ESPE Yearbook of Paediatric Endocrinology

Nat Metab 2025;7(5):1052-1072. PMID: 40329008 doi: 10.1038/s42255-025-01281-2

Brief summary: This experimental study showed that, in a mouse model of streptozotocin-induced diabetes, increased expression of the pro-inflammatory chemokine CCL2 in neurons leads to an increase in anxiety-like behaviours during hyperglycemia. Blocking CCL2 signalling in the brain caused notable reductions in these behaviours, which suggests that this chemokine has a role in anxiety induced by diabetes.

Anxiety disorders are frequently observed in individuals with diabetes and may be linked to various diabetes-related factors (1). This study provides strong evidence that hyperglycemia is a major cause for the development of anxiety disorders through a C-C motif chemokine ligand 2 (CCL2)-dependent mechanism, at least in a mouse model of diabetes.

CCL2 levels were increased in brain samples (medial prefrontal cortex and ventral hippocampus) from streptozotocin-induced diabetic mice and were directly linked to the anxiety-like behaviors in this animal model. The increase in neuronal CCL2 emerged to be related to the activation of the Transcription factor tonicity-responsive enhancer-binding protein (TonEBP) pathway. It was shown that once activated, neuronal CCL2 binds to its receptor CCR2, leading to the activation of microglia and peripheral monocytes, which drive neuroinflammation in the brain.

Intracerebroventricular injection of an anti-CCL2 antibody led to reduced anxiety-like behaviors in the diabetic mice. Clinical transcriptomic analyses of human diabetic brains showed a marked activation of the TonEBP-CCL2-inflammatory pathway, confirming the relevance of these findings in humans.

These findings suggest that CCL2–CCR2 signaling is activated by hyperglycemia and promotes neuroinflammation, thereby exacerbating anxiety. These results offer new insights into the connection between diabetes and mental health disorders. Future research should explore the involvement of additional brain regions in hyperglycemia-induced anxiety.

Reference: 1. Akbarizadeh M, Naderi Far M, Ghaljaei F. Prevalence of depression and anxiety among children with type 1 and type 2 diabetes: a systematic review and meta-analysis. World J Pediatr 2022;18(1):16-26.