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Prenatal malnutrition is known to affect the phenotype of the offspring through changes in epigenetic regulation. Growing evidence suggests that epigenetics is one of the mechanisms by which nutrients and minerals affect metabolic traits. Although the perinatal period is the time of highest phenotypic plasticity, which contributes largely to developmental programming, there is evidence of nutritional influence on epigenetic regulation during adulthood. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. This brief review aims to identify the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in the offspring. Those findings demonstrate that maternal Ca deficiency during pregnancy may affect the epigenetic regulation of gene expression and thereby induce different metabolic phenotypes. We aim to address the need for Ca during pregnancy and propose the scaling-up of clinical and public health approaches that improved pregnancy outcomes.

Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Osteocalcin (OC), a bone formation biomarker, acts directly on β-cells and increases insulin secretion. We determined the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in offspring. Female Wistar rats consumed either a Ca-deficient or control diet ad libitum from three weeks preconception to 21 days postparturition. Pups were allowed to nurse their original mothers until weaning. The offspring were fed a control diet beginning at weaning and were killed on day 180. Serum carboxylated OC (Gla-OC) and undercarboxylated OC (Glu-OC), insulin and adipokines in offspring were measured. In males, mean levels of insulin, glucose, and HOMA-IR were higher in the Ca-deficient group than in the control group. In addition, ionized Ca (iCa) was inversely associated with serum Glu-OC and adiponectin in males. In females, mean levels of Glu-OC and Gla-OC in the Ca-deficient group were higher than in the control group. In all offspring, serum leptin levels were correlated with serum insulin levels, and inversely correlated with iCa. In conclusion, maternal Ca restriction during pregnancy and/or lactation influences postnatal offspring Ca metabolism and insulin resistance in a sex-specific manner.

Background: Prenatal malnutrition can affect the phenotype of offspring by altering epigenetic regulation. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome., Aims: We hypothesized that a Ca-deficient diet during pregnancy would alter insulin resistance and secretion in more than 1 generation of offspring., Methods: Female Wistar rats consumed either a Ca-deficient or a control diet ad libitum from 3 weeks before conception to 21 days after parturition and were mated with control males. Randomly selected F1 and F2 females were mated with males of each generation on postnatal day 70. The F1 and F2 dams were fed a control diet ad libitum during pregnancy and lactation. All offspring were fed a control diet starting at the time of weaning and were sacrificed on day 180., Results: HOMA-β% decreased in F1 through F3, and levels in F2 and F3 males and females were significantly lower than in controls. The mean levels of insulin and HOMA-IR were higher in F1 males but lower in F3 males than in control males. The HOMA-IR did not differ between any of the female offspring and controls., Conclusions: Maternal Ca restriction during pregnancy and/or lactation influences insulin secretion in 3 generations of offspring., (© 2017 S. Karger AG, Basel.)

Background: Prenatal malnutrition can affect the phenotype of offspring by changing epigenetic regulation of specific genes. Several lines of evidence demonstrate that calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. We hypothesized that pregnant female rats fed a Ca-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and that lactation would modify these alterations., Methodology: We determined the effects of Ca deficiency during pregnancy and/or lactation on hepatic 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1) expression in offspring. Female Wistar rats consumed either a Ca-deficient (D: 0.008% Ca) or control (C: 0.90% Ca) diet ad libitum from 3 weeks preconception to 21 days postparturition. On postnatal day 1, pups were cross-fostered to the same or opposite dams and divided into the following four groups: CC, DD, CD, and DC (first letter: original mother's diet; second letter: nursing mother's diet). All offspring were fed a control diet beginning at weaning (day 21) and were killed on day 200 ± 7. Serum insulin and adipokines in offspring were measured using ELISA kits., Principal Findings: In males, mean levels of insulin, glucose, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were higher in the DD and DC groups than in the CC group. We found no difference in HOMA-IR between the CC and CD groups in either males or females. Expression of Hsd11b1 was lower in male DD rats than in CC rats. Hsd11b1 expression in male offspring nursed by cross-fostered dams was higher than that in those nursed by dams fed the same diet; CC vs. CD and DD vs. DC. In females, Hsd11b1 expression in DC rats was higher than that in CC rats., Conclusions: These findings indicated that maternal Ca restriction during pregnancy and/or lactation alters postnatal growth, Hsd11b1 expression, and insulin resistance in a sex-specific manner.

Prenatal undernutrition affects offspring phenotype via changes in the epigenetic regulation of specific genes. We hypothesized that pregnant females that were fed a calcium (Ca)-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and altered epigenetic gene regulation. Female Wistar rats ate either a Ca-deficient or control diet from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and then euthanized on day 21. Methylation of individual cytosine-guanine dinucleotides in the phosphoenolpyruvate carboxykinase (Pck1), peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1), 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1), and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters was measured in liver tissue using pyrosequencing. For each gene, quantitative real-time polymerase chain reaction was used to assess mRNA levels in liver tissue. Overall Hsd11b1 methylation was lower in the Ca-deficient group than in the control group; however, overall methylation of each other gene did not differ between groups. Serum corticosterone levels in male pups from Ca-deficient dams were higher than those in control pups. Expression of Pck1 and Nr3c1 was lower in the Ca-deficient group than in the control group. A Ca-deficient diet for a dam during gestation and early nursing may alter glucocorticoid metabolism and lead to higher intracellular glucocorticoid concentrations in the hepatic cells of her offspring; moreover, this abnormal glucocorticoid metabolism may induce the metabolic complications that are associated with Ca deficiency. These findings indicated that prenatal nutrition affected glucocorticoid metabolism in offspring in part by affecting the epigenome of offspring., (© 2013.)

Background: Many epidemiologic studies have reported a link between calcium (Ca) deficiency and metabolic syndrome. In this study, we examine Ca deficiency in rats and whether changes in glucocorticoid metabolism are induced., Methods: Twelve-week-old female Wistar rats were weaned onto a very-low-Ca diet (low-Ca group) or a control diet (control group) for 2 weeks. Quantitative real-time PCR was used to assess mRNA for 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), 11β-HSD2, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor-α, and glucocorticoid receptor in the liver. Concentrations of adiponectin, leptin, corticosterone, intact parathyroid hormone, asymmetrical dimethylarginine and insulin in fasting serum were determined using a rat-specific enzyme-linked immunosorbent assay. Glucose concentrations were measured using a glucose oxidase system. Serum ionized Ca levels were measured with an automatic ion-selective electrode analyzer. Serum nitrite/nitrate levels were measured using a colorimetric assay kit., Results: After 2 weeks, no differences in serum glucose, corticosterone or insulin levels were observed. The low-Ca group rats showed higher homeostasis model assessment insulin resistance, lower adiponectin and higher intact parathyroid hormone levels. Serum nitrite/nitrate and asymmetrical dimethylarginine were significantly higher in the low-Ca group than in the control group. The expression of hepatic 11β-HSD1 mRNA was upregulated, while hepatic phosphoenolpyruvate carboxykinase expression was downregulated in the low-Ca group. Glucocorticoid receptor, peroxisome proliferator-activated receptor-α and 11β-HSD2 expression levels showed a similar tendency., Conclusion: A low-Ca diet alters glucocorticoid metabolism, which leads to hepatic upregulation of 11β-HSD1, and is possibly a key mechanism inducing the metabolic complications of Ca deficiency., (Copyright © 2011 S. Karger AG, Basel.)

Background: Neutrophils of patients with Down syndrome (DS) are known to have numerous abnormalities associated with diminished resistance to infection. The intracellular calcium (Ca(2+)i) acts as a second messenger and regulates diverse functions in many cell types. The purpose of the present study was to compare the intracellular calcium concentration ([Ca(2+)]i) at baseline and stimulated conditions in DS patients and in normal subjects to investigate [Ca(2+)]i regulation in neutrophils., Methods: The study group consisted of 27 subjects with DS (age, 8.6 +/- 4.6 years) and 14 healthy subjects (age, 12.0 +/- 3.9 years). Using a fluorescent probe, fura-2, the baseline levels and changes in [Ca(2+)]i were examined after stimulation of neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP)., Results: At baseline, the [Ca(2+)]i of neutrophils from DS subjects was significantly higher than that of the controls (70.6 +/- 28.0 nmol/L vs 44.4 +/- 16.0 nmol/L, P < 0.01). The absolute [Ca(2+)]i after addition of fMLP in the DS subjects was also significantly higher than that of the control group (250 +/- 91 nmol/L vs 167 +/- 60 nmol/L, respectively: P < 0.01). The neutrophils from the DS subjects had a consistently and significantly prolonged response to fMLP as compared to the neutrophils of control subjects., Conclusions: The higher [Ca(2+)]i and the prolonged response of [Ca(2+)]i to fMLP appear to be phenotypic traits of neutrophils in subjects with DS. This suggests intrinsic cellular defects in DS.

Intracellular calcium ([Ca2+]i) and phorbol ester binding were studied in intact platelets of young patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. Our objective was to evaluate disturbances in calcium regulation and signal transduction in platelets of diabetics. [Ca2+]i in platelets of the IDDM group (135 +/- 20 nmol/L) under basal conditions was significantly higher than that of the control group (81 +/- 8 nmol/L, P = .019), whereas at 60 seconds after stimulation with 0.1 National Institutes of Health (NIH) U/mL thrombin, [Ca2+]i in the NIDDM group (484 +/- 36 nmol/L) was significantly higher than that of the controls (347 +/- 22 nmol/L, P = .003) and IDDM group (360 +/- 45 nmol/L, P = .04), respectively. Phorbol 12,13-dibutyrate (PdBu) maximal binding capacity (Bmax) in the IDDM group was significantly lower than that in the control group either under basal conditions or after stimulation with thrombin (P = .0034 and P = .015, respectively). Bmax in the NIDDM group was significantly lower than that in the controls only after stimulation with thrombin (P = .047). The Kd for PdBu of the IDDM group was lower than that of the control group under basal conditions (P = .017). When analyzing the pooled data of all subjects, a significant correlation was observed between Bmax and Kd (under basal conditions, r = .544, P < .0001; after stimulation, r = .601, P < .0001). Our results support the idea that the increased affinity for PdBu may compensate for the decreased binding capacity. We interpret the data as indicating that the change in the binding of phorbol ester to protein kinase C (PKC) units may result in an altered PKC/calcium interaction in the pathogenesis of diabetes mellitus. Our study indicates that such metabolic derangements of [Ca2+]i have already been developing in young diabetic patients.

The study was designed to examine cytosolic free calcium ((Ca2+)i) and phorbol dibutyryl ester binding in intact platelets of young obese subjects as compared with the platelets of age-matched subjects with non-insulin-dependent diabetes mellitus (NIDDM) and those of healthy control subjects. The assay was studied in basal and thrombin-stimulated conditions. The binding parameter of phorbol ester is a criterion for active protein kinase C (PKC) units in the platelet plasma membrane. The resting (Ca2+)i correlated with body mass index (BMI)(r = 0.385, p = 0.0034) and plasma insulin level (r = 0.316, p = 0.0269), and the resting (Ca2+)i level was higher in the obesity group (160.6 +/- 15.8 nmol/L; n = 25) than controls (78.9 +/- 7.6 nmol/L; n = 24, p < 0.0001). Among the obesity and control groups, there was a correlation between BMI and fasting plasma insulin level (r = 0.399, p = 0.0237). Systolic blood pressure correlated with BMI(r = 0.504, p = 0.0005). The mean systolic blood pressure of the obesity group was higher than those of the other two groups. The mean Hill coefficient for thrombin-treated platelets of phorbol dibutyrate binding was higher in the obesity group when compared with healthy controls and the subjects with NIDDM (1.47 +/- 0.21 vs 1.06 +/- 0.16 and 0.99 +/- 0.09, respectively; p < 0.05). In conclusion, young subjects with simple obesity have already developed altered platelet Ca2+ regulation that is usually observed in adult patients with a number of metabolic diseases. These data are interpreted to indicate that a relationship exists between dysregulation of PKC and impaired glucose tolerance that precedes other complications of obesity.

The role of Ca2+ was examined in regulating the binding of phorbol 12,13-dibutyrate (PdBu) to intact human platelets. Alterations in the cytosolic free Ca2+ concn. [( Ca2+]i), but not extracellular Ca2+, substantially influenced the binding parameters of the phorbol ester. Ca(2+)-depleted platelets demonstrated a significant decline in the maximal binding capacity (Bmax), an increase in equilibrium dissociation constant (Kd) and a decrease in the Hill coefficient (h), suggesting the presence of Ca(2+)-sensitive and Ca(2+)-insensitive populations of PdBu-binding sites. In 1 mM-Ca2+ buffer, thrombin (0.1 NIH unit/ml) and ionomycin (0.5 microM) evoked a rise in [Ca2+]i to approx. 300-500 nM, associated with a significant decline in Kd, but without an apparent effect on Bmax. No effect of thrombin was observed on PdBu binding in Ca(2+)-depleted platelets. Inhibition of protein kinase C (PKC) by H7 was associated with a greater thrombin-evoked [Ca2+]i transient and a decline in Kd. Staurosporine also decreased the Kd for PdBu binding. We propose that this effect of the PKC inhibitors on the Kd was also [Ca2+]i-dependent. These observations in intact platelets indicate that the primary role of agonist- or non-agonist-induced rise in [Ca2+]i is to increase the affinity of PKC for PdBu and, presumably, endogenous diacylglycerol. However, in itself a rise in [Ca2+]i does not increase the Bmax, for PdBu binding.