Leptin Receptor Deficiency-Associated Diabetes Disrupts Lacrimal Gland Circadian Rhythms and Contributes to Dry Eye Syndrome.

PURPOSE

This study investigated the impact of hyperglycemia in type 2 diabetes mellitus (T2DM) on the circadian rhythms and function of lacrimal glands (LGs) in contributing to dry eye syndrome. We assessed the effects of hyperglycemia on circadian gene expression, immune cell recruitment, neural activity, and metabolic pathways, and evaluated the effectiveness of insulin in restoring normal LG function.

METHODS

Using a T2DM mouse model (db/db mice), circadian transcriptomic changes in LGs were analyzed through RNA sequencing over a 24-hour period. Rhythmic expression of core clock genes, immune and neural activity, and metabolic pathways were evaluated. The effects of insulin treatment on these parameters were also assessed.

RESULTS

Hyperglycemia disrupted the circadian expression of core clock genes in LGs, leading to a 50% reduction in rhythmic gene expression. This was associated with altered immune cell recruitment, impaired neural activity, and metabolic changes. Insulin treatment lowered blood glucose levels but did not restore normal circadian function or tear secretion, exacerbating dry eye syndrome in diabetic mice.

CONCLUSIONS

T2DM significantly disrupts circadian rhythms and function in lacrimal glands, contributing to dry eye syndrome. The limited efficacy of insulin in restoring circadian regulation suggests that hyperglycemia-induced dysfunction in LGs is not solely dependent on blood glucose levels, highlighting the need for therapies targeting circadian rhythms in diabetic ocular complications.