# Circadian Control of Pancreatic Beta-cell Maturation

> **NIH NIH K01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $153,846

## Abstract

PROJECT SUMMARY/ABSTRACT
Following developmental specification, pancreatic beta cells adapt to changes in the postnatal environment
through functional maturation. They gain glucose-responsive insulin secretion, and gradually refine it by
increasing the glucose threshold for secretion and expanding secretory capacity. While factors promoting beta
cell maturation have been described, the underlying molecular mechanisms and their physiological triggers
remain unclear. New insights into how beta cells acquire their mature phenotype are needed to develop efforts
to curb loss of this phenotype during the onset of type 1 and type 2 diabetes, and to generate functionally
mature beta cells from stem cells that can be used as transplantation therapy.
The transcription factor Dec1 is a modulator of the circadian clock mechanism that is specifically activated
during postnatal beta cell maturation. Dec1 binds promoter/enhancers of genes encoding key mediators of
mature glucose sensing and insulin secretion, and loss of Dec1 in beta cells renders mice diabetic due to
physiologically immature islets. Dr. Alvarez proposes to investigate the molecular basis for these phenotypes,
by 1) examining the impact of Dec1 loss on the epigenome, transcriptome, and proteome of single pancreatic
beta cells, and 2) determining the functional partners and molecular mechanisms by which Dec1 modulates
beta cell maturity.
These innovative experiments complement Dr. Alvarez' prior skills while conferring new training in circadian
live-animal studies and single-cell technologies. A world-class team of mentors and collaborators with leading
experience in these methods and in beta cell, diabetes, and circadian physiology ensures exceptional
guidance. In addition, a series of formal, structured didactic and experiential training activities aimed at
fostering Dr. Alvarez' development as an independent investigator are proposed.
In all, the proposed research and career development activities will be critical to Dr. Alvarez developing a new
independent research program focused on linking circadian biology to beta cell physiology. Results from this
research program will be important to identify and exploit therapeutic opportunities to manage, prevent, or even
restore the loss of mature beta cell function in diabetic patients.

## Key facts

- **NIH application ID:** 10455667
- **Project number:** 5K01DK129442-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Juan R Alvarez
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $153,846
- **Award type:** 5
- **Project period:** 2021-07-22 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455667

## Citation

> US National Institutes of Health, RePORTER application 10455667, Circadian Control of Pancreatic Beta-cell Maturation (5K01DK129442-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10455667. Licensed CC0.

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