABA exerts anti-inflammatory effects and is directly inhibitory to T cells and macrophages,” the authors note. “This might contribute to the reduction of insulitis and recovery of β-cell mass in diabetic mice.”
Summarizing their findings the St. Michael’s team stresses the key finding that GABA exerts depolarizing effects and ultimately activates Akt-mediated cell growth and survival signaling pathways in β-cells. This GABA-stimulated Akt activation was abolished on administration of a GABAAR antagonist or calcium channel blocker. This suggests that GABA caused β-cell depolarization, followed by the opening of voltage-dependent calcium channels, and then the subsequent activation of the Ca2+/PI3K/Akt signaling pathway, which may represent a molecular mechanism underlying its in vivo trophic effects exerted on the islet β-cells.
Moreover, previous research has found that GABA stimulates insulin secretion in the presence of low or physiological concentrations of glucose, and this may provide additive effects to activation of the Ca2+/PI3K/Akt pathway.