# Splanchno-Hormonal Mechanisms of Cystic Fibrosis Related Diabetes

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $469,490

## Abstract

Project Summary
Cystic fibrosis related diabetes (CFRD) is a unique form of diabetes which develops in the majority of patients
with non-mild cystic fibrosis (CF) by middle age. Even when the degree of hyperglycemia is minimal, CFRD
worsens lung disease and shortens life expectancy. The causes of CFRD are multifactorial and include
insufficient insulin secretion, hepatic insulin resistance, and exocrine pancreatic insufficiency. While exocrine
insufficiency is explained by deficient pancreatic ductal anion transport due to loss of cystic fibrosis
transmembrane conductance regulator (CFTR) function, the causes of diminished insulin secretion and hepatic
insulin resistance are not fully understood. CF induces significant primary disease not only in the exocrine
pancreas, but also in stomach and intestine owing to loss of CFTR function in the gut epithelium. Relatedly, a
variety of gut / splanchnic hormones are disrupted in CF, and these alterations have been postulated to
contribute to CFRD. The most consistently altered splanchnic hormone in CF is pancreatic polypeptide (PP), a
hormone whose metabolic actions have been neglected following the finding that PP-knockout (PP-KO) mice
lack a glucose metabolism phenotype. PP levels are universally low in CF and unresponsive to physiological
stimuli that normally induce secretion. We find circulating PP deficiency is present even in very young children
with CF and in CFTR-KO ferrets despite abundant PP-cells in the pancreas. Using these CF ferrets and newly
generated PP-KO ferrets, we find that supplementation and deficiency of PP have broad effects on glucose
metabolism, representing the first molecular genetic data confirming classic physiological studies indicating
metabolic effects of PP. We hypothesize that PP deficiency in CF represents an underlying parasympathetic
neuronal defect in islet function and contributes to insulin resistance in the liver of individuals with CF. To
determine the mechanism causing deficient PP secretion in CF, we will test the functional, structural, and
neurochemical integrity of parasympathetic neuronal innervation to the PP-secreting cells of the pancreas.
Using traced euglycemic hyperinsulinemic clamps, we will determine the mechanism by which PP
supplementation, using peptide and genetic approaches, improves glucose tolerance in PP-KO and CF ferrets
and determine the PP-receptor involved in this action. We will examine whether PP supplementation, through
its pancreatostatic actions, lessens exocrine pancreatic destruction in CF. Finally, through a newly created
CFTR-G551D mutant knock-in ferret, where the function of the CFTR mutant can be restored by a small
molecule potentiator, we will investigate the connections between early exocrine pancreatic disease in CF and
subsequent endocrine pancreas dysfunction including poor PP secretion. Our studies will not only increase
understanding of the glucoregulatory actions of PP, but are expected to unlock new understanding ...

## Key facts

- **NIH application ID:** 9853014
- **Project number:** 5R01DK115791-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** JOHN F ENGELHARDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,490
- **Award type:** 5
- **Project period:** 2018-01-25 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853014

## Citation

> US National Institutes of Health, RePORTER application 9853014, Splanchno-Hormonal Mechanisms of Cystic Fibrosis Related Diabetes (5R01DK115791-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9853014. Licensed CC0.

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