A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human beta-Cells and Is Impaired in Type 2 Diabetes

作者：Yan Do Richard; Duong Eric; Fox Jocelyn E Manning; Dai Xiaoqing; Suzuki Kunimasa; Khan Shara; Bautista Austin; Ferdaoussi Mourad; Lyon James; Wu Xichen; Cheley Stephen; MacDonald Patrick E^*; Braun Matthias

来源：Diabetes, 2016, 65(8): 2311-2321.

DOI：10.2337/db15-1272

The secretion of insulin from pancreatic islet beta-cells is critical for glucose homeostasis. Disrupted insulin secretion underlies almost all forms of diabetes, including the most common form, type 2 diabetes (T2D). The control of insulin secretion is complex and affected by circulating nutrients, neuronal inputs, and local signaling. In the current study, we examined the contribution of glycine, an amino acid and neurotransmitter that activates ligand-gated Cl- currents, to insulin secretion from islets of human donors with and without T2D. We find that human islet beta-cells express glycine receptors (GlyR), notably the GlyR alpha 1 subunit, and the glycine transporter (GlyT) isoforms GlyT1 and GlyT2. beta-Cells exhibit significant glycine-induced Cl- currents that promote membrane depolarization, Ca2+ entry, and insulin secretion from beta-cells from donors without T2D. However, GlyR alpha 1 expression and glycine-induced currents are reduced in beta-cells from donors with T2D. Glycine is actively cleared by the GlyT expressed within beta-cells, which store and release glycine that acts in an autocrine manner. Finally, a significant positive relationship exists between insulin and GlyR, because insulin enhances the glycine-activated current in a phosphoinositide 3-kinase-dependent manner, a positive feedback loop that we find is completely lost in beta-cells from donors with T2D.

• 出版日期2016-8