INS and Hyperglycemia: Acting as AMPK-related kinases, SIKs exhibit a similar activation property with AMPK,19,22 in an LKB1-mediated phosphorylation dependent manner (Fig. 1a, b).18–20,28 Importantly, physiological changes, such as energy deprivation, insulin, or glucagon perturbation, all manipulate SIK kinase activity.29 For example, insulin stimulation or chronic hyperglycemia could increase SIK protein level and kinase activity.30–32 By contrast, Patel et al.33 reported that insulin did not regulate SIK2 phosphorylation and activity.