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Maternal vitamin D deficiency found to increase lifetime diabetes risk in offspring

Maternal vitamin D deficiency increases lifetime diabetes risk in offspring
Top genes, networks, and pathways identified in transcriptome analysis of bone marrow from recipient mice transplanted with HSCs isolated from embryos from VD-sufficient and -deficient dams. VD(−) vs. VD( + ) FL-HSCs were transplanted into VD(+) mice, and global mRNA expression was evaluated by microarray in recipient BM cells at 16 weeks post-transplant. A Volcano plot showing top differentially expressed genes. Red dots indicate those array probes with P < 0.05. Black represents the non-significant probes. Genes of the Jarid2-PGC1-MEF2 pathway are highlighted in blue. P values for each probe were calculated using a two-tailed t test between five replicates in each condition. B Genes with significant changes were used for manual and automated pathway analysis. The figure shows EnrichR (PMID 23586463; 27141961; 33780170) top pathway hits from the ESCAPE database. Asterisks indicate those pathways that pass multiple testing corrections. EnrichR used Fisher’s exact test for P value calculation and Benjamini–Hochberg test for multiple testing corrections (C) Illustration of the Jarid2-MEF2-PGC1 network and the target genes that are differentially expressed in the array data. D Heatmap table showing normalized gene expression for Jarid2, MEF2-PGC1 target genes. Red indicates upregulation, and blue indicates downregulation. E, F Quantitative RT-PCR in FL-HSC transplant recipient BM to confirm expression changes in Jarid2 and PGC1α network-related genes (n = 6/group). Data presented as mean ± SEM. ***P < 0.001 vs. VD( + ) FL-HSCs recipients by two-tailed unpaired t test. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-38849-z

Researchers at Washington University School of Medicine in St. Louis have identified a process in immune cells that links vitamin D deficiency during pregnancy to an increased risk of type 2 diabetes in offspring. The researchers also found that these immune cells and their embedded genes can be used to transfer type 2 diabetes into otherwise healthy mice. The research is published June 13 in Nature Communications.

Some theories of disease suggest that conditions in utero may have irreversible, lifelong consequences in offspring. The new study's principal investigator, Carlos Bernal-Mizrachi, MD, said that could be happening to the children of mothers who don't have adequate levels of D during pregnancy.

"The identification of modifiable, environmental risk factors that may contribute to the later development of metabolic diseases is critical to prevent and treat those diseases," said Bernal-Mizrachi, a professor of medicine in the Division of Endocrinology, Metabolism & Lipid Research. "As the incidence of and prediabetes has tripled in recent decades, particularly in children and , we are analyzing during pregnancy that may help explain the increase."

About 37 million Americans have been diagnosed with diabetes, and at least 98 million more have prediabetes, a condition marked by the body's resistance to insulin. Vitamin D deficiency during pregnancy, a deficiency that affects an estimated 80% of Black American women and 60% of Caucasian women, may be one of the factors contributing to insulin resistance and elevated risk for diabetes in offspring.

"In studies of mice born to vitamin D-deficient mothers, we have found that the animals go on to develop insulin resistance and diabetes later in life," Bernal-Mizrachi said. "That was true even when pups were treated with adequate amounts of vitamin D after birth. Those animals improved their glucose control, but they never normalized."

The researchers have identified a type of stem cell that may be irreversibly affected by vitamin D deficiency during development in utero. The stem cells develop into , and the researchers discovered that they could transplant diabetes into other animals by placing these stem cells into mice with normal vitamin D levels. The researchers concluded that insufficient levels of vitamin D in utero can program the immune cells to promote the development of diabetes, providing a target to potentially prevent this process.

In those experiments, the researchers found that the immune cells activated a genetic process that is the same such process activated in immune cells collected from delivering mothers who had insufficient vitamin D levels when they gave birth.

Although prenatal vitamins are prescribed to ensure adequate levels of key nutrients during pregnancy, these findings from Bernal-Mizarachi and his colleagues suggest that the recommended doses of vitamin D are not sufficient to normalize vitamin D levels in women who had low vitamin D levels prior to pregnancy.

The process the researchers identified in mouse fetuses was characterized by alterations in . The modified gene program was identified in the stem cells that later developed into immune cells, including macrophages. The research team discovered that these macrophages secrete a molecule that impairs the ability of fat tissue to store glucose, resulting in increased blood sugar levels.

"Macrophages that come from vitamin D-deficient get into the fat tissue and contribute to inflammation, causing the fat tissue to become insulin resistant," said Bernal-Mizrachi, who also is chief of medicine at the Veterans Affairs St. Louis Health Care System.

Importantly, the researchers found evidence that the same processes that promote inflammation and in fat tissue also are at work in people. Immune cells isolated from cord blood from vitamin D-deficient pregnant patients who were cared for by physicians at Washington University showed similar changes in immune cell genes and secreted molecules that had been identified previously in mice.

More information: Jisu Oh et al, Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes, Nature Communications (2023). DOI: 10.1038/s41467-023-38849-z

Journal information: Nature Communications

Citation: Maternal vitamin D deficiency found to increase lifetime diabetes risk in offspring (2023, June 13) retrieved 5 December 2023 from
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