Diet-treated Gestational Diabetes Mellitus Research Articles

Glycemic control and neonatal outcomes in twin pregnancies with gestational diabetes mellitus

Preliminary data suggest that strict glycemic control in twin pregnancies with gestational diabetes mellitus may not improve outcomes but might increase the risk of fetal growth restriction. This study aimed to investigate the association of maternal glycemic control with the risk of gestational diabetes mellitus-related complications and small for gestational age in twin pregnancies complicated by gestational diabetes mellitus. This was a retrospective cohort study of all patients with a twin pregnancy complicated by gestational diabetes mellitus in a single tertiary center between 2011 and 2020, and a matched control group of patients with a twin pregnancy without gestational diabetes mellitus in a 1:3 ratio. The exposure was the level of glycemic control, described as the proportion of fasting, postprandial, and overall glucose values within target. Good glycemic control was defined as a proportion of values within target above the 50th percentile. The first coprimary outcome was a composite variable of neonatal morbidity, defined as at least 1 of the following: birthweight >90th centile for gestational age, hypoglycemia requiring treatment, jaundice requiring phototherapy, birth trauma, or admission to the neonatal intensive care unit at term. A second coprimary outcome was small for gestational age, defined as birthweight <10th centile or <3rd centile for gestational age. Associations between the level of glycemic control and the study outcomes were estimated using logistic regression analysis and were expressed as adjusted odds ratio with 95% confidence interval. A total of 105 patients with gestational diabetes mellitus in a twin pregnancy met the study criteria. The overall rate of the primary outcome was 32.4% (34/105), and the overall proportion of pregnancies with a small for gestational age newborn at birth was 43.8% (46/105). Good glycemic control was not associated with a reduction in the risk of composite neonatal morbidity when compared with suboptimal glycemic control (32.1% vs 32.7%; adjusted odds ratio, 2.06 [95% confidence interval, 0.77-5.49]). However, good glycemic control was associated with higher odds of small for gestational age compared with nongestational diabetes mellitus pregnancies, especially in the subgroup of diet-treated gestational diabetes mellitus (65.5% vs 34.0%, respectively; adjusted odds ratio, 4.17 [95% confidence interval, 1.74-10.01] for small for gestational age <10th centile; and 24.1% vs 7.0%, respectively; adjusted odds ratio, 3.97 [95% confidence interval, 1.42-11.10] for small for gestational age <3rd centile). In contrast, the rate of small for gestational age in gestational diabetes mellitus pregnancies with suboptimal control was not considerably different when compared with non-gestational diabetes mellitus pregnancies. In addition, in cases of diet-treated gestational diabetes mellitus, good glycemic control was associated with a left-shift of the distribution of birthweight centiles, whereas the distribution of birthweight centiles among gestational diabetes mellitus pregnancies with suboptimal control was similar to that of nongestational diabetes mellitus pregnancies. In patients with gestational diabetes mellitus in a twin pregnancy, good glycemic control is not associated with a reduction in the risk of gestational diabetes mellitus-related complications but may increase the risk of a small for gestational age newborn in the subgroup of patients with mild (diet-treated) gestational diabetes mellitus. These findings further question whether the gestational diabetes mellitus glycemic targets used in singleton pregnancies also apply to twin pregnancies and support the concern that applying the same diagnostic criteria and glycemic targets in twin pregnancies may result in overdiagnosis and overtreatment of gestational diabetes mellitus and potential neonatal harm.

Increased Oral Care Needs and Third Molar Symptoms in Women with Gestational Diabetes Mellitus: A Finnish Gestational Diabetes Case-Control Study.

(1) Hyperglycemia and oral pathology accelerate each other in diabetes. We evaluated whether gestational diabetes mellitus (GDM) is associated with self-reported increased oral health care needs and oral symptoms, including third molar symptoms, during pregnancy. (2) Pregnant women with (n = 1030) and without GDM (n = 935) were recruited in this multicenter Finnish Gestational Diabetes study in 2009–2012. Of the women with GDM, 196 (19.0%) receiving pharmacological treatment, 797 (77.0%) receiving diet treatment and 233 (23.0%) with recurrent GDM were analyzed separately. Oral health was assessed using structured questionnaires and analyzed by multivariable logistic regression adjusted for background risk factors. (3) Women with GDM were more likely to report a higher need for oral care than controls (31.1% vs. 24.5%; odds ratio (OR) 1.39; 95% confidence interval (CI) 1.14–1.69), particularly women with recurrent GDM (38.1% vs. 24.5%; OR 1.90; 95% CI 1.40–2.58). Women with pharmacologically treated GDM (46.9%) more often had third molar symptoms than controls (36.1%; OR 1.57; 95% CI 1.15–2.15) than women with diet-treated GDM (38.0%; OR 1.47; 95% CI 1.07–2.02). (4) GDM is associated with perceived oral care needs. Third molar symptoms were associated with pharmacologically treated GDM.

Diet-Treated Gestational Diabetes Mellitus Is an Underestimated Risk Factor for Adverse Pregnancy Outcomes: A Swedish Population-Based Cohort Study.

In Sweden, diet-treated gestational diabetes mellitus (GDM) pregnancies have been managed as low risk. The aim was to evaluate the risk of adverse perinatal outcomes among women with diet-treated GDM compared with the background population and with insulin-treated GDM. This is a population-based cohort study using national register data between 1998 and 2012, before new GDM management guidelines and diagnostic criteria in Sweden were introduced. Singleton pregnancies (n = 1,455,580) without pregestational diabetes were included. Among 14,242 (1.0%) women diagnosed with GDM, 8851 (62.1%) were treated with diet and 5391 (37.9%) with insulin. In logistic regression analysis, the risk was significantly increased in both diet- and insulin-treated groups (vs. background) for large-for-gestational-age newborns, preeclampsia, cesarean section, birth trauma and preterm delivery. The risk was higher in the insulin-treated group (vs. diet) for most outcomes, but perinatal mortality rates neither differed between treatment groups nor compared to the background population. Diet as a treatment for GDM did not normalize pregnancy outcomes. Pregnancies with diet-treated GDM should therefore not be considered as low risk. Whether changes in surveillance and treatment improve outcomes needs to be evaluated.

Differential placental ceramide levels during gestational diabetes mellitus (GDM)

BackgroundGestational diabetes mellitus (GDM) is associated with important factors that influence fetal development. Sphingolipids are known to be associated with the development of diabetes. Our objective was to examine ceramide, a key sphingolipid, hyperosmolarity, and apoptosis in placentas from GDM patients treated with insulin or diet.MethodsCeramide levels were assessed in placental tissues using immunohistochemistry. Immunoblot was performed to quantify serine palmitoyltransferase (SPT), the rate-limiting enzyme in ceramide biosynthesis, NFAT5, SMIT, AR, caspase 3 and the X-linked inhibitor of apoptosis. Trophoblast cells were treated with insulin or ceramide and assessments for mitochondrial respiration, caspase 3 and XIAP were also performed.ResultsImmunohistochemistry showed increased ceramides in the placental villous trophoblasts of the insulin-treated GDM patients. Nuclear SPT was upregulated only in the insulin-treated GDM placenta when compared to controls. Nuclear NFAT5 was also increased in the GDM placenta. Active caspase 3 was elevated in placentas from both insulin- and diet-treated GDM patients. Mitochondrial respiration was decreased in trophoblasts treated with ceramide. Active caspase was not changed while XIAP protein was increased in trophoblasts treated with ceramide.ConclusionsOur findings confirm the presence of ceramide in the human placenta of control and GDM patients. Furthermore, we conclude that ceramide is increased in the placental trophoblast during insulin treatment and that its upregulation correlates with elevated NFAT5, SMIT, increased apoptosis and decreased trophoblast mitochondrial respiration.

Incidence and risk factors for gestational diabetes mellitus in twin versus singleton pregnancies.

To compare the incidence and risk factors for gestational diabetes mellitus (GDM) between women with twin and singleton pregnancies. Retrospective study of all women who had a twin or singleton birth in Ontario (2012-2016). Risk ratios (RR) and 95% CIs for GDM (stratified by type of treatment) were adjusted for relevant confounding variables. Multivariable Poisson regression analysis was used to identify risk factors for GDM in twin and singleton gestations. Of 270,843 women who met inclusion criteria, 266,942 (98.6%) and 3901 (1.4%) had a singleton and a twin pregnancy, respectively. Women with twins had a significantly higher risk for overall GDM (aRR = 1.13, 95% CI 1.01-1.28) and diet-treated GDM (aRR = 1.20, 95% CI 1.01-1.42) while the association with insulin-treated GDM was not significant (aRR = 1.07, 95% CI 0.89-1.28). Maternal age ≥ 35years, non-Caucasian ethnicity and BMI > 30kg/m2 were independent risk factors for GDM among women with twins and singletons, and the magnitude of the association of these factors with GDM was similar. Women with twins are at increased risk of GDM, mainly due to a higher rate of diet-treated GDM. Despite higher baseline risk of GDM in women with twins, the effect of known risk factors for GDM is similar to that observed in singletons.

Recurrence of diet-treated gestational diabetes in primiparous women in northern Zhejiang, China: Epidemiology, risk factors and implications.

This study sought to determine the rate of recurrence of gestational diabetes mellitus (GDM) recurrence during the second pregnancies of women who were diagnosed with GDM during their first pregnancies, to identify risk factors associated with the probability of such recurrence and to evaluate the influence of GDM recurrence on pregnancy outcomes in north Zhejiang, China, after the recent adjustment to the nation's childbirth policy. A retrospective longitudinal study was performed in north Zhejiang, China (at Jiaxing Maternal and Child Health Hospital). A total of 128 women who delivered two sequential live singleton infants and were diagnosed with diet-treated GDM during their first pregnancies were included. According to the 2013 World Health Organization diagnostic criteria for diabetes during pregnancy, the prevalence of gestational diabetes was 11.02% in northern Zhejiang. The recurrence rate of GDM in northern Zhejiang was 43.75% (56/128). The age at second pregnancy, weight gain during pregnancy, interpregnancy interval and macrosomia during the index pregnancy were risk factors for GDM recurrence. Among those women with recurrent GDM, GDM developed earlier and caesarean section was more frequently required during the second pregnancy; in addition, the second pregnancy was associated with more premature and low birthweight infants but less macrosomia. The recurrence rate of GDM is high in northern Zhejiang. Glucose monitoring and management are needed during subsequent pregnancies for patients who previously presented with GDM to improve maternal and fetal outcomes.

Maternal gestational diabetes mellitus: is it associated with long-term pediatric ophthalmic morbidity of the offspring?

Purpose: To determine whether children born to mothers with gestational diabetes mellitus (GDM) are at increased risk to develop of pediatric ophthalmic morbidity.Materials and methods: In this population based cohort study, all deliveries between 1991 and 2014 were included. Congenital malformations, multiple gestations, and patients lacking prenatal care were excluded from analysis. Mothers were defined as either having no GDM, having diet-treated GDM, or medically treated GDM. Outcomes were defined as different ophthalmic morbidities of the offspring until the age of 18. Kaplan–Meier curves were used to compare the cumulative morbidity in each group, and a Cox proportional hazard model was used to control for possible confounders.Results: During the study period, 238,622 deliveries met the inclusion criteria, of those 4.0% (n = 9601) of mothers were diagnosed with GDM treated by diet, and an additional 1.0% (n = 2398) were diagnosed with GDM treated by medication. Offsprings of patients with GDM treated by medication had a higher cumulative incidence of ophthalmic morbidity when compared to the other groups (Kaplan–Meier log rank test p = .038). GDM treated by medication was found to be an independent risk factor for long-term ophthalmic morbidity, in a cox multivariable model (adjusted HR: 1.5, 95%CI: 1.05–2.1, p = .025).Conclusions: Gestational diabetes mellitus treated by medication is associated with an increased risk for long-term pediatric ophthalmic morbidity.

Birth weight and its relation with medical nutrition therapy in gestational diabetes

The cornerstone in treatment of gestational diabetes mellitus (GDM) is medical nutrition therapy (MNT), but the effect on birth weight is disputed. The birth weight was evaluated with respect to length of MNT and adherence to diet. We performed a cohort study on 436 women with GDM and 254 non-diabetic women. Women with a normal oral glucose tolerance test were included as controls as they had similar background predisposition as the women with GDM. The GDM women were subdivided according to MNT and the nutritional status was further stratified according to adherence to the current dietary guidelines. Birth weight above 4kg was more prevalent in the non-diabetic women compared to the diet-treated GDM women (27 vs. 18%, p=0.012) but similar to the GDM women who had no MNT (24%). Lower birth weight was associated with longer duration of MNT (r=-0.13, p=0.021). The birth weight was 1.2g lower per day of treatment. Medical nutrition therapy was associated with reduction of the fetal weight in women with GDM and the weight decreases with length of treatment. Birth weight above 4kg was as prominent in the non-diabetic women as in the women with GDM without MNT.

High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus.

Context:Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with first recognition during pregnancy, is a heterogeneous form of diabetes characterized by various degrees of β-cell dysfunction.Objectives:We aimed to estimate the prevalence of possibly pathogenic variants in the maturity-onset diabetes of the young genes GCK, HNF1A, HNF4A, HNF1B, and INS among women with GDM. Furthermore, we examined the glucose tolerance status in variant carriers vs noncarriers at follow-up.Design, Setting, and Patients:We sequenced the coding regions and intron/exon boundaries of GCK, HNF1A, HNF4A, HNF1B, and INS using targeted region capture and next-generation sequencing in 354 Danish women with diet-treated GDM. Glucose tolerance was examined at follow-up 10 years after the index pregnancy.Main Outcome Measures:The prevalence of possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, and INS was estimated, and differences in anthropometric traits, high-sensitivity C-Reactive Protein (CRP), and glucose metabolism were measured.Results:At baseline, 17 possibly disease-causing variants were found in 21 women, revealing a combined GCK, HNF1A, HNF4A, HNF1B, and INS variant prevalence of 5.9% (95% confidence interval: 3.5% to 8.4%). At follow-up, 15 out of 135 women with diabetes (11%) were carriers of variants in GCK, HNF1A, HNF4A, HNF1B, or INS.Conclusions:Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, HNF4A, HNF1B, or INS. These women are at high risk of developing diabetes after pregnancy. Thus screening for variants in GCK, HNF1A, HNF4A, HNF1B, and INS should be considered among women with GDM.

Gestational weight gain among nutritionally treated GDM patients

Objective: We aimed to evaluate pregnancy outcome in diet-treated gestational diabetes mellitus (GDM) patients according to the 2009 Institute of Medicine (IOM) guidelines concerning gestational weight gain (GWG). Design and patients: This was a retrospective cohort study, limited to women with singleton pregnancies and diet-treated GDM. Women with preexisting diabetes or women with pharmaceutical treatment were excluded. We compared patients with adequate GWG with patients with excess GWG according to the 2009 IOM guidelines. Results: Overall, 142 women were evaluated, of which 99 (69.7%) had adequate GWG and 43 (30.3%) had excess GWG. All demonstrated good glycemic control. Patients in the excess GWG group had higher mean pre-pregnancy weight and body mass index (BMI). No other obstetrical or perinatal statistically significant differences were demonstrated, although there was a trend for higher birth weight percentile and higher rate of respiratory distress among the excess GWG group. Conclusions: Higher pre-pregnancy BMI is a risk factor for failing to comply with the 2009 IOM GWG guidelines. However, it seems that in pregnancies complicated by diet-treated GDM, GWG is not a reliable marker for adverse pregnancy outcome if glycemic control is adequate.

Gestational diabetes and adverse perinatal outcomes from 716,152 births in France in 2012

Aims/hypothesisThe aim of this study was to assess the risk of adverse perinatal outcomes in gestational diabetes mellitus (GDM) in a large national cohort.MethodsAll deliveries taking place after 22 weeks in France in 2012 were included by extracting data from the hospital discharge database and the national health insurance system. The diabetic status of mothers was determined by the use of glucose-lowering agents and by hospital diagnosis. Outcomes were analysed according to the type of diabetes and, in the GDM group, whether or not diabetes was insulin-treated.ResultsThe cohort of 796,346 deliveries involved 57,629 (7.24%) mothers with GDM. Mother–infant linkage was obtained for 705,198 deliveries. The risks of adverse outcomes were much lower with GDM than with pregestational diabetes. After limiting the analysis to deliveries after 28 weeks to reduce immortal time bias, the risks of preterm birth (OR 1.3 [95% CI 1.3, 1.4]), Caesarean section (OR 1.4 [95% CI 1.4, 1.4]), pre-eclampsia/eclampsia (OR 1.7 [95% CI 1.6, 1.7]), macrosomia (OR 1.8 [95% CI 1.7, 1.8]), respiratory distress (OR 1.1 [95% CI 1.0, 1.3]), birth trauma (OR 1.3 [95% CI 1.1, 1.5]) and cardiac malformations (OR 1.3 [95% CI 1.1, 1.4]) were increased in women with GDM compared with the non-diabetic population. Higher risks were observed in women with insulin-treated GDM than those with diet-treated GDM. After limiting the analysis to term deliveries, an increased risk of perinatal mortality was observed. After excluding women suspected to have undiagnosed pregestational diabetes, the risk remained moderately increased only for those with diet-treated GDM (OR 1.3 [95% CI 1.0, 1.6]).Conclusions/interpretationGDM is associated with a moderately increased risk of adverse perinatal outcomes, which is higher in insulin-treated GDM than in non-insulin-treated GDM for most outcomes.

Insulin requires A1 adenosine receptors expression to reverse gestational diabetes-increased L-arginine transport in human umbilical vein endothelium.

Gestational diabetes mellitus (GDM) associates with increased L-arginine transport and extracellular concentration of adenosine in human umbilical vein endothelial cells (HUVECs). In this study we aim to determine whether insulin reverses GDM-increased L-arginine transport requiring adenosine receptors expression in HUVECs. Primary cultured HUVECs from full-term normal (n = 38) and diet-treated GDM (n = 38) pregnancies were used. Insulin effect was assayed on human cationic amino acid transporter 1 (hCAT1) expression (protein, mRNA, SLC7A1 promoter activity) and activity (initial rates of L-arginine transport) in the absence or presence of adenosine receptors agonists or antagonists. A1 adenosine receptors (A1AR) and A2AAR expression (Western blot, quantitative PCR) was determined. Experiments were done in cells expressing or siRNA-suppressed expression of A1AR or A2AAR. HUVECs from GDM exhibit higher maximal transport capacity (maximal velocity (V max)/apparent Michaelis Menten constant (K m), V max/K m), which is blocked by insulin by reducing the V max to values in cells from normal pregnancies. Insulin also reversed the GDM-associated increase in hCAT-1 protein abundance and mRNA expression, and SLC7A1 promoter activity for the fragment -606bp from the transcription start point. Insulin effects required A1AR, but not A2AAR expression and activity in this cell type. In the absence of insulin, GDM-increased hCAT-1 expression and activity required A2AAR expression and activity. HUVECs from GDM pregnancies exhibit a differential requirement of A1AR or A2AAR depending on the level of insulin, a phenomenon that represent a condition where adenosine or analogues of this nucleoside could be acting as helpers of insulin biological effects in GDM.

Treatment With Diet and Exercise for Women With Gestational Diabetes Mellitus Diagnosed Using IADPSG Criteria.

Prevalence of gestational diabetes mellitus (GDM) and obesity continue to increase. This study aimed to ascertain whether diet and exercise is a successful intervention for women with GDM and whether a subset of these women have comparable outcomes to those with normal glucose tolerance (NGT). This was a retrospective cohort study of five antenatal centers along the Irish Atlantic seaboard of 567 women diagnosed with GDM and 2499 women with NGT during pregnancy. Diet and exercise therapy on diagnosis of GDM were prescribed and multiple maternal and neonatal outcomes were examined. Infants of women with GDM were more likely to be hypoglycemic (adjusted odds ratio [aOR], 7.25; 95% confidence interval [CI], 2.94-17.9) at birth. They were more likely to be admitted to the neonatal intensive care unit (aOR, 2.16; 95% CI, 1.60-2.91). Macrosomia and large-for-gestational-age rates were lower in the GDM group (aOR, 0.48; 95% CI, 0.37-0.64 and aOR, 0.61; 95% CI, 0.46-0.82, respectively). There was no increase in small for gestational age among offspring of women with GDM (aOR, 0.81; 95% CI, 0.49-1.34). Women with diet-treated GDM and body mass index (BMI) < 25 kg/m(2) had similar outcomes to those with NGT of the same BMI group. Obesity increased risk for poor pregnancy outcomes regardless of diabetes status. Medical nutritional therapy and exercise for women with GDM may be successful in lowering rates of large for gestational age and macrosomia without increasing small-for-gestational-age rates. Women with GDM and a BMI less than 25 kg/m(2) had outcomes similar to those with NGT suggesting that these women could potentially be treated in a less resource intensive setting.

Recurrence of gestational diabetes in primiparous women.

Gestational diabetes mellitus (GDM) increases the risk for diabetes in the next pregnancy and later in life. Thus, estimating the risk of GDM in further pregnancies provides a time frame for possible preventive measures. We aimed to calculate the recurrence rate of GDM in primiparous women and evaluate the factors involved such as age, body mass index, weight gain, time between pregnancy and postpartum OGTT results. We established a prospective cohort during a 5-year period at the Department of Obstetrics at Kolding Hospital. Women with diet-treated GDM in their first pregnancy and a subsequent pregnancy constituted our study population. Multiparity and insulin-treated GDM were exclusion criteria. Among 15 735 deliveries, 535 women were diagnosed with GDM (3.4%). Of these, 209 (39.1%) were nulliparous women, treated with diet only. Seventy-two of these women had a subsequent pregnancy and they all attended the recommended screening procedure, a 75-g oral glucose tolerance test at 14-20 (early) or 27-30 (late) weeks' gestation. The recurrence rate of GDM was 47.2%. The risk of recurrence was less in women who lost weight between the first and the subsequent pregnancy. Recurrence of diet-treated GDM was 47.2% in primiparous women with previous GDM and the recurrence was associated with weight gain between pregnancies.

Incretin and glucagon levels in adult offspring exposed to maternal diabetes in pregnancy.

Fetal exposure to maternal diabetes is associated with increased risk of type 2 diabetes mellitus (T2DM) later in life. The pathogenesis of T2DM involves dysfunction of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as hyperglucagonemia. Our aim was to investigate circulating plasma levels of GLP-1, GIP, and glucagon during the oral glucose tolerance test (OGTT) in adult offspring of women with diabetes in pregnancy. We conducted a follow-up study of 567 offspring, aged 18-27 years. We included two groups exposed to maternal diabetes in utero: offspring of women with diet-treated gestational diabetes mellitus (O-GDM; n = 163) or type 1 diabetes (O-T1DM; n = 146). Two reference groups were included: offspring of women with risk factors for GDM, but normoglycemia during pregnancy (O-NoGDM; n = 133) and offspring from the background population (O-BP; n = 125). The subjects underwent a 75-g OGTT with venous samples at 0, 30, and 120 minutes. Fasting plasma levels of GLP-1 were lower in the two diabetes-exposed groups compared to O-BP (O-GDM, P = .040; O-T1DM, P = .008). Increasing maternal blood glucose during OGTT in pregnancy was associated with reduced postprandial suppression of glucagon in the offspring. Lower levels of GLP-1 and higher levels of glucagon during the OGTT were present in offspring characterized by overweight or prediabetes/T2DM at follow-up, irrespective of exposure status. Lower levels of fasting GLP-1 and impaired glucagon suppression in adult offspring exposed to maternal diabetes during pregnancy are diabetogenic traits that may contribute to glucose intolerance in these persons, but further investigations are needed.

Insulin therapy and fetoplacental vascular function in gestational diabetes mellitus.

What is the topic of this review? This review focuses on the effects of insulin therapy on fetoplacental vasculature in gestational diabetes mellitus and the potentiating effects of adenosine on this therapy. What advances does it highlight? This review highlights recent studies exploring a potential functional link between insulin receptors and their dependence on adenosine receptor activation (insulin-adenosine axis) to restore placental endothelial function in gestational diabetes mellitus. Gestational diabetes mellitus (GDM) is a disease that occurs during pregnancy and is associated with maternal and fetal hyperglycaemia. Women with GDM are treated via diet to control their glycaemia; however, a proportion of these patients do not achieve the recommended values of glycaemia and are subjected to insulin therapy until delivery. Even if a diet-treated GDM pregnancy leads to normal maternal and newborn glucose levels, fetoplacental vascular dysfunction remains evident. Thus, control of glycaemia via diet does not prevent GDM-associated fetoplacental vascular and metabolic alterations. We review the available information regarding insulin therapy in the context of its potential consequences for fetoplacental vascular function in GDM. We propose the possibility that insulin therapy to produce normoglycaemia in the mother and newborn may require additional therapeutic measures to restore the normal metabolic condition of the vascular network in GDM. A role for A1 and A2A adenosine receptors and insulin receptors A and B as well as a potential functional link in the cell signalling associated with the activation of these receptors is proposed. This possibility could be helpful for the planning of strategies, including adenosine receptor-improved insulin therapy, for the treatment of GDM patients, thereby promoting the wellbeing of the growing fetus, newborn and mother.

Normal Long-Term Health for Infants of Diabetic Mothers: Can We Achieve It?

We are increasingly being made aware of the adverse risks associated with maternal pregestational (type1and type2diabetes) or gestationaldiabetesmellitus (GDM) to the long-term metabolic health of affected offspring (1–5). A key question relates to the extent to which the increased rates of obesity, metabolic syndrome, and type 2 diabetes in these individuals are acquired vs genetically predetermined because the former could be potentially preventable. The Developmental Origins of Health and Disease (DOHaD) hypothesis, supported by considerable research in animals and humans, suggests that acquired susceptibility is a very important component of the total risk for metabolic diseases and that much of this risk is programmed in utero and during early childhood years (6, 7). If this is the case, the objectives of managing diabetes in pregnancy should focus not only on reducing perinatal complications but also on reducing long-term adverse outcomes for offspring. The goal of the 1989 St Vincent Declaration was to approximate the pregnancy outcomes of women with diabetes to those of the background population (8). Unfortunately, despite definite improvements, this still is a long way from being realized for type 1 and type 2 diabetic pregnancies; serious adverse outcomes, including congenital malformations, perinatal mortality, prematurity, and large for gestational age neonates, still occur commonly (9, 10). Continued efforts to reduce these complications in women with pre-existing diabetes is therefore paramount, but this must be accompanied by increased vigilance of longer-term outcomes. For GDM, short-term outcomes with current treatment approaches are quite effective in reducing adverse pregnancy outcomes (11, 12), but quite possibly without the desired beneficial effects on the longterm health of offspring. For example, the standard approach used to treat GDM in the Australian Carbohydrate Intolerance Study (ACHOIS) markedly lowered macrosomia rates but had no effect on the body mass index of the children at 4–5 years of age (11, 13). Future advances in the management of GDM pregnancies, therefore, must move the focus to improving the long-term outcomes of these offspring. An obvious challenge to achieving this is the need for long-term follow-up studies—both difficult to conduct and quite costly. In this issue of the JCEM, new results are presented from one of the few cohort studies of the offspring of diabetic mothers into adulthood. Kelstrup et al (14) report insulin sensitivity and insulin secretion data from a Danish cohort of young adult offspring (mean age, 21–22 y) of mothers who had type 1 diabetes (O-type 1), diet-treated GDM (O-GDM), or risk factors for GDM but with normoglycemia (O-NoGDM), or were from the background population (O-BP). Previously in this cohort, the authors had reported increased occurrence of overweight, metabolic syndrome, glucose intolerance, and type 2 diabetes in the offspring of the diabetic mothers (4, 15). In this new work, the investigators now demonstrate that the glucose intolerance in these affected offspring is due to the combination of impaired insulin secretion and insulin sensitivity (14). They propose that it is the exposure to intrauterine hyperglycemia that causes the subsequent impairments of insulin secretion and insulin sensitivity in the young adults. Considering that the O-type 1 are unlikely to be genetically predisposed to type 2 diabetes, this is highly likely to be causative in this group. Also consistent with this view is the previous finding that the risk of impaired glucose tolerance and type 2 diabetes in the O-

Cognitive Function in Adult Offspring of Women with Gestational Diabetes–The Role of Glucose and Other Factors

ObjectiveWe aimed to evaluate cognitive function in adult offspring of women with diet-treated gestational diabetes and to study potential associations with maternal glucose values.Materials and MethodsIn 2003–2005 cognitive function was assessed in a cohort of 18–27 year old offspring of women with diet-treated gestational diabetes mellitus (n = 153) and offspring from the background population (n = 118). The main outcome measure was global cognitive score derived from Raven’s Progressive Matrices and three verbal subtests from the Weschler Adult Intelligence Scale. Maternal fasting- and 2-hour blood glucose values from the diagnostic oral glucose tolerance test were used as exposure variables.ResultsOffspring of women with gestational diabetes mellitus had a lower global cognitive score, than offspring from the background population (93.1 vs. 100.0, P<0.001). However, when adjusted for maternal age at delivery, parity, smoking during pregnancy, pre-pregnancy overweight, family social class, parental educational level, gender, birth weight, gestational age, perinatal complications and offspring age at follow-up, the difference was no longer statistically significant. Offspring global cognitive score decreased significantly with increasing maternal fasting glucose (β = −4.5, 95% CI −8.0 to −0.9, P = 0.01) and 2-hour glucose (β = −1.5, −2.9 to −0.2, P = 0.03) in univariate general linear models, but not when adjusted for family social class and parental educational level.ConclusionsLower cognitive test scores in adult offspring of women with diet-treated gestational diabetes were explained by well known predictors of cognitive function, but not by maternal hyperglycaemia during pregnancy. We find it reassuring that mild intrauterine hyperglycaemia does not seem to have adverse effect on offspring cognitive function.

Differential expression of placental 11β-hydroxysteroid dehydrogenases in pregnant women with diet-treated gestational diabetes mellitus

Fetal exposure to excess glucocorticoid is one of the critical factors for the fetal origins of adult diseases. However, the mechanism of the local regulation of glucocorticoid activity in the human placenta of pregnancies complicated with gestational diabetes mellitus (GDM) has not been fully understood. We investigated placental 11β-hydroxysteroid dehydrogenases (11β-HSDs) expression, and analyzed their relationship with cortisol levels in maternal and umbilical vein. Pregnant women with GDM after diet intervention (n=23) or normal glucose tolerance (NGT, n=22) were studied at the community-based hospital. We collected maternal and umbilical venous cord blood and placental tissues from both groups. Explanted placentas from NGT were cultured with palmitic acid, dexamethasone, insulin or their mixture for 24-h. We examined plasma cortisol, cortisone to cortisol ratio, insulin, the homeostasis model assessment of insulin resistance index (HOMA-IR) and the insulin secretion index. Quantitative real-time PCR, Western blot and immunohistochemical assay were applied for the measurement of 11β-HSD1 and 11β-HSD2 mRNA and protein. GDM had higher maternal cortisol levels, HOMA-IR, insulin secretion index and higher cortisone to cortisol ratio in umbilical vein. No significant change in cortisol levels in umbilical vein and newborn weight was found. GDM placental 11β-HSD1 levels decreased while 11β-HSD2 increased. Treatment of placenta explants from NGT with palmitic acid, dexamethasone, insulin or their combination resulted in a significant drop of 11β-HSD1 and increase in 11β-HSD2. Differential expression of 11β-HSDs in diet-treated GDM placenta provides a protective mechanism for the fetus throughout the adverse environment of pregnancy by limiting excessive exposure of the fetus to glucocorticoid.

Glycated hemoglobin in pregnancies at increased risk for gestational diabetes mellitus

The glycated hemoglobin (HbA(1c)) value is increasingly used for the detection of (pre)diabetes, but HbA(1c) decreases during pregnancy. We sought to identify clinical and metabolic correlates of HbA(1c) in pregnancies at increased risk for gestational diabetes mellitus (GDM). We prospectively studied 335 gravidas who received a 3-h 100g oral glucose tolerance test (OGTT) at 24-32 weeks, in most cases after an abnormal glucose challenge test. Several indices of insulin sensitivity and secretion were computed from fasting measurements and the OGTT. HbA(1c) concentrations gradually increased in diet-treated and insulin-treated GDM gravidas compared with non-GDM gravidas. HbA(1c) was higher if the insulin peak was delayed until 180 min compared with 60 or 120 min. Stepwise regression identified the homeostasis modeling assessment of insulin resistance (HOMA-IR) as the first-rank correlate. Other correlates were ethnicity, a low insulin-to-glucose response at 60 min, and gestational age. The HbA(1c) value corresponding to a fasting glucose of 5.1 mmol/l (diagnostic of GDM) was 2 mmol/mol (~0.2%) higher if sampling occurred at 29-32 vs. 24-28 weeks or if ancestry was non-European vs. European. HbA(1c) is strongly associated with insulin resistance; in addition, HbA(1c) captures the first-phase insulin response. However, HbA(1c) varies with gestational age and ethnicity.