Gabaergic system in the endocrine pancreas: A new target for diabetes treatment

Diabetes, Metabolic Syndrome and Obesity

Volumn 8, Issue , 2015, Pages 79-87

  Wan, Yun ^a   Wang, Qinghua ^a,b,c   Prud’homme, Gerald J ^b,d  

^a FUDAN UNIVERSITY   (China)

^b ST MICHAEL'S HOSPITAL   (Canada)

^c Departments of Physiology   (Canada)

^d UNIVERSITY OF TORONTO   (Canada)

Author keywords

Apoptosis; Diabetes; GABA; Glucagon; Inflammation; Insulin; Ion channel; Proliferation; cell

Indexed keywords

4 AMINOBUTYRIC ACID DERIVATIVE; 4 AMINOBUTYRIC ACID RECEPTOR; BACLOFEN; GLUTAMATE DECARBOXYLASE; INSULIN;

4 AMINOBUTYRIC ACID RELEASE; CELL REGENERATION; CLINICAL EFFECTIVENESS; DIABETES CONTROL; DIABETES MELLITUS; DRUG EFFICACY; ENDOCRINE SYSTEM; GABAERGIC SYSTEM; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS; PANCREAS ISLET ALPHA CELL; PANCREAS ISLET BETA CELL; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

EID: 84922376793     PISSN: None     EISSN: 11787007     Source Type: Journal    
DOI: 10.2147/DMSO.S50642     Document Type: Review

References (95)

1. Roberts E, Frankel S. γ-Aminobutyric acid in brain: its formation from glutamic acid. J Biol Chem. 1950;187(1):55-63.
2. Owens DF, Kriegstein AR. Is there more to GABA than synaptic inhibition? Nat Rev Neurosci. 2002;3(9):715-727.
3. Represa A, Ben-Ari Y. Trophic actions of GABA on neuronal development. Trends Neurosci. 2005;28(6):278-283.
4. Fiszman ML, Schousboe A. Role of calcium and kinases on the neurotrophic effect induced by gamma-aminobutyric acid. J Neurosci Res. 2004;76(4):435-441.
5. Adeghate E, Ponery AS. GABA in the endocrine pancreas: cellular localization and function in normal and diabetic rats. Tissue Cell. 2002;34(1):1-6.
6. Reetz A, Solimena M, Matteoli M, Folli F, Takei K, De Camilli P. GABA and pancreatic beta-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion. EMBO J. 1991;10(5): 1275-1284.
7. Taniguchi H, Okada Y, Seguchi H, et al. High concentration of gamma-aminobutyric acid in pancreatic beta cells. Diabetes. 1979;28(7): 629-633.
8. Gerber JC 3rd, Hare TA. Gamma-aminobutyric acid in peripheral tissue, with emphasis on the endocrine pancreas: presence in two species and reduction by streptozotocin. Diabetes. 1979;28(12): 1073-1076.
9. Vincent SR, Hökfelt T, Wu JY, Elde RP, Morgan LM, Kimmel JR. Immunohistochemical studies of the GABA system in the pancreas. Neuroendocrinology. 1983;36(3):197-204.
10. Okada Y, Taniguchi H, Schimada C. High concentration of GABA and high glutamate decarboxylase activity in rat pancreatic islets and human insulinoma. Science. 1976;194(4265):620-622.
11. Xu E, Kumar M, Zhang Y, et al. Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metab. 2006;3(1): 47-58.
12. Rorsman P, Berggren PO, Bokvist K, et al. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature. 1989;341(6239):233-236.
13. Purwana I, Zheng J, Li X, et al. GABA promotes human β-cell proliferation and modulates glucose homeostasis. Diabetes. 2014;63(12):4197-4205.
14. Soltani N, Qiu H, Aleksic M, et al. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011;108(28):11692-11697.
15. Prud’Homme GJ, Glinka Y, Hasilo C, Paraskevas S, Li X, Wang Q. GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone. Transplantation. 2013;96(7):616-623.
16. Tian J, Dang H, Chen Z, et al. γ-Aminobutyric acid regulates both the survival and replication of human β-cells. Diabetes. 2013;62(11): 3760-3765.
17. Gladkevich A, Korf J, Hakobyan VP, Melkonyan KV. The peripheral GABAergic system as a target in endocrine disorders. Auton Neurosci. 2006;124(1-2):1-8.
18. Thomas-Reetz AC, De Camilli P. A role for synaptic vesicles in non-neuronal cells: clues from pancreatic beta cells and from chromaffin cells. FASEB J. 1994;8(2):209-216.
19. Glykys J, Mody I. Activation of GABAA receptors: views from outside the synaptic cleft. Neuron. 2007;56(5):763-770.
20. Sorenson RL, Garry DG, Brelje TC. Structural and functional considerations of GABA in islets of Langerhans. Beta-cells and nerves. Diabetes. 1991;40(11):1365-1374.
21. Gammelsaeter R, Frøyland M, Aragón C, et al. Glycine, GABA and their transporters in pancreatic islets of Langerhans: evidence for a paracrine transmitter interplay. J Cell Sci. 2004;117(17 PART): 3749-3758.
22. Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov. 2011;10(9):685-697.
23. Olsen RW, Tobin AJ. Molecular biology of GABAA receptors. FASEB J. 1990;4(5):1469-1480.
24. Lüddens H, Korpi ER, Seeburg PH. GABAA/benzodiazepine receptor heterogeneity: neurophysiological implications. Neuropharmacology. 1995;34(3):245-254.
25. Mody I, Pearce RA. Diversity of inhibitory neurotransmission through GABA(A) receptors. Trends Neurosci. 2004;27(9):569-575.
26. Lüscher B, Keller CA. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther. 2004;102(3):195-221.
27. White JH, Wise A, Main MJ, et al. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature. 1998; 396(6712):679-682.
28. Hashimoto T, Kuriyama K. In vivo evidence that GABA(B) receptors are negatively coupled to adenylate cyclase in rat striatum. J Neurochem. 1997;69(1):365-370.
29. Bettler B, Kaupmann K, Mosbacher J, Gassmann M. Molecular structure and physiological functions of GABA(B) receptors. Physiol Rev. 2004;84(3):835-867.
30. Bowery NG. GABAB receptor pharmacology. Annu Rev Pharmacol Toxicol. 1993;33:109-147.
31. Kittler JT, Moss SJ. Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition. Curr Opin Neurobiology. 2003;13(3): 341-347.
32. Ludwig A, Li H, Saarma M, Kaila K, Rivera C. Developmental upregulation of KCC2 in the absence of GABAergic and glutamatergic transmission. Eur J Neurosci. 2003;18(12):3199-3206.
33. Davies SL, Roussa E, Le Rouzic P, et al. Expression of K+-Cl-cotransporters in the alpha-cells of rat endocrine pancreas. Biochim Biophys Acta. 2004;1667(1):7-14.
34. Fernández-Pascual S, Mukala-Nsengu-Tshibangu A, Martín Del Río R, Tamarit-Rodríguez J. Conversion into GABA (gamma-aminobutyric acid) may reduce the capacity of L-glutamine as an insulin secretagogue. Biochem J. 2004;379(3 PART):721-729.
35. Pizarro-Delgado J, Braun M, Hernández-Fisac I, Martín-Del-Río R, Tamarit-Rodriguez J. Glucose promotion of GABA metabolism contributes to the stimulation of insulin secretion in beta-cells. Biochem J. 2010;431(3):381-389.
36. Smismans A, Schuit F, Pipeleers D. Nutrient regulation of gamma-aminobutyric acid release from islet beta cells. Diabetologia. 1997;40(12):1411-1415.
37. Winnock F, Ling Z, De Proft R, et al. Correlation between GABA release from rat islet beta-cells and their metabolic state. Am J Physiol Endocrinol Metab. 2002;282(4):E937-E942.
38. Braun M, Wendt A, Karanauskaite J, et al. Corelease and differential exit via the fusion pore of GABA, serotonin, and ATP from LDCV in rat pancreatic beta cells. J Gen Physiol. 2007;129(3):221-231.
39. Moulder KL, Cormier RJ, Shute AA, Zorumski CF, Mennerick S. Homeostatic effects of depolarization on Ca2+ influx, synaptic signaling, and survival. J Neurosci. 2003;23(5):1825-1831.
40. Vithlani M, Moss SJ. The role of GABAAR phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition. Biochem Soc Trans. 2009;37(6 PART):1355-1358.
41. Fukura H, Komiya Y, Igarashi M. Signaling pathway downstream of GABAA receptor in the growth cone. J Neurochem. 1996;67(4): 1426-1434.
42. Porcher C, Hatchett C, Longbottom RE, et al. Positive feedback regulation between gamma-aminobutyric acid type A (GABA(A)) receptor signaling and brain-derived neurotrophic factor (BDNF) release in developing neurons. J Biol Chem. 2011;286(24):21667-21677.
43. Terunuma M, Pangalos MN, Moss SJ. Functional modulation of GABAB receptors by protein kinases and receptor trafficking. Adv Pharmacol. 2010;58:113-122.
44. Chou WH, Wang D, McMahon T, et al. GABAA receptor trafficking is regulated by protein kinase Cε and the N-ethylmaleimide-sensitive factor. J Neurosci. 2010;30(42):13955-13965.
45. Birnir B, Korpi ER. The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors. Curr Pharm Des. 2007;13(31):3169-3177.
46. Braun M, Ramracheya R, Bengtsson M, et al. Gamma-aminobutyric acid (GABA) is an autocrine excitatory transmitter in human pancreatic beta-cells. Diabetes. 2010;59(7):1694-1701.
47. Dong H, Kumar M, Zhang Y, et al. Gamma-aminobutyric acid up-and downregulates insulin secretion from beta cells in concert with changes in glucose concentration. Diabetologia. 2006;49(4): 697-705.
48. Schwirtlich M, Emri Z, Antal K, Máté Z, Katarova Z, Szabó G. GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca(2+). FASEB J. 2010;24(4):1218-1228.
49. Jhala US, Canettieri G, Screaton RA, et al. cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev. 2003;17(13):1575-1580.
50. Withers DJ, Gutierrez JS, Towery H, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391(6670):900-904.
51. Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998;273(49):32377-32379.
52. Gu XH, Kurose T, Kato S, et al. Suppressive effect of GABA on insulin secretion from the pancreatic beta-cells in the rat. Life Sci. 1993;52(8):687-694.
53. Brice NL, Varadi A, Ashcroft SJ, Molnar E. Metabotropic glutamate and GABA(B) receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells. Diabetologia. 2002;45(2):242-252.
54. Beales PE, Hawa M, Williams AJ, Albertini MC, Giorgini A, Pozzilli P. Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the non-obese diabetic mouse. Acta Diabetol. 1995;32(1): 53-56.
55. Ligon B, Yang J, Morin SB, Ruberti MF, Steer ML. Regulation of pancreatic islet cell survival and replication by gamma-aminobutyric acid. Diabetologia. 2007;50(4):764-773.
56. Crivello M, Bonaventura MM, Chamson-Reig A, et al. Postnatal development of the endocrine pancreas in mice lacking functional GABAB receptors. Am J Physiol Endocrinol Metab. 2013;304(10): E1064-E1076.
57. Bonaventura MM, Catalano PN, Chamson-Reig A, et al. GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice. Am J Physiol Endocrinol Metab. 2008;294(1):E157-E167.
58. Pizarro-Delgado J, Hernández-Fisac I, Martín-Del-Río R, Tamarit-Rodriguez J. Branched-chain 2-oxoacid transamination increases GABA-shunt metabolism and insulin secretion in isolated islets. Biochem J. 2009;419(2):359-368.
59. Hernández-Fisac I, Fernández-Pascual S, Ortsäter H, et al. Oxo-4-methylpentanoic acid directs the metabolism of GABA into the Krebs cycle in rat pancreatic islets. Biochem J. 2006;400(1):81-89.
60. Alam S, Laughton DL, Walding A, Wolstenholme AJ. Human peripheral blood mononuclear cells express GABAA receptor subunits. Mol Immunol. 2006;43(9):1432-1442.
61. Dionisio L, Jose De Rosa M, Bouzat C, Esandi Mdel C. An intrinsic GABAergic system in human lymphocytes. Neuropharmacology. 2011;60(2-3):513-519.
62. Mendu SK, Bhandage A, Jin Z, Birnir B. Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes. PloS One. 2012;7(8):e42959.
63. Tian J, Chau C, Hales TG, Kaufman DL. GABA(A) receptors mediate inhibition of T cell responses. J Neuroimmunol. 1999;96(1):21-28.
64. Tian J, Lu Y, Zhang H, Chau CH, Dang HN, Kaufman DL. Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. J Immunol. 2004;173(8):5298-5304.
65. Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol. 2009;5(4): 219-226.
66. Kolb-Bachofen V, Epstein S, Kiesel U, Kolb H. Low-dose streptozocin-induced diabetes in mice. Electron microscopy reveals single-cell insulitis before diabetes onset. Diabetes. 1988;37(1):21-27.
67. Cockfield SM, Ramassar V, Urmson J, Halloran PF. Multiple low dose streptozotocin induces systemic MHC expression in mice by triggering T cells to release IFN-gamma. J Immunol. 1989;142(4):1120-1128.
68. Tian J, Dang HN, Yong J, et al. Oral treatment with gamma-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice. PloS One. 2011;6(9):e25338.
69. Bjurstöm H, Wang J, Ericsson I, et al. GABA, a natural immunomodulator of T lymphocytes. J Neuroimmunol. 2008;205(1-2):44-50.
70. Bhat R, Axtell R, Mitra A, et al. Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A. 2010;107(6):2580-2585.
71. Prud’homme GJ, Glinka Y, Udovyk O, Hasilo C, Paraskevas S, Wang Q. GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity. Biochem Biophys Res Commun. 2014; 452(3):649-654.
72. Barlow AD, Xie J, Moore CE, et al. Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia. 2012;55(5):1355-1365.
73. Bell E, Cao X, Moibi JA, et al. Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. Diabetes. 2003;52(11): 2731-2739.
74. Johnson JD, Ao Z, Ao P, et al. Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transplant. 2009;18(8):833-845.
75. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358(9277):221-229.
76. Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10(7):501-513.
77. Pipeleers D, Chintinne M, Denys B, Martens G, Keymeulen B, Gorus F. Restoring a functional beta-cell mass in diabetes. Diabetes Obes Metab. 2008;10 Suppl 4:54-62.
78. Kim J, Richter W, Aanstoot HJ, et al. Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes. 1993;42(12):1799-1808.
79. Ryden AK, Wesley JD, Coppieters KT, Von Herrath MG. Non-antigenic and antigenic interventions in type 1 diabetes. Hum Vaccin Immunother. 2014;10(4):838-846.
80. Agardh CD, Cilio CM, Lethagen A, et al. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications. 2005;19(4):238-246.
81. Ludvigsson J, Faresjö M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18): 1909-1920.
82. Ludvigsson J, Hjorth M, Chéramy M, et al. Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. Ðiabetologia. 2011;54(3):634-640.
83. Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012;366(5): 433-442.
84. Tian J, Dang H, Nguyen AV, Chen Z, Kaufman DL. Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting beta-cell replication in newly diabetic NOD mice. Diabetes. 2014;63(9):3128-3134.
85. Harrison LC, Wentworth JM, Zhang Y, et al. Antigen-based vaccination and prevention of type 1 diabetes. Curr Diab Rep. 2013;13(5): 616-623.
86. Tian J, Dang H, Kaufman DL. Combining antigen-based therapy with GABA treatment synergistically prolongs survival of transplanted ss-cells in diabetic NOD mice. PloS One. 2011;6(9):e25337.
87. Tower DB. The administration of gamma-aminobutyric acid to man: systemic effects and anticonvulsant action. In: Tower DB, Roberts E, editors. Inhibition in the Nervous System and γ-Aminobutyric Acid. New York: Pergamon; 1960:562-578.
88. Cavagnini F, Pinto M, Dubini A, Invitti C, Cappelletti G, Polli EE. Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man. Metabolism. 1982;31(1):73-77.
89. Passariello N, Giugliano D, Torella R, Sgambato S, Coppola L, Frascolla N. A possible role of gamma-aminobutyric acid in the control of the endocrine pancreas. J Clin Endocrinol Metab. 1982;54(6): 1145-1149.
90. Khumarian NG, Mamikonian RS. [On the role of gamma aminobutyric acid in the regulation of the level of glycemia in diabetes mellitus]. Zh Eksp Klin Med. 1967;7(2):3-9. Russian.
91. Bansal P, Wang Q. Insulin as a physiological modulator of glucagon secretion. Am J Physiol Endocrinol Metab. 2008;295(4):E751-E761.
92. Wang Q, Jin T. The role of insulin signaling in the development of beta-cell dysfunction and diabetes. Islets. 2009;1(2):95-101.
93. Egea J, Espinet C, Soler RM, et al. Neuronal survival induced by neurotrophins requires calmodulin. J Cell Biol. 2001;154(3):585-597.
94. Bito H, Deisseroth K, Tsien RW. CREB phosphorylation and dephosphorylation: a Ca(2+)-and stimulus duration-dependent switch for hippocampal gene expression. Cell. 1996;87(7):1203-1214.
95. Park S, Dong X, Fisher TL, et al. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem. 2006; 281(2):1159-1168.