Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth

Cilvik, Sarah N.; Wesolowski, Stephanie R.; Anthony, R. V.; Brown, Laura D.; Rozance, Paul J.

doi:10.1113/jp281288

Cited by 19 publications

(8 citation statements)

References 104 publications

(176 reference statements)

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“…While considerable effort has been expended on examining maternal glucose, insulin and IGF1 in normal and compromised pregnancies, the role of maternal glucagon for the most part has been overlooked, although Qiao et al [ 52 ] recently reported that pregnancy in mice induces an expansion of maternal α-cell mass, and an increase in maternal glucagon concentrations during early pregnancy. Furthermore, the demonstration [ 53 ] that fetal hyperglucagonemia during late-gestation results in significant reductions in uterine artery blood flow and placental CSH production and secretion into maternal circulation, without impacting umbilical blood flow or CSH concentrations, highlights not only the importance of glucagon during pregnancy, but also that the three compartments (maternal, placental and fetal) are intimately integrated and need to be investigated together [ 54 ]. This research, therefore, also exemplifies the utility of integrating in vivo RNAi in an animal model that can allow steady-state assessment of altered maternal-placental-fetal physiology [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation

Lynch

Kennedy

Tanner

et al. 2022

IJMS

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In the ruminant placenta, glucose uptake and transfer are mediated by facilitative glucose transporters SLC2A1 (GLUT1) and SLC2A3 (GLUT3). SLC2A1 is located on the basolateral trophoblast membrane, whereas SLC2A3 is located solely on the maternal-facing, apical trophoblast membrane. While SLC2A3 is less abundant than SLC2A1, SLC2A3 has a five-fold greater affinity and transport capacity. Based on its location, SLC2A3 likely plays a significant role in the uptake of glucose into the trophoblast. Fetal hypoglycemia is a hallmark of fetal growth restriction (FGR), and as such, any deficiency in SLC2A3 could impact trophoblast glucose uptake and transfer to the fetus, thus potentially setting the stage for FGR. By utilizing in vivo placenta-specific lentiviral-mediated RNA interference (RNAi) in sheep, we were able to significantly diminish (p ≤ 0.05) placental SLC2A3 concentration, and determine the impact at mid-gestation (75 dGA). In response to SLC2A3 RNAi (n = 6), the fetuses were hypoglycemic (p ≤ 0.05), exhibited reduced fetal growth, including reduced fetal pancreas weight (p ≤ 0.05), which was associated with reduced umbilical artery insulin and glucagon concentrations, when compared to the non-targeting sequence (NTS) RNAi controls (n = 6). By contrast, fetal liver weights were not impacted, nor were umbilical artery concentrations of IGF1, possibly resulting from a 70% increase (p ≤ 0.05) in umbilical vein chorionic somatomammotropin (CSH) concentrations. Thus, during the first half of gestation, a deficiency in SLC2A3 results in fetal hypoglycemia, reduced fetal development, and altered metabolic hormone concentrations. These results suggest that SLC2A3 may be the rate-limiting placental glucose transporter during the first-half of gestation in sheep.

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Section: Discussionmentioning

confidence: 99%

Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation

Lynch

Kennedy

Tanner

et al. 2022

IJMS

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“…As described extensively in Table 1 , uterine and umbilical blood flows were calculated by the transplacental diffusion technique described previously [ 13 , 49 , 50 ]. Uterine, umbilical, and uteroplacental utilization of oxygen, glucose, lactate and amino acids were calculated by the transplacental diffusion technique [ 51 ] and reported as an average of draws one through four.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma amino acids were measured by HPLC [ 13 ]. Maternal (uterine) and fetal (umbilical) concentrations of insulin, IGF1, and cortisol were assessed by enzyme-linked immunosorbent assay (ALPCO Immunoassays 80-INSOV-E01, 22-IGFHU-E01, and 11-CORHU-E01-SLV, respectively), as described previously [ 50 , 52 , 53 ]. Estradiol was analyzed by radioimmunoassay, as described by Gonzalez-Padilla et al [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction

Tanner

Lynch

Kennedy

et al. 2021

IJMS

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Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.

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“…Fetal–placental endothelial dysfunction is characterized by changes in the l -arginine-adenosine signaling pathway and inflammation ( 165 , 166 ). The mechanisms involved in these changes are hypothesized to be hyperglycemia, hyperinsulinemia, and oxidative stress ( 167 , 168 ). These conditions increase the release of exosomes.…”

Section: Exosomes As a Potential Therapeutic Target For Diabetes Mellitus And Diabetic Complicationsmentioning

confidence: 99%

The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications

Tao

Zhang

et al. 2021

Front. Endocrinol.

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Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications. Exosomes are nanoparticles containing bioactive molecules reflecting individual physiological status, regulating metabolism, and repairing damaged tissues. They function as biomarkers of diabetes mellitus and diabetic complications. Considering that exosomes are bioactive molecules, can be obtained from body fluid, and have cell-type specificity, in this review, we highlight the multifold effects of exosomes in the pathology and therapy of diabetes mellitus and diabetic complications.

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Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth

Cited by 19 publications

References 104 publications

Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation

Impact of Placental SLC2A3 Deficiency during the First-Half of Gestation

CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction

The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications

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