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. G estational diabetes mellitus (GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. Babies born to mothers with GDM are typically at increased risk of large for gestational age (LGA), low blood sugar, and jaundice (1). Women with GDM are at a higher risk for preeclampsia and Caesarean section (1) as well as developing diabetes mellitus type 2 (DM2) later in life (2). GDM affects 3-10% of pregnancies, depending on the population studied. No specific cause has been identified, but it is believed that in particular sex hormones (i.e., estrogen, progesterone, prolactin) produced during pregnancy increases a woman's resistance to insulin, resulting in impaired glucose tolerance (1, 3). Moreover, pregnant women are prone to lose magnesium (Mg 2+ ). Bardicef et al. (4) demonstrated that pregnancy itself is a condition of intracellular Mg 2+ depletion. This depletion was more pronounced in women affected by GDM. The elevation in female hormones as well as Mg 2+ deficiency during pregnancy impairs insulin sensitivity and these disturbances may even act synergistically.There is growing evidence suggesting that Mg 2+ deficiency is a significant risk factor for the development of insulin resistance and subsequently hypertension and DM2 (5-8), but the underlying molecular mechanism is unknown. The first evidence suggesting a direct connection between Mg 2+ deficiency and the occurrence of metabolic diseases came from the identification of a monogenic disease primarily characterized by significant hypomagnesemia that was caused by a mutation in a mitochondrial tRNA (9). Moreover, in a recent genome-wide association (GWA) study, it was demonstrated that certain SNPs nominally associated with hypomagnesemia also correlate with fasting glucose levels, again supporting the hypothesis of a direct link between Mg 2+ a...

Magnesium in Man: Implications for Health and Disease

“…Interestingly, common SNPs in the TRPM6 gene are associated with an increased risk of developing diabetes mellitus type 2 (489). TRPM6 cannot be activated by insulin when these SNPs are present (361). These results suggest that Mg 2ϩ levels may influence the onset and development of diabetes mellitus type 2.…”

“…Insulin may directly affect TRPM6 activity through cylin-dependent kinase 5 (cdk5)-dependent phosphorylation of the channel. Patients with reduced EGFR or insulin receptor (IR) activity are therefore more susceptible to hypomagnesemia (361,459). Additionally, estrogens increase TRPM6 mRNA expression (196).…”

Hypomagnesemia in Type 2 Diabetes: A Vicious Circle?

“…Two SNPs in TRPM6 (p.Val1393Ile [rs3750425] and p.Lys1584Glu [rs2274924]) are associated with increased susceptibility for gestational diabetes mellitus (71). Patch clamp analysis showed that these mutations render the channel insensitive to insulin stimulation (94). Follow-up studies could not confirm associations between serum Mg 2+ values and these two SNPs (69,95).…”

“…In contrast, insulin resistance has been proposed to explain the reduced TRPM6 activity and hypomagnesemia in T2DM (94). Until now, it has been widely accepted that Na + and Mg 2+ transport in the DCT go hand in hand, since reduced NCC activity causes hypomagnesemia as shown in patients with Gitelman syndrome and in users of thiazide diuretics (105,106 Reports on diabetic retinopathy suggest that insulin regulates the potassium channel Kir4.1 in the retina (107,108).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Insulin was reported to enhance surface expression of TRPM6 in human b cells. Two TRPM6 variants (V1393I and K1584E) were recently described in women with gestational DM (Nair et al, 2012).…”