Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy

Nair, Anil V; Hocher, Berthold; Verkaart, Sjoerd; van Zeeland, Femke; Pfab, Thiemo; Slowinski, Torsten; Chen, You-Peng; Schlingmann, Karl Peter; Schaller, André; Gallati, Sabina; Bindels, René J; Konrad, Martin; Hoenderop, Joost G (2012). Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 109(28), pp. 11324-9. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.1113811109

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
UniBE Contributor:	Schaller, André, Gallati, Sabina
ISSN:	0027-8424
Publisher:	National Academy of Sciences NAS
Language:	English
Submitter:	Anette van Dorland
Date Deposited:	04 Oct 2013 14:24
Last Modified:	05 Dec 2022 14:07
Publisher DOI:	10.1073/pnas.1113811109
PubMed ID:	22733750
Web of Science ID:	000306642100061
URI:	https://boris.unibe.ch/id/eprint/8316 (FactScience: 213835)