GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity

• Published in: Biochemical and biophysical research communications 2014-09, Vol.452 (3), p.649-654
• Main Authors: Prud’homme, Gérald J., Glinka, Yelena, Udovyk, Oleksandr, Hasilo, Craig, Paraskevas, Steven, Wang, Qinghua
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Baclofen - analogs & derivatives; Baclofen - pharmacology; Cell Line, Tumor; Diabetes; GABA; GABA Agonists - pharmacology; GABA Antagonists - pharmacology; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacology; Gene Expression Regulation; Humans; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Muscimol - pharmacology; NAD; NAD - metabolism; NF-kappaB; Picrotoxin - pharmacology; Primary Cell Culture; Rats; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Receptors, GABA-B - genetics; Receptors, GABA-B - metabolism; Signal Transduction; Sirtuin 1; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.08.135

•GABA enhances the expression of SIRT1 (an NAD+-dependent deacetylase) in islet beta cells.•GABA increases intra-cellular NAD+, an essential substrate of SIRT1, in beta cells.•SIRT1 activity is increased and the NF-kappaB component p65 is deacetylated.•SIRT1 mediates the anti-apoptotic effects of GABA on a beta-cell line and newly isolated human islet cells.•Insulin secretion is increased in a SIRT1-dependent fashion. We have previously shown that GABA protects pancreatic islet cells against apoptosis and exerts anti-inflammatory effects. Notably, GABA inhibited the activation of NF-κB in both islet cells and lymphocytes. NF-κB activation is detrimental to beta cells by promoting apoptosis. However, the mechanisms by which GABA mediates these effects are unknown. Because the above-mentioned effects mimic the activity of sirtuin 1 (SIRT1) in beta cells, we investigated whether it is involved. SIRT1 is an NAD+-dependent deacetylase that enhances insulin secretion, and counteracts inflammatory signals in beta cells. We found that the incubation of a clonal beta-cell line (rat INS-1) with GABA increased the expression of SIRT1, as did GABA receptor agonists acting on either type A or B receptors. NAD+ (an essential cofactor of SIRT1) was also increased. GABA augmented SIRT1 enzymatic activity, which resulted in deacetylation of the p65 component of NF-κB, and this is known to interfere with the activation this pathway. GABA increased insulin production and reduced drug-induced apoptosis, and these actions were reversed by SIRT1 inhibitors. We examined whether SIRT1 is similarly induced in newly isolated human islet cells. Indeed, GABA increased both NAD+ and SIRT1 (but not sirtuins 2, 3 and 6). It protected human islet cells against spontaneous apoptosis in culture, and this was negated by a SIRT1 inhibitor. Thus, our findings suggest that major beneficial effects of GABA on beta cells are due to increased SIRT1 and NAD+, and point to a new pathway for diabetes therapy.