Journal article
CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors
Endocrinology (Philadelphia), Vol.158(10), pp.3325-3338
10/01/2017
DOI: 10.1210/en.2017-00187
PMCID: PMC5659686
PMID: 28977592
Abstract
Although β-cell dysfunction in cystic fibrosis (CF) leads to diabetes, the mechanism by which the cystic fibrosis transmembrane conductance regulator (CFTR) channel influences islet insulin secretion remains debated. We investigated the CFTR-dependent islet-autonomous mechanisms affecting insulin secretion by using islets isolated from CFTR knockout ferrets. Total insulin content was lower in CF as compared with wild-type (WT) islets. Furthermore, glucose-stimulated insulin secretion (GSIS) was impaired in perifused neonatal CF islets, with reduced first, second, and amplifying phase secretion. Interestingly, CF islets compensated for reduced insulin content under static low-glucose conditions by secreting a larger fraction of islet insulin than WT islets, probably because of elevated SLC2A1 transcripts, increased basal inhibition of adenosine triphosphate-sensitive potassium channels (K-ATP), and elevated basal intracellular Ca2+. Interleukin (IL)-6 secretion by CF islets was higher relative to WT, and IL-6 treatment of WT ferret islets produced a CF-like phenotype with reduced islet insulin content and elevated percentage insulin secretion in low glucose. CF islets exhibited altered expression of INS, CELA3B, and several β-cell maturation and proliferation genes. Pharmacologic inhibition of CFTR reduced GSIS by WT ferret and human islets but similarly reduced insulin secretion and intracellular Ca2+ in CFTR knockout ferret islets, indicating that the mechanism of action is not through CFTR. Single-molecule fluorescent in situ hybridization, on isolated ferret and human islets and ferret pancreas, demonstrated that CFTR RNA colocalized within KRT7+ ductal cells but not endocrine cells. These results suggest that CFTR affects β-cell function via a paracrine mechanism involving proinflammatory factors secreted from islet-associated exocrine-derived cell types.
Details
- Title: Subtitle
- CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors
- Creators
- Xingshen Sun - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Yaling Yi - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Weiliang Xie - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Bo Liang - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Michael C Winter - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Nan He - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Xiaoming Liu - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Meihui Luo - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Yu Yang - Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242Katie Larson Ode - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242Aliye Uc - Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242Andrew W Norris - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242John F Engelhardt - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- Endocrinology (Philadelphia), Vol.158(10), pp.3325-3338
- Publisher
- United States
- DOI
- 10.1210/en.2017-00187
- PMID
- 28977592
- PMCID
- PMC5659686
- ISSN
- 0013-7227
- eISSN
- 1945-7170
- Grant note
- P30 ES005605 / NIEHS NIH HHS R24 HL123482 / NHLBI NIH HHS R01 DK097820 / NIDDK NIH HHS R24 DK096518 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 10/01/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Endocrinology and Diabetes; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Radiation Oncology; Gastroenterology, Hepatology, Pancreatology, and Nutrition; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984025372302771
Metrics
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