Background: Whether suppression of glucose production by metformin is through AMPK-dependent inhibition of gluconeogenic gene expression remains controversial. Results: Metformin inhibits gluconeogenic gene expression in hepatocytes. Conclusion: Low metformin concentrations found in the portal vein suppress glucose production via AMPK-dependent mechanism. Significance: The hyperglucagonemia of diabetes mellitus decreases metformin suppression of glucose production through a PKA-mediated phosphorylation of the AMPK ␣ subunit at Ser-485/497.

Background:The mechanism underlying the activation of AMPK by metformin remains unclear. Results: Metformin promotes the formation of AMPK ␣␤␥ heterotrimeric complex. Conclusion: The formation of the AMPK ␣␤␥ heterotrimeric complex augments AMPK␣ phosphorylation by LKB1 and prevents dephosphorylation by protein phosphatase. Significance: Metformin-mediated formation of the AMPK ␣␤␥ heterotrimeric complex results in AMPK activation by elevating AMPK phosphorylation at Thr-172.

Background: The mechanism driving hepatic gene expression of Foxo1 in the fasted state remains unclear.Results: Activation of cAMP-PKA pathway induces Foxo1 gene expression through CREB and co-activator P300.Conclusion: P300 mediates Foxo1 gene expression by binding to Foxo1 proximal promoter.Significance: Induction of the Foxo1 gene by cAMP-PKA via P300 fully activates the gluconeogenic program during fasting to maintain euglycemia.

Background: Previous characterization of NHERF dimerizations is inconsistent and any physiological function is largely unknown. Results: NHERF2/NHERF3 heterodimerization is the strongest NHERF dimerization and is necessary for carbachol inhibition of NHE3. Conclusion: NHERF2/NHERF3 heterodimerization brings PDZ domains together to assemble macrocomplexes for NHE3 regulation. Significance: Macrocomplexes mediated by NHERF dimerizations could increase the complicity of their regulation of NHE3 and other proteins.