GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis.

Indri Purwana, Juan Zheng, Xiaoming Li, Marielle Deurloo, Dong Ok Son, Zhaoyun Zhang, Christie Liang, Eddie Shen, Akshaya Tadkase, Zhong-Ping Feng, Yiming Li, Craig Hasilo, Steven Paraskevas, Rita Bortell, Dale L Greiner, Mark Atkinson, Gerald J Prud'homme, Qinghua Wang

Index: Diabetes 63(12) , 4197-205, (2014)

Full Text: HTML

Abstract

γ-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-γ mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase-Akt and CREB-IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.