Circadian rhythms in diabetic retinopathy: an overview of pathogenesis and investigational drugs

ABSTRACT

Introduction

Circadian rhythm is a natural endogenous process occurring roughly every 24 hours. Circadian rhythm dysfunction is involved in diabetic retinopathy (DR) pathogenesis. Interestingly, there are investigational drugs that exhibit potential in the treatment of DR by targeting circadian rhythm dysfunction.

Areas covered

We performed a literature search in June 2020 using PubMed’s Medical Subject Heading (MeSH) terms ‘circadian clock,’ ‘circadian rhythms,’ and ‘diabetic retinopathy.’ This article offers an overview of the physiology of the biological clock and clock regulatory genes and presents an examination of the retinal clock. It discusses the pathogenic mechanisms of DR and emphasizes how circadian rhythm dysfunction at structural, physiological, metabolic and cellular levels, plays a critical role in the development of DR. The latter part of the paper sheds light on those investigational drugs (such as melatonin, tasimelteon and metformin) which exhibit potential in the treatment of DR by the targeting of circadian rhythm dysfunction.

Expert opinion

An enhanced understanding of circadian rhythm and its role in DR could offer therapeutic potential by targeting of circadian rhythm dysfunction.

KEYWORDS:

• Diabetic retinopathy
• circadian rhythms
• clock genes
• melatonin

Article Highlights

• Diabetic retinopathy (DR) is the most common complications of diabetes and its incidence is increasing alarmingly due to the global rise in the number of diabetics

• The pathogenesis of DR is multifactorial, and the precise mechanism remains unknown

• Emerging studies suggest that circadian rhythms may play an integral role in DR pathogenesis

• The suprachiasmatic nucleus (SCN) is a centrally located master pacemaker of circadian rhythms, whereas a complex set of clock genes via self-regulatory transcriptional and translational loops regulate the circadian rhythm peripherally

• In DR, the circadian rhythm is disturbed at multiple levels: the altered rhythm of retinal thickness, pupillary diameter, decrease in melatonin, metabolic dysfunction, and decrease/dysfunctional clock genes in retinal cell types

• Melatonin, which is at the forefront of the investigational drugs, acts at multiple levels by reducing inflammation, oxidative stress, and apoptosis of retinal cells, thus helping in DR treatment. Clinical trials for melatonin are underway with results expected by the end of 2020

• Other FDA approved candidate molecules such as metformin and tasimelteon could be promising in treating DR based on their mode of action; however further studies are required

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose