Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth

Pfab, Thiemo; Slowinski, Torsten; Godes, Michael; Halle, H; Priem, Friedrich; Hocher, Berthold

doi:10.1161/circulationaha.106.625848

Cited by 55 publications

(57 citation statements)

References 24 publications

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“…To assess the clinical relevance of our unique finding that, unlike TRPM6, TRPM6(V 1393 I) and TRPM6(K 1584 E) were not stimulated by insulin, 997 women from the Berlin Birth Cohort (BBC) (13,14) were analyzed. Detailed data analysis of the entire study population including the maternal TRPM6(V 1393 I) and TRPM6 (K 1584 E) genotypes is shown in Table 1 and Tables S1 and S2.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 997 women from the previously described Berlin Birth Cohort (BBC) (13,14) were included in the study. Mean weight and mean blood pressure were calculated every trimester.…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, the two TRPM6 SNPs, V 1391 I and K 1584 E, were not activated by insulin. The clinical significance of our hypothesis was further substantiated by analyzing these specific SNPs in pregnant women from the Berlin Birth Cohort (BBC) (13,14). …”

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confidence: 87%

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

Nair

Hocher

Verkaart

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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125

137

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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 (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...

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Section: Resultsmentioning

confidence: 99%

“…A total of 997 women from the previously described Berlin Birth Cohort (BBC) (13,14) were included in the study. Mean weight and mean blood pressure were calculated every trimester.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Nair

Hocher

Verkaart

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

125

137

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“…16 As the system works independently of the haemoglobin type, it allowed quantifying glycosylation of fetal haemoglobin (HbF) as well as adult haemoglobin. Briefly, glycated haemoglobin was separated from non-glycated haemoglobin by boronate affinity chromatography.…”

Section: Total Glycated Haemoglobinmentioning

confidence: 99%

Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy

Hocher

Schlemm

Haumann

et al. 2011

J Renin Angiotensin Aldosterone Syst

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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 Charité 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.

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“…In case-control studies including French subjects selected from a population-based registry of births 33,34 , individuals born SGA demonstrated hyperinsulinemia and insulin resistance as early as the age of 20 years when compared with controls born with normal size. In a recent German study, lower birth weight was associated with higher HbA1c among healthy non-diabetic youth 35,36 . Exposure to maternal DM Several reports have convincingly shown that exposure to maternal DM in utero isa significant risk factor for obesity, IGT, and Type 2DM in youth 37 .…”

Section: Psychosocial Factorsmentioning

confidence: 92%

Type 2 Diabetes mellitus in children

Kini¹,

Patil²,

Nawarathna³

et al. 2015

JIMD

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Abstract:While Type 2 diabetes mellitus (T2DM) continues to be a disease of the elderly and the middle aged, currently there has been an upsurge in the incidence of T2DM in the adolescents and the young. Family history, maternal gestational diabetes, low birth weight have contributory role to play in the pathophysiology of T2DM. The pathophysiology underlying the development of alterations in glucose metabolism ranging from abnormal fasting glucose (AFG) to impaired glucose intolerance (IGT) is multifactorial. The early onset of diabetes in childhood or adolescence heralds a long disease interval with resultant escalation of the probability of development of co-morbidities and the entire range of macro-and microvascular complications.

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Low Birth Weight, a Risk Factor for Cardiovascular Diseases in Later Life, Is Already Associated With Elevated Fetal Glycosylated Hemoglobin at Birth

Cited by 55 publications

References 24 publications

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

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

Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy

Type 2 Diabetes mellitus in children

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