# Dynorphin, a novel paracrine factor that regulates insulin secretion

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $368,400

## Abstract

Dynorphin, a novel paracrine factor that regulates insulin secretion
 The inability to maintain glucose homeostasis leads to diabetes, a life-threatening disease of epidemic
proportions. The adaptation of pancreatic islets to insulin resistance is a significant determinant of developing
type 2 diabetes (T2D). Within the pancreatic islet, the crosstalk between different islet cells through paracrine
signals orchestrates a hormonal response that controls glucose levels. Dysregulation of these signals contributes
to impaired glucose homeostasis and diabetes.
 The long-term goal of my research program is to understand how paracrine interactions within islet cells
regulate hormone secretion and glucose homeostasis in physiological and pathological conditions. The objective
of this proposal is to assess the β- to δ-cell Dynorphin (Dyn)/Kappa opioid receptor (KOR) negative feedback
loop during physiology and pathological states. The central hypothesis is that insulin secretion is regulated by a
novel β- to δ-cell Dyn/KOR negative feedback loop, and this feedback loop regulates glucose homeostasis and
contributes to hyperglycemia in diabetes. The rationale underlying this proposal is that completion will identify
key targets for improving insulin secretion in conditions of insulin resistance and diabetes. The central hypothesis
will be tested by pursuing two specific aims:
 1) Characterize the Dyn secretion in mouse and human β-cells and determine the contribution to islet function
and glucose homeostasis (First component of the feedback loop).
 2) Determine the role of δ-cell KOR and examine the potential of the Dyn/KOR axis as a therapeutic target in
diabetes (Second component of the feedback loop).
 We will pursue these aims using an innovative combination of newly generated mice models with specific
deletion of KOR in δ-cells and overexpression and deletion of Dyn in β-cells.
 The proposed research is significant because it will identify that the endogenous opioid peptide Dyn, is a key
intra-islet paracrine molecule that regulates insulin secretion and glucose homeostasis. It is also significant
because it will reveal how the regulation of KOR impacts islet secretion in diabetogenic conditions. This work will
develop foundational knowledge of how Dyn and its function in islet cells impact glucose metabolism and insulin
resistance. The proximate expected outcome of this work is understanding the mechanism of how the Dyn/KOR
axis participates in the adaptation of β-cells to insulin resistance and β-cell injury.
The results will have an important positive impact immediately. After all, we will uncover the role of the
Dyn/KOR axis in islet function. Resolving the in vivo mechanisms of β- to δ-cell Dyn/KOR negative feedback
loop will have profound implications for glucose homeostasis and serve to develop potential targets for T2D.

## Key facts

- **NIH application ID:** 10828868
- **Project number:** 5R01DK132095-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Manuel Blandino-Rosano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $368,400
- **Award type:** 5
- **Project period:** 2023-04-17 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828868

## Citation

> US National Institutes of Health, RePORTER application 10828868, Dynorphin, a novel paracrine factor that regulates insulin secretion (5R01DK132095-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10828868. Licensed CC0.

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