Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis

in Journal of Endocrinology
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  • 1 Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
  • 2 Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
  • 3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada
  • 4 Division of Advanced Diagnostics, Toronto General Research Institutes, University Health Network, Toronto, Ontario, Canada
  • 5 Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
  • 6 Department of Laboratory Medicine and Pathobiology, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

Correspondence should be addressed to G J Prud’homme or Q Wang: gerald.prudhomme@utoronto.ca or Qinghua.Wang@unityhealth.to
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γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

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  • Accili D, Ahren B, Boitard C, Cerasi E, Henquin JC & Seino S 2010 What ails the beta-cell? Diabetes, Obesity and Metabolism 12 (Supplement 2) 13. (https://doi.org/10.1111/j.1463-1326.2010.01296.x)

    • Search Google Scholar
    • Export Citation
  • Baeyens L, Lemper M, Staels W, De Groef S, De Leu N, Heremans Y, German MS & Heimberg H 2018 (Re)generating human beta cells: status, pitfalls, and perspectives. Physiological Reviews 98 11431167. (https://doi.org/10.1152/physrev.00034.2016)

    • Search Google Scholar
    • Export Citation
  • Batchuluun B, Al Rijjal D, Prentice KJ, Eversley JA, Burdett E, Mohan H, Bhattacharjee A, Gunderson EP, Liu Y & Wheeler MB 2018 Elevated medium-chain acylcarnitines are associated with gestational diabetes mellitus and early progression to type 2 diabetes and induce pancreatic beta-cell dysfunction. Diabetes 67 885897. (https://doi.org/10.2337/db17-1150)

    • Search Google Scholar
    • Export Citation
  • Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, Hadzic B, Druelle N, Napolitano T & Navarro-Sanz S et al. 2017 Long-term GABA administration induces alpha cell-mediated beta-like cell neogenesis. Cell 168 73 .e1185.e11. (https://doi.org/10.1016/j.cell.2016.11.002)

    • Search Google Scholar
    • Export Citation
  • Buendia P, Carracedo J, Soriano S, Madueno JA, Ortiz A, Martin-Malo A, Aljama P & Ramirez R 2015 Klotho prevents NFkappaB translocation and protects endothelial cell from senescence induced by uremia. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 70 11981 209. (https://doi.org/10.1093/gerona/glu170)

    • Search Google Scholar
    • Export Citation
  • Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL & Shultz LD et al. 2017 Age-dependent human beta cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. Journal of Clinical Investigation 127 38353844. (https://doi.org/10.1172/JCI91761)

    • Search Google Scholar
    • Export Citation
  • Deacon CF 2004 Circulation and degradation of GIP and GLP-1. Hormone and Metabolic Research 36 76176 5. (https://doi.org/10.1055/s-2004-826160)

    • Search Google Scholar
    • Export Citation
  • Drucker DJ 2006 The biology of incretin hormones. Cell Metabolism 3 1531 65. (https://doi.org/10.1016/j.cmet.2006.01.004)

  • Drucker DJ 2013 Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 62 331633 23. (https://doi.org/10.2337/db13-0822)

    • Search Google Scholar
    • Export Citation
  • Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, Bertolotto C, Di Mario U, Harlan DM & Perfetti R 2003 Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144 51495 15 8. (https://doi.org/10.1210/en.2003-0323)

    • Search Google Scholar
    • Export Citation
  • Gamble A, Pepper AR, Bruni A & Shapiro AMJ 2018 The journey of islet cell transplantation and future development. Islets 10 8094. (https://doi.org/10.1080/19382014.2018.1428511)

    • Search Google Scholar
    • Export Citation
  • Gershengorn MC, Hardikar AA, Wei C, Geras-Raaka E, Marcus-Samuels B & Raaka BM 2004 Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells. Science 306 2261226 4. (https://doi.org/10.1126/science.1101968)

    • Search Google Scholar
    • Export Citation
  • Griffin KJ, Thompson PA, Gottschalk M, Kyllo JH & Rabinovitch A 2014 Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial. Lancet: Diabetes and Endocrinology 2 71071 8. (https://doi.org/10.1016/S2213-8587(1470115-9)

    • Search Google Scholar
    • Export Citation
  • Jin T & Weng J 2016 Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives. American Journal of Physiology: Endocrinology and Metabolism 311 E620E62 7. (https://doi.org/10.1152/ajpendo.00069.2016)

    • Search Google Scholar
    • Export Citation
  • Keles N, Dogan B, Kalcik M, Caliskan M, Keles NN, Aksu F, Bulut M, Kostek O, Isbilen B & Yilmaz Y et al. 2016 Is serum klotho protective against atherosclerosis in patients with type 1 diabetes mellitus? Journal of Diabetes and its Complications 30 1261 32. (https://doi.org/10.1016/j.jdiacomp.2015.09.013)

    • Search Google Scholar
    • Export Citation
  • Lin Y & Sun Z 2015a Antiaging gene klotho attenuates pancreatic beta-cell apoptosis in type 1 diabetes. Diabetes 64 42984 311. (https://doi.org/10.2337/db15-0066)

    • Search Google Scholar
    • Export Citation
  • Lin Y & Sun Z 2015b In vivo pancreatic beta-cell-specific expression of antiaging gene klotho: a novel approach for preserving beta-cells in type 2 diabetes. Diabetes 64 144414 58. (https://doi.org/10.2337/db14-0632)

    • Search Google Scholar
    • Export Citation
  • Liu W, Son DO, Lau HK, Zhou Y, Prud’homme GJ, Jin T & Wang Q 2017 Combined oral administration of GABA and DPP-4 inhibitor prevents beta cell damage and promotes beta cell regeneration in mice. Frontiers in Pharmacology 8 362. (https://doi.org/10.3389/fphar.2017.00362)

    • Search Google Scholar
    • Export Citation
  • Moibi JA, Gupta D, Jetton TL, Peshavaria M, Desai R & Leahy JL 2007 Peroxisome proliferator-activated receptor-gamma regulates expression of PDX-1 and NKX6.1 in INS-1 cells. Diabetes 56 8895. (https://doi.org/10.2337/db06-0948)

    • Search Google Scholar
    • Export Citation
  • Negi S, Jetha A, Aikin R, Hasilo C, Sladek R & Paraskevas S 2012 Analysis of beta-cell gene expression reveals inflammatory signaling and evidence of dedifferentiation following human islet isolation and culture. PLoS ONE 7 e30415. (https://doi.org/10.1371/journal.pone.0030415)

    • Search Google Scholar
    • Export Citation
  • Nie F, Wu D, Du H, Yang X, Yang M, Pang X & Xu Y 2017 Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus. Journal of Diabetes and its Complications 31 594598. (https://doi.org/10.1016/j.jdiacomp.2016.11.008)

    • Search Google Scholar
    • Export Citation
  • Pettus J, Hirsch I & Edelman S 2013 GLP-1 agonists in type 1 diabetes. Clinical Immunology 149 3173 23. (https://doi.org/10.1016/j.clim.2013.04.006)

    • Search Google Scholar
    • Export Citation
  • Prud’homme GJ, Glinka Y, Hasilo C, Paraskevas S, Li X & Wang Q 2013 GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone. Transplantation 96 6166 23. (https://doi.org/10.1097/TP.0b013e31829c24be)

    • Search Google Scholar
    • Export Citation
  • Prud’homme GJ, Glinka Y, Udovyk O, Hasilo C, Paraskevas S & Wang Q 2014 GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity. Biochemical and Biophysical Research Communications 452 6496 54. (https://doi.org/10.1016/j.bbrc.2014.08.135)

    • Search Google Scholar
    • Export Citation
  • Prud’homme GJ, Glinka Y, Kurt M, Liu W & Wang Q 2017 The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells. Biochemical and Biophysical Research Communications 493 15421547. (https://doi.org/10.1016/j.bbrc.2017.10.029)

    • Search Google Scholar
    • Export Citation
  • Purwana I, Zheng J, Li X, Deurloo M, Son DO, Zhang Z, Liang C, Shen E, Tadkase A & Feng ZP et al. 2014 GABA promotes human beta-cell proliferation and modulates glucose homeostasis. Diabetes 63 41974 205. (https://doi.org/10.2337/db14-0153)

    • Search Google Scholar
    • Export Citation
  • Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer JP & Brooks-Worrell B et al. 2009 Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care 32 2251225 7. (https://doi.org/10.2337/dc09-0773)

    • Search Google Scholar
    • Export Citation
  • Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R & Ng T et al. 2011 GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. PNAS 108 116921169 7. (https://doi.org/10.1073/pnas.1102715108)

    • Search Google Scholar
    • Export Citation
  • Son DO, Liu W, Li X, Prud’homme GJ & Wang Q 2018 Combined effect of GABA and glucagon-like peptide-1 receptor agonist on cytokine-induced apoptosis in pancreatic beta-cell line and isolated human islets. Journal of Diabetes 11 563572. (https://doi.org/10.1111/1753-0407.12881)

    • Search Google Scholar
    • Export Citation
  • Talchai C, Xuan S, Lin HV, Sussel L & Accili D 2012 Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150 122312 34. (https://doi.org/10.1016/j.cell.2012.07.029)

    • Search Google Scholar
    • Export Citation
  • Taylor BL, Liu FF & Sander M 2013 Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Reports 4 126212 75. (https://doi.org/10.1016/j.celrep.2013.08.010)

    • Search Google Scholar
    • Export Citation
  • Tian L, Gao J, Weng G, Yi H, Tian B, O’brien TD & Guo Z 2011 Comparison of exendin-4 on beta-cell replication in mouse and human islet grafts. Transplant International 24 8568 64. (https://doi.org/10.1111/j.1432-2277.2011.01275.x)

    • Search Google Scholar
    • Export Citation
  • Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA & Kaufman DL 2013 Gamma-aminobutyric acid regulates both the survival and replication of human beta-cells. Diabetes 62 3760376 5. (https://doi.org/10.2337/db13-0931)

    • Search Google Scholar
    • Export Citation
  • Tomas E & Habener JF 2010 Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis. Trends in Endocrinology and Metabolism 21 5967. (https://doi.org/10.1016/j.tem.2009.11.007)

    • Search Google Scholar
    • Export Citation
  • Tomas E, Stanojevic V, Mcmanus K, Khatri A, Everill P, Bachovchin WW & Habener JF 2015 GLP-1(32–36)amide pentapeptide increases basal energy expenditure and inhibits weight gain in obese mice. Diabetes 64 240924 19. (https://doi.org/10.2337/db14-1708)

    • Search Google Scholar
    • Export Citation
  • Wan Y, Wang Q & Prud’homme GJ 2015 GABAergic system in the endocrine pancreas: a new target for diabetes treatment. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 8 7987. (https://doi.org/10.2147/DMSO.S50642)

    • Search Google Scholar
    • Export Citation
  • Wang Q & Brubaker PL 2002 Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia 45 126312 73. (https://doi.org/10.1007/s00125-002-0828-3)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Qi M, Mcgarrigle JJ, Rady B, Davis ME, Vaca P & Oberholzer J 2013 Use of glucagon-like peptide-1 agonists to improve islet graft performance. Current Diabetes Reports 13 7237 32. (https://doi.org/10.1007/s11892-013-0402-z)

    • Search Google Scholar
    • Export Citation
  • Wang Q, Ren L, Wan Y & Prud’homme GJ 2019 GABAergic regulation of pancreatic islet cells: physiology and antidiabetic effects. Journal of Cellular Physiology 2019 113. (https://doi.org/10.1002/jcp.28214)

    • Search Google Scholar
    • Export Citation
  • Weinberg N, Ouziel-Yahalom L, Knoller S, Efrat S & Dor Y 2007 Lineage tracing evidence for in vitro dedifferentiation but rare proliferation of mouse pancreatic beta-cells. Diabetes 56 12991 304. (https://doi.org/10.2337/db06-1654)

    • Search Google Scholar
    • Export Citation
  • Wood JR, Miller KM, Maahs DM, Beck RW, Dimeglio LA, Libman IM, Quinn M, Tamborlane WV, Woerner SENetwork TDEC 2013 Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes Care 36 2035203 7. (https://doi.org/10.2337/dc12-1959)

    • Search Google Scholar
    • Export Citation
  • Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S & Ebina Y et al. 2006 Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system. Cell Metabolism 3 4758. (https://doi.org/10.1016/j.cmet.2005.11.015)

    • Search Google Scholar
    • Export Citation
  • Zhao Y, Yang L, Xiang Y, Liu L, Huang G, Long Z, Li X, Leslie RD, Wang X & Zhou Z 2014 Dipeptidyl peptidase 4 inhibitor sitagliptin maintains beta-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. Journal of Clinical Endocrinology and Metabolism 99 E876E8 80. (https://doi.org/10.1210/jc.2013-3633)

    • Search Google Scholar
    • Export Citation