# Role of the Renin-Angiotensin System in Glucose Homeostasis

> **NIH NIH R01** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2022 · $378,012

## Abstract

PROJECT SUMMARY/ABSTRACT
 In treating type 2 diabetes (T2D), there is a paucity of medications simultaneously targeting deficits in both
β-cell function and mass. Angiotensin(1-7), a metabolite of the renin-angiotensin system, may fill this gap;
however, its underlying mechanisms of action are incompletely understood. Our data reveal that the
insulinotropic action of angiotensin(1-7) is dependent on its hydrolysis to the dipeptide, angiotensin(1-2), the
latter also conveying pro-survival and proliferative effects in β cells. Angiotensin(1-2) activates G-protein-
coupled receptor family C group 6 member A (GPRC6A), which we show is expressed in islet a cells. Further,
angiotensin(1-2) increases a cell-derived glucagon-like peptide-1 (GLP-1) release, suggesting it acts via
GPRC6A on the a cell to promote insulin secretion in a paracrine fashion. Indeed, in GLP-1 receptor deficient
islets, we find that angiotensin(1-2) fails to potentiate insulin secretion; however, its ability to enhance β-cell
survival and proliferation is retained. The latter suggests angiotensin(1-2)’s action is, in part, GLP-1 receptor-
independent. Based on these novel data, we hypothesize angiotensin(1-2) enhances β-cell function via intra-
islet paracrine signaling, and promotes β-cell survival/proliferation via a novel GLP-1-independent mechanism.
 The following specific aims address this hypothesis, with the goal of improving treatment options in T2D:
Specific Aim 1. To determine the mechanism by which angiotensin(1-2) increases islet-derived GLP-1
and insulin secretion. Mice (in vivo) and islets (in vitro) with diphtheria toxin-induced a-cell destruction or a
cell-specific GPRC6A knockout will be used to determine whether angiotensin(1-2)-mediated increases in
insulin release require a cells or a-cell GPRC6A, respectively. We will probe mechanisms for increased GLP-1
release, and confirm key findings in human islets with and without GLP-1 receptor or GPRC6A blockade.
Specific Aim 2. To identify signaling pathways/proteins mediating the β-cell survival and proliferative
effects of Ang(1-2) in human islets. The ability of angiotensin(1-2) to inhibit apoptosis, reduce
dedifferentiation and enhance proliferation of β cells will be examined in human islets under non-diabetic and
diabetic conditions. The contribution of mechanisms independent of GLP-1 or GPRC6A will be determined.
Effectors of angiotensin(1-2) action will be identified using non-biased phosphoproteomics, then loss-/gain-of-
function studies in islets will serve as a preliminary screen for effectors that could be targeted therapeutically.
Specific Aim 3. To determine whether Ang(1-2) improves human islet function/survival in vivo, and
whether hydrolysis of Ang(1-7) is required for its anti-diabetic effects. We will utilize a human islet
transplant model to determine the ability of angiotensin(1-2) to improve β-cell function/survival and glycemia in
diabetic mice. Further, we will test whether the insulinotropic ...

## Key facts

- **NIH application ID:** 10499747
- **Project number:** 1R01DK133317-01
- **Recipient organization:** SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
- **Principal Investigator:** Sakeneh Zraika
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,012
- **Award type:** 1
- **Project period:** 2022-07-14 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499747

## Citation

> US National Institutes of Health, RePORTER application 10499747, Role of the Renin-Angiotensin System in Glucose Homeostasis (1R01DK133317-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10499747. Licensed CC0.

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