Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia
Résumé
AMP-activated protein kinase (AMPK) signalling plays a key role in whole-body energy homeostasis although its precise role in pancreatic ß-cell function remains unclear. We therefore investigated whether AMPK plays a critical function in ß-cell glucose sensing and is required for the maintenance of normal glucose homeostasis. Mice lacking AMPKa2 in ß-cells and a population of hypothalamic neurons (RIPCrea2KO mice) and RIPCrea2KO mice lacking AMPKa1 globally were assessed for whole body glucose homeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose stimulated insulin secretion and gene expression changes. Cultured ß-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCrea2KO mice exhibited glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS) and this was exacerbated in a1KORIPCrea2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCrea2KO and a1KORIPCrea2KO mice and conversely GSIS was impaired. ß-cells lacking AMPKa2 or expressing a kinase dead AMPKa2 failed to hyperpolarize in response to low glucose, although KATP channel function was intact. We could detect no alteration of GLUT2, glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 expression was reduced in RIPCrea2KO islets and the UCP2 inhibitor genipin suppressed low-glucose mediated wild type mouse ß-cell hyperpolarization, mimicking the effect of AMPKa2 loss. These data show that AMPKa2 activity is necessary to maintain normal pancreatic ß-cell glucose sensing, possibly by maintaining high ß-cell levels of UCP2.
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