Cystic fibrosis–related diabetes is caused by islet loss and inflammation
Nathaniel J. Hart, … , Patrick E. MacDonald, Alvin C. Powers
Nathaniel J. Hart, … , Patrick E. MacDonald, Alvin C. Powers
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e98240. https://doi.org/10.1172/jci.insight.98240.
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Research Article Cell biology Endocrinology

Cystic fibrosis–related diabetes is caused by islet loss and inflammation

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.

Authors

Nathaniel J. Hart, Radhika Aramandla, Gregory Poffenberger, Cody Fayolle, Ariel H. Thames, Austin Bautista, Aliya F. Spigelman, Jenny Aurielle B. Babon, Megan E. DeNicola, Prasanna K. Dadi, William S. Bush, Appakalai N. Balamurugan, Marcela Brissova, Chunhua Dai, Nripesh Prasad, Rita Bottino, David A. Jacobson, Mitchell L. Drumm, Sally C. Kent, Patrick E. MacDonald, Alvin C. Powers

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Figure 1

β Cell CFTR deletion did not alter murine oral glucose tolerance or islet insulin secretion.

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β Cell CFTR deletion did not alter murine oral glucose tolerance or isle...
(A) Murine models created to excise Cftr exon 11 from β cells in an inducible fashion (β Δ11) or from the pancreas with constitutive Cre action (Panc Δ11). (B) Experimental timeline of murine models. Analyses included oral glucose tolerance testing (OGTT) on conscious animals, insulin secretion assays, and RNA sequencing of whole islets. OGTT of (C) male β cell–specific/inducible mice prior to (Pre-Tx; n = 46) and after treatment with vehicle (V; n = 17) or tamoxifen (β Δ11; n = 23) and (D) pancreatic/constitutive mice homozygous for the Cftr wt allele (Panc wt; n = 8) and mice homozygous for the Cftr FL11 allele (Panc Δ11; n = 11). Insulin secretion from isolated islets incubated in medium containing (E and H) 5.6 mM glucose (5.6 G), 16.7 mM glucose (16.7 G), or (F and I) 16.7 mM glucose and 100 μM 3-isobutyl-1-methylxanthine (16.7 G + IBMX), and (G and J) islet insulin content from β cell–specific/inducible mice (E–G: V, n = 8, 5 male, 3 female; β Δ11, n = 9, 6 male, 3 female) and pancreatic/constitutive mice (H–J: Panc wt, n = 13, 6 male, 7 female; Panc Δ11, n = 20, 10 male, 10 female). We observed slight differences in glucose-stimulated insulin secretion, cAMP-potentiated GSIS, and islet insulin content between the control animals of the β Δ11 and Panc Δ11 models. However, the control animals were individualized for each model and differ in the type of Cre recombinase expressed as well as the expression promotor (A). Red represents the β cell–specific/inducible model (β Δ11), blue the pancreatic constitutive model (Panc Δ11). Data represent mean ± SEM. No statistical significance (P < 0.05) was observed in OGTT AUC, insulin secretion, or insulin content in either model. Statistical data were calculated with 1-way ANOVA (C and D) or unpaired 2-tailed Student’s t test (E–J).