Pancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of glucose intolerance and insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion from aged islets, to fulfill the increased demand for insulin. However, the mechanism underlying enhanced insulin secretion remains unknown. Glutamic acid decarboxylase 67 (GAD67) catalyzes the conversion of glutamate into γ-aminobutyric acid (GABA) and CO₂. Both glutamate and GABA can affect islet function. Here, we investigated the role of GAD67 in insulin secretion in young (3 month old) and aged (24 month old) C57BL/6J male mice. Unlike young mice, aged mice displayed glucose-intolerance and insulin-resistance. However, aged mice secreted more insulin and showed lower fed blood glucose levels than young mice. GAD67 levels in primary islets increased with aging and in response to high glucose levels. Inhibition of GAD67 activity using a potent inhibitor of GAD, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from a pancreatic β-cell line and from young and aged islets. Collectively, our results suggest that blood glucose levels regulate GAD67 expression, which contributes to β-cell responses to impaired glucose homeostasis caused by advanced aging.

胰岛在调节血糖水平中起重要作用。葡萄糖耐受不良和胰岛素抵抗的年龄依赖性发展会导致高血糖症，进而刺激胰岛素合成和老年胰岛的分泌，从而满足对胰岛素日益增长的需求。然而，胰岛素分泌增强的潜在机制仍然未知。谷氨酸脱羧酶67（GAD67）催化谷氨酸转化为γ-氨基丁酸（GABA）和CO ₂。谷氨酸和GABA均可影响胰岛功能。在这里，我们调查了GAD67在年轻（3个月大）和年龄大（24个月大）C57BL / 6J雄性小鼠胰岛素分泌中的作用。与年轻小鼠不同，老年小鼠表现出葡萄糖耐量和胰岛素抵抗。但是，年老的小鼠比年幼的小鼠分泌更多的胰岛素，并显示出较低的进食血糖水平。随着年龄的增长以及对高葡萄糖水平的反应，原发性胰岛中的GAD67水平升高。使用有效的GAD抑制剂3-巯基丙酸抑制GAD67活性，可消除胰岛β细胞系以及年轻和老年胰岛的葡萄糖刺激的胰岛素分泌。总的来说，我们的结果表明血糖水平调节GAD67的表达，这有助于β细胞对由晚期衰老引起的葡萄糖稳态失衡的反应。