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JCI Insight. 2018 Apr 19;3(8). pii: 98240. doi: 10.1172/jci.insight.98240. eCollection 2018 Apr 19.

Cystic fibrosis-related diabetes is caused by islet loss and inflammation.

Author information

1
Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
2
Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
3
Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
4
School of Medicine, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
5
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
6
Center for Cellular Transplantation, Department of Surgery, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA.
7
Hudson Alpha Institute of Biotechnology, Huntsville, Alabama, USA.
8
Allegheny Singer Research Institute, Pittsburgh, Pennsylvania, USA.
9
School of Medicine, Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
10
VA Tennessee Valley Healthcare, Nashville, Tennessee, USA.

Abstract

Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of β cell CFTR deletion and normal and CF human pancreas and islets. Specific deletion of CFTR from murine β cells did not affect β cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein and electrical activity were not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion, with few changes in key islet-regulatory transcripts. Furthermore, approximately 65% of β cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is caused by β cell loss and intraislet inflammation in the setting of a complex pleiotropic disease and not by intrinsic islet dysfunction from CFTR mutation.

KEYWORDS:

Cell Biology; Diabetes; Endocrinology; Genetic diseases; Islet cells

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