# A novel paracrine role for GLP-1 in the islet

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $176,329

## Abstract

Project Summary: A novel paracrine role for GLP-1 in the islet
The preproglucagon gene (Gcg), expressed in the intestine, the pancreas, and a small cluster of neurons in the
hindbrain, encodes multiple peptides in a tissue-specific manner. One of these peptides, glucagon like
peptide-1 (GLP-1) increases following meals, functions to stimulate insulin secretion, and is essential for
normal glucose tolerance. The dogma is that intestinally-derived GLP-1 acts as a hormone binding to
pancreatic GLP-1 receptors (GLP-1r) to stimulate insulin secretion. However, in both human and rodent
models, there is emerging in vitro and pathophysiological evidence to support the production of GLP-1 in the
endocrine pancreas. Our preliminary data reveal in vivo evidence that not only does a pancreatic source of
GLP-1 exist, but that this pool of active peptide plays a necessary physiological role in normal glucose
tolerance. These data represent a paradigm shift in our understanding of the GLP-1 system. In this model, the
acute insulinotropic effects of endogenous GLP-1 are paracrine rather than endocrine, derived from islet α-
cells and acting on β-cell GLP-1r to stimulate insulin secretion. This model would address many of the
questions faced when arguing that GLP-1 has classical endocrine action on the islets. Limited by rapid
intravascular metabolism, the plasma concentrations of GLP-1 are relatively low and are only modestly
elevated during meal ingestion. Interestingly, there are multiple experimental models available that manipulate
plasma and/or pancreatic GLP-1 and even more interesting is that two, in particular, represent extremes in β-
cell function. Both streptozotocin-induced diabetes and bariatric surgery raise plasma and/or pancreatic GLP-1
with opposite effects on islet function. In this proposal, we will use our unique genetic models combined with
pharmacological and surgical interventions in order to advance the understanding of the in vivo role of
pancreatic GLP-1 and in the process will help elucidate many controversies surrounding this source of GLP-1.
We propose to do this in 2 specific aims: Specific Aim 1 is focused on understanding the physiological
function of pancreatic GLP-1 and will test the hypothesis that pancreatic GLP-1 stimulates insulin
secretion and production through paracrine mechanisms. Specific Aim 2 is focused on the
pharmacological function of pancreatic GLP-1 and will test the hypothesis that the contribution of
pancreatic GLP-1 to β-cell function increases in bariatric surgery and streptozotocin-induced diabetes.

## Key facts

- **NIH application ID:** 10313382
- **Project number:** 7R01DK107282-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** DARLEEN A. SANDOVAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $176,329
- **Award type:** 7
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313382

## Citation

> US National Institutes of Health, RePORTER application 10313382, A novel paracrine role for GLP-1 in the islet (7R01DK107282-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10313382. Licensed CC0.

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