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

Cellular Physiology and Biochemistry

关键词: Cystic fibrosis transmembrane conductance regulator;    CFTR AMP;    PKA AMP-activated protein kinase;    S573C;    Pancreatitis;    Metformin;    Pancreas;    Chloride secretion;   

DOI  :  10.1159/000303043

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND