Metformin treatment of diabetes mellitus increases the risk for pancreatitis in patients bearing the CFTR-mutation S573C

Cell Physiol Biochem. 2010;25(4-5):389-96. doi: 10.1159/000303043. Epub 2010 Mar 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Diabetes Mellitus / drug therapy*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Metformin / therapeutic use*
  • Oocytes / metabolism
  • Pancreatitis / etiology*
  • Patch-Clamp Techniques
  • Phosphorylation
  • Point Mutation
  • Protein Binding
  • Protein Structure, Tertiary
  • Risk Factors
  • Xenopus laevis

Substances

  • Hypoglycemic Agents
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin
  • Metformin
  • Cyclic AMP