# A novel role for 14-3-3-ζ in regulating islet cell crosstalk

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,972

## Abstract

PROJECT SUMMARY
Dysregulation of pancreatic islet function is a hallmark of type 2 diabetes mellitus (T2DM) progression. Thus,
understanding the exact mechanisms by which islet function can be preserved and regulated is crucial. It is
increasingly evident that α-cells play an important role in the potentiation of glucose-stimulated insulin secretion
(GSIS), thereby expanding their function beyond that of the traditional counterregulatory role. However, the
regulation of intra-islet communication and its role in maintaining normal islet function remains incompletely
defined. Endogenous potentiators of β-cell function include glucagon and glucagon-like peptide-1 (GLP-1). While
GLP-1 and glucagon both potentiate GSIS by binding to the GLP-1 receptor (GLP-1R) on the β-cell, GLP-1 is
300-fold more potent at promoting GSIS than glucagon. Canonically, glucagon is produced by the α-cell, and
GLP-1 is produced by the enteroendocrine L-cells in the gut. However, a growing body of literature reports that
under pathophysiological conditions, α-cells can produce and secrete active GLP-1. Our lab has identified the
signaling protein 14-3-3-ζ as a key regulator of α-cell endocrine profile. Specifically, we have found that β-cell
14-3-3-ζ ablation and inhibition increases GSIS and activates α-cell active GLP-1 production and secretion in
mouse and human islets in vitro. How β-cell 14-3-3-ζ expression is regulated and the role of the α-cell in the
impact of β-cell 14-3-3-ζ on islet function is unknown. Therefore, the driving hypothesis of this project is that
β-cell 14-3-3-ζ is a crucial regulator of α-cell to β-cell crosstalk. I will pursue our hypothesis in the following
aims: Aim 1 will define a new pathway regulating β-cell14-3-3-ζ expression. Specifically, our lab has found that
enhanced β-cell GLP-1R signaling decreases 14-3-3-ζ expression in the β-cell. I will study β-cells and mouse
and human islets to define the key signaling nodes by which β-cell GLP-1R signaling decreases 14-3-3-ζ
expression. Aim 2 will determine the efficacy of targeting 14-3-3-ζ in the β-cell to improve islet function in high
fat diet-fed mice. Aim 3 will determine the effect of β-cell 14-3-3-ζ ablation on bidirectional islet cell crosstalk.
Through these carefully designed experiments, I aim to shed light on a new crosstalk mechanism between α-
cells and β-cells, potentially opening new avenues for understanding and treating T2DM. The training plan will
be facilitated by the mentorship of my sponsor, mentorship team and the exceptional facilities and graduate
student support at UC Davis. This proposal describes an integrative and comprehensive training plan to support
my scientific and professional development and propel me toward my long-term goal of becoming an
independent researcher focused on the molecular underpinnings of metabolic disease.

## Key facts

- **NIH application ID:** 10998351
- **Project number:** 1F31DK139734-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Rahaf Shishani
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,972
- **Award type:** 1
- **Project period:** 2024-07-15 → 2027-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998351

## Citation

> US National Institutes of Health, RePORTER application 10998351, A novel role for 14-3-3-ζ in regulating islet cell crosstalk (1F31DK139734-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10998351. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*