Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia
Open Access
- 28 June 2010
- journal article
- research article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 429 (2), 323-333
- https://doi.org/10.1042/bj20100231
Abstract
AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic β-cell function remains unclear. In the present stusy, we therefore investigated whether AMPK plays a critical function in β-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPKα2 in β-cells and a population of hypothalamic neurons (RIPCreα2KO mice) and RIPCreα2KO mice lacking AMPKα1 (α1KORIPCreα2KO) 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 β-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCreα2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in α1KORIPCreα2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCreα2KO and α1KORIPCreα2KO mice, and conversely GSIS was impaired. β-Cells lacking AMPKα2 or expressing a kinase-dead AMPKα2 failed to hyperpolarize in response to low glucose, although KATP (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 RIPCreα2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse β-cell hyperpolarization, mimicking the effect of AMPKα2 loss. These results show that AMPKα2 activity is necessary to maintain normal pancreatic β-cell glucose sensing, possibly by maintaining high β-cell levels of UCP2.Keywords
This publication has 53 references indexed in Scilit:
- ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell functionToxicology and Applied Pharmacology, 2010
- LKB1 Regulates Pancreatic β Cell Size, Polarity, and FunctionCell Metabolism, 2009
- Glucose Deprivation Regulates KATP Channel Trafficking via AMP-Activated Protein Kinase in Pancreatic β-CellsDiabetes, 2009
- Deletion of the von Hippel–Lindau gene in pancreatic β cells impairs glucose homeostasis in miceJCI Insight, 2008
- Glucokinase (GCK) and other susceptibility genes for β-cell dysfunction: the candidate approachBiochemical Society Transactions, 2008
- AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neuronsJCI Insight, 2007
- Mechanisms linking obesity to insulin resistance and type 2 diabetesNature, 2006
- AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissuesThe Journal of Physiology, 2006
- A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cellsThe EMBO Journal, 2006
- 5-Amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by KATP channel-dependent and -independent pathwaysBiochemical and Biophysical Research Communications, 2005