**Background:** Type 2 diabetes mellitus (T2DM) frequently leads to visual impairment, with cataract and diabetic retinopathy (DR) being major causes of blindness. Circadian rhythm disruption is implicated in T2DM and its complications, but most animal studies use nocturnal rodents, which differ from humans in circadian biology and retinal structure. Diurnal sand rats (Psammomys obesus) are more suitable models. Previous work showed that short photoperiod (SP) and standard rodent diet (SRD) induce T2DM and cataract in sand rats. This study aimed to dissect the effects of photoperiod and diet on glucose tolerance and ocular pathology, testing whether ocular changes arise from diabetes alone, circadian disruption alone, or their combination.
**Methods:** Forty-eight male sand rats were assigned to four groups (n=12 each) in a 2x2 design: neutral photoperiod (NP, 12h light:12h dark) with low-energy diet (LED) or SRD, and short photoperiod (SP, 5h light:19h dark) with LED or SRD. Baseline blood glucose and oral glucose tolerance tests (OGTT) were performed at week 20. At week 21, masked slit-lamp examination graded cataracts (0=clear, 1=incipient, 2=partial, 3=mature). At week 22, eyes were enucleated, sectioned, and stained with hematoxylin-eosin. Cell counts in the inner nuclear layer (INL) and outer nuclear layer (ONL) were performed at 60X magnification, and retinal thickness was measured at 20X. Factorial ANOVA with LSD post-hoc tests was used.
**Key Results:** Baseline blood glucose was significantly higher in the SP+SRD (SPSR) group compared to all others (photoperiod effect: F(1,43)=22.124, p<0.001; diet effect: F(1,43)=13.353, p<0.001; no interaction). OGTT at 120 min showed SPSR had significantly higher glucose than all groups (photoperiod: F(1,43)=21.297, p<0.001; diet: F(1,43)=13.414, p<0.001; interaction: F(1,43)=5.433, p<0.05). INL cell counts did not differ among groups. ONL cell counts were significantly lower in SPSR vs. all others (photoperiod: F(1,43)=15.185, p<0.001; interaction: F(1,43)=6.163, p<0.05; no diet main effect). Total retinal cell count was lower in SPSR (photoperiod: F(1,43)=7.628, p<0.01; no diet or interaction). Retinal thickness was significantly greater in SP groups (photoperiod: F(1,43)=44.963, p<0.001; diet borderline p=0.054; no interaction). Cataract incidence: NPLE 0%, NPSR 0%, SPLE 27% (grade 1 only), SPSR 67% (grades 2-3). Photoperiod and diet both significantly affected cataract (photoperiod: F(1,43)=24.090, p<0.0001; diet: F(1,43)=13.582, p<0.001; interaction: F(1,43)=13.582, p<0.001). Higher OGTT glucose correlated with lower INL cells (R=-0.551, p<0.001), lower ONL cells (R=-0.567, p<0.001), lower total retinal cells (R=-0.642, p<0.001), greater retinal thickness (R=0.643, p<0.001), and higher cataract grade (R=0.836, p<0.001).
**Clinical Implications:** This study demonstrates that circadian disruption (short photoperiod) combined with a high-energy diet induces glucose intolerance and ocular pathology in a diurnal rodent model. The SPLE group, which did not develop hyperglycemia, still showed some retinal changes (thickening) and mild cataracts, indicating a direct effect of circadian disruption. The SPSR group, with severe hyperglycemia, had more pronounced retinal cell loss and cataracts, suggesting an additional indirect effect via metabolic dysregulation. The strong correlations between glucose levels and retinal/cataract measures support the role of hyperglycemia in exacerbating ocular damage. These findings underscore the importance of circadian rhythm integrity in preventing diabetic eye complications and suggest that non-pharmacological interventions targeting circadian alignment (e.g., light exposure, meal timing) could be beneficial. The sand rat model, with its diurnal nature and retinal similarity to humans, offers advantages over nocturnal rodents for studying circadian-related ocular diseases.