Maternal Protein Restriction Leads to Pancreatic Failure in Offspring: Role of Misexpressed MicroRNA-375

Dumortier, Olivier; Hinault, Charlotte; Gautier, Nadine; Patouraux, Stéphanie; Casamento, Virginie; Obberghen, Emmanuel Van

doi:10.2337/db13-1431

Cited by 67 publications

(62 citation statements)

References 50 publications

(54 reference statements)

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“…Interestingly, increased levels of miR-375 were observed in the islets of the offspring of rats fed a low-protein diet during pregnancy. The level of miR-375 remained elevated until the adulthood, suggesting that deregulation of this miRNA contributes to defective endocrine pancreas activity and to the increased risk of developing T2DM typically observed upon in utero malnutrition [34].…”

Section: Role Of Specific Mirnas In the Development Of β-Cells And Inmentioning

confidence: 99%

MicroRNAs and the functional β cell mass: For better or worse

Guay

Regazzi

2015

Diabetes & Metabolism

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Insulin secretion from pancreatic β-cells plays a central role in the control of blood glucose levels. The amount of insulin released by β-cells is precisely adjusted to match the organism requirements. A number of conditions occurring during life, including pregnancy and obesity, can result in a decrease in the sensitivity of insulin target tissues and in the consequent rise in the insulin needs. To preserve glucose homeostasis, the augmented insulin demand requires a compensatory expansion of the mass of pancreatic β-cells and an increase in their secretory activity. This compensatory process is known to be accompanied by modifications in β-cell gene expression but the molecular mechanisms underlying this phenomenon are still poorly understood. Emerging evidence indicate that at least part of these compensatory events may be orchestrated by changes in the level of a novel class of gene regulators, the microRNAs.Indeed, several of these small non-coding RNAs have either positive or negative impacts on β-cell proliferation and survival. The studies reviewed in this paper suggest that the balance between the actions of these two groups of microRNAs with opposing functional effects determines whether β-cells expand sufficiently to maintain blood glucose levels in the normal range or fail to meet the insulin demand with a consequent progression toward diabetes manifestation. A better understanding of the mechanisms governing the changes in the microRNA profile will open the way for the development of new strategies to prevent and/or treat type 2 and gestational diabetes.

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Section: Role Of Specific Mirnas In the Development Of β-Cells And Inmentioning

confidence: 99%

MicroRNAs and the functional β cell mass: For better or worse

Guay

Regazzi

2015

Diabetes & Metabolism

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“…Epigenetic regulation contributes to differences in fetal gene expression [12,23,36,40,41]. For example, we discovered that hepatic Hsd11b1 is hypomethylated in day 21 offspring of dams fed a Ca-deficient diet during pregnancy [18].…”

Section: Discussionmentioning

confidence: 99%

“…In a number of animal models, the offspring of mothers given poor nutrition during pregnancy exhibit pathophysiological changes similar to those observed in human diseases [12,13,14]. Some experimental and observational findings from humans and other animals indicate an association between maternal Ca intake during pregnancy and blood pressure in offspring [15,16], while others do not [17].…”

Section: Introductionmentioning

confidence: 99%

A Calcium-Deficient Diet in Rat Dams during Gestation Decreases HOMA-β% in 3 Generations of Offspring

Takaya

Yamanouchi²,

Tanabe³

et al. 2016

Lifestyle Genomics

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Background: Prenatal malnutrition can affect the phenotype of offspring by altering epigenetic regulation. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Aims: We hypothesized that a Ca-deficient diet during pregnancy would alter insulin resistance and secretion in more than 1 generation of offspring. Methods: Female Wistar rats consumed either a Ca-deficient or a control diet ad libitum from 3 weeks before conception to 21 days after parturition and were mated with control males. Randomly selected F1 and F2 females were mated with males of each generation on postnatal day 70. The F1 and F2 dams were fed a control diet ad libitum during pregnancy and lactation. All offspring were fed a control diet starting at the time of weaning and were sacrificed on day 180. Results: HOMA-β% decreased in F1 through F3, and levels in F2 and F3 males and females were significantly lower than in controls. The mean levels of insulin and HOMA-IR were higher in F1 males but lower in F3 males than in control males. The HOMA-IR did not differ between any of the female offspring and controls. Conclusions: Maternal Ca restriction during pregnancy and/or lactation influences insulin secretion in 3 generations of offspring.

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“…Emerging evidence suggests that miRs contribute to the pathogenesis of diabetes and diabetic complications (5,15,31,43). Since each miR has its potential targeting genes, information of miR involvement in diabetes is helpful for identification of the targeted molecules as well.…”

Section: Discussionmentioning

confidence: 99%

The SUR2B subunit of rat vascular K_ATPchannel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal

Jin

et al. 2015

American Journal of Physiology-Cell Physiology

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. The SUR2B subunit of rat vascular KATP channel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal. Am J Physiol Cell Physiol 308: C139-C145, 2015. First published October 29, 2014; doi:10.1152/ajpcell.00311.2014.-ATP-sensitive K ϩ (KATP) channels regulate plasma membrane excitability. The Kir6.1/ SUR2B isoform of KATP channels is expressed in vascular smooth muscles and plays an important role in vascular tone regulation. This KATP channel is targeted by several reactive species. One of them is methylglyoxal (MGO), which is overly produced with persistent hyperglycemia and contributes to diabetic vascular complications. We have previously found that MGO causes posttranscriptional inhibition of the KATP channel, aggravating vascular tone regulation. Here we show evidence for the underlying molecular mechanisms. We screened microRNA databases and found several candidates. Of them, miR-9a-3p, increased its expression level by ϳ240% when the cultured smooth muscle cell line was exposed to micromolar concentrations of MGO. Treatments with exogenous miR-9a-3p downregulated the SUR2B but not Kir6.1 mRNA. Antisense nucleotides of miR9a-3p alleviated the effects of MGO. Quantitative PCR showed that the targeting sites of the miR-9a-3p were likely to be in the coding region of SUR2B. The effects of miR-9a-3p were mostly eliminated when the potential targeting site in SUR2B was site-specifically mutated. Our functional assays showed that KATP currents were impaired by miR-9a-3p induced with MGO treatment. These results suggest that MGO exposure raises the expression of miR-9a-3p, which subsequently downregulates the SUR2B mRNA, compromising KATP channel function in vascular smooth muscle.microRNA; ATP-sensitive potassium channel; diabetes DIABETES MELLITUS is a major challenge to biomedical sciences (12). Diabetes causes metabolic alterations leading to excessive production of various intermediary metabolites (4). One of them is methylglyoxal (MGO), a highly reactive carbonyl species (RCS) (2,16,39). MGO can react with proteins, nucleotides, and lipids, damaging these molecules and promoting inflammation and cell injuries (10,17,26). Normally, MGO is rapidly detoxified by metabolic and redox enzymes so that it is maintained at a rather low level (37). Under diabetic conditions, however, the increased production of precursor molecules and impaired carbonyl detoxification system result in overproduction and accumulation of this RCS (38). The imbalance in the production and clearance of RCS then leads to carbonyl stress, which is known to play an important role in the development of diabetic complications, especially in the vasculature (1, 7, 11).In the vasculature, an increase in MGO levels can impair structure and function of the vascular walls by acting on the vascular smooth muscle (VSM), endothelium, or both. This in turn disrupts the signaling network in these cells, triggers structural remodeling of the vascular wall, propagates vascular inflammation, and causes vascular dysfunction (40 -42). Ind...

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Maternal Protein Restriction Leads to Pancreatic Failure in Offspring: Role of Misexpressed MicroRNA-375

Cited by 67 publications

References 50 publications

MicroRNAs and the functional β cell mass: For better or worse

MicroRNAs and the functional β cell mass: For better or worse

A Calcium-Deficient Diet in Rat Dams during Gestation Decreases HOMA-β% in 3 Generations of Offspring

The SUR2B subunit of rat vascular K_ATPchannel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal

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Maternal Protein Restriction Leads to Pancreatic Failure in Offspring: Role of Misexpressed MicroRNA-375

Cited by 67 publications

References 50 publications

MicroRNAs and the functional β cell mass: For better or worse

MicroRNAs and the functional β cell mass: For better or worse

A Calcium-Deficient Diet in Rat Dams during Gestation Decreases HOMA-β% in 3 Generations of Offspring

The SUR2B subunit of rat vascular KATPchannel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal

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The SUR2B subunit of rat vascular K_ATPchannel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal