Anil V. Nair, Berthold Hocher, 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
- 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.…
MetadatenAuthor details: | Anil V. Nair, Berthold HocherORCiDGND, 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 |
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DOI: | https://doi.org/10.1073/pnas.1113811109 |
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ISSN: | 0027-8424 |
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Title of parent work (English): | Proceedings of the National Academy of Sciences of the United States of America |
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Publisher: | National Acad. of Sciences |
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Place of publishing: | Washington |
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Publication type: | Article |
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Language: | English |
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Year of first publication: | 2012 |
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Publication year: | 2012 |
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Release date: | 2017/03/26 |
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Tag: | distal convoluted tubule; kidney; transient receptor potential; vesicular trafficking |
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Volume: | 109 |
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Issue: | 28 |
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Number of pages: | 6 |
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First page: | 11324 |
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Last Page: | 11329 |
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Funding institution: | Netherlands Organization for Scientific Research [ZonMw 9120.8026];
European Science Foundation [C05.2134]; Dutch Kidney Foundation;
Peter-Stiftung fur die Nierenwissenschaft (Nephrologie) |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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Peer review: | Referiert |
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