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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 ((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 ofHypomagnesemia 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.show moreshow less

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Metadaten
Author:Anil V. Nair, Berthold HocherGND, Sjoerd Verkaart, Femke van Zeeland, Thiemo Pfab, Torsten Slowinski, You-Peng Chen, Karl Peter Schlingmann, Andre Schaller, Sabina Gallati, Rene J. Bindels, Martin Konrad, Joost G. Hönderop
DOI:https://doi.org/10.1073/pnas.1113811109
ISSN:0027-8424 (print)
Parent Title (English):Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Acad. of Sciences
Place of publication:Washington
Document Type:Article
Language:English
Year of first Publication:2012
Year of Completion:2012
Release Date:2017/03/26
Tag:distal convoluted tubule; kidney; transient receptor potential; vesicular trafficking
Volume:109
Issue:28
Pagenumber:6
First Page:11324
Last Page:11329
Funder:Netherlands Organization for Scientific Research [ZonMw 9120.8026]; European Science Foundation [C05.2134]; Dutch Kidney Foundation; Peter-Stiftung fur die Nierenwissenschaft (Nephrologie)
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
Peer Review:Referiert