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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 ((VI)-I-1393, (KE)-E-1584) 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 ((VI)-I-1393) and TRPM6((KE)-E-1584), 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((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
Background: The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of insulin resistance and type 2 diabetes in the general population. The RAAS is activated during pregnancy. However, it is unknown whether the RAAS contributes to glycemia in pregnant women.
Methods: Plasma renin activity (PRA) and plasma aldosterone levels were quantified at delivery in 689 Chinese mothers. An oral glucose tolerance test in fasted women was performed in the second trimester of pregnancy. The diagnosis of gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy were made according to the guidelines of the Chinese Society of Obstetrics.
Results: Plasma aldosterone was significantly higher in pregnant women with GDM as compared to those without impairment of glycemic control (normal pregnancies: 0.27 +/- 0.21 ng/mL, GDM: 0.36 +/- 0.30 ng/mL; p<0.05). Regression analyses revealed that PRA was negatively correlated with fasting blood glucose (FBG) (R-2 = 0.03, p = 0.007), whereas plasma aldosterone and aldosterone/PRA ratio were positively correlated with FBG (R-2 = 0.05, p<0.001 and R-2 = 0.03, p = 0.007, respectively). Multivariable regression analysis models considering relevant confounding factors confirmed these findings.
Conclusions: This study demonstrated that fasting blood glucose in pregnant women is inversely correlated with the PRA, whereas plasma aldosterone showed a highly significant positive correlation with fasting blood glucose during pregnancy. Moreover, plasma aldosterone is significantly higher in pregnant women with GDM as compared to those women with normal glucose tolerance during pregnancy. Although causality cannot be proven in association studies, these data may indicate that the RAAS during pregnancy contributes to the pathogenesis of insulin resistance/new onset of diabetes during pregnancy.
Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life.
Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain.
Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.
Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism.
Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done.
Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70% vs. 6.21 +/- 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80%) compared to II mothers delivering boys (6.21 +/- 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension.
Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.