Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring

Alejandro, Emilyn U.; Gregg, Brigid; Wallen, Taylor; Kumusoglu, Doga; Meister, Daniel; Chen, Angela; Merrins, Matthew J.; Satin, Leslie S.; Liu, Ming; Arvan, Peter; Bernal-Mizrachi, Ernesto

doi:10.1172/jci74237

Cited by 101 publications

(110 citation statements)

References 63 publications

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“…Degradation of Drosha results in reduced miRNA processing and global downregulation of steady-state miRNA levels. These new findings emphasize the impact that nutrients and the cellular environment have on miRNA biogenesis and compliment results observed in mouse studies, where maternal diet was shown to alter a subset of miRNAs in the offspring through mTORC1 (Alejandro et al, 2014). …”

supporting

confidence: 82%

Micro(RNA) Managing by mTORC1

2015

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supporting

confidence: 82%

Micro(RNA) Managing by mTORC1

2015

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“…found that maternal chromium restriction increases plasma glucose (from 9 months), and the area under the curve of glucose during oral glucose tolerance test (from 15 months) in the offspring [16]. The offspring of dams fed a low-protein diet have impaired glucose tolerance at weaning [29] and adulthood [30]. At 12 months of age, offspring from vitamin B 12 -restricted dams have higher blood glucose and impaired glucose tolerance [31].…”

Section: Discussionmentioning

confidence: 99%

Dietary Chromium Restriction of Pregnant Mice Changes the Methylation Status of Hepatic Genes Involved with Insulin Signaling in Adult Male Offspring

et al. 2017

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Maternal undernutrition is linked with an elevated risk of diabetes mellitus in offspring regardless of the postnatal dietary status. This is also found in maternal micro-nutrition deficiency, especial chromium which is a key glucose regulator. We investigated whether maternal chromium restriction contributes to the development of diabetes in offspring by affecting DNA methylation status in liver tissue. After being mated with control males, female weanling 8-week-old C57BL mice were fed a control diet (CON, 1.19 mg chromium/kg diet) or a low chromium diet (LC, 0.14 mg chromium/kg diet) during pregnancy and lactation. After weaning, some offspring were shifted to the other diet (CON-LC, or LC-CON), while others remained on the same diet (CON-CON, or LC-LC) for 29 weeks. Fasting blood glucose, serum insulin, and oral glucose tolerance test was performed to evaluate the glucose metabolism condition. Methylation differences in liver from the LC-CON group and CON-CON groups were studied by using a DNA methylation array. Bisulfite sequencing was carried out to validate the results of the methylation array. Maternal chromium limitation diet increased the body weight, blood glucose, and serum insulin levels. Even when switched to the control diet after weaning, the offspring also showed impaired glucose tolerance and insulin resistance. DNA methylation profiling of the offspring livers revealed 935 differentially methylated genes in livers of the maternal chromium restriction diet group. Pathway analysis identified the insulin signaling pathway was the main process affected by hypermethylated genes. Bisulfite sequencing confirmed that some genes in insulin signaling pathway were hypermethylated in livers of the LC-CON and LC-LC group. Accordingly, the expression of genes in insulin signaling pathway was downregulated. There findings suggest that maternal chromium restriction diet results in glucose intolerance in male offspring through alterations in DNA methylation which is associated with the insulin signaling pathway in the mice livers.

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“…Protein restriction during pregnancy caused a β-cell secretory defect in adult offspring by increase in the expression of non-coding RNA miR199a-3p and miR-342. Interestingly, these miRNAs were also shown to reduce mTOR levels in isolated β-cells from mice exposed to protein restriction during fetal life 77 . In terms of developmental programming by high fat diet, paternal high fat diet exposure prior to mating induces islet expression of Il13ra2, a protein related to the Jak-Stat signaling pathway, and this change was accompanied by changes in methylation in the transcription start site 79 .…”

Section: Environmental Factors Regulating β-Cell Development and Neonmentioning

confidence: 99%

“…In addition, Hnf4α P2 promoter is epigenetically silenced in islets of the offspring of dams exposed to low protein during gestation 76 . The importance of miR species in developmental programming of β-cell has been recently established 77,78 . Protein restriction during pregnancy caused a β-cell secretory defect in adult offspring by increase in the expression of non-coding RNA miR199a-3p and miR-342.…”

Section: Environmental Factors Regulating β-Cell Development and Neonmentioning

confidence: 99%

Natural history of β-cell adaptation and failure in type 2 diabetes

Alejandro

Gregg

Blandino-Rosano

et al. 2015

Molecular Aspects of Medicine

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Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure.

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Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring

Abstract: data indicate that mTORC1 signaling is essential for attenuating β cell dysfunction induced by maternal low-protein diet.

Cited by 101 publications

References 63 publications

Micro(RNA) Managing by mTORC1

Micro(RNA) Managing by mTORC1

Dietary Chromium Restriction of Pregnant Mice Changes the Methylation Status of Hepatic Genes Involved with Insulin Signaling in Adult Male Offspring

Natural history of β-cell adaptation and failure in type 2 diabetes

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