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Aims/hypothesis: Experimental studies have suggested that apoptosis is involved in diabetic embryopathy through oxidative stress. However, the precise mechanism of diabetic embryopathy is not yet clear. Thioredoxin (TRX) is a small, ubiquitous, multifunctional protein, which has recently been shown to protect cells from oxidative stress and apoptosis. Using transgenic mice that overproduce human TRX-1 (TRX-Tg mice), we examined whether oxidative stress is involved in fetal dysmorphogenesis in diabetic pregnancies., Methods: Non-diabetic and streptozotocin-induced diabetic (DM) female mice were mated with male TRX-Tg mice. Pregnant mice were killed either at day 10 or day 17 of gestation, and viable fetuses and their placentas were recovered, weighed and assessed for gross and histological morphology, biochemical markers and gene expression., Results: In both wild-type (WT) and transgenic (Tg) groups, fetal and placental weights in the diabetic group were significantly decreased compared with the non-diabetic group. The incidence of malformation was higher in the diabetic group, and was significantly decreased in the TRX-Tg group (DM-WT vs DM-Tg; 28.6% vs 10.4%). Oxidative stress markers such as thiobarbituric acid reactive substances and 8-hydroxy-2'-deoxyguanosine were increased in DM-WT group fetuses but were decreased in fetuses from the DM-Tg group. Furthermore, immunohistochemically assayed apoptosis and cleaved caspase-3 production in embryonic neuroepithelial cells was significantly increased in the DM-WT group, and was significantly decreased in the DM-Tg group., Conclusions/interpretation: These results indicate that oxidative stress is involved in diabetic embryopathy, and that the antioxidative protein TRX at least partially prevents diabetic embryopathy via suppression of apoptosis.

Aims/hypothesis: Several studies have shown that maternal diabetes increases the risk of congenital malformations in various organ systems including the neural tube. The present study analysed molecular and morphological changes in the forebrain of embryos from diabetic Albino Swiss mice., Methods: Maternal diabetes-induced morphological changes in the forebrain were examined histologically. Cell proliferation index was assayed by BrdU labelling. In situ hybridisation and quantitative real-time PCR were used to analyse the expression of genes coding for sonic hedgehog ( Shh), Nkx2.1, brain factor-1 ( BF-1) and bone morphogenetic protein-4 ( Bmp4) that control forebrain patterning., Results: There were no distinguishable abnormalities in the forebrain of embryos from diabetic pregnancies on embryonic day 0.5. At embryonic day 11.5, embryos of diabetic pregnancies displayed a fusion and thickening of the ventral telencephalic neuroepithelium and a partial absence of the dorsal telencephalon, indicating a severe patterning defect in the dorsoventral axis of the telencephalon. The cell proliferation index was also higher in the ventral telencephalon of these embryos. Molecular analyses indicated that expression of Shh, Nkx2.1 and BF-1 was increased and their expression domains expanded dorsally in the ventral telencephalon in embryos of diabetic mice at embryonic day 11.5. The expression of Bmp4 was reduced in the dorsal forebrain of these embryos. At embryonic day 8.5, only Shh expression was increased., Conclusions/interpretation: Altered expression of various genes involved in dorsoventral patterning of the forebrain is associated with forebrain malformations in embryos of diabetic mice.

Short stature has been associated with various degrees of abnormal glucose tolerance in middle-aged people, where the effects of age and metabolic control would be difficult to exclude. We chose to examine body stature in women with gestational diabetes mellitus (GDM), a prediabetic state affecting a young group of people. A sample of 2772 Greek pregnant women, referred for GDM screening was examined. After a 100-g oral glucose tolerance test, 1787 women were classified as normal (N), 300 women were found with one abnormal glucose value (OAV) and 685 women with GDM. Basal insulin resistance was calculated in 640 women by homeostasis model assessment. In addition, 51 pregnant women with pre-existing Type II (non-insulin-dependent) diabetes mellitus and 109 with pre-existing Type I (insulin-dependent) diabetes mellitus were included in the study. There was a gradual decrease in mean height (cm) as glucose intolerance became more severe: N: 161.0 +/- 6.2, OAV:160.2 +/- 6.1, GDM:158.7 +/- 6.3, Type II diabetes 158.2 +/- 7.0 (p < 0.001, analysis of variance]. Height in Type I diabetes (160.1 +/- 5.9) did not differ from the normal group. The difference in height between the normal and GDM groups remained (p < 0.001) when body weight, age, birth before or after 1960 and educational status were also taken into account. An independent correlation was also found between height and insulin resistance (n = 640) adjusted for the above mentioned variables. In conclusion, short stature appears to be associated with glucose intolerance as an independent variable, even when this intolerance is both mild and temporary. The previously unrecognised independent association of stature with basal insulin resistance merits further investigation.

Mitochondrial DNA is exclusively maternally inherited. We recently found the prevalence of diabetic patients with an A to G transition at position 3243 of leucine tRNA (3243 base pair (bp) mutation) to be nearly 1% in randomly selected Japanese subjects. Here, we report the higher prevalence of diabetic patients with the 3243 bp mutation in a specific Japanese population of women attending a diabetic pregnancy clinic. Of 102 patients with non-insulin-dependent diabetes mellitus 6 (5.9%) were positive for the mutation, 1 (8.3%) of 12 patients with gestational diabetes and 2 (5.9%) out of 34 borderline diabetic patients. In contrast, none of 64 patients (0%) with insulin-dependent diabetes mellitus had the 3243 bp mutation. Moreover, there was a difference in the prevalence of spontaneous abortions between patients with and without this mutation (27.3 vs 12.4%). Among nine probands with the mutation, four had a history of one spontaneous abortion (p = 0.0518) and two had a history of two abortions (p = 0.0479). Two probands had a spontaneous abortion even while under strict diabetic metabolic control. The 3243 bp mutation thus may cause spontaneous abortion during pregnancy.

Mutations of the glucokinase gene result in early-onset familial Type 2 (non-insulin-dependent) diabetes mellitus, and several members of the mutant glucokinase kindreds were originally diagnosed as having gestational diabetes. This study examined the glucokinase gene in 270 American Black women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed Type 2 diabetes after pregnancy (overt diabetes), and 99 normal control subjects who were recruited during the peripartum period. Two simple sequence repeat polymorphisms flanking either end of the glucokinase gene were evaluated. No association was found between glucokinase alleles and gestational diabetes only or overt diabetes, after adjustment for multiple comparisons. To detect single base changes, all 11 exons and proximal islet and liver promoter regions were examined by polymerase chain reaction plus single-stranded conformational polymorphism analysis in 45 gestational diabetes only patients who had not yet developed Type 2 diabetes. Nine coding region variants were identified: Ala11 (GCC) to Thr11 (ACC) in islet exon 1, and 8 variants either in untranslated regions or in the third base of a codon. Four variant sites were found in introns, but none in splicing consensus sequences. Analysis of the promoter regions revealed two common variants, G-->A at islet -30 (24%), and G-->A at liver -258 (42%). The frequencies of the promoter variants, determined by allele specific polymerase chain reaction analysis, but did not differ among the three groups. Thus, no significant coding sequence glucokinase mutations were found in 90 alleles from 45 patients with gestational diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

No difference was found at paediatric assessment, or by a psychologically-based maternal and teacher questionnaire of the emotional state or academic achievement, between 123 children of Type 1 (insulin-dependent) diabetic mothers and 124 children of non-diabetic mothers. The groups were closely matched for maternal age, sex and position in sibship of the child, and age and home environment of the mother. The children of diabetic mothers had all been delivered before week 38 of gestation.