Fetal Hyperinsulinemia Research Articles

Maternal and fetal lipid metabolism under normal and gestational diabetic conditions.

Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus (GDM) pregnancies. During early pregnancy, the increase in maternal fat depots is facilitated by insulin, followed by increased adipose tissue breakdown and subsequent hypertriglyceridemia, mainly as a result of insulin resistance (IR) and estrogen effects. The response to diabetes is variable as a result of greater IR but decreased estrogen levels. The vast majority of fatty acids (FAs) in the maternal circulation are esterified and associated with lipoproteins. These are taken up by the placenta and hydrolyzed by lipases. The released FAs enter various metabolic routes and are released into fetal circulation. Although these determinants are modified in maternal GDM, the fetus does not seem to receive more FAs than in non-GDM pregnancies. Long-chain polyunsaturated FAs are essential for fetal development and are obtained from the mother. Mitochondrial FA oxidation occurs in fetal tissue and in placenta and contributes to energy production. Fetal fat accretion during the last weeks of gestation occurs very rapidly and is sustained not only by FAs crossing the placenta, but also by fetal lipogenesis. Fetal hyperinsulinemia in GDM mothers promotes excess accretion of adipose tissue, which gives rise to altered adipocytokine profiles. Fetal lipoproteins are low at birth, but the GDM effects are unclear. The increase in body fat in neonates of GDM women is a risk factor for obesity in early childhood and later life.

ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.

Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the β-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus.

Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 ± 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P < .05). There was no change in β-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P < .05) and higher norepinephrine (1160 ± 438 vs 522 ± 106 pg/mL; P < .005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.

Placental dysfunction in obese women and antenatal surveillance strategies

This review is aimed at discussing placental dysfunction in obesity and its clinical implication in pregnancy as well as an antenatal surveillance strategy for these women. Maternal obesity is associated with adverse perinatal outcome. Obesity is an independent risk factor for fetal hyperinsulinaemia, birthweight and newborn adiposity. Maternal obesity is associated with childhood obesity and obesity in adult life. Obesity induces a low-grade inflammatory response in placenta, which results in short- and long-term programming of obesity in fetal life. Preconception and antenatal counselling on obstetrics risk in pregnancy, on diet and lifestyle in pregnancy and on gestational weight gain is associated with a better outcome. Fetal growth velocity is closely associated with maternal weight and gestational weight gain. Careful monitoring of gestational weight gain and fetal growth, and screening and management of obstetrical complications such as gestational diabetes and pre-eclampsia, improves perinatal outcome. The use of metformin in non-diabetic obese women is under investigation; further evidence is required before recommending it.

The Feto-placental Dialogue and Diabesity

Recent studies have established that the neonate born to a pregnancy with maternal diabetes or obesity ('diabesity') is characterized by increased fat accumulation. The neonatal fat is the result of triglyceride synthesis and deposition stimulated by elevated fetal insulin levels combined with insulin's mitogenic activity directly stimulating the growth of the white adipocytes. Fetal insulin levels are determined by fetal glucose and some amino acids such as arginine. Although the placenta plays a key role in providing maternally derived nutrients to the growing fetus, there is currently no evidence that it actively contributes to an excessive maternal-to-fetal glucose flux at the end of gestation. Early in gestation, the maternal environment in diabesity, and in particular the glucose-insulin axis, can modify placental growth and development, which may contribute to an enhanced glucose flux to the fetus already early in pregnancy. This may have long-lasting effects on the fetal pancreas and accelerate beta-cell maturation. The association of fetal and neonatal insulin levels and the proportion of body fat with obesity later in the offspring's life calls for interventions during pregnancy to prevent or reduce fetal hyperinsulinaemia. Dietary and/or physical activity interventions initiated before or in early pregnancy would likely be most effective. Results from the very few studies with fetal insulin as the outcome are inconsistent. However, there is a major lack of randomized intervention trials on this topic.

Effect of hyperglycaemia in pregnancy on adiposity in their infants in India: a protocol of a multicentre cohort study

IntroductionThe carbohydrate ‘fuel’ metabolism in a pregnant woman may have a long-term impact on the development of her offspring (‘fuel-mediated teratogenesis’ hypothesis) including in utero exposure to maternal hyperglycaemia leading...

Changes in fetal mannose and other carbohydrates induced by a maternal insulin infusion in pregnant sheep.

BackgroundThe importance of non-glucose carbohydrates, especially mannose and inositol, for normal development is increasingly recognized. Whether pregnancies complicated by abnormal glucose transfer to the fetus also affect the regulation of non-glucose carbohydrates is unknown. In pregnant sheep, maternal insulin infusions were used to reduce glucose supply to the fetus for both short (2-wk) and long (8-wk) durations to test the hypothesis that a maternal insulin infusion would suppress fetal mannose and inositol concentrations. We also used direct fetal insulin infusions (1-wk hyperinsulinemic-isoglycemic clamp) to determine the relative importance of fetal glucose and insulin for regulating non-glucose carbohydrates.ResultsA maternal insulin infusion resulted in lower maternal (50%, P < 0.01) and fetal (35-45%, P < 0.01) mannose concentrations, which were highly correlated (r2 = 0.69, P < 0.01). A fetal insulin infusion resulted in a 50% reduction of fetal mannose (P < 0.05). Neither maternal nor fetal plasma inositol changed with exogenous insulin infusions. Additionally, maternal insulin infusion resulted in lower fetal sorbitol and fructose (P < 0.01).ConclusionsChronically decreased glucose supply to the fetus as well as fetal hyperinsulinemia both reduce fetal non-glucose carbohydrates. Given the role of these carbohydrates in protein glycosylation and lipid production, more research on their metabolism in pregnancies complicated by abnormal glucose metabolism is clearly warranted.

Is diabetes mellitus worth treating?

The aim of the paper was to present data that enable us to determine whether treatment of hyperglycemia diagnosed during pregnancy in the era of a steadily growing number of women with gestational diabetes mellitus (GDM) and an ongoing debate about new criteria and diagnostic strategies, is a valid option. GDM is the main metabolic disorder developing during pregnancy complicating around 6% of all pregnancies. Mistreatment of hyperglycemia during pregnancy may cause several fetal complications, especially neonatal overgrowth (macrosomia or LGA). The risk of macrosomia is directly related to maternal hyperglycemia (twice as high as in the control group with glucose levels exceeding 130 mg/dl). Apart from maternal hyperglycemia and fetal hyperinsulinemia, insulin-like growth factors and selected adipocytokines produced by adipose tissue and placenta are among the factors contributing to the development of diabetic fetopathy, whose risk increases by 2-fold with glucose levels exceeding 130 mg/dl. The role of hyperglycemia as a factor inducing several perinatal complications was confirmed by the HAPO study but it is not the sole reason of adverse effects. Also, maternal obesity weight gain during pregnancy and maternal hyperlipidemia seem to be involved in the pathogenesis of feto-maternal complications. Changes in fetal growth, disturbances in the perinatal period, there just some of the negative consequences of maternal GDM. Disturbance of carbohydrate metabolism during pregnancy causes long-lasting consequences for both, the mother and the child, including increased risk of overt diabetes, metabolic syndrome and cardiovascular complications. Children born to GDM mothers are at a significant risk of psycho-motoric disability and a higher risk of schizophrenia. ACHOIS and MFMU studies have confirmed that even mild hyperglycemia, detected and treated in a timely manner significantly improves maternal and fetal outcome. Various meta-analyses have revealed a positive effect of GDM treatment. To the best of our knowledge, no clinical study has revealed negative effects of such treatment, with the exception of an increased number of perinatal visits.

Glucose, insulin, and oxygen interplay in placental hypervascularisation in diabetes mellitus.

The placental vasculature rapidly expands during the course of pregnancy in order to sustain the growing needs of the fetus. Angiogenesis and vascular growth are stimulated and regulated by a variety of growth factors expressed in the placenta or present in the fetal circulation. Like in tumors, hypoxia is a major regulator of angiogenesis because of its ability to stimulate expression of various proangiogenic factors. Chronic fetal hypoxia is often found in pregnancies complicated by maternal diabetes as a result of fetal hyperglycaemia and hyperinsulinemia. Both are associated with altered levels of hormones, growth factors, and proinflammatory cytokines, which may act in a proangiogenic manner and, hence, affect placental angiogenesis and vascular development. Indeed, the placenta in diabetes is characterized by hypervascularisation, demonstrating high placental plasticity in response to diabetic metabolic derangements. This review describes the major regulators of placental angiogenesis and how the diabetic environment in utero alters their expression. In the light of hypervascularized diabetic placenta, the focus was placed on proangiogenic factors.

La hipótesis de Pedersen no es suficiente: Otros nutrientes además de la glucosaexplicarían la macrosomía fetal enpacientes diabéticas gestacionales consobrepeso y buen control glicémico

Since 1964, the hypothesis of Pedersen has been used to explain fetal macrosomia observed in gestational diabetes mellitus (GDM), by a mechanism involving maternal hyperglycemia--fetal hyperglycemia--fetal hyperinsulinemia. However, since the 1980-89 decade, it is known that pregnant women with pre-gestational overweight not suffering from GDM still have a higher frequency of fetal macrosomia. Furthermore, pregnant women with GDM, despite being subjected to optimal glycemic control, still show unacceptably high frequencies of fetal macrosomia, a phenomenon that is concentrated in pregnancies with overweight or obesity prior to pregnancy. If glucose is not the single nutrient responsible for fetal macrosomia in pregnant women with gestational diabetes that undergo strict glycemic control, other nutrients may cause excessive fetal growth in pre-pregnancy overweight mothers. In this review, we propose that triglycerides (TG) could be responsible for this accelerated fetal growth. If this hypothesis is validated in animal models and clinical studies, then normal and pathological ranges of TG should be defined, and monitoring of triglyceride levels during pregnancy should be advised as a possible new alternative, besides a good glycemic control, for the management of fetal macrosomia in GDM women with overweight prior to pregnancy.

Gestational diabetes and childhood obesity

To review recently published studies examining the role of prepregnancy obesity in the relationship between gestational diabetes mellitus and childhood obesity. Seven epidemiologic studies published from January 2011 to February 2012 differentiate between preexisting diabetes mellitus and gestational diabetes mellitus, and six of them examine the role of maternal obesity. In studies that account for maternal obesity as a covariate, the association between gestational diabetes mellitus and childhood obesity is attenuated significantly after adjustment for prepregnancy BMI. In the one study that does not adjust for maternal obesity, maternal glucose level during pregnancy is associated with greater offspring adiposity, independent of the child's diet and lifestyle. This review shows a positive association between maternal gestational diabetes mellitus and offspring overweight and obesity that is attenuated significantly after adjustment for prepregnancy BMI. The relationship between maternal gestational diabetes mellitus and offspring overweight and obesity could reflect fetal programming, shared genes and/or shared environments, such as postnatal diet and physical activity. Maternal gestational hyperglycemia and subsequent fetal hyperinsulinemia may predispose offspring to increased adiposity, impaired glucose tolerance, hyperinsulinemia, and insulin resistance. Because maternal obesity is a more prevalent condition than gestational diabetes mellitus and strongly associated with offspring obesity, effective interventions addressing prepregnancy obesity need to be further explored as they may have a greater public health impact on childhood overweight and obesity than those targeting women with gestational diabetes mellitus.

Role of glycemic variability in gestational diabetes mellitus (GDM): still an uphill climb

Insulin resistance tends to increase in physiological pregnancy because of the gradually rising levels of feto-placental hormones such as progesterone, cortisol, growth hormone, prolactin, and human placental lactogen. In response to this imbalance, the pancreas normally compensates with a higher insulin secretion. When this compensatory mechanism fails, glucose intolerance develops and, in pregnancy, this is called gestational diabetes mellitus (GDM) [1]. The resulting maternal hyperglycemia gives rise to a concomitant fetal hyperinsulinemia via the placenta, leading primarily to fetal macrosomia, which is the main cause of well-known complications relating to the fetus’s development (e.g., shoulder dystocia, Erb’s paralysis, hypoxia, and acidosis) and to the course of labor (e.g., perineal laceration, cesarean section) [2]. Clinical evidence has confirmed that the main goal of glycemic management in GDM is to keep the mother’s blood glucose levels as close as possible to the normal range. A number of studies have demonstrated that macrosomia correlate with glycemic control in pregnancy complicated by diabetes [3]. It has recently been suggested that glucose variability, characterized by significant glucose excursions, may overlap with HbA1c levels in determining the risk of diabetes-related complications [4]. Oscillating blood sugar levels have been shown to increase free radicals and endothelial dysfunction, which are the links between hyperglycemia and the activation of pathological pathways that lead to tissue damage [5], and it has been reported that containing these hyperglycemic spikes coincides with a reduction in some markers of oxidative stress. In pregnancy complicated by diabetes even transient periods of hyperglycemia may lead to accelerated fetal growth, resulting in macrosomic infants. These peaks are difficult to capture using common glucose monitoring methods based on six to eight glucose measurements a day, whereas continuous glucose monitoring (CGM) systems are more revealing because they enable glucose levels to be monitored constantly throughout the day [6]. Despite recent opportunities to shed further light on the subject, glucose variability is still a poorly understood factor in GDM patients, especially its link with maternal and fetal complications. In one study, 48-h CGM was performed in all three trimesters in 31 women with GDM, and showed a close relationship between babies’ ponderal index and their mothers’ glucose variability indicators and mean glycemia in the 2nd trimester, irrespective of their HbA1c levels. This study emphasized that fetal growth in the early stages of gestation could be affected even in patients whose glycemic variability indices were only slightly higher than in controls [7]. In this issue of Endocrine, Su et al. [8] set out to use 72-h CGM to analyze several glycemic variability parameters in 30 patients with GDM, as compared with 20 healthy pregnant women and 20 healthy non-pregnant women, seeking a possible association with markers of beta-cell function. As indicators of glucose variability, they took into account the mean amplitude of glycemic excursion (MAGE), the mean of daily differences (MODD), and the standard deviation of blood glucose (SDBG); the HOMA-IR index was calculated to assess insulin resistance. The early insulinogenic index (DI30/DG30) and the area under the curve of insulin (AUCI 180) derived from 75 g oral glucose tolerance test (OGTT) were calculated to A. Lapolla (&) N. C. Chilelli Department of Medicine (DIMED), University of Padua, Via Giustiniani n 2, 35128 Padua, Italy e-mail: annunziata.lapolla@unipd.it

Hypoxaemia‐induced catecholamine secretion from adrenal chromaffin cells inhibits glucose‐stimulated hyperinsulinaemia in fetal sheep

Abstract Hypoxaemia elicits adrenergic suppression of fetal glucose-stimulated hyperinsulinaemia. We postulate that this effect is mediated by catecholamines, exclusively, from fetal adrenal chromaffin cells. To investigate this hypothesis, square-wave hyperglycaemic clamp studies were performed under normoxaemic (26 ± 0.9 mmHg) and hypoxaemic (14 ± 0.3 mmHg) steady-state conditions in near-term fetal sheep that had undergone either surgical sham or bilateral adrenal demedullation (AD), values mentioned are ± SEM. Under normoxaemic conditions plasma noradrenaline concentrations were lower in AD fetuses than in sham-operated fetuses (457 ± 122 versus 1073 ± 103 pg ml(-1), P < 0.05). Plasma insulin concentrations were not different at euglycaemia between shams (0.46 ± 0.07 ng ml(-1)) and AD fetuses (0.44 ± 0.04 ng ml(-1)) and increased (P < 0.05) with hyperglycaemia in both groups although to a lesser extent in AD fetuses (0.94 ± 0.19 ng ml(-1)) compared to shams (1.31 ± 0.15 ng ml(-1); P < 0.05). Hypoxaemia increased plasma adrenaline (26-fold) and noradrenaline (5-fold) in shams but elicited no change in AD fetuses. Under hypoxaemic conditions, euglycaemic plasma insulin concentrations were reduced (P < 0.05) in both sham and AD fetuses to 0.30 ± 0.05 ng ml(-1) and 0.27 ± 0.01 ng ml(-1) respectively, and the insulin response to hyperglycaemia was abolished in shams but not affected in AD fetuses (0.33 ± 0.06 versus 0.73 ± 0.02 ng ml(-1), P < 0.05). Hypoxaemia also induced hyperlactacaemia and hypocarbia to a greater extent in shams than in AD fetuses, indicating that catecholamines potentiate reductions in oxidative metabolism independently of insulin. These findings demonstrate that the fetal adrenal chromaffin cells are the source for acute hypoxaemia-induced elevations in fetal plasma catecholamines and suppression of glucose-stimulated hyperinsulinaemia, but other factors reduce plasma insulin at euglycaemia.

Point: The American Diabetes Association and the International Association of Diabetes and Pregnancy Study Groups Recommendations for Diagnosing Gestational Diabetes Should Be Used Worldwide

Various challenge tests have been used around the world for the diagnosis of gestational diabetes mellitus (GDM)2, and substantial variation among these methods has been noted, not only in the amount of glucose for the challenge and the testing intervals but also in the concentration thresholds used for interpretation. The interpretive criteria for these testing approaches have variably been based on the value for predicting future maternal diabetes or been adopted from standards developed with nonpregnant individuals, despite the changes in glucose metabolism known to occur during pregnancy. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was an observational study of values obtained in blinded 75-g, 2-h oral glucose tolerance tests (OGTTs) for >23 000 pregnancies from 9 different countries around the world (1). The adverse pregnancy outcomes evaluated included birth weight >90th percentile (large for gestational age), fetal hyperinsulinemia, primary cesarean section, neonatal hypoglycemia, neonatal adiposity, shoulder dystocia, and preeclampsia. All adverse outcomes were related directly and significantly to the glucose concentration at each OGTT time point, but there was no obvious inflection point in any of the curves. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) undertook a process to reach consensus on the diagnostic criteria for GDM with respect to their value for predicting adverse pregnancy outcomes and recommended that GDM be diagnosed when one or more of the following plasma glucose values in the 75-g, 2-h OGTT was met or exceeded: fasting, 92 mg/dL (5.1 mmol/L); 1 h, 180 mg/dL (10 mmol/L); 2 h, 153 mg/dL (8.5 mmol/L) (2). According to the HAPO Study data, patients with GDM have an approximate doubling of the likelihood of a baby with a birth weight above the 90th percentile, 2.6 times the likelihood of fetal hyperinsulinemia, twice the likelihood of preeclampsia, and a 40% increase …

Is a deceptive role of IGF-1 in Sirt1–PARP1 interactions the primary step of postnatal regression of hypertrophic cardiomyopathy in infants of diabetic mothers?

Is a deceptive role of IGF-1 in Sirt1–PARP1 interactions the primary step of postnatal regression of hypertrophic cardiomyopathy in infants of diabetic mothers?

Functional Link Between Adenosine and Insulin: A Hypothesis for Fetoplacental Vascular Endothelial Dysfunction in Gestational Diabetes

Gestational diabetes mellitus (GDM) is a syndrome compromising the health of the mother and the fetus. Endothelial damage and reduced metabolism of the vasodilator adenosine occur and fetal hyperinsulinemia associated with deficient insulin response and a metabolic rather than mitogenic phenotype is characteristic of this pathology. These phenomena lead to endothelial dysfunction of the fetoplacental unit. Major databases were searched for the relevant literature in the field. Special attention was placed on publications related with diabetes and hormone/metabolic disorders. We aimed to summarize the information regarding insulin sensitivity changes in GDM and the role of adenosine in this phenomenon. Evidence supporting the possibility that fetal endothelial dysfunction involves a functional link between adenosine and insulin signaling in the fetal endothelium from GDM pregnancies is summarized. Since insulin acts via membrane receptors type A (preferentially associated with mitogenic responses) or type B (preferentially associated with metabolic responses), a differential activation of these receptors in this syndrome is proposed.

Aiming at New Targets to Achieve Normoglycemia During Pregnancy

In a recent issue of Diabetes Care , Hernandez et al. (1) from the University of Colorado presented a comprehensive review of the 24-h glucose profile during pregnancy in women without diabetes. In the current issue, Harmon et al. (2) from the same institution present new observations on the glycemic profile of pregnant nondiabetic women, examining differences between obese and normal-weight mothers and between different trimesters of pregnancy. Why are articles about women without diabetes being published in a journal whose very title declares that it is about the care of diabetes? The answer is that these two reports give us an idea of what is truly “normal” glucose during pregnancy, and this has important implications for the way we all manage diabetes during pregnancy. The articles are startling in that they both show that normal glucose values are substantially lower than the target values currently recommended for treatment of diabetes during pregnancy. Hernandez et al. (1) propose that we ought to change these targets to more closely approximate nondiabetic norms. Contemporary management of diabetes during pregnancy is guided by the Pedersen Hypothesis, which holds that diabetic fetal macrosomia and various newborn metabolic sequelae are caused by endogenous fetal hyperinsulinemia, which is a response to fetal hyperglycemia. This, in turn, is a direct reflection of maternal hyperglycemia because glucose readily traverses the placenta whereas insulin does not (3). The corollary is that diabetic fetopathy should largely be preventable by preventing maternal hyperglycemia. The cornerstone of diabetes management in pregnancy, then, is to attempt to keep maternal glucose as close to normal as possible. But what exactly is a “normal” glucose during pregnancy? The articles by Hernandez et al. (1) and Harmon et al. (2) help us to answer this question. The review by Hernandez et al. (1) reported on literature …

Higher cord C-peptide concentrations are associated with slower growth rate in the 1st year of life in girls but not in boys.

OBJECTIVETo understand the relationships between maternal glycemia during pregnancy and prenatal and early postnatal growth by evaluating cord C-peptide and IGF-I as mediating biomarkers in boys and girls separately.RESEARCH DESIGN AND METHODSWe evaluated 342 neonates within the EDEN mother-child cohort study born to mothers without diabetes diagnosis before pregnancy. We measured maternal glycemia at 24–28 weeks of gestation and neonates’ cord blood C-peptide (used as a proxy for fetal insulin) and IGF-I at birth. Reported maternal prepregnancy BMI and all measured infant weights and lengths in the 1st year were recorded. Growth modeling was used to obtain an individual growth curve for each infant in the 1st year. Path models, a type of structural equation modeling, were used for statistical analysis. Path analysis is a multivariate method associated with a graphical display that allows evaluation of mediating factors and distinguishes direct, indirect, and total effects.RESULTSCord C-peptide at birth was positively correlated with maternal prepregnancy BMI and maternal glycemia and was higher in girls. In a path model that represented prenatal growth, there was no significant direct effect of maternal glycemia on birth weight, but the effect of maternal glycemia on birth weight was mediated by fetal insulin and IGF-I in both girls and boys. However, in girls only, higher concentrations of cord C-peptide (but not cord IGF-I or maternal glucose) were associated with slower weight growth in the first 3 months of life.CONCLUSIONSOur study underlines the role of the fetal insulin–IGF-I axis in the relationship between maternal glycemia during pregnancy and birth weight. We also show for the first time that high insulin concentration in female fetuses is associated with slower early postnatal growth. This slow, early growth pattern may be programmed by fetal hyperinsulinemia, and girls may be more susceptible than boys to its consequences.

Patterns of Glycemia in Normal Pregnancy

Despite the well-known influence of maternal glucose on infant birth weight (BW), the prevalence of large for gestational age (LGA) infants (≥90th percentile for age) has been increasing steadily over decades, particularly in pregnancies complicated by pregestational or gestational diabetes mellitus (1). Although the overall prevalence of macrosomia (BW ≥4,000 g) is 17–29% in women with untreated gestational diabetes, the majority of macrosomic infants are born to women with obesity but no gestational diabetes (2,3). Moreover, epidemiologic data show that a higher BW is associated with higher BMI and glucose intolerance later in life (4,5), suggesting life-long metabolic implications for offspring. Recent data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study suggested that concentrations of maternal glucose below the previously accepted diagnostic thresholds for gestational diabetes are predictive of LGA and fetal hyperinsulinemia (6). On the basis of this landmark study, the International Association of Diabetes in Pregnancy Study Group and the American Diabetes Association (ADA) recommended new lower diagnostic criteria for gestational diabetes (7,8). However, a significant number of women with gestational diabetes whose glucose values are within the current targeted therapeutic ranges deliver macrosomic infants (9). Although glucose plays a major role in fetal growth, this paradox underscores the likely role of other nutrients in fetal growth, but also the need to critically reexamine our definition of “normal” maternal patterns of glycemia and the effects on fetal growth. The new diagnostic criteria recommended by the International Association of Diabetes in Pregnancy Study Group and ADA are expected to increase the prevalence of gestational diabetes to 18%. Thus, treatment targets may need to be reevaluated. Historically, the treatment goal in pregnancies complicated by diabetes has been to mimic patterns of glycemia in normal pregnancy (1). Although the HAPO study better defined abnormal …

Management of gestational diabetes mellitus: how well are we doing?

Gestational diabetes mellitus (GDM) affects up to 14% of women annually. Abnormal glucose tolerance leads to fetal hyperinsulinaemia and macrosomia, thus increasing perinatal morbidity. Randomized controlled trials have shown that...