Glutamate decarboxylase 67 contributes to compensatory insulin secretion in aged pancreatic islets

Abstract

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 γaminobutyric acid (GABA) and CO 2. 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.

Vitamin D Rescues Pancreatic β Cell Dysfunction due to Iron Overload via Elevation of the Vitamin D Receptor and Maintenance of Ca2+ Homeostasis

“…Notably, when the aged mice were fed a vitamin D3‐supplemented diet (20 000 IU kg −1 ), fasting hyperinsulinemia and the abnormal expansion of the islet mass were significantly reduced. Consistent with previous works, [ 33,35 ] the fasting glucose level in aged mice remained low due to hyperinsulinemia (Figure 5C). Vitamin D 3 supplementation increased serum vitamin D 3 levels in young and aged mice (Figure 5D), but there was no difference in serum ferritin levels (Figure 5E).…”

Perfluoroalkyl Substances Stimulate Insulin Secretion by Islet β Cells via G Protein-Coupled Receptor 40

“…To further investigate the effect of PFOS on the insulin secretion activity of β cells, we detected the insulin level of supernatant on the glucose-stimulated insulin secretion (GSIS) by using mouse β-TC-6 cells in vitro . In previous studies, KRBH buffer with BSA was used in the GSIS experiment. ,− BSA is a common protein used in cell related experiments. It can increase cell adhesion and prevent mechanical damage.…”

The role of GABA in islet function

“…Functional consequences of diabetes-related loss of islet GABA have not been studied in vivo . Pharmacological studies that manipulate GABA synthesis and catabolism or GABA receptor signaling, show that loss of GABAergic input profoundly impacts glucose-responsive insulin and glucagon secretion in vitro ( 12 , 46 , 47 ). Islets from donors with T2D attempt to compensate for reduction in GABA by increasing the affinity of GABA A R, possibly by expressing higher affinity receptor subunits ( 10 ).…”