Delayed lung maturation in the macrosomic offspring of genetically determined diabetic (db/+) mice

We studied a genetically determined diabetes in pregnancy, the heterozygous diabetes (db/+) mouse. We found that fetal mice from these pregnancies are macrosomic with increased body, lung, and placenta wt, have altered organ protein, DNA and phospholipid content, and exhibit abnormal carbohydrate metabolism with increased liver and glycogen content. We further studied the effect of increased substrate availability and utilization on lung growth and maturation in (db/+) fetal mice, by measuring lung phospholipid synthesis as represented by the incorporation of the radiolabeled precursors, [3H]choline and [14C]glycerol, in fetal lung at 18 days' gestation (term = 19). Diabetic fetuses incorporated significantly more [3H]choline into disaturated phosphatidylcholine than controls (1.32 +/- 0.10 X 10(-2) versus 0.78 +/- 0.05 X 10(-2) nmol/g protein/min, mean +/- SE; p less than 0.001), but significantly less [14C]glycerol into phosphatidylglycerol than controls (3.18 +/- 0.38 versus 4.91 +/- 0.53 nmol/g protein/min, mean +/- SE; p less than 0.002), and their phosphatidylglycerol/phosphatidylinositol synthesis ratios were decreased (1.81 +/- 0.18 versus 3.17 +/- 0.14; mean +/- SE; p less than 0.001). Diabetic fetal lungs appeared morphologically less mature than controls at 18 days' gestation, as shown by a significantly decreased air space density (0.27 +/- 0.01 versus 0.43 +/- 0.02, mean +/- SE; p less than 0.001) and alveolar epithelial cell/total tissue ratio (0.54 +/- 0.02 versus 0.66 +/- 0.03, mean +/- SE; p less than 0.01). The increased synthesis of lung disaturated phosphatidylcholine in diabetic fetal mice may reflect the enhancement of body and lung growth in these macrosomic fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of metabolic markers of insulin resistance in offspring of gestational diabetes pregnancies

In utero hyperglycemia has been associated with insulin resistance (IR) in children; however, there are limited data in low-risk populations. The purpose of this study was to describe the prevalence of metabolic markers of IR in a primarily Caucasian cohort of gestational diabetes mellitus (GDM) offspring aged 7-11 yr (mean 9.1) and to correlate offspring with maternal indexes. Sixty-eight children were recruited through a follow-up study of women who participated in a randomized controlled trial of minimal intervention vs. tight glycemic control for GDM. All participants had a fasting plasma glucose (FPG), insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-chol), triglyceride (TG) level, and a 2-h oral glucose tolerance test. We calculated homeostasis model assessment (HOMA) and recorded body mass index and waist circumference (WC). Criteria for metabolic syndrome for children included: FPG > 6.0 mmol/L, HDL-chol < 1.03 mmol/L, TG > 1.24 mmol/L, WC > 90% for age and gender, and 2-h glucose > 7.8 mmol/L. Among these children, 45 (66%), 17 (25%), 5 (7%), and 1 (1.5%) had zero, one, two, or three metabolic markers of IR, respectively. Hypertriglyceridemia (21%) was most prevalent, with no child having an elevated FPG. WC (p = 0.018) and TG (p = 0.005) were strong predictors of IR in the offspring after adjustment for age, gender, birthweight, family history, and maternal IR. Maternal and offspring HDL-chol, TG, WC, and HOMA but not fasting or 2-h glucose levels were significantly correlated. We conclude that metabolic markers of IR in children exposed to GDM may be present in the absence of abnormal fasting or 2-h glucose values. Screening strategies that focus on glucose levels may need to be reconsidered to institute early intervention with lifestyle changes for children at risk.     

Maternal type 1 and gestational diabetes: postnatal differences in insulin secretion in offspring at preschool age

Background: It is well known that children born to mothers with diabetes in pregnancy are more likely to develop metabolic abnormalities in later life. Most prior studies have not differentiated between offspring of mothers with type 1 diabetes (T1DM) and gestational diabetes (GDM) or lack a control group of non‐exposed offspring. Subjects: Offspring of T1DM (n = 16), GDM (n = 22) and mothers without diabetes (n = 25) born at Oulu University Hospital. Aim: To assess insulin secretion and insulin resistance in the offspring of T1DM and GDM at preschool age in comparison with offspring of non‐diabetic mothers. Methods: Anthropometric measurements and intravenous glucose tolerance testing were performed. First‐phase insulin response (FPIR) and homoeostasis model assessment (HOMA) values were calculated. Pregnancy and birth data were analysed in relation to later metabolic parameters in all three groups using one‐way analysis of variance (anova ) and analysis of covariance (ancova ). Results: At a mean age of 4.9 yr, offspring of T1DM had increased fasting serum insulin concentrations (p = 0.044), FPIR (p = 0.034) and HOMA‐B values (p = 0.008) compared with offspring of GDM or with offspring of healthy controls (statistically non‐significant). The GDM gained least weight during pregnancy, and when adjusted for maternal weight gain during pregnancy, there were no statistically significant differences between study groups. Conclusions: Prenatal exposures to maternal type 1 and gestational diabetes may have different effects on postnatal glucose metabolism in the offspring assessed at a mean age close to 5 yr. Maternal weight gain in pregnancy may affect the postnatal glucose metabolism in the offspring.     

Placental pathology and abnormal fetal heart rate patterns in gestational diabetes

Infants of diabetic mothers are considered to be at increased risk of fetal distress. We suggest that umbilical vasculitis is strongly associated with abnormal fetal rate patterns, which indicate fetal tissue hypoxia even in the absence of clinical evidence of intrapartum infection. In the present series, 132 term deliveries with Class A diabetes mellitus were compared with 159 uncomplicated term deliveries. Umbilical vasculitis and gestational age greater than 281 days were both highly correlated with abnormal fetal heart rate patterns in diabetic pregnancies (p less than 0.001). These effects were shown to be independent by multiple logistic regression. There was no difference in mean birthweight between infants of diabetic mothers and those of uncomplicated pregnancies, but infants of diabetic mothers had heavier placentas (p less than 0.01). These data further support our hypothesis that umbilical vasculitis may affect umbilical hemodynamics and predispose to development of fetal heart rate patterns.     

Leptin,fetal growth and insulin resistance in non-diabetic pregnancies

Background

Interrogation of the association between leptin, insulin resistance and fetal growth may provide a biological link for the fetal programming of later metabolic health.

Aims

Our aim was to clarify the relationship between maternal and fetal leptin, insulin resistance and fetal growth.

Study design

Maternal leptin, glucose and insulin were measured in early pregnancy and at 28 weeks and the HOMA index calculated. At 34 weeks, ultrasound scan assessed fetal weight and adiposity (abdominal wall width). At delivery birthweight was recorded and cord blood analyzed for fetal c-peptide and leptin. Analysis was performed using a multivariate linear regression model.

Subjects

574 non-diabetic pregnant women.

Outcome measures

Fetal growth and maternal and fetal insulin resistance.

Results

On multivariate analysis a relationship was identified between maternal and fetal leptin concentrations at each time point and maternal body mass index. Maternal leptin was related to insulin resistance in early pregnancy (β = 0.15, p = 0.02) and at 28 week gestation (β = 0.27, p < 0.001). Fetal insulin resistance correlated with maternal leptin in early pregnancy (β = 0.17, p = 0.004); at 28 weeks (β = 0.12, p = 0.05), and with leptin in cord blood (r = 0.28, p < 0.001).Fetal weight at 34 weeks was related to maternal leptin in early pregnancy (β = 0.16, p = 0.02). Both maternal and fetal leptin correlated with infant size at birth (β = 0.12, p = 0.07 in early pregnancy, β = 0.21, p = 0.004 in cord blood), independent of all other outcome measures.

Conclusion

Our findings have confirmed that in a non-diabetic cohort there is a link between maternal and fetal leptin and insulin resistance. We also established a link between maternal leptin in early pregnancy and both fetal and neonatal size. These results add to the growing body of evidence suggesting a role for leptin in the fetal programming of childhood obesity and metabolic dysfunction.     

链脲霉素致大鼠妊娠糖尿病影响子鼠发育的实验模型研究

目的 建立SD大鼠腹腔注射链脲霉素(STZ)致妊娠糖尿病的实验动物模型,为研究妊娠糖尿病对胎儿发育影响提供实验基础.方法 将54只SD孕鼠随机分为STZ注射组(30只)和柠檬酸缓冲液注射对照组(24只),两组又按取材时孕龄不同随机分为第13、16天和19天3个亚组.对STZ注射组孕鼠,给予新配2%STZ溶液,按STZ 40 mg/kg,一次性腹腔注射,3 d后空腹尾静脉采血监测血糖、尿糖和体重.对照组用同样方法注射等量的柠檬酸钠缓冲液.孕鼠于孕龄13、16、19 d随机分批剖宫,观察完全流产、吸收胎、死胎及存活胎数等情况,检查子鼠的外部形态,测量子鼠体重.子鼠心脏切片经常规HE染色后,进行病理分析.结果 STZ注射组孕鼠用药后出现"三多一少"现象,3 d后血糖水平明显高于对照组(14.65±1.12)mmol/L比(3.06±0.39)mmol/L,t:48.29,P＜0.01,尿糖均阳性,体重明显低于对照组(260.7±14.0)g比(273.7±16.7)g,t=3.11,P＜0.01;13、16 d和19 d流产率均高于对照组,χ2分别为4.37、7.51和11.05,P＜0.05;子鼠液化吸收胎、死胎、畸心胎例数较相应对照组高,χ2=77.21,P＜0.01.STZ注射组子鼠心脏发育异常数较对照组多,F=196,P＜0.01.结论 该动物实验模型与人类妊娠糖尿病(GDM)拟合较好,且操作简便,重复性高,是研究妊娠糖尿病致胎儿发育异常较理想的实验模型.     

Effect of lithium on reproduction and postnatal growth of mice

Mating pairs of mice were maintained continuously on drinking water containing 50 mEq/l LiCl and its effects on reproduction and postnatal development were monitored. In mating pairs put on lithium at 6-8 weeks of age, the lithium does not appear to reduce litter size at birth but it does increase postnatal mortality and the length of time between litters, and reduces the total number of litters a mating pair may have. In mating pairs put on lithium at 3 weeks of age, it severely delays postnatal growth and development of all pups in the litter. With the exception of the liver, this delayed growth and development does not appear to affect internal organs as severely as somatic body parts. This delayed growth may be the result of some effect lithium may have on certain hormones such as prolactin, thyroxine and growth hormone.     

妊娠糖尿病母亲母乳中真胰岛素水平及对婴儿生长的影响

目的:探讨妊娠糖尿病(GDM)哺乳期妇女初乳、42天和90天成熟乳中真胰岛素水平,分析其相关因素及其对婴儿体格发育的影响.方法:采用双位点单克隆抗体夹心放大酶联免疫分析法(BA-ELISA)测定GDM产妇和健康产妇初乳、42天和90天成熟乳及新生儿脐血中真胰岛素水平,监测婴儿90天内生长情况.结果GDM组初乳及90天成熟乳中真胰岛素水平均高于对照组(22.8μU/ml比20.4μU/ml,33.6μU/ml比23.5μU/ml,P均<0.05).母亲孕前、产前、产后42天和90天的体质指数(BMI)与90天成熟乳中真胰岛素水平正相关,产后42天BMI与42天成熟乳中真胰岛素水平正相关,孕期糖化血红蛋白百分比与90天成熟乳中真胰岛素水平正相关,剖宫产者初乳真胰岛素水平低于阴道分娩者(21.2μU/ml比96.3μU/ml,P<0.05).42天时高母乳喂养组母乳中真胰岛素水平低于低母乳喂养组(29.7μU/ml比69.6μU/ml,P<0.05).脐血中真胰岛素水平与出生体重和身长正相关,42天成熟乳中真胰岛素水平与出生至42天的体重增长值负相关,90天成熟乳中真胰岛素水平与90天头围负相关.结论:GDM哺乳期妇女母乳中真胰岛素水平较正常哺乳期妇女高,分娩方式和喂养方式对成熟乳中真胰岛素水平有影响,母乳中真胰岛素水平与孕产妇的BMI值呈正相关,对婴儿体格生长起调节作用.     

Effect of partially purified human somatomedin on human fetal and postnatal cartilage in vitro

Partly purified somatomedin prepared from adult human plasma stimulated [³h]thymidine and [³⁵s]sulphate uptake into human cartilage. At a final concentration of 0.1 U/ml somatomedin the uptake of [³H]thymidine into fetal cartilage at 18 weeks of gestation was 162 ± 23% compared with controls. Somatomedin also increased the incorporation of [³⁵s]sulphate into fetal cartilage to 137 ± 22% at 18 weeks compared to controls.The same concentration of somatomedin (0.1 U/ml) also increased the incorporation of [³h]thymidine into postnatal articular cartilage to 239 ± 69% and [³⁵s]sulphate to 133 ± 28% compared to controls.Human somatomedin prepared from adult plasma thus has a mitogenic effect on both fetal and postnatal cartilage. The smaller effect on fetal cartilage may reflect different forms of somatomedin and/or differences in receptors for somatomedins on adult and fetal chondrocytes.     

Severe insulin resistance and diabetes mellitus in mandibuloacral dysplasia.

Mandibuloacral dysplasia (MAD) is a syndrome with onset in midchildhood. The predominant characteristics of MAD include flexion contractures; mandibular hypoplasia; loss of body fat; atrophic, speckled skin; and progressive osteolysis of the clavicles. We studied three males with MAD. Each had lipodystrophy of the extremities, with sparing of the face and neck. All had moderate hyperlipidemia. In response to oral glucose, each had a diabetic response, with peak insulin levels between 2870 and 22,960 pmol/L. Insulin-stimulated glucose disposal was determined in two patients with MAD. At an insulin infusion rate of 120 mU/m2 per minute, glucose disposal was less than 25% of that measured at similar levels of insulinemia in nondiabetic control subjects, indicating marked insulin resistance in patients with MAD. The insulin resistance occurred without obesity, excessive levels of counterregulatory hormones, or anti-insulin-receptor antibodies. We suggest that MAD is a previously undescribed form of lipodystrophic insulin-resistant diabetes mellitus.     

妊娠期糖尿病胎鼠心脏T-同源盒转录因子表达研究

目的 探讨T-同源盒转录因子5（TBX-5）在母鼠妊娠糖尿病（GDM）胎鼠心脏中的分布、表达规律及其在胎鼠心脏发育异常中的作用。方法 将成年SD雌鼠随机分成GDM组和对照组,通过阴道涂片确定怀孕后分别注射链脲佐菌素（STZ）及柠檬酸-柠檬酸钠缓冲液（PBS）制备GDM模型,于孕0、3、6、9、12、15、19天对母鼠进行尾静脉采血测血糖,并分别于孕后第12、15、19天进行胎鼠心脏取材,HE染色观察心脏组织病理变化,免疫组化检测TBX-5的表达并进行半定量检测。结果 与对照组相比,GDM组胎鼠出现液化吸收胎、死胎、畸心胎的例数增多（P〈0.01）。在大体观及高倍镜下,GDM组12、15、19天胎鼠心脏发育异常比例多于对照组（P〈0.01）。在正常对照组及GDM组各亚组中,TBX-5均在第12天时表达最强,明显高于15、19天（P〈0.01）。TBX-5在15天及19天时的表达无明显差别（P〉0.05）。孕12、15、19天GDM组TBX-5在心肌细胞表达显著增强,与相应时间点的对照组相比均明显增高（P〈0.01）。结论 TBX-5蛋白在妊娠糖尿病母鼠孕12、15、19天三个观察点胎鼠心脏的表达水平明显增高,提示其过度表达可能与妊娠期糖尿病致胎鼠心脏畸形的发生存在关联。     

Effect of insulin on serum lipids in juvenile diabetes.

In diabetic children, the effect on serum lipids of insulin by itself and combined with glucose of with Aminosol + glucose has been studied. The level of serum free fatty acids decreased significantly in every case. The cephalin level decreased under the effect of insulin and insulin + Aminosol, whereas it rose after insulin and glucose infusion. The triglyceride level remained unchanged when insulin was applied by itself, and decreased significantly under the effect of insulin + Aminosol, while it showed a rising tendency after insulin + glucose infusion.     

Effect of maternal diabetes on the fetal exocrine pancreas

To test the hypothesis that fetal pancreatic exocrine and endocrine function are stimulated in parallel in the diabetic pregnancy, 68 mothers with gestational and pregestational diabetes who underwent amniocenteses after 34 weeks' for the evaluation of fetal lung maturity were enrolled. Amniotic fluid specimens were analyzed for C-peptide and trypsin content. Amniotic fluid specimens were obtained from 92 non-diabetic women undergoing amniocenteses for lung maturity, preterm labor, or premature rupture of membranes. Groups were compared using the Wilcoxon rank-sum test, Kruskal Wallis rank sum test, and Spearman's rank correlation test. C-peptide amniotic fluid concentrations were significantly greater in diabetics (median 0.6 ng/ml) than non-diabetics (median 0.4 ng/ml, P= 0.0001), in pregestational (median 0.6 ng/ml) vs. gestational diabetics (median 0.4 ng/ml, P = 0.006), and greater in proportion to severity of disease according to diabetic class (A1 = 0.4 ng/ml, A2 = 0.55 ng/ml, B = 0.6 ng/ml, C = 0.7 ng/ml, D = 0.85 ng/ml, P = 0.04). No significant differences were detected in amniotic fluid trypsin between the diabetic and non-diabetic or the gestational and non-gestational diabetic groups. There was no correlation between C-peptide and trypsin within the diabetic groups. Stimulation of the exocrine and endocrine pancreas does not occur in parallel in the fetus of the diabetic mother. Although originating as a single organ, pancreatic exocrine and endocrine functions are distinct in both physiologic and pathologic conditions.     

Dermatoglyphics, fetal growth, and insulin dependent diabetes in children under 5 years

Examination of dermatoglyphic patterns in 112 diabetic children under 5 years and matched controls found no difference between the groups. Either those developing diabetes under 5 do not experience the same genetic and environmental conditions that influence its development in later life or the dermatoglyphic abnormalities described in later onset insulin dependent diabetes mellitus reflect the vast number of pattern formations available for study, which has inevitably led to some statistically significant associations.     

Transient neonatal diabetes and later onset diabetes: a case of inherited insulin resistance.

A 13 year old girl who had had transient neonatal diabetes developed permanent diabetes. She had raised fasting insulin concentrations suggestive of insulin resistance with a suboptimal insulin response to glucose loading. Both her mother and sister had profound insulin resistance; neither had clinical diabetes. This is the first time inherited insulin resistance has been implicated in the pathogenesis of permanent diabetes developing after transient neonatal diabetes.     

Effect of insulin on the distribution of cardiac output in the fetal lamb

Three to five measurements of fetal cardiac output and its distribution were made using radiolabeled microspheres in each of 12 sheep fetuses in whom fetal plasma insulin concentration was varied by exogenous infusion of insulin to the fetus. Blood concentrations of oxygen and glucose as well as blood gases, pH, hematocrit, and plasma insulin concentrations were also measured. Both fetal arterial oxygen content and whole blood glucose concentration fell as fetal insulin concentration rose. Fetal cardiac output rose as insulin concentration increased and was accompanied by an increase in fetal heart rate. Increased insulin concentration was associated with increased flow to the heart, stomach, placenta, and carcass while blood flow to the fetal brain, lungs, liver, kidneys, spleen, and intestines was not affected. As plasma insulin concentration rose, the percentage of the cardiac output distributed to the fetal heart and upper carcass increased; that distributed to the fetal brain, lungs, liver, stomach, intestines, and lower carcass remained unchanged; while that distributed to the kidneys, spleen, and placenta decreased. When expressed as a fraction of cardiac output, an additional 7% (from 39 to 46%) of the cardiac output was distributed to carcass over the range of insulin concentrations studied. Most of the increased portion of the fetal cardiac output distributed to the fetal carcass during hyperinsulinemia was accounted for by a decrease in the percentage of fetal cardiac output perfusing the placenta.     

外源性甲状腺素对胎儿酒精效果出生后大鼠小脑发育的改善作用

目的 研究胎儿酒精效果对大鼠小脑皮质中脑源性神经营养因子(BDNF)和酪氨酸激酶B(TrkB)的影响及外源性甲状腺素(T4)的效应.方法 选择怀孕第6天的SD孕鼠随机分为酒精组、正常组、酒精 + T4组以及代理母鼠组.酒精组孕鼠摄取1 475 J/d的酒精;正常组孕鼠摄取与酒精组同热卡的奶粉;酒精 + T4组孕鼠摄取与酒精组同量的酒精,同时皮下注射5 μg/(kg·d)甲状腺素;代理母鼠组摄取正常鼠食.酒精组、正常组、酒精 + T4组母鼠分娩6 h后处死采血,测试血中酒精浓度和甲状腺素含量.三组仔鼠由代理母鼠养育,并分别于生后第7、14、21、28、60、90天麻醉处死,采用免疫组织化学染色法,观察小脑皮质中BDNF和TrkB阳性浦肯野细胞的分布及形态,并测算小脑4/5小叶中单位面积所含的BDNF或TrkB阳性浦肯野细胞数.结果 三组18只母鼠(每组6只)及其所生仔鼠中144只(每组均选择48只)纳入分析.酒精组、酒精 + T4组母鼠的血液酒精浓度高于正常组,差异有统计学意义(P ＜ 0.05);酒精 + T4组母鼠血液甲状腺素含量高于酒精组,差异有统计学意义(P ＜ 0.05).酒精 + T4组仔鼠从第14天开始,小脑皮质中出现分布及形态与正常组类似的BDNF和TrkB阳性浦肯野细胞,酒精组仔鼠小脑皮质中始终未出现BDNF和TrkB阳性浦肯野细胞.酒精 + T4组仔鼠小脑中BDNF和TrkB阳性浦肯野细胞数,从第14天起与正常组无差异(P ＞ 0.05);酒精组仔鼠小脑中BDNF和TrkB阳性浦肯野细胞数,从第28天起较正常组及酒精 + T4组显著减少(P ＜ 0.01),并持续到第90天.结论 外源性甲状腺素能促进小脑皮质中BDNF和其特异性受体TrkB的合成,促进BDNF-及TrkB-阳性浦肯野细胞的发育,进而改善胎儿酒精效果致低甲状腺素所引起的小脑发育障碍.     

1型糖尿病患儿皮下连续输注胰岛素疗效观察

目的　观察胰岛素泵连续皮下输注胰岛素 (CSII)与皮下多次注射胰岛素 (MSII)治疗 1型糖尿病(T1DM)疗效。方法　利用CSII控制血糖为一组。MSII控制血糖分为两组 ,A组予MSII合用二甲双胍 ;B组单用MSII;并测定 3餐前后及凌晨 2∶0 0时血糖。结果　 3组血糖均可控制达标。CSII平均达标天数、胰岛素用量明显短于MSII组 ,A组达标天数也短于B组。结论　CSII控制血糖 ,达标时间短 ,血糖平稳下降 ,能够抑制黎明现象 ,低血糖及高血糖发生率低 ,适合T1DM治疗。