# Investigating mechanisms underlying diabetes associated with exocrine pancreas diseases

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $577,694

## Abstract

Summary
 Exocrine pancreas diseases like chronic pancreatitis (CP) and pancreatic ductal
adenocarcinoma (PDAC) can engender type 3c diabetes mellitus (T3cD: also called
pancreatogenic diabetes), a form of human diabetes that is distinct, but shares some features of
type 1 and 2 diabetes. It is increasingly recognized that T3cD likely represents a substantial
fraction of all diabetes in some populations, but the cellular, genetic and signaling basis of T3cD
are poorly understood. To address this knowledge 'gap' we created a tissue procurement
workflow focused on CP patients, and investigated primary islets from these subjects. We found
evidence for deranged gene expression in islet alpha cells and excessive glucagon secretion,
preceding overt T3cD. Other analysis suggests that a combination of increased pro-
inflammatory and reduced anti-inflammatory signaling may lead to dysregulated incretin
signaling in alpha cells.
 Thus, we postulate that CP could promote early stages of T3cD by impairing alpha cell
regulation. To test this, we propose in Aim 1 to study gene regulation and electrophysiology in
primary human islet cells procured from subjects with CP and CP with prediabetes, and to test
the hypothesis that incretin-regulated glucagon secretion is enhanced in prediabetes. In Aim 2
we will use modern multiplexed imaging methods (CODEX) and in vitro islet studies to test the
hypothesis that specific inflammatory signaling pathways in CP alter alpha cell gene regulation
and function, leading to excessive glucagon secretion. Together, our studies could identify
mechanisms of alpha cell dysfunction that occur very early in the development of T3cD.
Development of T3cD in CP is thought to presage PDAC; thus, our work could strongly
influence work on identifying biomarkers of PDAC at stages when surgery and other
therapeutics can be applied with curative intent.

## Key facts

- **NIH application ID:** 10978799
- **Project number:** 1R01DK138632-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Seung K Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $577,694
- **Award type:** 1
- **Project period:** 2024-08-07 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978799

## Citation

> US National Institutes of Health, RePORTER application 10978799, Investigating mechanisms underlying diabetes associated with exocrine pancreas diseases (1R01DK138632-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10978799. Licensed CC0.

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