Glucose production by the liver is key to the maintenance of glucose homeostasis and is regulated by the actions of hormones such as insulin and glucagon. Two new studies uncover details of how glucagon regulates glucogenic transcription factors, highlighting a role for calcium signaling in hepatic glucose homeostasis.
Previous studies had linked intracellular calcium to regulation of gluconeogenesis, so Lale Ozcan et al. (Cell Metab. doi:10.1016/j.cmet.2012.03.002) focused on the calcium-sensing enzyme calcium calmodulin-dependent kinase II (CaMKII). They showed that this enzyme is activated by cyclic AMP (cAMP) and glucagon in a calcium-dependent and inositol 1,4,5-triphopshate receptor (IP3R)-dependent manner in hepatocytes. IP3R channels in the endoplasmic reticulum release calcium in response to ligand binding and are important in calcium homeostasis. CaMKII was also activated in the livers of mice in response to glucagon and fasting. A mouse knockout of CaMKIIγ had defective hepatic glucose production and failed to show the phosphorylation and nuclear translocation of the glucogenic transcription factor FoxO1 observed when wild-type mice were subjected to fasting. By contrast, a constitutively active CaMKII mutant had the opposite effects.
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