Contribution of glutamate decarboxylase 67 to compensatory insulin secretion in aged pancreatic islets

Pancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion in the aged islets to fulfill the increased demand for insulin. Glutamic acid decarboxylase 67 (GAD67) hydrolyzes glutamate into γ-aminobutyric acid (GABA) and CO 2 .However, not much is known about the physiological function of GAD67 in pancreatic islets during the aging process. Since both glutamate and GABA have been known to affect islet function, in the current study, we aimed to investigate the role of GAD67 in insulin secretion in C57BL/6J male mice fed a normal diet that were 3 months (young), 12 months (middle-aged), and 24 months (aged) old. In comparison to young mice, middle-aged and aged mice were glucose-intolerant and insulin-resistant. However, insulin synthesis and secretory capacity were retained in aged mouse islets. The amount of GAD67 in primary islets increased with aging and high glucose levels. The functional inhibition of GAD67 activity by its specific inhibitor, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from the pancreatic b-cell line and primary islets. Glucose-induced GAD67 expression was inhibited by suppressing the Akt/FoxO1/Pdx1 cascade. These results suggest that GAD67 contributes to the β-cell responses to insulin resistance caused by advanced aging, and indicate that high blood glucose levels enhance GAD67 expression via Akt/FoxO1/Pdx1 insulin downstream signaling. [This work was supported by the Institute for Basic Science (IBS-R013-D1 to HGN) and in part by DGIST (HRHR creative research project grant to WBJ)]