Two Genetic Variants of TRPM6 Increase Risk for Hypomagnesemia Associated with Diabetes Mellitus Type 2

Abstract

Diabetes mellitus type 2 (DM2) is characterized by high serum glucose levels, insulin resistance and hypomagnesemia. DM2-related hypomagnesemia has been linked to several chronic diabetic complications. Transient receptor potential melastatin 6 (TRPM6) channel plays an essential role in whole body Mg2+ homeostasis. It has been suggested by conducting nested case control study that two non-synonymous single nucleotide polymorphisms (SNP) of TRPM6, TRPM6(V1393I) & TRPM6(K1584E) might increase risk for DM2 in elderly women. Here, by measuring Total Glycosylated Hemoglobin (TGH) from 997 women in their last weeks of pregnancy as a measure of glucose control, we show that the two SNPs (6.8 %) have higher TGH compared to control subjects (6.3 %). Upon overexpression in a human kidney cell line, whole-cell patch clamp analysis showed that insulin activates (EC50 = 0.16 nM) TRPM6, but not the SNPs. Inability to phosphorylate T1391 was the identified factor for lack of insulin-mediated V1393I activation. We further demonstrate that TRPM6 stimulation is independent of its own kinase activity, but relied on both Phosphoinositide 3-kinase and Rac1. The impaired response of the SNPs to insulin may lead to hypomagnesemia causing insulin resistance. These SNPs could be used as markers to improve diagnosis and identify those at risk for developing DM2.