AMPK and macrophage crosstalk in diabetes: Mechanisms, inflammation, and therapeutic perspectives.

Diabetes mellitus, especially type 2 diabetes (T2DM), is a complex metabolic disease marked by persistent low-grade inflammation and insulin resistance. In diabetes, adipose tissue macrophages adopt a pro-inflammatory M1 phenotype, secreting cytokines including TNF-α, IL-6, and IL-1β that disrupt insulin signaling and cause metabolic dysfunction. AMP-activated protein kinase (AMPK), a cellular energy sensor, is a key regulator of macrophage polarization. It suppresses M1 responses by inhibiting NF-κB and JNK signaling, activating CREB/SIRT1 pathways, and promoting oxidative metabolism. Therefore, this review investigates the bidirectional interaction between AMPK signaling and macrophage function in diabetes, focusing on how metabolic stress affects AMPK activity, increasing inflammation and insulin resistance, whereas AMPK activation restores immune-metabolic balance. The gut microbiome further influences this axis, with short-chain fatty acids activating AMPK via GPR41/43, promoting M2 polarization and improving metabolic outcomes. Metformin, SGLT2 inhibitors, new direct AMPK activators such as PXL770, and lifestyle changes are also potential therapeutic treatments. However, considerable hurdles remain, including the prevalence of preclinical findings, a lack of macrophage-specific AMPK activators, simplicity of the M1/M2 paradigm, and uncertainty about long-term safety. Future research must focus on macrophage-targeted drug delivery, tissue-specific regulatory networks, biomarker discovery, and rigorous clinical trials with immunological outcomes. In conclusion, the AMPK-macrophage axis is a critical immune-metabolic gatekeeper in diabetes, and targeting this pathway offers a potential technique for restoring immune-metabolic balance, while significant difficulties must be overcome before practical use.