AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic beta-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in beta-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPK alpha 2 in beta-cells and a population of hypothalamic neurons (RIPCre alpha 2KO mice) and RIPCre alpha 2KO mice lacking AMPK alpha 1 (alpha 1KORIP-Cre alpha 2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured beta-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCre alpha 2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in alpha IKORIPCre alpha 2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCre alpha 2KO and alpha IKORIPCre alpha 2KO mice, and conversely GSIS was impaired. beta-Cells lacking AMPK alpha 2 or expressing a kinase-dead AMPK alpha 2 failed to hyperpolarize in response to low glucose, although K-ATP (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCre alpha 2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wildtype mouse beta-cell hyperpolarization, mimicking the effect of AMPK alpha 2 loss. These results show that AMPK alpha 2 activity is necessary to maintain normal pancreatic beta-cell glucose sensing, possibly by maintaining high beta-cell levels of UCP2.
- AMP-activated protein kinase (AMPK)
- ATP-sensitive potassium channel (K-ATP)
- uncoupling protein 2 (UCP2)
- K-ATP CHANNEL
- UNCOUPLING PROTEIN-2
- GLUCOKINASE GCK