Robarts Research Institute, Rome: 7240, University of Western Ontario, 1151 Richmond Street North, London, ON, N6A 5B7, Canada.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Diabetologia. 2017 Jun;60(6):1033-1042. doi: 10.1007/s00125-017-4239-x. Epub 2017 Mar 9.
AIMS/HYPOTHESIS: This study aimed to elucidate the mechanism of increased proliferation of alpha cells in recent-onset type 1 diabetes. Pancreatic beta cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits alpha cell secretion of glucagon. We explored the roles of GABA in alpha cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro.
Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10 mg/kg daily) for 12 days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2 days. The effects of GABA treatment on STZ-induced alpha cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 cell proliferation was also examined.
STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta cells 12 h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the alpha cells at day 1, and a significant increase in alpha cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive cells, alpha cell mass and hyperglucagonaemia. STZ treatment also increased alpha cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca and p-mTOR, and decreased the proliferation rate of αTC1-6 cells.
CONCLUSIONS/INTERPRETATION: GABA signalling critically controls the alpha cell population in pancreatic islets. Low intraislet GABA may contribute to alpha cell hyperplasia in early type 1 diabetes.
目的/假设：本研究旨在阐明新近诊断的 1 型糖尿病中α细胞增殖增加的机制。胰岛β细胞表达 GAD 并产生γ-氨基丁酸（GABA），GABA 抑制α细胞分泌胰高血糖素。我们在 1 型糖尿病小鼠模型和体外条件下探索了 GABA 在α细胞增殖中的作用。
通过注射链脲佐菌素（STZ）诱导 1 型糖尿病。部分 STZ 注射的小鼠用 GABA（10mg/kg 每日）治疗 12 天。用 STZ 或 STZ 联合 GABA 处理分离的胰岛 2 天。评估 GABA 处理对体内和体外 STZ 诱导的α细胞增殖的影响。还研究了 GABA 受体激动剂 muscimol 对αTC1-6 细胞增殖的影响。
STZ 注射后 12 小时，β细胞中 GAD、GABA 和胰岛素水平显著下降；随后，第 1 天α细胞中磷酸化雷帕霉素靶蛋白（p-mTOR）激增，第 3 天α细胞数量显著增加。用 GABA 处理 STZ 注射的小鼠可在β细胞中基本恢复可检测到的胰岛素和 GAD 水平，并显著减少醛脱氢酶 1 家族成员 A3（ALDH1a3）阳性细胞、α细胞质量和高血糖素血症的数量。STZ 处理还增加了分离胰岛中的α细胞增殖，GABA 共处理可逆转这种增殖。Muscimol 与胰岛素一起显著降低了细胞质 Ca 和 p-mTOR 水平，并降低了αTC1-6 细胞的增殖速率。
结论/解释：GABA 信号对胰岛中的α细胞群具有重要的控制作用。胰岛内 GABA 水平低可能导致 1 型糖尿病早期的α细胞增生。
