# The effect of endogenous GLP-1 secretion on islet function in vivo

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $510,636

## Abstract

The overall aim of this application is to better understand the role of endogenous Glucagon-Like Peptide-1(GLP-1) signaling, primarily in the fasting state, to influence α-cell and β-cell function both during the fasting state and in response to subsequent meal challenges. This has been an ignored aspect of GLP-1 physiology, given its primarily post-prandial effects. However, therapeutic agents that harness the GLP-1 pathway lower both fasting and postprandial glucose concentrations. In addition, a non-synonymous Single Nucleotide Polymorphism in the GLP-1 receptor, rs3765467, previously shown by us to enhance response to hyperglycemia and to GLP-1, lowers fasting glucose and protects from type 2 diabetes (T2DM). GLP-1 arises by post-translational processing of proglucagon by a specific prohormone convertase enzyme (PC-1/3). There is evidence that this enzyme can be expressed within the islet enabling local production of GLP-1. This may function in a paracrine fashion to augment glucose-stimulated insulin secretion and glucose mediated suppression of glucagon. Expression of PC-1/3 and GLP-1 is increased in T2DM and also by exposure to hyperglycemia and free fatty acids. An explanation of these observations is that GLP-1 may help islet adaptation to metabolic stressors at least early in the course of T2DM. Intriguingly, our preliminary data shows that the effect of antagonizing fasting endogenous GLP-1 secretion differs between people with and without T2DM. Another aspect of α-cell to β-cell communication is that intra-islet glucagon concentrations can act as stimulus to insulin secretion, signaling partially through the GLP-1 receptor. The importance of this in normal physiology and in T2DM is unknown. The proposed experiments will elucidate how rs3765467 alters islet function in the presence and absence of GLP-1 receptor blockade. In addition, we will examine the role of endogenous GLP-1 secretion in T2DM and compare responses to metabolic stress. The experimental conditions will also enable us to examine the role of GLP-1 signaling in the insulin secretory response to glucagon. Successful completion of these experiments will clarify the role of endogenous GLP-1 in vivo.

## Key facts

- **NIH application ID:** 10197125
- **Project number:** 5R01DK126206-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Adrian Vella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $510,636
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197125

## Citation

> US National Institutes of Health, RePORTER application 10197125, The effect of endogenous GLP-1 secretion on islet function in vivo (5R01DK126206-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10197125. Licensed CC0.

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