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

Abstract:

: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.

authors

Nair AV,Hocher B,Verkaart S,van Zeeland F,Pfab T,Slowinski T,Chen YP,Schlingmann KP,Schaller A,Gallati S,Bindels RJ,Konrad M,Hoenderop JG

doi

10.1073/pnas.1113811109

subject

Has Abstract

pub_date

2012-07-10 00:00:00

pages

11324-9

issue

28

eissn

0027-8424

issn

1091-6490

pii

1113811109

journal_volume

109

pub_type

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