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The 4-vessel Sampling Approach to Integrative Studies of Human Placental Physiology In Vivo
Published on: August 2, 2017
Transgenerational metabolic outcomes associated with uteroplacental insufficiency
Melanie Tran1, Linda A Gallo, Andrew J Jefferies
1Department of Physiology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Insights
Intrauterine growth restriction in mothers leads to metabolic issues in their grandchildren (F2 generation). Granddaughters showed impaired insulin response, while grandsons had insulin resistance and higher triglycerides, indicating transgenerational metabolic disease risk.
Area of Science:
- Endocrinology
- Reproductive Biology
- Metabolic Disease Research
Background:
- Intrauterine growth restriction (IUGR) is linked to adult metabolic disease.
- Suboptimal in-utero conditions may cause transgenerational health effects.
- The impact of IUGR on subsequent generations' metabolic health requires further investigation.
Purpose of the Study:
- To determine if second-generation (F2) offspring of growth-restricted rats exhibit impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits.
- To investigate gender-specific effects of maternal IUGR on F2 offspring metabolism and pancreatic morphology.
- To assess the transgenerational impact of uteroplacental insufficiency on metabolic health.
Main Methods:
- Uteroplacental insufficiency induced via bilateral uterine vessel ligation in Wistar-Kyoto rats.
- First-generation (F1) females from restricted and control groups mated with normal males.
- Second-generation (F2) offspring assessed for glucose tolerance, insulin secretion/sensitivity, and pancreatic morphology at multiple ages (postnatal day 35, 6, and 12 months).
Main Results:
- F2 male offspring from restricted mothers showed a blunted first-phase insulin response (-35%) and reduced pancreatic beta-cell mass (-29%) at 6 months.
- F2 female offspring from restricted mothers had increased beta-cell mass but a reduced first-phase insulin response (-38%).
- F2 males exhibited reduced insulin sensitivity and elevated triglycerides compared to females, irrespective of maternal birth weight.
Conclusions:
- Maternal intrauterine growth restriction is associated with impaired first-phase insulin response and gender-specific pancreatic changes in the F2 generation.
- These findings suggest a transgenerational transmission of metabolic dysfunction originating from in-utero insults.
- Further research is needed to elucidate the precise mechanisms of disease transmission across generations.
Abstract:
Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (-35%), which was associated with reduced pancreatic β-cell mass (-29%). By contrast, F2 restricted females had increased β-cell mass despite reduced first-phase insulin response (-38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.
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