# Vitamin D and Developmental Origins of Insulin Resistance

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2020 · —

## Abstract

Abstract
Type 2 diabetes (T2DM) is the leading cause of death and disability worldwide. Nearly one in four veterans
have T2DM and this prevalence is estimated to increase to 36% by 2025. Lifestyle interventions aiming at
weight loss are successful at reducing risk of diabetes but long-term weight-maintenance strategies have been
found to be unsustainable. More interestingly, substantial diabetes risk (~40-50%) remains even after
successful weight loss, suggesting that other determinants play a role in disease susceptibility. Multiple studies
provide evidence for the hypothesis that environmental factors in utero affect patterns of fetal and infant growth
that result in increased susceptibility to insulin resistance (IR) and metabolic disorders later in life.
Approximately one million veterans are women of childbearing age and half are vitamin D-deficient. Vitamin D
deficiency during pregnancy has been linked to IR in prepubertal children. However, no prior interventional
studies in humans have evaluated the effects of antenatal vitamin D supplementation on offspring IR and
metabolic complications. In rodents, maternal vitamin D deficiency results in a pro-inflammatory immune cell
program in the offspring and increased levels of systemic inflammatory cytokines prior to the development of
IR. Postnatal vitamin D supplementation does not reverse any of these immune or metabolic changes,
suggesting that persistent epigenetic programming of immune cells is involved. Our preliminary data shows for
the first time that IR is transplantable. Hematopoietic stem cells (HSCs) from fetuses subjected to vitamin D
deficiency in utero confer permanent IR and shift bone marrow (BM) hematopoiesis toward greater progenitors
and myeloid cells in vitamin D-sufficient adult mice, implying epigenetic immune reprogramming. Methylation
analysis of BM from recipients of vitamin D-deficient vs. –sufficient HSCs identified multiple differentially
methylated regions. This project focuses on a hypermethylated region in the promoter of Jarid2, a
methyltransferase known to be upregulated by active vitamin D. Analysis of corresponding gene expression
data identified that regulation of the Mef2-PGC1α-miR106b network by Jarid2 could be a potential pathway
mediating the immunometabolic phenotype. Thus, we hypothesize that Jarid2 suppression and PGC1α
upregulation in HSCs during embryogenesis program myeloid cells to promote IR, and that this
process can be reversed with maternal antenatal vitamin D supplementation. To test this epigenetic
immune program in vivo, we propose to determine the influence of altering myeloid expression of the
Jarid2/PGC1α/miR106b pathway in mice on the development of IR. Additionally, we will utilize a unique
opportunity to obtain human samples and data from the multicenter Vitamin D Antenatal Asthma Reduction
Trial (VDAART) to determine the role of antenatal vitamin D supplementation (4000 IU/d vs. placebo) in
offspring IR and metabolic outcomes later i...

## Key facts

- **NIH application ID:** 9933784
- **Project number:** 5I01BX003648-03
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Carlos Bernal-Mizrachi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933784

## Citation

> US National Institutes of Health, RePORTER application 9933784, Vitamin D and Developmental Origins of Insulin Resistance (5I01BX003648-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9933784. Licensed CC0.

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