Diabetes mellitus (DM) is characterized by chronic hyperglycemia. Studies have shown a significantly higher prevalence of anxiety disorders in diabetic populations whose anxiety symptoms impair treatment adherence and exacerbate disease progression. Effective interventions for diabetes-anxiety comorbidity remain limited. 

Recent animal studies have revealed that global brain insulin receptor knockout mice lack anxiety phenotypes, challenging the classical "central insulin resistance" theory which posits this mechanism as the primary driver of anxiety in diabetes. Elevated peripheral chemokine levels in both diabetic and psychiatric patients have led to the hypothesis that hyperglycemia may trigger anxiety through specific chemokines, such as C-C motif ligand 2 (CCL2).

A study published in Nature Metabolism and led by Prof. LI Jia from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences and Prof. ZANG Yi from Lingang Laboratory reported that hyperglycemia increases anxiety-like behavior in diabetic mice by boosting neuronal CCL2 and triggering neuroimmune responses. It is the first to identify chemokine CCL2 in neurons as a key driver of anxiety behavior in the diabetic context.

Using diabetic mouse models, researchers identified elevated CCL2 levels in anxiety-related brain regions and peripheral tissues through behavioral assays and multi-omics analyses. Global or brain-specific CCL2 knockout experiments confirmed that only central CCL2 depletion alleviated anxiety. 

Mechanistically, hyperglycemia transcriptionally upregulated neuronal CCL2 via the Transcription factor tonicity-responsive enhancer-binding protein (TonEBP) pathway. CCL2 then bound to its receptor CCR2, activating microglia and peripheral monocytes to drive neuroinflammation. Clinical transcriptomic analyses revealed marked activation of the TonEBP-CCL2-inflammatory pathway in diabetic human brains, highlighting the translational relevance.

This study not only identifies a promising therapeutic target for diabetes-related anxiety, but also provides a theoretical basis for developing safer and more effective treatments. Besides, it provides a novel perspective on the pathogenesis of diabetes-related mental disorders