LKB1 and AMPKalpha1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia
Sun G., da Silva Xavier G., Gorman T., Priest C., Solomou A., Hodson DJ., Foretz M., Viollet B., Herrera PL., Parker H., Reimann F., Gribble FM., Migrenne S., Magnan C., Marley A., Rutter GA.
AIMS/HYPOTHESIS: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear. METHODS: Here, we ablated LKB1 (alphaLKB1KO), or the catalytic alpha subunits of AMPK (alphaAMPKdKO, -alpha1KO, -alpha2KO), selectively in approximately 45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre. RESULTS: Blood glucose levels in male alphaLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). alphaLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in alphaAMPKalpha1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in alphaLKB1KO, alphaAMPKdKO, and -alpha1KO, but not -alpha2KO islets. CONCLUSIONS/INTERPRETATION: An LKB1-dependent signalling cassette, involving but not restricted to AMPKalpha1, is required in pancreatic alpha cells for the control of glucagon release by glucose.