Regulation of pancreatic islet cell survival and replication by γ-aminobutyric acid

Abstract

Aims/hypothesis Pancreatic islets have evolved remarkable, though poorly understood mechanisms to modify beta cell mass when nutrient intake fluctuates or cells are damaged. We hypothesised that appropriate and timely adjustments in cell number occur because beta cells release proliferative signals to surrounding cells when stimulated by nutrients and 'bleed' these growth factors upon injury. Materials and methods In rat pancreatic islets, we measured DNA content, insulin content, insulin secretion after treatment, immunoblots of apoptotic proteins and the uptake of nucleoside analogues to assess the ability of γ-aminobutyric acid (GABA), which is highly concentrated in beta cells, to act as a growth and survival factor. This focus is supported by work from others demonstrating that GABA increases cell proliferation in the developing nervous system, acts as a survival factor for differentiated neurons and, interestingly, protects plants under stress. Results Our results show that DNA, insulin content and insulin secretion are higher in freshly isolated islets treated with GABA or GABA B receptor agonists. Exposure to GABA upregulated the anti-apoptotic protein B-cell chronic lymphocytic leukaemia XL and limited activation of caspase 3 in islets. The cellular proliferation rate in GABA-treated islets was twice that of untreated controls. Conclusions/interpretation We conclude that GABA serves diverse purposes in the islet, meeting a number of functional criteria to act as an endogenous co-regulator of beta cell mass.

Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting β-Cell Replication in Newly Diabetic NOD Mice

“…These observations underscore the need for systematic studies to identify an effective GABA dose and frequency of administration to inhibit inflammatory responses in humans. The therapeutic effects of GABA may be mediated by the ability of GABA to inhibit autoreactive Th1 responses (7,10,11), enhance Treg responses (13,16), and promote the functional recovery and replication of β-cells (13,18,19). …”

“…Because of its rapid anti-inflammatory effects, GABA is an excellent candidate for therapeutic testing in combination with ABTs. Importantly, GABA also promotes mouse and human β-cell survival and replication (13,15,18,19). Long-term treatment with GABA neither induces leukopenia (10) nor desensitizes immune cells to GABA (10,11), and GABA appears to be safe for human consumption (20–22).…”

Postnatal development of the endocrine pancreas in mice lacking functional GABABreceptors

“…This discrepancy between genetic expression and protein levels may be due to the antibody recognizing both GAD65 and GAD67 isoforms, although we only evaluated Gad1 expression. An increase in GAD protein-positive area would probably imply an increased number of cells synthesizing GABA in the islets, which, in addition to its effects on islet hormone secretion, can also modify proliferation, viability, and apoptosis (45,64,67,68). In this way, the moderate increase in GAD in GABA B1 KO mice could help explain the increased ␣-and ␤-cell proliferation observed in adults in the cluster population.…”

“…Recently, Taneera et al (66) demonstrated that a GABA B antagonist was able to increase high-glucose-stimulated insulin secretion in both type 2 diabetic and normal human islets. In contrast, others have reported an increase in insulin secretion after GABA B receptor stimulation in rat islets, although the experiment conditions differed (45). GABA B receptors were shown to be expressed exclusively in ␤-cells in mice (14), whereas the presence of GABA B receptor subunits was described in rat ␣-and ␤-cells (12), again suggesting that species differences may exist.…”

GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets

“…Another aspect of GABA activity in regard to pancreatic beta cells has been only recently reported. Through activation of GABA B receptors, GABA significantly increases beta-cell viability [135] and replication [136]. In mouse models, GABA administration prevented and even reversed T1D [107].…”