An emerging link between the negative EGFR feedback regulator Mig6 and hepatic glucose production (1115.5)

Abstract

Hepatic glucose production (HGP) from either glycogenolysis or de novo gluconeogenesis requires the hydrolytic cleavage of glucose‐6‐phosphate to glucose and inorganic phosphate by the glucose‐6‐phosphatase catalytic subunit (G6Pase). G6Pase is induced during fasting, type 2 diabetes (T2D), and endoplasmic reticulum (ER) stress to promote HGP. In contrast, G6Pase can be suppressed by hormonal signals including activation of the epidermal growth factor receptor (EGFR). As a negative regulator of EGFR, Mitogen‐inducible gene 6 (Mig6) could be a novel target for modulating HGP. Thus, we hypothesized that Mig6 induction increases HGP by inhibiting EGFR‐mediated suppression of G6Pase. Using C57Bl/6 mice and HepG2 cells, we determined that Mig6, like G6Pase, is induced during fasting, diabetes, and ER stress. To further study this regulation, we generated liver‐specific Mig6 knockout (LKO) mice by crossing Mig6flox/flox mice with albumin‐Cre transgenic mice. Compared to wild‐type littermates, LKO mice had a 2‐fold increase in liver weight and an increase in total liver glycogen. Moreover, LKO had reduced G6Pase expression with no change in glucokinase or PEPCK gene expression, suggesting that EGFR signaling restrains G6Pase expression in vivo. We conclude that similar to G6Pase, Mig6 is dynamically regulated during fasting, obesity‐induced diabetes, and ER stress, thus providing a new therapeutic target for unrestrained HGP in T2D.Grant Funding Source: Supported by a Showalter Research Trust Award from IUSM