The major findings of this work include: (1) p52 was activated by glucagon in livers of HFD-fed mice, and the activated p52 in turn augmented glucagon response as a positive feedback loop; (2) liver-specific p52 knockdown lowered glucagon-stimulated hyperglycemia, while p52 overexpression augmented glucagon response; (3) p52 inhibited PDE4B gene promoter activity to promote cAMP accumulation, augmenting glucagon response via cAMP/PKA signaling; (4) metformin and ginsenoside lowered blood glucose at least in part by inhibiting p52 activation. The gene discussed is NFKB2; the disease is Hyperglycemia.