Limits...
Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus.

Sobrevia L, Salsoso R, Fuenzalida B, Barros E, Toledo L, Silva L, Pizarro C, Subiabre M, Villalobos R, Araos J, Toledo F, González M, Gutiérrez J, Farías M, Chiarello DI, Pardo F, Leiva A - Front Physiol (2016)

Bottom Line: GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis.This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature.Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

View Article: PubMed Central - PubMed

Affiliation: Cellular and Molecular Physiology Laboratory, Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, Pontificia Universidad Católica de ChileSantiago, Chile; Faculty of Medicine and Biomedical Sciences, University of Queensland Centre for Clinical Research, University of QueenslandHerston, QLD, Australia; Department of Physiology, Faculty of Pharmacy, Universidad de SevillaSeville, Spain.

ABSTRACT
Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

No MeSH data available.


Related in: MedlinePlus

Fetal insulinemia and altered angiogenesis in fetoplacental endothelium from gestational diabetes mellitus. With the progression of pregnancy up to the 40th weeks of gestation, the maternal glycaemia increases, and could reach supraphysiological levels in pregnancies where the mother is diagnosed with gestational diabetes mellitus. The maternal hyperglycaemia results in increased fetal glycaemia from about the 5th week of gestation (dotted line), a condition resulting in a supraphysiological increase of fetal insulinemia from the 12th week of gestation. Increased fetal insulinemia results in altered placental vascular development and growth leading to angiogenesis alterations (Placental vasculogenesis and angiogenesis). Thus, an adverse fetal outcome is seen as a result of abnormal angiogenesis. Cell signaling mechanisms involved in this phenomenon include altered expression and/or activity of several molecules that are responsive to insulin (IR-A, MMPs, cadherin, b-catenin). Equally, a low oxygen level at the beginning of pregnancy increases the expression of proangiogenic growth factors (VEGF, PlGF, IGF, FGF-2) and increased (GRP78, CHOP, IRE-1α, ATF6, PERK) or reduced (AMPK) expression and/or activity. Composed from information reported by Babawale et al. (2000), Jirkovská et al. (2002), Easwaran et al. (2003), Baumüller et al. (2015), Westermeier et al. (2015b).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4815008&req=5

Figure 2: Fetal insulinemia and altered angiogenesis in fetoplacental endothelium from gestational diabetes mellitus. With the progression of pregnancy up to the 40th weeks of gestation, the maternal glycaemia increases, and could reach supraphysiological levels in pregnancies where the mother is diagnosed with gestational diabetes mellitus. The maternal hyperglycaemia results in increased fetal glycaemia from about the 5th week of gestation (dotted line), a condition resulting in a supraphysiological increase of fetal insulinemia from the 12th week of gestation. Increased fetal insulinemia results in altered placental vascular development and growth leading to angiogenesis alterations (Placental vasculogenesis and angiogenesis). Thus, an adverse fetal outcome is seen as a result of abnormal angiogenesis. Cell signaling mechanisms involved in this phenomenon include altered expression and/or activity of several molecules that are responsive to insulin (IR-A, MMPs, cadherin, b-catenin). Equally, a low oxygen level at the beginning of pregnancy increases the expression of proangiogenic growth factors (VEGF, PlGF, IGF, FGF-2) and increased (GRP78, CHOP, IRE-1α, ATF6, PERK) or reduced (AMPK) expression and/or activity. Composed from information reported by Babawale et al. (2000), Jirkovská et al. (2002), Easwaran et al. (2003), Baumüller et al. (2015), Westermeier et al. (2015b).

Mentions: Placenta hypervascularization in women with DMT1, DMT2, or GDM, is reported (Cvitic et al., 2014; Huynh et al., 2015; Jarmuzek et al., 2015). DMT1 and DMT2 affect the entire process (vasculogenesis and angiogenesis; Jirkovská et al., 2002; Nelson et al., 2009; Jarmuzek et al., 2015) while GDM seems to impact the microvascular remodeling at angiogenesis (Jarmuzek et al., 2015). At 3rd trimester of pregnancy, the effect of DMT1, DMT2, and GDM on these phenomena is similar resulting in increased branching and surface area of villous capillaries (Teasdale, 1981; Jirkovská et al., 2002). Since GDM associates with developing longer umbilical cords compared with normal pregnancies (Georgiadis et al., 2014), it is suggested that placental hypervascularization in diabetes mellitus is mainly attributed to increased angiogenesis (Jirkovská et al., 2002; Leach, 2011; Figure 2). The later is partially explained by a placental hypoxia condition resulting from the fetal hyperglycaemia in diabetes mellitus. Fetal hyperglycaemia triggers fetal hyperinsulinemia, over-activating fetal metabolism leading to increased oxygen demand (Hytinantti et al., 2000; Taricco et al., 2009; Jarmuzek et al., 2015). Thus, it is likely that fetal hypoxia promotes the expression of angiogenic factors during the physiological placental angiogenesis at the 1st trimester of pregnancy when the oxygen level is reduced (Jauniaux et al., 2000). Since the level of FGF-2 is also regulated by hypoxia (Wang et al., 2009; Seo et al., 2013) and is increased in both the placenta and umbilical cord blood in diabetic pregnancies (Arany and Hill, 1998; Grissa et al., 2010), this growth factor emerges as a candidate to explain the hypervascularization in placentas from diabetes mellitus. Knowing that insulin is an angiogenic factor in endothelial cells (Liu et al., 2009), fetal hyperinsulinemia would have profound effects on placental and fetal vascular changes associated with maternal diabetes mellitus in pregnancy (Lassance et al., 2013). Interestingly, in another set of studies VEGF expression was shown to be lower in human placentas likely due to increased expression of the ERS-maker GRP78 (Aditiawarman, 2014). Thus, responses of ERS to a stressor will also result in an altered synthesis and/or release of proangiogenic factors in the human placenta vascular bed. This information is complemented by the proposed role of IRE1α, ATF6, and PERK as sensors of ERS (Marciniak and Ron, 2006; Zhang and Kaufman, 2006; Ron and Walter, 2007) or UPR (Ghosh et al., 2010; Hetz et al., 2015) constituting potential novel upstream regulatory pathways of angiogenesis via modulation of VEGF transcription in the human placenta (Iwawaki et al., 2009). Whether insulin modulates angiogenesis in the human placenta via changes in expression and/or function of ERS markers is unknown.


Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus.

Sobrevia L, Salsoso R, Fuenzalida B, Barros E, Toledo L, Silva L, Pizarro C, Subiabre M, Villalobos R, Araos J, Toledo F, González M, Gutiérrez J, Farías M, Chiarello DI, Pardo F, Leiva A - Front Physiol (2016)

Fetal insulinemia and altered angiogenesis in fetoplacental endothelium from gestational diabetes mellitus. With the progression of pregnancy up to the 40th weeks of gestation, the maternal glycaemia increases, and could reach supraphysiological levels in pregnancies where the mother is diagnosed with gestational diabetes mellitus. The maternal hyperglycaemia results in increased fetal glycaemia from about the 5th week of gestation (dotted line), a condition resulting in a supraphysiological increase of fetal insulinemia from the 12th week of gestation. Increased fetal insulinemia results in altered placental vascular development and growth leading to angiogenesis alterations (Placental vasculogenesis and angiogenesis). Thus, an adverse fetal outcome is seen as a result of abnormal angiogenesis. Cell signaling mechanisms involved in this phenomenon include altered expression and/or activity of several molecules that are responsive to insulin (IR-A, MMPs, cadherin, b-catenin). Equally, a low oxygen level at the beginning of pregnancy increases the expression of proangiogenic growth factors (VEGF, PlGF, IGF, FGF-2) and increased (GRP78, CHOP, IRE-1α, ATF6, PERK) or reduced (AMPK) expression and/or activity. Composed from information reported by Babawale et al. (2000), Jirkovská et al. (2002), Easwaran et al. (2003), Baumüller et al. (2015), Westermeier et al. (2015b).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4815008&req=5

Figure 2: Fetal insulinemia and altered angiogenesis in fetoplacental endothelium from gestational diabetes mellitus. With the progression of pregnancy up to the 40th weeks of gestation, the maternal glycaemia increases, and could reach supraphysiological levels in pregnancies where the mother is diagnosed with gestational diabetes mellitus. The maternal hyperglycaemia results in increased fetal glycaemia from about the 5th week of gestation (dotted line), a condition resulting in a supraphysiological increase of fetal insulinemia from the 12th week of gestation. Increased fetal insulinemia results in altered placental vascular development and growth leading to angiogenesis alterations (Placental vasculogenesis and angiogenesis). Thus, an adverse fetal outcome is seen as a result of abnormal angiogenesis. Cell signaling mechanisms involved in this phenomenon include altered expression and/or activity of several molecules that are responsive to insulin (IR-A, MMPs, cadherin, b-catenin). Equally, a low oxygen level at the beginning of pregnancy increases the expression of proangiogenic growth factors (VEGF, PlGF, IGF, FGF-2) and increased (GRP78, CHOP, IRE-1α, ATF6, PERK) or reduced (AMPK) expression and/or activity. Composed from information reported by Babawale et al. (2000), Jirkovská et al. (2002), Easwaran et al. (2003), Baumüller et al. (2015), Westermeier et al. (2015b).
Mentions: Placenta hypervascularization in women with DMT1, DMT2, or GDM, is reported (Cvitic et al., 2014; Huynh et al., 2015; Jarmuzek et al., 2015). DMT1 and DMT2 affect the entire process (vasculogenesis and angiogenesis; Jirkovská et al., 2002; Nelson et al., 2009; Jarmuzek et al., 2015) while GDM seems to impact the microvascular remodeling at angiogenesis (Jarmuzek et al., 2015). At 3rd trimester of pregnancy, the effect of DMT1, DMT2, and GDM on these phenomena is similar resulting in increased branching and surface area of villous capillaries (Teasdale, 1981; Jirkovská et al., 2002). Since GDM associates with developing longer umbilical cords compared with normal pregnancies (Georgiadis et al., 2014), it is suggested that placental hypervascularization in diabetes mellitus is mainly attributed to increased angiogenesis (Jirkovská et al., 2002; Leach, 2011; Figure 2). The later is partially explained by a placental hypoxia condition resulting from the fetal hyperglycaemia in diabetes mellitus. Fetal hyperglycaemia triggers fetal hyperinsulinemia, over-activating fetal metabolism leading to increased oxygen demand (Hytinantti et al., 2000; Taricco et al., 2009; Jarmuzek et al., 2015). Thus, it is likely that fetal hypoxia promotes the expression of angiogenic factors during the physiological placental angiogenesis at the 1st trimester of pregnancy when the oxygen level is reduced (Jauniaux et al., 2000). Since the level of FGF-2 is also regulated by hypoxia (Wang et al., 2009; Seo et al., 2013) and is increased in both the placenta and umbilical cord blood in diabetic pregnancies (Arany and Hill, 1998; Grissa et al., 2010), this growth factor emerges as a candidate to explain the hypervascularization in placentas from diabetes mellitus. Knowing that insulin is an angiogenic factor in endothelial cells (Liu et al., 2009), fetal hyperinsulinemia would have profound effects on placental and fetal vascular changes associated with maternal diabetes mellitus in pregnancy (Lassance et al., 2013). Interestingly, in another set of studies VEGF expression was shown to be lower in human placentas likely due to increased expression of the ERS-maker GRP78 (Aditiawarman, 2014). Thus, responses of ERS to a stressor will also result in an altered synthesis and/or release of proangiogenic factors in the human placenta vascular bed. This information is complemented by the proposed role of IRE1α, ATF6, and PERK as sensors of ERS (Marciniak and Ron, 2006; Zhang and Kaufman, 2006; Ron and Walter, 2007) or UPR (Ghosh et al., 2010; Hetz et al., 2015) constituting potential novel upstream regulatory pathways of angiogenesis via modulation of VEGF transcription in the human placenta (Iwawaki et al., 2009). Whether insulin modulates angiogenesis in the human placenta via changes in expression and/or function of ERS markers is unknown.

Bottom Line: GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis.This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature.Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

View Article: PubMed Central - PubMed

Affiliation: Cellular and Molecular Physiology Laboratory, Division of Obstetrics and Gynecology, Faculty of Medicine, School of Medicine, Pontificia Universidad Católica de ChileSantiago, Chile; Faculty of Medicine and Biomedical Sciences, University of Queensland Centre for Clinical Research, University of QueenslandHerston, QLD, Australia; Department of Physiology, Faculty of Pharmacy, Universidad de SevillaSeville, Spain.

ABSTRACT
Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

No MeSH data available.


Related in: MedlinePlus