Calcium-mediated control

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.

Ozcan et al. then examined the CaMKII pathway in two mouse models of obesity and found that the amounts of phospho-CaMKIIγ were higher in the livers of the obese mice than in those of wild-type mice. Genetic knockdown of CaMKII improved the metabolic deficits of the obese mice, lowering fasting glucose concentrations and the expression of FoxO1 target genes.

A second study by Yiguo Wang et al. (Nature doi:10.1038/nature10988) identifies how glucagon can affect the nuclear localization of another important glucogenic transcription factor, CRTC2, through a different calcium-sensing enzyme, calcineurin. This mechanism was also IP₃R dependent, and the authors showed that hepatic calcineurin activity was increased in two mouse models of diabetes and that knockdown of calcineurin or IP₃R could improve circulating glucose concentrations in these mice.

Together, these studies provide new mechanistic insights into the regulation of hepatic glucose production, and their findings may also be relevant in the settings of obesity and diabetes, although first it will be important to see whether these regulatory mechanisms also operate in humans.