TY  - JOUR
A1  - Nair, Anil V.
A1  - Hocher, Berthold
A1  - Verkaart, Sjoerd
A1  - van Zeeland, Femke
A1  - Pfab, Thiemo
A1  - Slowinski, Torsten
A1  - Chen, You-Peng
A1  - Schlingmann, Karl Peter
A1  - Schaller, Andre
A1  - Gallati, Sabina
A1  - Bindels, Rene J.
A1  - Konrad, Martin
A1  - Hönderop, Joost G.
T1  - Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy
T2  - Proceedings of the National Academy of Sciences of the United States of America
N2  - Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
KW  - kidney
KW  - distal convoluted tubule
KW  - transient receptor potential
KW  - vesicular trafficking
Y1  - 2012
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/35766
SN  - 0027-8424
VL  - 109
IS  - 28
SP  - 11324
EP  - 11329
PB  - National Acad. of Sciences
CY  - Washington
ER  -