Clearly, hormones/agonists that stimulate cAMP/PKA and/or PI3K–Akt in cells promote phosphorylation of SIK2 at multiple sites; however, since the discrepancies described above suggest cell/tissue-specific aspects to the regulation of SIK2, it is imperative to study these processes in precise detail in the liver, the key site of abnormal gluconeogenesis in metabolic disease. This evidence concerns the gene SIK2 and metabolic disease.