**1. Introduction**

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved cellular catabolic mechanism that facilitates the degradation of damaged cellular organelles and proteins, by targeting them to the lysosomes and recycling the macromolecules for the rebuilding of cellular machinery [**???** ]. Autophagy undergoes rhythmic variation in accordance with circadian patterns of rest/activity and feeding in adult mammals [**?** ]. Dysregulated autophagy has been implicated in several neurodegenerative disorders, hepatitis, cancer, aging associated diseases and in the general aging process [**?????** ]. Recently, a growing body of evidence indicates that dysregulated autophagy is also linked to diabetes [**????** ].

The disruption of circadian rhythm has a profound negative impact on health and is associated with elevated risk for several diseases [**?** ]. The physiological relevance of an altered circadian rhythm in diabetes is evidenced by the observation of a high incidence of myocardial dysfunction, acute coronary syndrome, sudden cardiac death, and ischemic stroke in diabetics during the night, compared to a higher frequency during the day in non-diabetics [**????** ]. In diabetic conditions, Bmal1 and Clock are inactivated, causing deregulated glucose homeostasis and suppressed diurnal variation in glucose and triglycerides, along with reduced gluconeogenesis [**?** ]. Streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice exhibits altered phase of the circadian clock in the heart [**?** ] and a significant reduction of circadian sensitivity to low-intensity light in the retina [**?** ]. Furthermore, STZ-mice develop a deficiency in their ability to re-entrain the circadian rhythm when subjected to a phase advance of the 12L/12D cycle [**?** ]. Bio-Breeding Zucker diabetic rat (BBZDR/Wor) and Goto-Kakizaki rat type 2 diabetes (T2D) models also show impairment of the molecular clock, suggesting that the disruption of the circadian clock is a common phenomenon in both T1D and T2D [**? ?** ].

Several hallmarks of diabetic retinopathy can be recapitulated in rodent retina deficient of clock genes [**? ?** ]. Reduced tube formation and increased senescence of endothelial cells coupled with impaired progenitor-mediated repair is observed in Per2 mutant mice, emphasizing the importance of the circadian clock in retinal homeostasis [**?** ]. Recent studies on autophagy in the retina have shed light on the association of key molecules of the autophagic pathway with phagocytosis of photoreceptor outer segments (POS) by the retinal pigmented epithelium (RPE) [**? ?** ]. Photoreceptor disk shedding has been widely reported to exhibit diurnal rhythmicity in the retina [**? ?** ] and the tight coupling of phagocytic ingestion and autophagic degradation of the POS to this diurnal rhythm is a critical aspect of retinal homeostasis [**? ?** ].

The role of the peripheral clock and diurnal variation on the regulation of autophagy in the normal and diabetic rodent retinas and the fate of autophagy in the diabetic retina remain unexplored. Understanding these control mechanisms may help find e ffective treatments for diabetic retinopathy. In this study, we demonstrate that the spatial distribution and temporal expression of autophagy proteins show a diurnal rhythm and that this is depressed and phase shifted in the diabetic retina.
