Hyperglycaemia that develops during pregnancy and resolves after birth has been recognized for over 50 years, but uniform worldwide consensus is lacking about threshold hyperglycaemic levels that merit a diagnosis of ‘gestational diabetes mellitus’ (GDM) and thus treatment during pregnancy. GDM is currently the most common medical complication of pregnancy, and prevalence of undiagnosed hyperglycaemia and even overt diabetes in young women is increasing. Maternal overweight and obesity, later age at childbearing, previous history of GDM, family history of type 2 diabetes mellitus and ethnicity are major GDM risk factors. Diagnosis is usually performed using an oral glucose tolerance test (OGTT), although a non-fasting, glucose challenge test (GCT) is used in some parts of the world to screen women for those requiring a full OGTT. Dietary modification and increased physical activity are the primary treatments for GDM, but pharmacotherapy, usually insulin, is used when normoglycaemia is not achieved. Oral hypoglycaemic agents, principally metformin and glibenclamide (glyburide), are also used in some countries. Treatment improves immediate pregnancy outcomes, reducing excess fetal growth and adiposity and pregnancy-related hypertensive disorders. GDM increases the risk of long-term complications, including obesity, impaired glucose metabolism and cardiovascular disease, in both the mother and infant. Optimal management of mother and infant during long-term follow-up remains challenging, with very limited implementation of preventive strategies in most parts of the world. Gestational diabetes mellitus (GDM) is the most common complication in pregnancy and has short-term and long-term effects in both mother and offspring. This Primer discusses the definitions of GDM, diagnosis and management of the disease and areas requiring further research.

Gestational diabetes mellitus.

One of the primary regulators of maternofetal glucose transfer is the density of glucose transporter proteins in the placenta. These transporters, members of the GLUT gene family of facilitated-diffusion transporters, are embedded in the microvillous (maternal-facing) and basal (fetal-facing) membranes of the syncytiotrophoblast, the main placental barrier layer. Eight members of this family have been described in human placental tissue, but only GLUT1 protein has been identified in the syncytium, where its distribution is asymmetric. The microvillous membrane contains markedly more transporter than the basal, and, as a result, the basal membrane acts as the rate-limiting step in transplacental glucose transport; thus, changes in the density of basal membrane GLUT1 will have a significant impact on transplacental glucose flux. What little is known about syncytial GLUT1 expression is restricted to factors associated with fetoplacental growth and metabolism; GLUT is inversely regulated by glucose concentration and basal membrane GLUT1 is positively regulated by insulin-like growth factor I, placental growth hormone, and hypoxia. In vivo, basal membrane GLUT1 is upregulated over gestation, increased in diabetic pregnancy, and decreased in chronic hypoxia, while microvillous membrane GLUT1 is unaffected. The contrast between in vitro and in vivo regulation and the specific changes in GLUT1 distribution suggest more complex regulatory interactions than those yet described.

Placental glucose transfer and fetal growth.

OBJECTIVE To verify whether the leptin gene epigenetic (DNA methylation) profile is altered in the offspring of mothers with gestational impaired glucose tolerance (IGT).

RESEARCH DESIGN AND METHODS Placental tissues and maternal and cord blood samples were obtained from 48 women at term including 23 subjects with gestational IGT. Leptin DNA methylation, gene expression levels, and circulating concentration were measured using the Sequenom EpiTYPER system, quantitative real-time RT-PCR, and enzyme-linked immunosorbent assay, respectively. IGT was assessed after a 75-g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation.

RESULTS We have shown that placental leptin gene DNA methylation levels were correlated with glucose levels (2-h post-OGTT) in women with IGT (fetal side: ρ = −0.44, P ≤ 0.05; maternal side: ρ = 0.53, P ≤ 0.01) and with decreased leptin gene expression ( n = 48; ρ ≥ −0.30, P ≤ 0.05) in the whole cohort. Placental leptin mRNA levels accounted for 16% of the variance in maternal circulating leptin concentration ( P < 0.05).

CONCLUSIONS IGT during pregnancy was associated with leptin gene DNA methylation adaptations with potential functional impacts. These epigenetic changes provide novel mechanisms that could contribute to explaining the detrimental health effects associated with fetal programming, such as long-term increased risk of developing obesity and type 2 diabetes.

https://care.diabetesjournals.org/content/diacare/33/11/2436.full.pdf

Leptin Gene Epigenetic Adaptation to Impaired Glucose Metabolism During Pregnancy

Pregnancy offers a window of opportunity to program the future health of both mothers and offspring. During gestation, women experience a series of physical and metabolic modifications and adaptations, which aim to protect the fetus development and are closely related to both pre-gestational nutritional status and gestational weight gain. Moreover, pre-gestational obesity represents a challenge of treatment, and nowadays there are new evidence as regard its management, especially the adequate weight gain. Recent evidence has highlighted the determinant role of nutritional status and maternal diet on both pregnancy outcomes and long-term risk of chronic diseases, through a transgenerational flow, conceptualized by the Development Origin of Health and Diseases (Dohad) theory. In this review we will analyse the physiological and endocrine adaptation in pregnancy, and the metabolic complications, thus the focal points for nutritional and therapeutic strategies that we must early implement, virtually before conception, to safeguard the health of both mother and progeny. We will summarize the current nutritional recommendations and the use of nutraceuticals in pregnancy, with a focus on the management of pregnancy complicated by obesity and hyperglycemia, assessing the most recent evidence about the effects of ante-natal nutrition on the long-term, on either maternal health or metabolic risk of the offspring.

/pdf/nutrition-and-metabolic-adaptations-in-physiological-and-3dw7riqnmr.pdf

Nutrition and Metabolic Adaptations in Physiological and Complicated Pregnancy: Focus on Obesity and Gestational Diabetes.

By its location between maternal and fetal bloodstreams the human placenta not only handles the materno-fetal transport of nutrients and gases, but may also be exposed to intrauterine conditions adversely affecting placental and fetal development. Such adverse conditions exist in pregnancies complicated by gestational diabetes mellitus (GDM), and have been associated with alterations in placental anatomy and physiology. These alterations are mainly based on changes on the micro-anatomical and/or even molecular level including aberrant villous vascularization, a disbalance of vasoactive molecules, and enhanced oxidative stress. The consequence thereof may be impaired fetal oxygenation and changes in transplacental nutrient supply. Although transplacental glucose flux is flow limited and independent of glucose transporter availability, transport of essential and nonessential amino acids and expression of genes involved in lipid transport and metabolism are significantly affected by GDM.

/pdf/the-placenta-and-gestational-diabetes-mellitus-37n1lju99a.pdf

The placenta and gestational diabetes mellitus

Aims/hypothesis. Gestational diabetes is associated with complications for the offspring before, during and after delivery. Poor maternal glucose control, however, is a weak predictor of these complications. Given its position at the interface of the maternal and fetal circulations, the placenta possibly plays a crucial part in protecting the fetus from adverse effects from the maternal diabetic milieu. We hypothesised that gestational diabetes may result in changes in placental function, particularly with respect to the uptake, transfer, and/or utilisation of glucose. We aimed to examine glucose transport and utilisation in intact human placental lobules from women with gestational diabetes and those from normal pregnancies. Method. Dual perfusion of an isolated placental lobule was done on placentae from diet treated gestational diabetic (n = 7) and normal pregnant patients (n = 9) using maternal glucose concentrations of 4, 8, 16 and 24 mmol/l in random order over a 4-h experiment. Results were expressed in μmol · min–1· g–1. Results. d-glucose uptake from the maternal circulation (control 0.492 vs gestational diabetes mellitus 0.248, at 8 mmol/l maternal glucose), d-glucose utilisation by the placenta (0.255 vs 0.129), d-glucose transfer to the fetal circulation (direct 0.979 vs 0.402; net transfer 0.269 vs 0.118) and l-lactate maternal release into both the fetal (0.052 vs 0.042) and maternal (0.255 vs 0.129) circulation were significantly reduced during in vitro perfusion of placentae from patients with gestational diabetic pregnancies. Transfer of 3H-l-glucose also significantly reduced in the diabetic group (8.1 % vs 2.6 %). Conclusion/interpretation. These results suggest that placental transport and metabolism of d-glucose is altered during gestational diabetes. [Diabetologia (2000) 43: 576–582]

/pdf/effects-of-gestational-diabetes-on-human-placental-glucose-2nomycrk7a.pdf

Effects of gestational diabetes on human placental glucose uptake, transfer, and utilisation.

We have previously shown that placentae from patients with gestational diabetes mellitus who did not receive insulin had lower glucose transport and utilisation than non-diabetic control subjects. To assess the placental glucose handling characteristics of women with gestational diabetes mellitus receiving insulin, we examined glucose transport and utilisation in placentae from three groups of women after term delivery: those with gestational diabetes mellitus and receiving insulin (n = 9, insulin group); those with gestational diabetes mellitus and not receiving insulin (n = 10, no insulin group); and those with normal, non-diabetic pregnancies (n = 9, control group). Dual perfusion of an isolated placental lobule was done using maternal glucose concentrations of 4, 8, 16 and 24 mmol/l. Glucose and l-lactate concentrations in the maternal and fetal effluents were measured. Direct glucose transfer from the maternal to the fetal effluent was measured using 14C-d-glucose. Mean rates in μmol ming–1 (wet tissue) at maternal glucose concentration of 8 mmol/l are shown. Glucose uptake from the maternal perfusate (insulin group 0.57, no insulin group 0.30) and net glucose transfer to the fetal effluent (insulin group 0.41, no insulin group 0.20) both increased in the placentae of women receiving insulin compared with the diabetic group not receiving insulin. Both groups of patients had lower placental glucose utilisation than the control group (insulin group 0.16, no insulin group 0.10, control group 0.25). These results suggest that materno-fetal glucose transport increases in the placentae of women with gestational diabetes mellitus who receive insulin compared with those women who do not receive insulin. [Diabetologia (2001) 44: 1133–1139]

/pdf/placental-glucose-transport-and-utilisation-is-altered-at-2rn1dgtzgf.pdf

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

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Effects of gestational diabetes on human placental glucose uptake, transfer, and utilisation.

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