# Early Pathogenesis of Cystic Fibrosis Related Diabetes > **NIH NIH RC2** · UNIVERSITY OF IOWA · 2021 · $1,493,139 ## Abstract 1 Project Summary 2 Cystic Fibrosis (CF) is the most common lethal autosomal recessive disorder in Caucasian populations and is 3 caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. CF is a multi-organ 4 disease affecting the lung, pancreas, liver, intestine, and gallbladder. Cystic fibrosis related diabetes (CFRD) is 5 the most common severe complication of CF and is associated with increased morbidity and mortality. CFRD, 6 which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly worsens the nutritional and 7 pulmonary health of CF patients. Our studies in CF ferrets and children 3 months to 6 years of age suggest that 8 the underpinnings of CFRD occur very early in life when acinar cells are lost and inflammatory/fibrotic remodeling 9 occurs. In CF ferrets, this exocrine-driven pancreatic remodeling leads to a glycemic crisis caused by b-cell loss 10 and/or dysfunction. Interestingly, the emergence of newly formed b-cells in CF ferrets coincides with a transient 11 recovery in glycemic control. Nonetheless, those CF ferrets with the greatest early-life glycemic disturbances go 12 on to develop CFRD later in life. We have also reported that a similar pattern of glycemic disturbance and 13 recovery occurs in young CF children. Our central hypothesis proposes that new b-cells in the CF ferret pancreas 14 are derived from exocrine progenitors and/or committed dedifferentiated b-cells. Three lineage tracing ferret 15 models will be used to fate map b-cell progenitors (INS-IRES-CreERT2), ductal-derived endocrine progenitors 16 (KRT7-IRES-CreERT2), and acinar-derived endocrine progenitors (PTF1A-IRES-CreERT2). The use of an additional 17 CFTRG551D ferret model, which affords temporal control of pancreatic disease onset using the CFTR modulator 18 VX-770, will allow for dissection of how the developmental timing of pancreatitis impact progenitor cell states 19 and longer-term progression of CFRD. Our in vivo and in vitro preliminary data also show that CF ferret ductal 20 cells acquire properties consistent with the transcriptional and epigenetic states found in pancreatic progenitors 21 during development. The mechanisms of this alteration will be investigated by using in vitro models and the study 22 of pancreatic progenitor cell specification during in utero development of the CF ferret pancreas. The proposed 23 research has brought together two institutions with expertise in animal modeling of CF pancreatic disease, 24 lineage-tracing of islet endocrine precursors, and integrated physiology of CFRD to delineate the mechanism of 25 islet resurgence in CF using the first ever non-rodent lineage-tracing models. These studies are expected to 26 identify mechanisms not only relevant to CFRD, but also other forms of pancreatogenic diabetes. ## Key facts - **NIH application ID:** 10174194 - **Project number:** 1RC2DK124207-01A1 - **Recipient organization:** UNIVERSITY OF IOWA - **Principal Investigator:** JOHN F ENGELHARDT - **Activity code:** RC2 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $1,493,139 - **Award type:** 1 - **Project period:** 2021-04-30 → 2024-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10174194 ## Citation > US National Institutes of Health, RePORTER application 10174194, Early Pathogenesis of Cystic Fibrosis Related Diabetes (1RC2DK124207-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10174194. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*