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Background Recent studies have suggested that fetal sex influences maternal glucose and insulin metabolism during pregnancy. We examined whether fetal sex is associated with maternal insulin resistance and the β-cell function during mid-pregnancy. Methods This retrospective study included singleton pregnant women who underwent a 75-g oral glucose tolerance test (OGTT) at 24–34 weeks of gestation due to positive diabetic screening. In addition to plasma glucose (PG), we measured plasma insulin during the OGTT to obtain surrogate indices associated with insulin resistance (IR), including homeostasis assessment model (HOMA) -IR and insulin sensitivity index (IsOGTT), and β-cell function, including insulinogenic index (II), HOMA-β, and area under the curve of insulin response. We compared these indices between women carrying male fetuses to those carrying female fetuses. Results The study population included 617 women (mean age, 32.4 ± 4.9 years) with a mean pre-pregnancy body mass index (BMI) of 22.6±4.5. They underwent the 75g-OGTT at 29.0 ± 2.5 weeks. Two hundred fifty-eight (42%) women were diagnosed with gestational diabetes (GDM). There was no significant difference in maternal age, pre-pregnancy BMI, gestational age at OGTT, PG at OGTT, or the prevalence of GDM between women with a male fetus (n=338) (male group) and those with a female fetus (n=279) (female group). Regarding the indices of IR, IR was significantly higher and insulin sensitivity was lower in the female group than in the male group (HOMA-IR: 7.0 [5-9.6] vs. 6.2 [4.6-8.8], p< 0.05; IsOGTT: 5.86 [4.29-7.83] vs. 6.29 [4.59-8.84], p< 0.01) (median [quartile range]). These differences remained significant after adjustment for maternal age, pre-pregnancy BMI, gestational age and fasting PG at OGTT, and the diagnosis of GDM. In contrast, the β-cell function did not differ between the two groups. Conclusion Maternal IR during mid-pregnancy was significantly higher in women carrying a female fetus than in those with a male fetus. The sex of the fetus may affect maternal insulin sensitivity during mid-pregnancy.

A 27-year-old woman with a history of gestational diabetes mellitus (GDM) developed type 1 diabetes mellitus (T1D) in the early postpartum period. Women with a history of GDM are at an increased risk of developing T1D, which is rarer than type 2 diabetes mellitus. A postpartum follow-up 75-g oral glucose tolerance test and the measurement of glutamic acid decarboxylase autoantibodies aided in the early detection of T1D in this patient. Careful attention should be paid to women with a history of GDM who exhibit clinical features suggestive of future development of T1D.

Background Although the onset of gestational diabetes (GDM) is known to be a significant risk factor for the future development of type 2 diabetes, this risk specifically in women with GDM diagnosed by the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria has not yet been thoroughly investigated. This study was performed to investigate the risk factors associated with the development of postpartum diabetes in Japanese women with a history of GDM, and the effects of the differences in the previous Japanese criteria and the IADPSG criteria. Methods This retrospective cohort study included Japanese women with GDM who underwent at least one postpartum oral glucose tolerance test (OGTT) between 2003 and 2014. Cases with overt diabetes in pregnancy were excluded. We investigated the risk factors including maternal baseline and pregnancy characteristics associated with the development of postpartum diabetes. Results Among 354 women diagnosed with GDM during the study period, 306 (86%) (116/136 [85.3%] and 190/218 [87.2%] under the previous criteria and the IADPSG criteria, respectively) who underwent at least 1 follow-up OGTT were included in the study. Thirty-two women (10.1%) developed diabetes within a median follow-up period of 57 weeks (range, 6–292 weeks). Eleven (9.5%) and 21 (11.1%) were diagnosed as GDM during pregnancy based on the previous Japanese criteria and the IADPSG criteria, respectively, which did not significantly differ between those criteria. A multivariate logistic regression analysis revealed that HbA1c and 2-h plasma glucose (PG) at the time of the diagnostic OGTT during pregnancy were independent predictors of the development of diabetes after adjusting for confounders. The adjusted relative risk of HbA1c ≥5.6% for the development of diabetes was 4.67 (95% confidence interval, 1.53-16.73), while that of 2-h PG ≥183 mg/dl was 7.02 (2.51-20.72). Conclusions A modest elevation of the HbA1c and 2-h PG values at the time of the diagnosis of GDM during pregnancy are independent predictors of the development of diabetes during the postpartum period in Japanese women with a history of GDM. The diagnostic criteria did not affect the incidence of postpartum diabetes.

Objective To investigate factors associated with high-risk gestational diabetes (GDM) among patients with GDM. Methods The present retrospective study included women with singleton pregnancies diagnosed with GDM using International Association of Diabetes and Pregnancy Study Group criteria at a single tertiary perinatal care center in Japan between July 1, 2010, and October 31, 2014. High-risk GDM was defined as patients who required at least 20 units of insulin therapy a day, delivering a large-for-gestational age neonate regardless of insulin therapy, or both. Maternal characteristics and diagnostic test results were investigated to identify associations with the high-risk criteria, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results Among 217 patients, 95 (43.8%) were categorized as high risk. After adjusting for confounders, a fasting plasma glucose level at diagnosis of at least 4.66 mmol/L (adjusted OR 2.88, 95% CI 1.51–5.58) and pre-pregnancy body mass index (calculated as weight in kilograms divided by the square of height in meters) of at least 24 (adjusted OR 3.27, 95% CI 1.60–6.90) were independently associated with meeting the high-risk criteria. Conclusion Among Japanese patients with GDM, pre-pregnancy body mass index and fasting plasma glucose levels could be used to identify high-risk patients requiring intensive care during pregnancy. This article is protected by copyright. All rights reserved.

Background Although breastfeeding is expected to reduce the incidence of diabetes in women with gestational diabetes, the effect has not been clearly confirmed. We examined whether or not high-intensity breastfeeding reduces the incidence of abnormal glucose tolerance and investigated the effect of high-intensity breastfeeding on insulin resistance during the first year postpartum in Japanese women with current gestational diabetes. Methods In this retrospective study, we included women with gestational diabetes who underwent postpartum 75 g oral glucose tolerance test during the first year (12-14 months) postpartum from 2009 to 2011 at a single tertiary perinatal care center in Japan. High-intensity breastfeeding was defined as the condition in which infants were fed by breastfeeding alone or 80% or more of the volume. We investigated the effect of high-intensity breastfeeding on the prevalence of postpartum abnormal glucose tolerance and the postpartum homeostasis model of assessment of insulin resistance (HOMA-IR), after controlling for confounders, including prepregnancy obesity and weight changes during pregnancy and postpartum. Results Among 88 women with gestational diabetes, 46 (52%) had abnormal glucose tolerance during the postpartum period. High-intensity breastfeeding women (n = 70) were significantly less likely to have abnormal glucose tolerance than non-high-intensity breastfeeding women (n = 18) (46% vs. 78%, p = 0.015). High-intensity breastfeeding was also associated with a lower HOMA-IR at 12-14 months postpartum than non-high-intensity breastfeeding (1.41 ± 1.02 vs. 2.28 ± 1.05, p = 0.035). Those associations remained significant after controlling for confounders. At least six months of high-intensity breastfeeding had a significant effect on lowering both the abnormal glucose tolerance prevalence and HOMA-IR compared with non-high-intensity breastfeeding. Conclusions In Japanese women with gestational diabetes, high-intensity breastfeeding ≥6 months had a protective effect against the development of abnormal glucose tolerance during the first year postpartum through improving insulin resistance, independent of obesity and postpartum weight change.

Aim To investigate whether high-intensity breastfeeding (HIB) reduces insulin resistance during early post-partum period in women with gestational diabetes (GDM), independent of post-partum weight change (PWC). Materials and methods In this multicentre prospective study, we included Japanese women with GDM who underwent a 75-g oral glucose tolerance test (OGTT) during early post-partum. We measured plasma insulin during OGTT to obtain a homeostasis model of assessment of insulin resistance (HOMA-IR). We defined the condition in which infants were fed by breastfeeding alone or greater than or equal to 80% of the volume as HIB, and other statuses, including partial and nonbreastfeeding, as non-HIB. We investigated the association between post-partum HOMA-IR and the breastfeeding status after adjusting for confounders including PWC. Results Among 222 women with GDM who underwent the OGTT at 7.9 ± 2.3 weeks post-partum with a PWC of -7.8 ± 3.4 kg, although the rate of abnormal glucose tolerance (prediabetes and diabetes) did not differ between the groups (33% vs 32%), the HOMA-IR in the HIB women (n = 166) was significantly lower than that in the non-HIB women (n = 56) (1.12 ± 0.85 vs 1.72 ± 1.43, P = 0.0002). The effect of the HIB was independently associated with lower HOMA-IR after adjusting for confounders including PMC. However, the subgroup analysis according to their pre-pregnancy obesity states showed that the effect was seen only in the obese subjects (BMI ≥ 25). Conclusions In obese Japanese women with GDM, HIB has a significant effect in reducing insulin resistance during early post-partum, independent of the post-partum weight loss.

Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM) pregnancy and is associated with increased risk of adult obesity and type II diabetes mellitus, however mechanisms linking GDM and later disease remain poorly understood. The heterozygous leptin receptor-deficient (Lepr(db/+)) mouse develops spontaneous GDM and the fetuses display characteristics similar to infants of GDM mothers. We examined the effects of GDM on maternal insulin resistance, fetal growth, and postnatal development of hepatic insulin resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p < 0.05) in pups from ad libitum-fed db/+ mothers compared with wild-type (WT) controls. Pair-feeding db/+ mothers to the intake of WT mothers normalized fetal weight despite less than normal maternal insulin sensitivity. More stringent caloric restriction reduced insulin and glucose levels below WT controls and resulted in fetal intrauterine growth restriction. The level of hepatic insulin receptor protein was decreased by 28% to 31% in both intrauterine growth restriction and fetuses from ad libitum-fed GDM mothers compared with offspring from WT mothers. In 24-wk-old adult offspring from GDM mothers, body weight was similar to WT offspring, however, the females from GDM mothers were fatter and hyperinsulinemic compared with offspring from WT mothers. Insulin-stimulated phosphorylation of Akt, a key intermediate in insulin signaling, was severely decreased in the livers of adult GDM offspring. Hepatic glucose-6-phosphatase activity was also inappropriately increased in the adult offspring from GDM mothers. These results suggest that spontaneous GDM in the pregnant Lepr(db/+) mouse is triggered by overfeeding, and this effect results in obesity and insulin resistance in the livers of the adult offspring. The specific decrease in Akt phosphorylation in livers of adult offspring suggests that this may be a mechanism for reduced insulin-dependent physiologic events, such as suppression of hepatic glucose production, a defect associated with susceptibility to type II diabetes mellitus.

Gestational diabetes mellitus (GDM) results from an interaction between susceptibility genes and the diabetogenic effects of pregnancy. During pregnancy, mice heterozygous for the lepin receptor (db/+) gain more weight, are glucose intolerant, and produce macrosomic fetuses compared with wild-type (+/+) mothers, suggesting that an alteration in leptin action may play a role in GDM and fetal overgrowth. To investigate whether leptin administration or pair-feeding can reduce adiposity and thereby prevent GDM and neonatal overgrowth, we examined energy balance, glucose and insulin tolerance, and fetal growth in pregnant db/+ and +/+ mice treated with recombinant human leptin-IgG during late pregnancy. Leptin reduced food intake and adiposity in pregnant db/+ mice to levels similar to pregnant +/+ mice and significantly reduced maternal weight gain. Maternal glucose levels were markedly lower during glucose and insulin challenge tests in leptin-treated db/+ mice relative to db/+ and pair-fed controls. Despite...

Recent progress suggests that postreceptor mechanisms that contribute to insulin resistance of pregnancy appear to be multifactorial, but are exerted at the beta-subunit of the insulin receptor and at the level of IRS-1. Gestational diabetes mellitus represents the combination of acquired and intrinsic abnormalities of insulin action. The resistance to insulin-mediated glucose transport appears to be greater in skeletal muscle from GDM subjects than from pregnancy alone. There is also a modest but significant decrease in maximal insulin receptor tyrosine phosphorylation in muscle from obese GDM subjects. Results also suggest that increased insulin receptor serine/threonine phosphorylation and PC-1 could underlie the insulin resistance of pregnancy and pathogenesis of GDM. Whether additional defects are exerted further downstream from IRS-1 remains to be investigated.

The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. Subjects (n = 6 for each group) were similar in age and degree of obesity (body fat >30%). IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. No significant differences were evident in basal insulin receptor tyrosine phosphorylation or IRTK activity in the three groups. After maximal insulin (10(-7) mol/l) stimulation, IRTK activity measured with the artificial substrate poly(Glu,Tyr) increased in all subjects but was lower in women with GDM by 25% (P < 0.05) and 39% (P < 0.001) compared with pregnant and nonpregnant control subjects, respectively. Similarly, insulin receptor tyrosine phosphorylation was significantly decreased in subjects with GDM (P < 0.05) compared with pregnant and nonpregnant control subjects. Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). PC-1 content in muscle from GDM subjects was increased by 63% compared with pregnant control subjects (P < 0.05) and by 206% compared with nonpregnant control subjects (P < 0.001). PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. These changes worsen in women with GDM when controlling for obesity. These postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life.

resistance in mid pregnancy and neonatal birth weight in uncomplicated pregnancies Hiroshi Yamashita, Masashi Fukuda, Yukari Kugishima, Yuki Yamauchi, Akiko Kuzume, Takashi Hashimoto, So Sugimi, Naoko Yatsunami, Sachie Suga, Nobuko Kusuda, Ichiro Yasuhi Nagasaki Medical Center, Obstetrics and Gynecology, Omura-city, Japan OBJECTIVE: The purpose of this study was to determine whether maternal insulin resistance measured by homeostasis model assessmentinsulin resistance (HOMA-IR) in mid pregnancy is associated with neonatal birth weight in uncomplicated pregnancies. STUDY DESIGN: We included singleton pregnant women who had a 75g oral glucose tolerance test (OGTT) during mid pregnancy because of a positive gestational diabetes (GDM) screen. We measured HOMA-IR derived from fasting plasma glucose and immuno-reactive insulin concentration at OGTT. Women with GDM, hypertension, or fetal malformation were excluded. Using multiple and logistic regression analysis to adjust for confounding variables including maternal age, prepregnancy body mass index (BMI), plasma glucose levels at OGTT, and gestational age (GA) at delivery, we tested the relation of mid pregnancy maternal HOMA-IR to neonatal birth weight and large for GA (LGA) infants. RESULTS: We included 557 Japanese pregnant women. The mean maternal age, prepregnancy BMI, GA at OGTT, and HOMA-IR, GA at delivery, and birth weight were 31.8 / 5.0 years, 22.0 / 3.7 kg/ m2, 30.5 / 4.0 weeks, and 1.46 / 0.8, 39.0 / 1.7 weeks, and 3,030 / 470 g, respectively. HOMA-IR was positively associated with birth weight after controlling confounding variables (p .05). Higher HOMA-IR was significantly associated with an increased incidence of LGA infants (n 38) with the adjusted odds ratio of 1.71 per one unit of HOMA-IR (95% confidence interval, 1.11-2.66). CONCLUSION: Our findings suggest that the degree of maternal insulin resistance measured by HOMA-IR during mid pregnancy is associated with birth weight in uncomplicated pregnancies. Mid pregnancy HOMA-IR could be a predictor of fetal overgrowth, independent of maternal glucose levels and obesity.