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Maternal vitamin D deficiency during pregnancy results in insulin resistance in rat offspring, which is associated with inflammation and Iκbα methylation

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Abstract

Aims/hypothesis

We aimed to investigate the impact of maternal vitamin D deficiency during pregnancy on insulin resistance in male offspring and examine its mechanism.

Methods

Pregnant Sprague–Dawley rats were maintained on a vitamin-D-free diet with ultraviolet-free light during pregnancy (early-VDD group). Insulin resistance in the male offspring was assessed by HOMA-IR, OGTT and euglycaemic clamp. NEFA, oxidative stress and inflammation levels were estimated as risk factors for insulin resistance. DNA methylation was examined by bisulfate sequencing PCR analysis. Luciferase reporter assay was performed to validate the effect of DNA methylation.

Results

The offspring in the early-VDD group had significantly higher fasting insulin and HOMA-IR levels, markedly reduced glucose tolerance and significantly lower tissue sensitivity to exogenous insulin at 16 weeks (all p < 0.05) compared with control offspring. Significantly higher serum and liver IL-1β, IL-6, IL-8 and TNF-α concentrations were observed in the offspring of the early-VDD group at 0, 3, 8 and 16 weeks. Expression of hepatic Iκbα (also known as Nfkbia) mRNA and nuclear factor κB inhibitor α (IκBα) protein was persistently lower in the early-VDD offspring at all time points, and their hepatic Iκbα methylation levels at the cytosine phosphate guanine site +331 were significantly higher at 0 and 16 weeks (all p < 0.01). Methylation at Iκbα first exon +331 markedly decreased the luciferase activity (p < 0.05).

Conclusions/interpretation

Maternal vitamin D deficiency during pregnancy results in insulin resistance in the offspring, which is associated with persistently increased inflammation. Persistently decreased Iκbα expression, potentially caused by changes in Iκbα methylation, plays an important role in persistent inflammation.

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Abbreviations

1,25(OH)D:

1,25-Dihydroxyvitamin D

25(OH)D:

25-Hydroxyvitamin D

CpG:

Cytosine phosphate guanine

Early-VDD:

Early-life vitamin D deficiency

FG:

Fasting glucose

FIN:

Fasting insulin

GIR:

Glucose infusion rate

GSH-Px:

Glutathione peroxidase

IκBα:

NFκB inhibitor α

IKK:

NFκB inhibitor kinase

IR:

Insulin resistance

MDA:

Malonaldehyde

NFκB:

Nuclear factor κB

P-IκBα:

Phosphorylated NFκB inhibitor α

PTH:

Parathyroid hormone

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TG:

Triacylglycerol

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Acknowledgements

We thank J. Li (Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, China) for helping with the revision and L. Y. Gong and J. N. Song (Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University) for their help with animal feeding and molecular biology experiments.

Funding

This study was supported by the State Key Program of National Natural Science of China (No. 81130049), the National ‘Twelfth Five-Year’ Plan for Science & Technology Support (No. 2012BAI02B02) and the Program for New Century Excellent Talents in University of Ministry of Education of China (grant NCET-10-0148).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

CS and YL designed the study, analysed and interpreted the data and reviewed and edited the manuscript. HZ designed and performed the study, acquired and analysed the data and wrote the draft of the manuscript. XC, YH, GL and YW were responsible for performing the study, data collection and interpretation and drafting the manuscript. All authors approved the final version of the manuscript. CS is responsible for the integrity of the work as a whole.

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Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, People’s Republic of China

    Huaqi Zhang, Xia Chu, Yifan Huang, Ying Li & Changhao Sun

  2. The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China

    Gang Li

  3. The Third Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China

    Yuxia Wang

Authors
  1. Huaqi Zhang
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  2. Xia Chu
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  3. Yifan Huang
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  4. Gang Li
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  5. Yuxia Wang
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  6. Ying Li
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  7. Changhao Sun
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Correspondence to Ying Li or Changhao Sun.

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Zhang, H., Chu, X., Huang, Y. et al. Maternal vitamin D deficiency during pregnancy results in insulin resistance in rat offspring, which is associated with inflammation and Iκbα methylation. Diabetologia 57, 2165–2172 (2014). https://doi.org/10.1007/s00125-014-3316-7

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  • DOI: https://doi.org/10.1007/s00125-014-3316-7

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