Insights into metformin’s neuroimmune effects: dendritic cell density and corneal nerve health in type 2 diabetes

Aims: Metformin’s potential effects on diabetic peripheral neuropathy (DPN) and immune modulation are not fully understood. This study investigated whether metformin therapy is associated with alterations in corneal nerve fiber morphology and immune cell presence, using corneal confocal microscopy (CCM).

Methods: This cross-sectional study included 97 individuals with type 2 diabetes (T2D) divided into three matched groups: “Metformin”, “Non-metformin”, and “Controls”. Participants underwent nerve conduction studies, assessment of signs and symptoms of DPN, and CCM to quantify corneal nerve fiber metrics, corneal dendritic cell (DC) density, and intraepithelial lymphocytes. Multivariate analyses were adjusted for glycemic control, diabetes duration, and use of other glucose-lowering therapies.

Results: Metformin group had significantly higher corneal nerve fiber density (p=0.020), length (p=0.020), and corneal fractal dimension (p=0.003) compared to Non-metformin group. Additionally, Metformin users showed lower densities of inferior whorl DCs, suggesting reduced corneal immune activation. These findings were present, even after adjustment for confounders. DCs were present in 36%, 69%, and 12% of Metformin, Non-metformin, and Controls groups, respectively. Sural nerve amplitude was not significantly higher in Metformin compared to Non-metformin group (9.5±1.2 µV Vs 7.6±1.2 µV; p=0.240).

Conclusions: These findings suggest that metformin is associated with improved corneal nerve integrity and reduced neuroimmune activation, independent of HbA1c levels.

Comments: This short communication provides valuable insight into metformin’s potential neuroprotective and immunomodulatory effects in people with T2D. A strength of the study is its use of CCM, alongside adjustment for key confounders. A unique aspect of this work is its dual focus on both neural and immune alterations, which are increasingly recognized as interconnected mechanisms in diabetic complications, including DPN. The ability of CCM to directly visualize immune cells in vivo—particularly dendritic cells and intraepithelial lymphocytes—adds an important dimension to the understanding of corneal neuroimmune interactions. The finding that dendritic cell density was lower in the metformin group, suggests that metformin may be associated with reduced corneal immune activation. Interestingly, there was no difference in HbA1c between metformin users and non-users, highlighting that the observed neuroimmune effects may be independent of glycemic control. The finding that metformin is associated with better nerve health and reduced immune activation supports emerging evidence that it may influence diabetic complications beyond its metabolic effects. These results are consistent with preclinical data suggesting that metformin modulates AMP-activated protein kinase (AMPK) signaling, a pathway relevant to both neuro-regeneration and immune regulation.

However, the cross-sectional design limits causal interpretation, and residual confounding cannot be excluded. Because medication use was not randomized, metformin users may differ in unmeasured ways from non-users. Nonetheless, this study underscores CCM's value in exploring neuroimmune dynamics in DPN and suggests metformin’s effects beyond metabolic regulation. Future interventional trials are needed to determine whether metformin actively promotes nerve repair or dampens immune activation—and whether these effects yield meaningful clinical benefits for individuals with DPN.

Mette Krabsmark Borbjerg

Reference: Tsoi AT, Sng J, Tummanapalli SS, Issar T, Poynten AM, Milner KL, Markoulli M, Dhanapalaratnam R, Krishnan AV. Metformin therapy modifies corneal neuroimmune abnormalities in people with type 2 diabetes. Diabetologia. 2025 Jun;68(6):1329-1334. doi: 10.1007/s00125-025-06399-2. Epub 2025 Mar 7. PMID: 40053106; PMCID: PMC12069440.

🔗 https://link.springer.com/article/10.1007/s00125-025-06399-2