title: GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity.
abstract: 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.
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. Electronic address: prudhommeg@smh.ca.
authors.forename: Gérald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: glinkay@smh.ca.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Glinka
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: oleks.udovyk@utoronto.ca.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Udovyk
authors.affiliation: Department of Surgery, McGill University, Montreal, Quebec, Canada; Human Islet Transplantation Laboratory, McGill University Health Centre, Montreal, Quebec, Canada. Electronic address: craig.hasilo@mail.mcgill.ca.
authors.forename: Craig
authors.initials: C
authors.lastname: Hasilo
authors.affiliation: Department of Surgery, McGill University, Montreal, Quebec, Canada; Human Islet Transplantation Laboratory, McGill University Health Centre, Montreal, Quebec, Canada. Electronic address: steven.paraskevas@mcgill.ca.
authors.forename: Steven
authors.initials: S
authors.lastname: Paraskevas
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada; Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Ontario, Canada; Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: wangq@smh.ca.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D010852:Picrotoxin / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001418:Baclofen; D018755:GABA Agonists; D018756:GABA Antagonists; D009118:Muscimol; D009243:NAD; D010852:Picrotoxin; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D056564:Sirtuin 1; D051996:Transcription Factor RelA; D005680:gamma-Aminobutyric Acid; C498145:Rela protein, rat; C488368:Sirt1 protein, rat; C080629:saclofen
keywords: Apoptosis; Diabetes; GABA; NAD; NF-kappaB; Sirtuin 1