Metformin Treatment of Diabetes Mellitus Increases the Risk for Pancreatitis in Patients Bearing the CFTR-mutation S573C

Patthara Kongsuphol, Diane Cassidy, Francisco Romeiras, Rainer Schreiber, Anil Mehta, Karl Kunzelmann

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    Metformin use in diabetes can cause acidosis and might be linked to pancreatitis. Here, we mechanistically focus on this relationship via a point mutation in the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7). CFTR is an ATP-hydrolyzing, cAMP/PKA-activated anion channel regulating pancreatic bicarbonate/chloride secretion across duct-facing apical membranes in epithelia. CFTR has two nucleotide binding domains (NBD1/2) which clamp two ATP molecules across their opposed, inverted interfacial surfaces which generates anion-conductance after ATP hydrolysis. Notably, CFTR mutations not causal for classical cystic fibrosis segregate with unexplained pancreatitis and one of these lies in NBD1 near its ATP-clamp (S573C; close to the Walker B aspartate D572). We recently showed that after raising [cAMP], wt-CFTR chloride-conductance, when expressed in Xenopus oocytes, remains elevated despite the presence of metformin. Yet here, we find that S573C-CFTR manifests a metformin-inhibitable whole cell chloride-conductance after cAMP elevation. In the absence of metformin, cAMP-activated S573C-CFTR also displays a reduced anion-conductance relative to wt-CFTR. Furthermore, intra-oocyte acidification inhibited wt-CFTR and abolished S573C-CFTR conductance. We conclude that defective S573C-CFTR remains both poorly conducting and inhibited by metformin and intracellular acidosis. This might explain the propensity to pancreatitis with this rare CF mutation. Copyright (C) 2010 S. Karger AG, Basel

    Original languageEnglish
    Pages (from-to)389-396
    Number of pages8
    JournalCellular Physiology and Biochemistry
    Volume25
    Issue number4-5
    DOIs
    Publication statusPublished - 2010

    Keywords

    • Cystic fibrosis transmembrane conductance regulator
    • CFTR AMP
    • PKA AMP-activated protein kinase
    • S573C
    • Pancreatitis
    • Metformin
    • Pancreas
    • Chloride secretion
    • ACTIVATED PROTEIN-KINASE
    • CYSTIC-FIBROSIS GENE
    • TRANSMEMBRANE CONDUCTANCE REGULATOR
    • HCO3-SECRETION
    • RENAL-FAILURE
    • BICARBONATE
    • CELLS
    • INHIBITION
    • TRANSPORT

    Cite this