<![CDATA[ABSTRACT Diabetes mellitus remains a significant global health challenge due to inadequate glycemic control, necessitating novel therapeutic approaches. Salt-inducible kinases (SIKs), part of the AMPK family, have been identified as crucial regulators of glucose by suppressing liver glucose production and enhancing glucose uptake in fat and muscle tissues, positioning them as potential therapeutic targets. The purpose of this literature was to discuss the role of SIKs in glucose and lipid metabolism and their involvement in diabetes pathogenesis and to evaluate their potential as therapeutic targets. The discussion reveals that SIKs, particularly SIK2, are crucial for enhancing insulin-stimulated glucose uptake and suppressing hepatic gluconeogenesis, thereby improving insulin sensitivity. However, SIK isoforms can have opposing, tissue-specific roles; for instance, SIK1 may inhibit insulin action in skeletal muscle, while SIK2 promotes it. Pharmacological modulation of SIKs presents a complex but promising strategy, though challenges remain regarding isoform selectivity and potential off-target effects, with ongoing debate on whether activation or inhibition is the ideal approach. In conclusion, SIKs are a multi-faceted and promising therapeutic target for type 2 diabetes, addressing hyperglycemia, insulin resistance, and β-cell dysfunction. However, clinical application is limited by the complexity of SIK regulation, highlighting the need for further research to develop selective modulators and confirm their long-term safety and efficacy. Keywords: Salt-inducible Kinases (SIKs); Diabetes Mellitus; Novel Therapy Correspondence: Nurrahmi E-mail: sarialfari@gmail.com Highlights: This study reviewed the role of SIKs in glucose regulation of patients with diabetes mellitus. Therapy targeting SIKs is expected to be a promising new therapy for glucose control in diabetes patients.]]>
