# Mechanisms Driving the Kinetics of Incretin-Mediated Beta Cell Responses

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,568

## Abstract

The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic
polypeptide receptor (GIPR), are therapeutic Type 2 Diabetes Mellitus (T2DM) targets. Incretins bind to their
respective receptors on beta () cells to activate adenylyl cyclases (ACs) and generate cAMP, the second
messenger necessary to potentiate glucose-stimulated insulin secretion. Although GIPR and GLP-1R are Gs-
coupled GPCRs that share the same downstream signaling cascades, I discovered that they elicit profoundly
different kinetics of cAMP generation in primary  cells. The mechanisms underlying the difference between
GIPR and GLP-1R signaling are unknown. Furthermore, a direct comparison of the signaling and trafficking
between GIPR and GLP-1R in primary  cells has not been performed. This knowledge gap prompts the need
to improve our understanding of incretin signaling towards more effective T2D treatments. Details of the kinetics
of incretin-induced cAMP responses and how they are affected by GPCR trafficking and the nutrient stimulated
Ca2+ responses, are not well established. By imaging genetically encoded cAMP sensors expressed in  cells, I
have identified differences in the cAMP kinetics of  cells to GIP and GLP-1 stimulation. I propose that these
stark differences connect to differences in receptor trafficking and may explain in part the known differences in
effectiveness between both incretins. Furthermore, I also discovered that incretin-mediated cAMP production is
paradoxically inhibited by Ca2+ induced by glucose and other stimuli, suggesting a dynamic interaction between
Ca2+ and Ca2+-regulated ACs that shapes the kinetics of cAMP formation and determines the  cell insulin
secretory response to nutrient and incretin co-stimulation. My overarching hypothesis is that receptor trafficking,
-Arrestin preferences, and the interplay between Ca2+ and ACs underlie dynamic cAMP kinetics of  cells in
response to nutrient and incretin co-stimulation. I will test this hypothesis in two separate aims that converge on
the functional imaging of primary  cells. In Aim 1, I will quantify trafficking of SNAP-tag incretin receptors co-
expressed with a genetically encoded cAMP sensor in HEK293 cells and primary mouse  cells to determine
how incretin receptor trafficking influences cAMP responses. I will also assess changes in incretin-mediated
cAMP responses in the absence of -Arrestins. In Aim 2 I will multiplex genetically encoded cAMP and Ca2+
sensors to determine the interplay between cAMP and Ca2+ across hundreds of  cells in islets that lack key
ACs. These approaches are innovative as they leverage novel transgenic mouse that expresses endogenous
SNAP-tag GLP-1R in every  cell in islets. Separately, I can quantify cAMP and Ca2+ dynamics in the same cells
using genetically encoded spectrally compatible fluorescent sensors. These proposed aims are significant as
they will provide a comprehensive understanding of the mechanisms ...

## Key facts

- **NIH application ID:** 10825157
- **Project number:** 1F31DK136313-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Michelle Ying-Ying Chan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,568
- **Award type:** 1
- **Project period:** 2024-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825157

## Citation

> US National Institutes of Health, RePORTER application 10825157, Mechanisms Driving the Kinetics of Incretin-Mediated Beta Cell Responses (1F31DK136313-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10825157. Licensed CC0.

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