# The role of GLP-1 and CCK in the pancreatic islet to promote beta-cell survival

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $376,140

## Abstract

Reduced β-cell mass and increased β-cell apoptosis are key to the pathophysiology of both type 1 and
type 2 diabetes. Therefore, identifying factors that can protect from β-cell apoptosis will meet a critical 
therapeutic need in the prevention and treatment of diabetes. Glucagon-like peptide-1 (GLP-1) and cholecystokinin
(CCK) are peptide hormones normally produced in the intestine with beneficial effects on β-cell mass and 
function. Both GLP-1 and CCK are produced within the pancreatic islet under conditions of islet stress. GLP-1
based therapies are in widespread use for the treatment of type 2 diabetes, and there is substantial evidence
in cell lines and rodent models that GLP-1 can protect from β-cell apoptosis. Similarly, we have shown that
CCK is necessary and sufficient to protect from β-cell apoptosis in mouse models. While CCK has been widely
studied in exocrine pancreatic cells, there is limited information about the role of CCK in the β-cell. We propose
that the production of these hormones in the islet represents a compensatory physiologic mechanism to 
promote β-cell survival. The long-term goal is to identify novel pathways critical in the preservation of β-cell mass.
The overall objective of this application is to determine the regulation of locally produced GLP-1 and CCK and
their role in protection from β-cell apoptosis. The central hypothesis is that an intra-islet signaling network 
exists, whereby GLP-1 produced in the α-cell and CCK produced in the β-cell are co-regulated and work together
to promote β-cell survival. To achieve the objective, three Specific Aims are proposed. In Aim 1, we will 
determine how GLP-1 and CCK production are regulated in the pancreatic islet. Preliminary evidence support the
hypothesis that CCK and GLP-1 signal in a paracrine manner within the islet to co-regulate one another. We
will use transgenic overexpression of β-cell CCK and receptor knockout mouse models to clarify how these
hormones regulate one another in the islet. In Aim 2, we will identify the mechanism of CCK-mediated 
protection from cytokine-induced apoptosis. We will use receptor antagonists and knockouts to determine which CCK
receptor regulates β-cell survival and we will determine the intracellular signaling pathways activated by CCK
in the β-cell. In Aim 3, we will determine if GLP-1 and CCK can synergistically and interdependently protect
human islets from apoptosis. We have intriguing evidence that the role of GLP-1 in β-cell survival is dependent
on CCK receptor signaling in a cell line. This suggests the innovative concept that the impact of GLP-1 on the
β-cell relies on its ability to stimulate CCK. As human islets have very different characteristics than mouse islet,
examining the role of GLP-1 and CCK specifically in human islets is of critical importance to translation of our
findings to diabetes therapies. These studies will contribute to our fundamental understanding of this novel 
intra-islet hormonal regulatory p...

## Key facts

- **NIH application ID:** 10002237
- **Project number:** 5R01DK110324-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Dawn B Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,140
- **Award type:** 5
- **Project period:** 2016-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002237

## Citation

> US National Institutes of Health, RePORTER application 10002237, The role of GLP-1 and CCK in the pancreatic islet to promote beta-cell survival (5R01DK110324-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10002237. Licensed CC0.

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