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

摘要

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.