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...

BackgroundEnvironmental alternations leading to fetal programming of cardiovascular diseases in later life have been attributed to maternal factors. However, animal studies showed that paternal obesity may program cardio-metabolic diseases in the offspring. In the current study we tested the hypothesis that paternal BMI may be associated with fetal growth.Methods and ResultsWe analyzed the relationship between paternal body mass index (BMI) and birth weight, ultrasound parameters describing the newborn's body shape as well as parameters describing the newborns endocrine system such as cortisol, aldosterone, renin activity and fetal glycated serum protein in a birth cohort of 899 father/mother/child triplets. Since fetal programming is an offspring sex specific process, male and female offspring were analyzed separately. Multivariable regression analyses considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal total glycated serum protein, parity and either gestational age (for birth weight) or time of ultrasound investigation (for ultrasound parameters) as confounding showed that paternal BMI is associated with growth of the male but not female offspring. Paternal BMI correlated with birth parameters of male offspring only: birth weight; biparietal diameter, head circumference; abdominal diameter, abdominal circumference; and pectoral diameter. Cortisol was likewise significantly correlated with paternal BMI in male newborns only.ConclusionsPaternal BMI affects growth of the male but not female offspring. Paternal BMI may thus represent a risk factor for cardiovascular diseases of male offspring in later life. It remains to be demonstrated whether this is linked to an offspring sex specific paternal programming of cortisol secretion.

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Sulfide oxidation is coupled with electricity generation in a sulfide-fed microbial fuel cell (MFC). This study demonstrated that both electrochemical reactions and microbial catalysis were involved in such a complex sulfide oxidation process in the anode of an MFC. The microbe-assisted sulfide oxidation generated a higher persistent current density than the sulfide oxidation via single electrochemical reactions only. Three valence states of S (-II), S (0), and S (+VI) were discovered from the sulfide oxidation, and So, Sx(2-), S4O6(2-), S2O3(2-), and SO4(2-) were detected as the intermediates. Based on the sulfur speciation and microbial community analysis, the sulfide oxidation pathways in the MFC were proposed. The oxidation of sulfide to So/Sx(2-) and further to S4O6(2-)/S2O3(2-) occurred spontaneously as electrochemical reactions, and electricity was generated. The formation of So/Sx(2-) and S2O3(2-) was accelerated by the bacteria in the MFC anode, and SO4(2-) was generated because of a microbial catalysis. The microbe-assisted production of S2O3(2-) and SO4(2-) resulted in a persistent current from the MFC.