# Defining alpha-cell proglucagon processing for type 2 diabetes treatment

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $387,216

## Abstract

PROJECT SUMMARY: We propose to use state-of-the-art mouse modeling, genetically modified human islets
and a unique single cell RNA-seq technique to generate new insights into the regulation of pancreatic islet
function that will serve as the basis for developing new therapeutics for type 2 diabetes mellitus (T2DM). The
proglucagon-derived peptides, glucagon and glucagon-like peptide-1 (GLP-1), potentiate glucose-stimulated
insulin secretion (GSIS). However, unlike GLP-1, glucagon promotes hepatic glucose production and is a
weaker inducer of GSIS. We identified a pathway that shifts the alpha cell from producing glucagon to
producing GLP-1. We propose to define this pathway to establish a new model describing GLP-1 function and
to identify drug targets that increase alpha cell GLP-1 production. Proglucagon is expressed in gut L cells and
islet alpha cells and is differentially cleaved depending on the prohormone convertase (PC) present.
Canonically, PC1/3 (Pcsk1) is expressed in L cells to produce GLP-1 and PC2 (Pcsk2) is expressed in alpha
cells to produce glucagon. However, our data reveal that beta cell GLP-1 receptor (GLP-1R) signaling
increases alpha cell GLP-1 and Pcsk1 expression. We hypothesize that beta cell GLP-1R signaling increases
alpha cell GLP-1 production to augment GSIS in a paracrine positive feedback loop. We will pursue three aims
to define the alpha cell to beta cell (aims 1 and 2) and the beta cell to alpha cell (aim 3) cross-talk involved in
our model of beta cell GLP-1R function to identify novel targets that raise alpha cell GLP-1:glucagon levels for
T2DM treatment. In aim 1, we will define the contribution of alpha cells to beta cell GLP-1R function in
response to endogenous GLP-1 in high fat diet-fed mice. To this end, we will assess glucose regulation and
GSIS in low fat diet-fed or high fat diet-fed beta cell GLP-1R wild-type and knockout mice, with or without alpha
cell ablation, with or without L cell-derived GLP-1 stimulation. In aim 2, we will define the contribution of alpha
cells to beta cell GLP-1R function in response to exogenous GLP-1. To this end, we will assess glucose
regulation and GSIS in beta cell GLP-1R wild-type and knockout mice, with or without alpha cell ablation, with
or without treatment with a GLP-1R agonist. In aim 3, we will determine the impact of beta cell GLP-1R
signaling on alpha cell fate. We show that beta cell GLP-1R signaling increases the expression of Pcsk1 and
other beta cell-specific genes in human alpha cells and extend upon previous work showing that alpha cells
that express GLP-1 are immature. Thus, we hypothesize that beta cell GLP-1R signaling regulates alpha cell
transcriptional programs to promote conversion of alpha cells into beta-like cells. To test this hypothesis and
identify putative mediators we will perform IHC, lineage tracing and conditioned media studies in mice. In
parallel, we will use a highly sensitive single cell RNA-seq platform that we have developed to as...

## Key facts

- **NIH application ID:** 10331361
- **Project number:** 7R56DK124853-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Bethany Paige Cummings
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,216
- **Award type:** 7
- **Project period:** 2020-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331361

## Citation

> US National Institutes of Health, RePORTER application 10331361, Defining alpha-cell proglucagon processing for type 2 diabetes treatment (7R56DK124853-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10331361. Licensed CC0.

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