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Research Article

GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes

Nepton Soltani, Hongmin Qiu, Mila Aleksic, Yelena Glinka, Fang Zhao, Rui Liu, Yiming Li, Nina Zhang, Rabindranath Chakrabarti, Tiffany Ng, Tianru Jin, Haibo Zhang, Wei-Yang Lu, Zhong-Ping Feng, Gerald J. Prud'homme, and Qinghua Wang
  1. aDivision of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8;
  2. bDepartments of Physiology and Medicine, University of Toronto, Toronto, ON, Canada M5S 1C6;
  3. cDepartment of Laboratory Medicine, St Michael's Hospital, Toronto, ON, Canada M5B 1W8;
  4. dDepartment of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China;
  5. eDepartment of Anesthesia, University of Toronto, Toronto, ON, Canada M5S 1C6; and
  6. fDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada N6A 5C2

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PNAS first published June 27, 2011; https://doi.org/10.1073/pnas.1102715108
Nepton Soltani
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Hongmin Qiu
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Mila Aleksic
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Yelena Glinka
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Fang Zhao
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Rui Liu
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Yiming Li
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Nina Zhang
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Rabindranath Chakrabarti
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Tiffany Ng
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Tianru Jin
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Haibo Zhang
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Wei-Yang Lu
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Zhong-Ping Feng
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Gerald J. Prud'homme
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Qinghua Wang
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  • For correspondence: qinghua.wang@utoronto.ca
  1. Edited* by Roger H. Unger, Touchstone Center for Diabetes Research, Dallas, TX, and approved June 2, 2011 (received for review February 23, 2011)

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Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet β-cell loss. Thus, an effective therapy may require β-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet β-cells and immune system. Unlike in adult brain or islet α-cells in which GABA exerts hyperpolarizing effects, in islet β-cells, GABA produces membrane depolarization and Ca2+ influx, leading to the activation of PI3-K/Akt–dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves β-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores β-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The β-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application.

  • insulin
  • inflammation
  • regulatory T-cell

Footnotes

  • ↵1Present address: Department of Physiology, Faculty of Medicine, Hormozgan University of Medical Science, Bandar-Abbas, 7919693116 Iran.

  • ↵2N.S. and H.Q. contributed equally to this work.

  • ↵3Present address: First Teaching Hospital of Xinjiang Medical University, Urumqi 830054, China.

  • ↵4To whom correspondence should be addressed. E-mail: qinghua.wang{at}utoronto.ca.
  • Author contributions: N.S., G.J.P., and Q.W. designed research; N.S., H.Q., M.A., Y.G., F.Z., R.L., N.Z., R.C., T.N., H.Z., Z.-P.F., and Q.W. performed research; N.S., H.Q., M.A., Y.G., F.Z., R.L., Y.L., N.Z., R.C., T.N., T.J., H.Z., W.-Y.L., Z.-P.F., G.J.P., and Q.W. analyzed data; and N.S., G.J.P., and Q.W. wrote the paper.

  • Conflict of interest statement: A patent application authored by N.S and Q.W. has been submitted for an invention related to this study.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1102715108/-/DCSupplemental.

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GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes
Nepton Soltani, Hongmin Qiu, Mila Aleksic, Yelena Glinka, Fang Zhao, Rui Liu, Yiming Li, Nina Zhang, Rabindranath Chakrabarti, Tiffany Ng, Tianru Jin, Haibo Zhang, Wei-Yang Lu, Zhong-Ping Feng, Gerald J. Prud'homme, Qinghua Wang
Proceedings of the National Academy of Sciences Jun 2011, 201102715; DOI: 10.1073/pnas.1102715108

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GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes
Nepton Soltani, Hongmin Qiu, Mila Aleksic, Yelena Glinka, Fang Zhao, Rui Liu, Yiming Li, Nina Zhang, Rabindranath Chakrabarti, Tiffany Ng, Tianru Jin, Haibo Zhang, Wei-Yang Lu, Zhong-Ping Feng, Gerald J. Prud'homme, Qinghua Wang
Proceedings of the National Academy of Sciences Jun 2011, 201102715; DOI: 10.1073/pnas.1102715108
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