GABAergic system in the endocrine pancreas: a new target for diabetes treatment

Abstract

Yun Wan,1 Qinghua Wang,1–3 Gerald J Prud’homme4,5 1Department of Endocrinology and Metabolism, Huashan Hospital, Medical College, Fudan University, Shanghai, People’s Republic of China; 2Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St Michael’s Hospital, 3Departments of Physiology and Medicine, Faculty of Medicine, 4Department of Laboratory Medicine and Pathobiology, University of Toronto, 5Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St Michael’s Hospital, Toronto, ON, Canada Abstract: Excessive loss of functional pancreatic β-cell mass, mainly due to apoptosis, is a major factor in the development of hyperglycemia in both type 1 and type 2 diabetes (T1D and T2D). In T1D, β-cells are destroyed by immunological mechanisms. In T2D, while metabolic factors are known to contribute to β-cell failure and subsequent apoptosis, mounting evidence suggests that islet inflammation also plays an important role in the loss of β-cell mass. Therefore, it is of great importance for clinical intervention to develop new therapies. γ-Aminobutyric acid (GABA), a major neurotransmitter, is also produced by islet β-cells, where it functions as an important intraislet transmitter in regulating islet-cell secretion and function. Importantly, recent studies performed in rodents, including in vivo studies of xenotransplanted human islets, reveal that GABA exerts β-cell regenerative effects. Moreover, it protects β-cells against apoptosis induced by cytokines, drugs, and other stresses, and has anti-inflammatory and immunoregulatory activities. It ameliorates the manifestations of diabetes in preclinical models, suggesting potential applications for the treatment of diabetic patients. This review outlines the actions of GABA relevant to β-cell regeneration, including its signaling mechanisms and potential interactions with other mediators. These studies increase our understanding of the regenerative processes of pancreatic β-cells, and help pave the way for the development of regenerative medicine for diabetes. Keywords: β-cell, proliferation, apoptosis, GABA, ion channel, insulin, glucagon, inflammation, diabetes