Lens Epithelial Cell Proliferation in Patients Suffering From Diabetes and Treated With Metformin in Vitro: a Pilot Study

Cataract remains a leading cause of visual impairment and blindness worldwide, particularly in aging populations. Although several pharmacological approaches have been explored, removal of the lens with phacoemulsification remains the gold standard of treatment. This surgical technique removes the opacified lens while preserving the capsular bag to hold an intraocular lens (IOL).

Despite its overall safety and efficacy, cataract surgery is frequently complicated by posterior capsule opacification (PCO), the most common long-term postoperative issue. PCO leads to secondary visual deterioration and is observed in approximately 20-30% of patients within five years of surgery. The standard treatment for visually significant PCO is neodymium-doped yttrium-aluminium-garnet (Nd:YAG) laser capsulotomy, a rapid and effective outpatient procedure, though not without risks such as increased intraocular pressure, cystoid macular edema, or retinal detachment.

The pathophysiology of PCO involves residual lens epithelial cells (LECs) proliferating, migrating, and undergoing epithelial-mesenchymal transition (EMT), ultimately leading to fibrotic or regenerative capsular changes. Fibrotic variants are characterized by matrix contraction and EMT, while regenerative types manifest as Elschnig pearls.

Multiple risk factors have been associated with PCO, including age, ocular inflammation, and systemic diseases. However, the current evidence remains inconsistent: some studies suggest diabetes may exert a protective effect against PCO, whereas others report an increased risk with longer disease duration. These discrepancies may be due to the lack of subgroup analyses with respect to antidiabetic therapy. In particular, metformin use might act as a protective factor, whereas diabetes without metformin treatment could increase PCO risk. The absence of stratification by medication may thus explain the heterogeneous findings. Beyond PCO, diabetes is linked to multiple ocular comorbidities including retinopathy, ocular surface disease, and a higher overall risk for cataract formation.

Metformin is the most widely prescribed oral antidiabetic drug and exerts pleiotropic effects beyond glucose control. It has demonstrated antifibrotic, antiproliferative, and anti-senescent properties in various tissues. Preclinical studies indicate that metformin suppresses LEC senescence and proliferation, and recent clinical data link metformin use to reduced rates of Nd:YAG laser capsulotomy. In systemic contexts, metformin modulates fibrotic and proliferative responses in hepatic, renal, cardiovascular, and neoplastic tissues primarily via activation of AMP-activated protein kinase (AMPK), inhibition of mTOR signaling, and reduction of oxidative stress and inflammatory pathways.