A New Activator of Hepatocyte CaMKII in Fasting and Type 2 Diabetes.

Abstract

Positive regulation of hepatic glucose production (HGP) and stimulation of glycogenolysis during fasting are critical processes to prevent hypoglycemia. A key hormone that carries out this function is glucagon, which is secreted by pancreatic α-cells in response to fasting and acts on its receptor on hepatocytes to promote HGP and glycogenolysis (1). However, as often happens, processes that are critical in physiology can promote disease processes in nonphysiological settings. As such, glucagon-induced HGP is a major contributor to excessive HGP and hyperglycemia in obesity and type 2 diabetes (T2D) (2). In this issue of Diabetes , Wang et al. (3) provide evidence that another circulating factor that is increased in fasting and obesity/T2D—prostaglandin F2α (PGF2α)—also promotes HGP in both fasting and obese, insulin-resistant mice. Previous work has elucidated a number of pathways through which activation of the hepatocyte glucagon receptor (GcgR), which is a G-protein–coupled receptor (GPCR), promotes HGP and glycogenolysis in both fasting and obesity. Specifically, adenylyl cyclase/cyclic AMP-mediated protein kinase A (PKA) activation by G proteins of the GcgR controls the transcriptional regulation of HGP and glycogenolysis through at least three distinct but complementary processes (Fig. 1): phosphorylation of CREB, which results in recruitment of its coactivators, CBP and p300; deactivation of a kinase called SIK2; and activation of inositol 3-phosphate receptors (IP3Rs), leading to release of endoplasmic reticulum calcium into the cytosol and subsequent activation of the phosphatase calcineurin and the kinase Ca2+/calmodulin-activated protein kinase IIγ …