Abstract
Backgrounds: Maternal malnutrition and the resulting low birth weight predispose offspring to various diseases, including adult-onset insulin resistance syndrome. Several lines of evidence demonstrate that calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome and obesity, suggesting that hypocalcemia is a risk factor for developing these conditions. We previously reported that maternal Ca deficiency during pregnancy can affect regulation of non-imprinted genes by altering epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. On the other hand, osteocalcin (OC), a bone formation biomarker, acts directly on β-cells to increase their mass and proliferation and, therefore, increases insulin secretion. Aims: We studied whether alterations in insulin resistance and secretion were induced in offspring by feeding dams a Ca-deficient diet during pregnancy and lactation, and to explore the association between bone and glucose metabolism. Methods: Female Wistar rats consumed either a Ca-deficient (0.008% Ca) or control (0.90% Ca) diet ad libitum from 3 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 (day 21) and were killed on day 180 ± 10. Serum carboxylated OC (Gla-OC) and undercarboxylated OC (Glu-OC), insulin and adipokines in offspring were measured using enzyme-linked immunosorbent assay kits. Ionized calcium (iCa) and magnesium (iMg) were measured by ion-selective electrodes. Results: In males, mean levels of insulin, glucose, and Homeostasis Model Assessment of Insulin Resistance were higher in the Ca-deficient group than in the control group. Mean adiponectin levels and iMg in Ca-deficient male offspring were higher than those in control male offspring. The serum ionized Ca/Mg ratio in Ca-deficient male offspring was lower than that in control male offspring. In addition, 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, whereas no significant difference was observed in these measures between the two groups in male offspring. In all offspring, serum leptin levels were correlated with iMg (p=0.0039, R=0.436) and serum insulin levels (p<0.0001, R=0.62), and inversely correlated with iCa (p=0.0025, R=-0.454). Conclusion: Maternal Ca restriction during pregnancy alters postnatal growth and insulin resistance in a sex- and window of exposure-specific manner. Increased Glu-OC may mitigate insulin resistance in female Ca-deficient offspring. The present study provided further support for the hypothesis that early postnatal lactation plays a sexually divergent role in programming the phenotype later in life.
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