The liver is a critical organ for regulating blood glucose levels. During fasting, it produces glucose to supply fuel for tissues that utilize glucose exclusively for energy, and after ingestion of a meal, it clears and stores a significant portion of the ingested glucose in the form of glycogen. These hepatic processes are mediated by the actions of two pancreas-derived hormones, insulin and glucagon, the two main regulators of glucose homeostasis. However, the hepatic signaling pathways activated by these key hormones can be modulated by the presence of other circulating factors, including cytokines. Of potential interest is Pancreatic Derived factor, a novel cytokine-like molecule secreted from the endocrine pancreas but whose its biological function is currently unknown. Here we examine how PANDER regulates glucose homeostasis with a focus on hepatic glucose metabolism and we discuss the potential implications of its effect in promoting metabolic disease states. Employing adenoviral gene delivery, we demonstrate that PANDER overexpression induces elevated fasting glucose, insulin and corticosterone levels in mice. Additionally, PANDER overexpressing mice displayed impaired glucose tolerance but had no defects in glucose-stimulated insulin secretion or peripheral insulin sensitivity. Concomitantly, fasted, hyperglycemic PANDER overexpressers had elevated transcription of hepatic gluconeogenic enzymes, PEPCK and G6Pase. Next we examined the means by which PANDER promotes fasting hyperglycemia and found that treatment of primary hepatocytes with PANDER adenovirus elevated gluconeogenic gene expression and increased glucose output. Furthermore, PANDER increased levels of intracellular cAMP and serine-133 phosphorylated cAMP response element-binding protein (CREB) upon stimulation with adenylate cyclase and glucagon receptor agonists respectively, but no impairment in insulin signaling or action was observed. Further investigation into the association between PANDER and fasting hyperglycemia revealed that loss of PANDER protected mice on a HFD from developing severe fasting hyperglycemia. Collectively, these findings have identified a biological role for PANDER in hepatic glucose regulation. PANDER serves as a novel factor that acts counterregulatory to insulin to induce gluconeogenic gene expression and glucose output by amplifying hepatic cAMP and CREB signaling
