# Clock modulation in circadian desynchrony induced diabetes and atherovascular disease - mechanisms and interventions

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $653,102

## Abstract

Circadian disruption, such as that seen in shift workers, predisposes to insulin resistance and type 2 diabetes
(T2D), and increases the rates of coronary and carotid atherovascular disease (AVD). AVD is the leading cause
of death in the United States and diabetes increases the risk of AVD by 4-fold. However, to date there are no
proven interventions that prevent or mitigate these deleterious effects of circadian disruption. It is, therefore,
imperative to define the molecular underpinnings of circadian disruption on diabetes and atherosclerosis and to
test targeted environmental and pharmacological circadian protective interventions. We have shown previously
that in mice genetic disruption of the circadian clock, by deletion of Bmal1, a non-redundant core clock gene
leads to oxidative stress in β-cells and diabetes. Our preliminary data demonstrates that in mice chronic rotating
shift work schedule-induced circadian disruption is associated with glucose intolerance and diabetes, and with
accelerated atherosclerosis and vulnerable plaque phenotypes. RNA-seq analysis from livers of these mice
demonstrated enrichment of genes involved in oxidative and ER stress. The overarching hypothesis for this
proposal is (1) loss of synchronization between environment, hypothalamic central clock and cell-intrinsic
peripheral clocks leads to dysregulation of cellular stress responses in insulin-sensitive tissues and arterial
macrophages, resulting in metabolic syndrome, T2D and AVD and (2) resynchronizing or enhancing the
molecular clock function will mitigate circadian desynchrony-induced diabetes and AVD. We will use inducible,
cell-type specific genetic Bmal1 deletion, rescue and gain-of-function mouse models to mechanistically test the
differential central and peripheral clock regulation of oxidative and endoplasmic-reticulum (ER) stress pathways
in the pathogenesis of T2D and AVD. These are coupled with clock-modulating environmental and
pharmacological interventional studies of potential translational significance to mitigate risk of T2D and AVD.
The SPECIFIC AIMS for this proposal are: Aim 1- To test if modulating light-dark patterns (circadian-blind but
vision-permissive) will prevent or mitigate circadian desynchrony-induced T2D and AVD. Aim 2-
Pharmacological clock modulation to mitigate circadian desynchrony-induced T2D and AVD. Aim 3- Genetic
deletion and rescue of Bmal1 in central and peripheral clocks to determine the cell-specific requirement of
intrinsic clocks in transcriptional regulation of cellular stress responses in the pathogenesis of circadian
desynchrony-induced T2D and AVD. This Multi-PI proposal is from an interdisciplinary team of three PIs with
complementary expertise in circadian biology, genetic models of circadian disruption diabetes and metabolism
(Dr. Yechoor), lighting interventions, work-related circadian disruption (Dr. Figueiro), AVD, its molecular
mechanisms and foam cell biology (Dr. Paul). The successful completion of th...

## Key facts

- **NIH application ID:** 10317791
- **Project number:** 1R01DK128972-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Mariana Gross Figueiro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $653,102
- **Award type:** 1
- **Project period:** 2021-07-20 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317791

## Citation

> US National Institutes of Health, RePORTER application 10317791, Clock modulation in circadian desynchrony induced diabetes and atherovascular disease - mechanisms and interventions (1R01DK128972-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10317791. Licensed CC0.

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