Placental glucose transport and utilisation is altered at term in insulin-treated, gestational-diabetic patients

Osmond, D; King, Roger G; Brennecke, Shaun P.; Gude, Neil M

doi:10.1007/s001250100609

Cited by 52 publications

(27 citation statements)

References 13 publications

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“…Alterations in the amounts of proteins, carbohydrates and fat that are supplied to the foetus may have long-term consequences (Jansson & Powell 2007). Changes in glucose metabolism (Osmond et al 2001) and increased oxidative stress are characteristics of pregnancies complicated with diabetes (Lappas et al 2011a). Excess uptake and transfer of maternal glucose across the placenta would lead to foetal hyperglycaemia with subsequent hyperinsulinaemia and its associated detrimental sequelae (Nold & Georgieff 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Their respective cellular localisations suggest that GLUT1 is responsible for supplying glucose for use as a placental fuel and that GLUT3 is important for glucose transfer to the foetus (Hauguel-de Mouzon et al 1997, Illsley 2000. Certainly, a number of significant pregnancy complications, including gestational diabetes mellitus (GDM) and pre-eclampsia (Hubel 1999, Myatt & Cui 2004, Siddiqui et al 2010, are associated with altered placental glucose metabolism (Osmond et al 2001, Jansson & Powell 2006. However, the molecular mechanisms of human placental glucose transport and its regulation remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxanthine–xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta

Lappas¹,

Andrikopoulos²,

Permezel³

2012

Journal of Endocrinology

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Appropriate foetal growth and development is dependent on adequate placental glucose uptake. Oxidative stress regulates glucose uptake in various tissues. The effect of oxidative stress on placental glucose transport is not known. Thus, the aim of this study was to determine the effect of oxidative stress on glucose uptake and glucose transporters (GLUTs) in human placenta. Human placenta was incubated in the absence or presence of 0 . 5 mM hypoxanthineC15 mU/ml xanthine oxidase (HX/XO) for 24 h. Gene and protein expressions of the GLUTs were analysed by quantitative RT-PCR and western blotting respectively. Glucose uptake was measured using radiolabelled ( 14 C) glucose. HX/XO significantly decreased GLUT1 gene and protein expression and resultant glucose uptake. There was no effect of the antioxidants N-acetylcysteine, catalase and superoxide dismutase or the NF-kB inhibitor BAY 11-0782 on HX/XO-induced decrease in glucose uptake. However, HX/XO treatment significantly decreased both gene and protein expression of SIRT1. In the presence of the SIRT1 activator resveratrol, the decrease in GLUT1 expression and glucose uptake mediated by HX/XO was abolished. Collectively, the data presented here demonstrate that oxidative stress reduces placental glucose uptake and GLUT1 expression by a SIRT1-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxanthine–xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta

Lappas¹,

Andrikopoulos²,

Permezel³

2012

Journal of Endocrinology

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“…In keeping with this, our previous studies have shown increased GLUT-1 expression in the GDM placenta (Colomiere et al 2009). Furthermore, studies have shown increased maternal-foetal glucose transport in placenta from women with insulin-controlled GDM (Osmond et al 2001). The combination of these factors suggests that defective glucose transport prior to birth may be involved in pre-programming the foetus for increased risk of diabetes and obesity in adulthood.…”

Section: Discussionmentioning

confidence: 99%

Diabetes and obesity during pregnancy alter insulin signalling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue

Colomiere¹,

Permezel²,

Lappas³

2009

Journal of Molecular Endocrinology

105

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Severe insulin resistance is a defining attribute of gestational diabetes mellitus (GDM). It is postulated that alterations in the insulin-signalling pathway and subsequent glucose disposal are the underlying cause of insulin resistance in patients with GDM. The purpose of this study was to profile the insulin-signalling pathway and intermediates in insulin-sensitive tissues. Subcutaneous adipose tissue and skeletal muscle were collected from normal glucose-tolerant (NGT) and insulin-controlled GDM in both non-obese and obese cohorts (nZ6-8 per subgroup). Expression studies of the insulin-signalling pathway were performed using western blotting and quantitative reverse transcription-PCR. This study demonstrated altered mRNA expression of insulin receptor substrate (IRS)-1, IRS-2, glucose transporter (GLUT)-1, GLUT-4 and glycogen synthase kinase (GSK)-3 isoforms genes in adipose tissue in GDM women in comparison to NGT pregnant controls. In skeletal muscle, insulin-controlled GDM was associated with decreased IRS-1, phosphatidylinositol-3-kinase (PI3-K) p85a, GLUT-1 and -4, GSK-3 isoforms and phosphoinositide-dependent kinase-1. Both adipose tissue and skeletal muscle from women with GDM displayed decreased IRS-1 and GLUT-4 and increased PI3-K p85a protein expression. Both skeletal muscle and adipose tissue from obese women demonstrated lower GLUT-1 and -4 mRNA expression and diminished GLUT-4 protein expression in skeletal muscle only. Collectively, our results suggest that diabetes and obesity during pregnancy cause defects in insulin-signalling transduction in adipose tissue and skeletal muscle and may be the underlying cause of GDM.

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“…The ubiquitously expressed GLUT-1 isoform is inversely related to extracellular glucose concentration in placenta (17) whereas GLUT-4, which is found to a lesser extent in the placenta, are insulin sensitive GLUTs (18). Studies have demonstrated diminished glucose uptake in placental tissue from individuals with GDM (19)(20)(21)(22) and furthermore, increased expression of GLUT-1 in placenta basal membranes from GDM women in comparison with normal controls (23,24).…”

Section: Introductionmentioning

confidence: 99%

Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus

Colomiere¹,

Permezel²,

Riley³

et al. 2009

European Journal of Endocrinology

177

125

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Objective: Studies in adipose tissue and skeletal muscle suggest that impaired insulin action is due to defects in the insulin signaling pathway and may play a role in the pathophysiology of insulin resistance associated with gestational diabetes mellitus (GDM) and obesity. The present study tested the hypothesis that endogenous expression levels in the human term placenta of insulin signaling components are altered in placental tissue from GDM women in comparison with normal controls and maternal obesity. Design and methods: Placental tissue was collected from normal, diet-controlled GDM, and insulincontrolled GDM in both non-obese and obese women (nZ6-7 per group). Western blotting and quantitative RT-PCR was performed to determine the level of expression in the insulin signaling pathway.Results: There was a significant increase in insulin receptor (IR) substrate (IRS)-1 protein expression with a concurrent decrease in IRS-2 protein expression in non-obese women with insulin-controlled GDM compared with diet-controlled GDM and normal controls. Furthermore, a decrease in both protein and mRNA expression of phosphatidyl-inositol-3-kinase (PI3-K) p85a and glucose transporter (GLUT)-4 was observed in non-obese and obese women with insulin controlled GDM compared with normal controls. When comparing non-obese to obese patients, significant decreases in mRNA expression of IR-b, PI3K p85a and GLUT-4 was found in obese patients. Conclusion: Our results suggest that post receptor defects are present in the insulin signaling pathway in placenta of women with pregnancies complicated by diabetes and obesity. In addition, expression studies demonstrate post receptor alterations in insulin signaling possibly under selective maternal regulation and not fetal regulation.

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Placental glucose transport and utilisation is altered at term in insulin-treated, gestational-diabetic patients

Cited by 52 publications

References 13 publications

Hypoxanthine–xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta

Hypoxanthine–xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta

Diabetes and obesity during pregnancy alter insulin signalling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue

Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus

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