Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy.
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 (V(1393)I, K(1584)E) 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(V(1393)I) and TRPM6(K(1584)E), 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(V(1393)I) and TRPM6(K(1584)E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V(1393)I) and TRPM6(K(1584)E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
Department of Physiology, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands.
Anil V
AV
Nair
Berthold
B
Hocher
Sjoerd
S
Verkaart
Femke
F
van Zeeland
Thiemo
T
Pfab
Torsten
T
Slowinski
You-Peng
YP
Chen
Karl Peter
KP
Schlingmann
André
A
Schaller
Sabina
S
Gallati
René J
RJ
Bindels
Martin
M
Konrad
Joost G
JG
Hoenderop
D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D016640:Diabetes, Gestational / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011247:Pregnancy; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*
D007328:Insulin; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D005947:Glucose