Role of CFTR in diabetes‐induced pancreatic ductal fluid and HCO3 secretion

Author:

Ébert Attila12ORCID,Gál Eleonóra1,Tóth Emese34,Szögi Titanilla5,Hegyi Péter3678ORCID,Venglovecz Viktória16ORCID

Affiliation:

1. Department of Pharmacology and Pharmacotherapy University of Szeged Szeged Hungary

2. ELI ALPS ELI‐HU Non‐Proft Ltd Szeged Hungary

3. Translational Pancreatology Research Group, Interdisciplinary Center of Excellence for Research Development and Innovation University of Szeged Szeged Hungary

4. Department of Health Sciences, Department of Theoretical and Integrative Health Sciences University of Debrecen Debrecen Hungary

5. Department of Pathology University of Szeged Szeged Hungary

6. Institute for Translational Medicine, Szentágothai Research Centre, Medical School University of Pécs Pécs Hungary

7. Centre for Translational Medicine Semmelweis University Budapest Hungary

8. Division of Pancreatic Diseases, Heart and Vascular Center Semmelweis University Budapest Hungary

Abstract

AbstractType 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild‐type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO3 secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real‐time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme‐linked immunosorbent assay. Ductal fluid and HCO3 secretion, CFTR activity, and the expression of CFTR, Na+/H+ exchanger‐1, anoctamine‐1 and aquaporin‐1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO3 secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO3 secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO3 secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. imageKey points There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditions The most common disease affecting the endocrine part is type‐1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiency Compared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO3 produced by ductal cells is essential for maintaining normal pancreatic functions Ductal fluid and HCO3 secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role. We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue.

Funder

National Research, Development and Innovation Office

Publisher

Wiley

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