Bmal1 overexpression in suprachiasmatic nucleus protects from retinal neurovascular deficits in a mouse model of diabetes

Apr 24, 2026Diabetologia

Increasing a key clock gene in the brain's daily rhythm center may protect eye nerve and blood vessel damage in diabetic mice

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Abstract

Bmal1 overexpression in db/db mice significantly decreased the free-running period and improved retinal neuronal function.

Bmal1 overexpression restored retinal neuronal function, as indicated by improvements in electroretinogram responses.
Visual acuity and optomotor behaviour were enhanced in mice with Bmal1 overexpression compared to untreated db/db mice.
Retinal vascular deficits were significantly reduced following Bmal1 overexpression.
Bmal1 overexpression led to decreased fat content in genetically predisposed obese db/db mice.
Improved glucose homeostasis was observed in Bmal1-overexpressing mice, along with reduced hepatic gluconeogenesis.
Levels of plasma noradrenaline and liver tyrosine hydroxylase were decreased, suggesting altered adrenergic signalling in response to Bmal1 overexpression.

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AIMS/HYPOTHESIS: The suprachiasmatic nucleus regulates circadian rhythms and influences physiological and behavioural functions. Clock genes not only play a critical role in orchestrating circadian rhythms, but also regulate a variety of bodily functions. While Bmal1, a clock gene, is vital for maintaining optimal circadian rhythms, its therapeutic potential in type 2 diabetes remains unexplored.

METHODS: In this study, db/db mice, a well-established model of type 2 diabetes exhibiting arrhythmic behaviour and complications, were injected stereotaxically with AAV-Bmal1 or a control virus into the suprachiasmatic nucleus to evaluate the protective effects of Bmal1 overexpression on neurovascular deficits of type 2 diabetes. Given the complex neurovascular network and the eye's unique accessibility as a transparent system, ocular complications were selected as a model to examine the neuronal functional, behavioural and vascular benefits of central overexpression of Bmal1.

RESULTS: Bmal1 overexpression decreased the free-running period, which otherwise is lengthened in db/db mice. Retinal neuronal function was restored on the electroretinogram, along with optomotor behaviour and visual acuity enhancements. Retinal vascular deficits were also significantly reduced. Notably, Bmal1 overexpression decreased fat content in genetically predisposed obese db/db mice compared with the untreated db/db group. As the suprachiasmatic nucleus is known to regulate hepatic glucose production via sympathetic mechanisms, glycaemic control and pyruvate tolerance tests were evaluated. Glucose homeostasis was improved in Bmal1-overexpressing mice, accompanied by a significant reduction in hepatic gluconeogenesis. Plasma noradrenaline (norepinephrine) and liver tyrosine hydroxylase levels were reduced, indicating a protective regulation of adrenergic signalling.

CONCLUSIONS/INTERPRETATION: Our study highlights the therapeutic potential of central overexpression of a clock gene, Bmal1, to mitigate metabolic and neurovascular deficits of type 2 diabetes, offering a compelling framework for incorporating circadian rhythms into managing diabetes and its complications.

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Bmal1 overexpression in suprachiasmatic nucleus protects from retinal neurovascular deficits in a mouse model of diabetes

Abstract

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