# Mechanisms of Somatostatin-Mediated Inhibition of Insulin and Glucagon

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,384

## Abstract

Somatostatin (SST) is a major inhibitory hormone that is capable of attenuating both glucagon and insulin
secretion from alpha (α) and beta (β) cells respectively within the pancreatic islet of Langerhans. However, there
is a critical gap in our understanding of the basic signaling mechanisms downstream of Somatostatin Receptor
(SSTR) activation, and how these favor the inhibition of insulin secretion under some circumstances and the
inhibition of glucagon secretion under others. Through transcriptomic analysis of purified α and β cell populations
I have identified key differences and potential similarities between both which may begin to explain their cell
specific SST response. Central to these observations, the SSTR profile which provides the input signal between
either cell type is fundamentally different between α and β cells, with both cell types expressing SSTR3 on
primary cilia, while α cells additionally express SSTR2 on their cell surface. Somatostatin signaling is typically
suggested to lead to the inhibition of calcium and/or cAMP in the islet, but the relative importance of SST’s effect
on these parallel signaling cascades is not understood. Furthermore, I have identified a novel SSTR mediated
effector mechanism that actively drives the remodeling of filamentous actin (F-actin) with implications for
secretory granule exocytosis. As such, my central hypothesis is that selective activation of SSTR3 on β cells
and SSTR2 or SSTR3 on α cells will attenuate insulin and glucagon secretion via distinct effects on the quality
and kinetics of Ca2+ and cAMP responses and downstream F-actin polymerization. I will pursue this hypothesis
through two separate aims anchored by high throughput functional imaging of intact islets. First, I will leverage
transgenic mouse lines in which fluorescent reporters of secondary messengers will be delivered to strictly α or
β cells. These islets will then be subjected to individual SSTR agonists and antagonists to understand the
individual contributions of identified cell specific SSTRs. Second, fluorescent reporters of F-actin dynamics will
be employed in live imaging experiments to functionally determine the contribution of SSTR activation on F-actin
polymerization and remodeling. These results will be coupled next generation sequencing data of purified
populations of α and β cells treated with SST and SSTR type specific antagonists. The results of this aim will
characterize an underlying F-actin response to SST contributing to overall hormone attenuation. These
approaches are innovative as they leverage the power of high throughput functional imaging of large populations
of cells to characterize both a novel mechanism and cell type specific response in high resolution. Collectively,
the results of these aims are significant as they will result in a more complete understanding of the mechanisms
by which SST succeeds in attenuating insulin and glucagon release under different metabolic conditions. This
underst...

## Key facts

- **NIH application ID:** 10860984
- **Project number:** 5F31DK132954-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Ryan Hart
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,384
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860984

## Citation

> US National Institutes of Health, RePORTER application 10860984, Mechanisms of Somatostatin-Mediated Inhibition of Insulin and Glucagon (5F31DK132954-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10860984. Licensed CC0.

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