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We report on a 25-year old female in whom idiopathic thrombozytopenic purpura and diabetes type I existed at the same time in pregnancy. In this constellation we decided to treat her with intravenous immunoglobulins for five days and delivered her by caesarean after recovery of the maternal thrombozytes. While this proved to be an effective treatment for the mother with few adverse effects we saw severely low thrombozytopenia of the child requiring intensive postnatal care. A longterm treatment with immunoglobulins for about three weeks could be a possible treatment for the fetal as well as the maternal thrombozytopenia. Reports on this question do not yet exist.

Inappropriate body weight gain during pregnancy has critical effects on the outcome for both mother and fetus. Therefore, body weight gain is an important issue in the management of pregnancy in women with diabetes. A Trp64Arg substitution in the beta3-AR gene has been reported to be associated with body weight gain and obesity in non-insulin-dependent diabetes mellitus (NIDDM) subjects. The aim of this study was to elucidate the contribution of the beta3-AR gene to body weight gain during pregnancy in subjects with diabetes. We analyzed 199 diabetic patients (NIDDM/IDDM; 131/68) and patient data was obtained from the first delivery of each individual. The mean age at diagnosis of diabetes was 22.9 +/- 7.5 years (mean +/- S.D.) and the mean age at delivery was 29.8 +/- 4.5 years. A polymorphism of the beta3-AR gene was detected by PCR-RFLP using Bst OI, which recognizes a Trp64Arg substitution. The frequency of the Trp64Arg allele was 0.15 in NIDDM and 0.17 in IDDM. Among the NIDDM subjects, excess weight gain during pregnancy, as defined by maximum BMI during pregnancy minus basal BMI before pregnancy exceeding five, was observed in 12.2% of the wild-type patients, 19.2% of heterozygotes and 28.6% of homozygotes. Homozygous subjects with NIDDM tended to show excess weight gain during pregnancy, however, this trend did not reach significance. None of the IDDM homozygotes showed excess weight gain. From our study, this beta3-AR gene polymorphism cannot be excluded as a contributing factor to excess weight gain during pregnancy in NIDDM subjects.

A male patient with aphallia, anal stenosis, tetralogy of Fallot, multiple vertebral anomalies including sacral agenesis and central nervous system (CNS) malformations was born after a pregnancy complicated by poorly controlled maternal diabetes. Aphallia is an extremely rare abnormality and can be part of the urorectal septum malformation sequence (URSMS). While aphallia has not been reported in infants of diabetic mothers, urogenital malformations are known to occur with increased frequency. Two female products of pregnancies complicated by diabetes presented with multiple malformations including anal atresia and recto-vaginal fistula consistent with the diagnosis of URSMS. The three patients share CNS, cardiac, and vertebral anomalies, abnormalities secondary to abnormal blastogenesis and characteristic of diabetic embryopathy. URSMS is also caused by abnormal blastogenesis. Therefore, this particular malformation should be viewed in the context of the multiple blastogenetic abnormalities in the cases reported here. The overlap of findings of URSMS in our cases with other abnormalities of blastogenesis, such as VATER association or sacral agenesis is not surprising, as these associations are known to lack clear diagnostic boundaries.

We have studied a new sample of 276 NIDDM patients from the population of Penne (Italy). Comparison of the new data with those of 214 diabetic pregnant women from the population of Rome reported in a previous paper has shown that the pattern of association between low molecular weight acid phosphatase genotype and degree of glycemic control is similar in the two classes of diabetic patients. Among nonobese subjects the proportion of ACP1*A (the allele showing the lowest enzymatic activity) is lower in diabetic patients with high glycemic levels (mean value greater than 8.9 mmol/l) than in diabetic patients with a low glycemic level (mean value less than 8.9 mmol/l). Among obese subjects no significant association is observed between glycemic levels and ACP1. Among nonobese subjects the concentration of f isoform of ACP1 is higher in patients showing a high glycemic level than in patients showing a low glycemic level. No significant difference is observed for s isoform.

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.

A family with maturity-onset diabetes of the young (MODY), a rare subtype of non-insulin-dependent diabetes mellitus (NIDDM), is described. This familial form of diabetes is characterized by an early age of onset and an autosomal dominant inheritance. All three patients developed diabetes at an early age and were not obese. The diabetes was always well controlled and none of the patients developed late complications. The clinical and molecular-genetic characteristics of the different forms of MODY are described, as well as the diagnostic work-up and therapeutic management.

In Europid populations, patients with non-insulin-dependent diabetes mellitus (NIDDM) are more than twice as likely to have a mother than a father with diabetes. We have examined this aspect in an Australian population. For this purpose records of 1,000 consecutive patients with NIDDM were reviewed. A history of diabetes was present in 193 mothers (19.3%) and in only 86 fathers (8.6%) (p < 0.0001). The predominance of maternal history of diabetes in patients with NIDDM is suggestive of a maternal transmission of this disorder. This metabolic tendency may develop due to an adverse intrauterine environment in women with undiagnosed gestational diabetes mellitus.

We describe a family which demonstrates and expands the extreme clinical variability now known to be associated with the A-->G transition at nucleotide position 3243 of the mitochondrial DNA. The propositus presented at birth with clinical manifestations consistent with diabetic embryopathy including anal atresia, caudal dysgenesis, and multicystic dysplastic kidneys. His co-twin was normal at birth, but at 3 months of life, presented with intractable seizures later associated with developmental delay. The twins' mother developed diabetes mellitus type I at the age of 20 years and gastrointestinal problems at 22 years. Since age 19 years, the maternal aunt has had recurrent strokes, seizures, mental deterioration and deafness, later diagnosed as MELAS syndrome due to the tRNA(Leu(UUR)) A-->G mutation. A maternal uncle had diabetes mellitus type I, deafness, and normal intellect, and died at 35 years after recurrent strokes. This pedigree expands the known clinical phenotype associated with tRNA(Leu(UUR)) A-->G mutation and raises the possibility that, in some cases, diabetic embryopathy may be due to a mitochondrial cytopathy that affects both the mother's pancreas (and results in diabetes mellitus and the metabolic dysfunction associated with it) and the embryonic/fetal and placental tissues which make the embryo more vulnerable to this insult.

We have studied the effect of moderately impaired maternal insulin secretion on oocyte chromosomal constitution, fertilization and zygote DNA synthesis. Female mice were injected with a single dose of streptozotocin (65 mg/kg) 14 days before fertilization/ovulation. Zygotes/oocytes were recovered from control and subdiabetic mice on day 1 of pregnancy. Compared with control animals, subdiabetic females showed a significant difference in the proportion of zygotes/oocytes. The subdiabetic mothers had a lower percentage of zygotes and a higher percentage of unfertilized and degenerated oocytes in comparison with control animals. The investigation of [3H]thymidine incorporation did not show any influence of the maternal subdiabetes on the initial zygote DNA synthesis. An analysis of the ovulated oocytes at the metaphase II stage isolated from subdiabetic mice did not reveal increased chromosomal anomalies in comparison with the controls. Control and subdiabetic mothers had a similar percentage of oocytes with a normal haploid set of chromosomes, and the incidence of aneuploidy/diploidy did not differ significantly. These observations suggest that insulin changes in subdiabetic mothers had a deleterious influence on oocyte fertilization in mice, but apparently they did not have any effect on the nuclear events.

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.

Objective: To test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero., Research Design and Methods: We enrolled offspring of women with pregestational diabetes (this included insulin-dependent diabetes mellitus [IDDM] and non-insulin-dependent diabetes mellitus [NIDDM]) and gestational diabetes in a prospective study from 1977 through 1983. Fetal beta-cell function was assessed by measurement of amniotic fluid insulin (AFI) at 32-38 weeks gestation. Postnatally, plasma glucose and insulin were measured yearly from 1.5 years of age after fasting and 2 h after 1.75 g/kg oral glucose. Control subjects had a single oral glucose challenge at 10-16 years., Results: In offspring of diabetic mothers, the prevalence of impaired glucose tolerance (IGT) (2-h glucose concentration > 7.8 mmol/l) was: 1.2% at < 5 years, 5.4% at 5-9 years, and 19.3% at 10-16 years. The 88 offspring of diabetic mothers (12.3 +/- 1.7 years), when compared with 80 control subjects of the same age and pubertal stage, had higher 2-h glucose (6.8 +/- 1.4 vs. 5.7 +/- 0.9 mmol/l, P < 0.001) and insulin (660 +/- 720 vs. 455 +/- 285 pmol/l, P < 0.03) concentrations. The 17 subjects with IGT at > 10 years of age (9 boys and 8 girls) include one girl with NIDDM. IGT was not associated with the etiology of the mother's diabetes (gestational versus pregestational) or macrosomia at birth. IGT was found in only 3.7% (1 of 27) of adolescents whose AFI was normal ( < or = 100 pmol/l) and 33.3% (12 of 36) of those with elevated AFI (P < 0.001). Although most of the children with IGT are obese, AFI and obesity are independently associated with IGT by multiple logistic analysis., Conclusions: In confirmation of our original hypothesis, IGT in the offspring is a long-term complication of maternal diabetes. Excessive insulin secretion in utero, as assessed by AFI concentration, is a strong predictor of IGT in childhood.

Congenital malformations are the leading cause of death in infants of insulin-dependent diabetic mothers. Although there are data to suggest that hyperglycemia itself is teratogenic, few mechanisms have been proposed to explain diabetic embryopathy. To address the possibility that DNA mutations play a role in the fetal malformations associated with diabetes, we developed a transgenic mouse model system to measure the mutation frequency of a neutral target gene, lacI, during embryonic development in a maternal hyperglycemic environment. Despite the short 21-day gestational period of the mouse, we observed a twofold increase in the mutant frequency of the lacI transgene in fetuses that developed in a mild diabetic environment (blood glucose > 8.3 mmol/l) compared with those that developed under normoglycemic conditions (blood glucose < 8.3 mmol/l). These data provide the first direct evidence of the genotoxic effect of diabetes in vivo and suggest a mechanism for the teratogenicity of the maternal diabetic environment.

Associations of nucleolar organizing regions (NORs) in the postimplantation stage embryos of nonobese diabetic (NOD) mice, and diabetic ICR mice induced by streptozotocin (ST), were studied to investigate the possible cause of the numerical anomalies of the chromosomes in their abnormal embryos. The incidence of NOR associations in abnormal embryos from diabetic NOD (NOD-DM) and STZ-diabetic mice was 11.7 and 7.7%, respectively. This incidence was significantly higher than that (1.2%, p < 0.05) of normal embryos from ICR mice which were used as control. From the results analyzed cytogenetically it was suggested that the higher incidence of chromosomal numerical anomalies in the embryos from NOD-DM and STZ-diabetic mice were caused by the chromosomal nondisjunction induced by associations of NORs. Furthermore, it was suggested that NOD-DM embryos have a tendency to increase the associations of NOR in a diabetic condition together with other factors such as autoimmune disease, however a diabetic condition alone induced chromosomal anomalies. Regarding relationships between the incidence of associations of NOR and the types of malformed embryos, it was also clear that all of the abnormal embryos from NOD-DM and STZ-diabetic mice had a high incidence of associations of NOR, and that the incidence was not related to the types of congenital anomalies. Furthermore, in the mal-developed tissue of embryos from STZ-diabetic mice, many chromosomal anomalies were found (26.6%), and the incidence was similar to that of whole embryos (22.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Ninety-nine pregnant women with insulin-dependent diabetes mellitus, 83 women with gestational diabetes, and a control sample of 315 nondiabetic consecutive puerperae have been studied along with their newborn infants. Neonatal macrosomia is less frequent among diabetic mothers with phosphoglucomutase (PGM1) genotype PGM1*1/*2 than among mothers with other PGM1 genotypes. In gestational diabetes the association is more evident among younger women than among older women. Diabetic women with the PGM1*1/*2 genotype show a reduced proportion of heterozygous PGM1*1/*2 offspring. The phenomenon is much more evident among women under 28 years of age and does not depend on the quality of metabolic control. The data suggest that when both mother and fetus share the PGM1*1/*2 genotype, the deleterious effects of a diabetic environment on fetal development are more severe, leading to an early loss of zygotes. This may contribute to a decrease incidence of macromosomia among live-born infants delivered by PGM1*1/*2 mothers.

Objective: To assess the reports that maternal phosphoglucomutase-1 (PGM1) phenotype is highly related to macrosomia in diabetic pregnancy. This could be either a direct metabolic phenomenon, or the PGM1 locus could be a marker for a tightly linked gene involved in the maternal control of fetal growth., Design: A comparative biochemical genetic study., Setting: A large diabetic pregnancy clinic., Subjects: One hundred and fifty-two women who had diabetes during pregnancy, 136 being insulin dependent before pregnancy. Two hundred and thirty-six women without pre-existing medical or pregnancy complications who functioned as a control group., Measures: PGM1 phenotype was assessed by conventional electrophoresis and subgroups were examined using iso-electric focusing., Outcome: Standardised birthweight was corrected for sex, maternal parity and gestation confirmed in every case by early pregnancy ultrasound. Maternal diabetes control was assessed by glycosylated haemoglobin., Results: No differences were found in the observed phenotype frequencies for diabetics and control pregnant women. No association between PGM1 phenotype and macrosomia in diabetic pregnancy was found. PGM1 did not make a significant contribution to birthweight, standardised birthweight, length or ponderal index of the baby as assessed by multiple regression., Conclusions: Our study of a larger number of insulin dependent diabetics in Scotland makes the claim that macrosomia in diabetic pregnancy is associated with PGM1 phenotype unlikely to be of general significance.

In insulin-dependent diabetes mellitus, maternal Phosphoglucomutase genotype is a predictor of fetal macrosomia much more important than quality of metabolic control during pregnancy. In gestational diabetes and in non insulin-dependent diabetes, on the contrary, the most important predictor is the metabolic control of diabetes.

The study of 230 diabetic mothers along with their newborn babies has shown that foetal macrosomia is associated with two specific genomic sites: phosphoglucomutase locus 1 (PGM1)-Rhesus blood group (Rh) linkage group (chromosome 1) and HindIII restriction fragment length polymorphism (RFLP) linked to insulin-like growth factor 1 (IGF1) (chromosome 12). In PGM(1)2-1 mothers carrying the E allele, there is a proportion of 8.7% of macrosomic newborns as compared with 39.6% in mothers with other genotypes. The relationship between the maternal PGM1-RhE genotype and neonatal macrosomia does not depend on the type of diabetes. The proportion of macrosomic infants is much lower among newborns carrying the IGF1HS allele of the HindIII RFLP linked to IGF1 (20%) than among IGF1F/IGF1HF newborns (55%).

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)

We report on 2 infants with the DiGeorge anomaly born to diabetic mothers treated with insulin. Both infants had unilateral renal agenesis. One of the mothers has manifestations suggestive of velo-cardio-facial syndrome (VCFS). Cytogenetic studies on both patients and the mother with apparent VCFS were normal. Molecular studies utilizing probes from the DiGeorge critical region did not demonstrate a 22q11 microdeletion in either patient or the mother with apparent VCFS. We conclude that maternal diabetes is a pathogenetic factor in the DiGeorge anomaly, and infants of diabetic mothers who have this anomaly should also be screened for renal agenesis.

Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to the development of late-onset NIDDM, linkage analyses between DNA polymorphisms at the glucokinase locus and NIDDM were performed in 79 multigenerational French families. In addition, all exons and the islet promoter region of glucokinase gene from 1 affected member from each family as well as from 17 unrelated women with previous gestational diabetes were amplified by polymerase chain reaction and screened for mutations by single-strand conformational polymorphism and DNA sequencing. Linkage of glucokinase and NIDDM was significantly rejected under all models tested. However, in 1 family, the lod score was 2.30, and we found a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase was found in the 79 NIDDM families. We identified a missense mutation (TGG257-->CGG257) in exon 7 of glucokinase gene from 1 of 17 women with gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabetes of the young, as 4 younger members, carrying this mutation, were subsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of onset NIDDM. Diabetic families with mutations in glucokinase must be carefully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals diabetes in women carrying a glucokinase defect.

The author reports on his 6-year experience (1. 1. 1985--31. 12. 1990) in screening for gestational diabetes at the Clinic of Gynecology and Obstetrics of the Medical University of Debrecen. The results of screening performed on a group of 1124 pregnant women with risk factors are evaluated. The diagnosis was established on the basis of postprandial glucose determinations and 75 g oral glucose challenge. The examinations revealed that gestational diabetes developed in 24% of patients with positive urinary glucose test, in 31% of patients with poor obstetrical history, and in 52% of those having family history of diabetes. The overall incidence of gestational diabetes was found to be 34% in the screened group of patients. At the time of the study the number of gravid women in Debrecen was 15.749. The prevalence of gestational diabetes was 1.95%.

Gestational diabetes constitutes 90% of all pregnant diabetic patients, whereas insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) together account for the remaining 10%. Diabetes is considered a heterogeneous disease with a continuous spectrum between IDDM and NIDDM. It is believed that gestational diabetes is also a heterogeneous disorder representing, at least in part, patients who are destined to develop in later life either IDDM or NIDDM. Studies in identical twins have shown clear-cut differences in the genetic inheritance of IDDM and NIDDM. Nearly 100% of identical twins were found to be concordant for NIDDM; whereas in IDDM the concordance rate ranges between 20 and 50%. This concordant pattern indicates a higher genetic contribution in NIDDM than IDDM. Furthermore, IDDM is an HLA-linked disorder, and NIDDM is not. The exact mechanism of inheritance of IDDM and NIDDM is not known; therefore the information used in genetic counseling is based on empirical risk estimates. Recent information demonstrates that IDDM is transmitted less frequently to the offspring of diabetic mothers than diabetic fathers (1.3% versus 6%). The estimated risk of recurrence of IDDM to offsprings with one already affected sibling and unaffected parents is 5 to 6%. Additionally, the empirical risk of NIDDM first-degree relatives developing diabetes is much higher than the observed in IDDM relatives, 15% for first-degree relatives and 60 to 75% when both parents have NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

The blood glucose levels of pregnant women with insulin-dependent diabetes mellitus and the blood glucose levels of newborns during the first few hours of life show an association with maternal Rh genotype. Distortions of joint maternal-fetal Rh phenotype distribution have also been observed. Because a cluster of genes involved in glycide metabolism is located on the short arm of chromosome 1, the present observations may reflect the action of these genes.

A kindred with a diabetic mother is described with one sibling with a radial deficiency (type 1 radial dysplasia (Bayne) with a hypoplastic thumb type 3 of Blauth) and one with an ulnar ray deficiency (type 2 of Ogden or type 1 of Swanson). A metabolic cause is probable, although the diabetes was well controlled during pregnancy.

It has now become clear that certain HLA antigens are associated with disease susceptibility more than any other genetic markers. Insulin-dependent diabetes mellitus (IDDM or type I) is an HLA-associated condition. Moreover, there is evidence to show that IDDM is a genetically programmed autoimmune disease. Studies of the HLA-DR region have shown a strong association with IDDM, with over 90 per cent of IDDM patients possessing DR3 and/or DR4. Although the HLA-DR region is a major component in the inherited disease susceptibility, it is not the only gene region involved. Recent studies demonstrated that HLA-DQ may be more closely linked to the disease locus than HLA-DR. Sequence analysis of the HLA-DQ3 gene products suggest that a single amino acid (aspartic acid) at position 57 is uniquely important for determining susceptibility or resistance to IDDM. Although there is a strong association of certain HLA loci with IDDM, it may not explain nor account for all the genetic susceptibility to the disease. It seems that 60 per cent of the genetic basis of IDDM is related to the HLA gene (chromosome 6) and another 40 per cent is non-HLA-associated (i.e., chromosomes 2, 7, 11, and 14). Even though great progress has been made in the understanding of the genetics of IDDM, the mode of inheritance of the disease remains controversial. The present review discusses various aspects of the autoimmune process believed to be involved in pancreatic beta cell destruction in individuals genetically susceptible to IDDM. The possible modes of inheritance and new data regarding estimated risks of transmitting the disease are presented.

We report on a term stillborn female infant with multiple congenital anomalies (MCA) which have not previously been reported as occurring together. The malformations include a first and second branchial arch sequence, ectopia cordis with congenital heart defect, caudal "regression" sequence with absent sacrum and hypoplastic right femur, ectrodactyly, left radial abnormality, islet cell hyperplasia, and skin lesions. The pregnancy was complicated by abdominal cramping with exercise, heavy vaginal bleeding, maternal obesity, and a normal screening glucose tolerance test at 6 months gestation. The infant was born to 20-year-old G3P1SAB2 Mexican-American parents who are first cousins. There was strong maternal family history of adult-onset diabetes. The malformations have some findings in common with those seen in infants of diabetic mothers. Structural defects similar to, but not inclusive of, those in our infant have been reported in 2 sibs born to a prediabetic mother with a first cousin marriage as well as in focal dermal hypoplasia. Parental consanguinity is suggestive of an autosomal recessive disorder. Alternatively, it may represent a combined multifactorial effect making the conceptus more sensitive to metabolic teratogens and thus placing it at increased risk for disruption of normal development.

The chromosomes of postimplantation stage embryos of nonobese diabetic (NOD) mice were analyzed to investigate the causal mechanism of congenital anomalies in diabetic pregnancies. Postimplantation stage embryos (day 12 of gestation) in diabetic (NOD-DM) and nondiabetic (NOD-N) NOD mice had either a high or low incidence of chromosomal abnormalities. A large majority of externally normal embryos from NOD-DM and NOD-N mice had low incidences. A high incidence of chromosomal abnormalities was found in externally abnormal embryos of NOD-DM and NOD-N mice, and in a smaller number of externally normal NOD-N and NOD-DM embryos. No control ICR embryo manifested a high incidence of chromosomal abnormalities. In the NOD-DM embryos, the chromosomes appeared to be influenced by long-term maternal diabetic conditions, while high incidences of chromosomal abnormalities in the NOD-N embryos suggested a probable cause by other factor(s) (e.g. a genetic predisposition) or by a very mild diabetic condition because the NOD-N mice were prediabetic.

Existing data concerning the effect of gestational diabetes on perinatal outcome in twin pregnancies is scant. We hypothesized that altered carbohydrate metabolism would worsen perinatal outcome in twin gestation in a manner similar to singleton gestation. Thirteen twin pregnancies complicated by gestational diabetes mellitus were matched by gestational age at delivery to 13 twin pregnancies unaffected by gestational diabetes. Comparing infants of diabetic mothers to infants of control mothers, there was a trend of greater likelihood of respiratory distress syndrome, hyperbilirubinemia, and prolonged neonatal intensive care nursery admissions. Our experience suggests that altered carbohydrate metabolism in multiple gestations increases the potential for neonatal morbidity.

Low activity genetic variants of acid phosphatase (ACP1) are positively associated with extreme body mass deviations in obese subjects. The same pattern has been found in non-diabetic children, in diabetic pregnant women, and in non-diabetic adult subjects. Low activity variants of ACP1 also show a positive association with family history of obesity, supporting the hypothesis of an enhancing action of these variants on expressivity of obesity.

In a long-term longitudinal study of gestational diabetes mellitus in Black women, risk factors that were identified were age, obesity, a family history of diabetes, and the presence of hypertension. Poor predictors were a history of a previous large-for-date infant, parity, and age at first pregnancy. The prevalence of smooth muscle and nuclear autoantibodies was higher in gestational diabetic subjects. Gestational diabetic subjects who required insulin for glycemic control were more obese, had a lower frequency of the Bf-F phenotype and a higher frequency of the Bf-F1 phenotype, and had a lower frequency of the type 2 allele at the polymorphic locus adjacent to the insulin gene. Restriction-fragment-length polymorphisms flanking the insulin and apolipoprotein A-I and C-III genes, although not associated with gestational diabetes mellitus, may be associated with hyperlipidemia and subsequent atherosclerosis.

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)

The obstetrics histories of all the pregnances were studied, including the deliveries and abortions, the perinatal mortality of fetuses and the frequency of congenital malformations among newborns in 239 repeatedly pregnant women heterozygous for the gene of phenylketonuria (PKU), 40 women with the latent form of diabetes mellitus (LDM) and 96 women heterozygous for Dushenne's myopathy (MD). It was established that the frequency of women suffering from spontaneous abortions (SA) was increased as well as the SA frequency among all the pregnancies with natural results in heterozygotes for the PKU gene; it was also established that the frequency of stillborns and of the early mortality of newborns was considerably higher among women with LDM. In both these groups the frequency of congenital malformations among the newborns was also relatively high. In women heterozygous for the PKU gene the pathogenic effect was realized only during the first three months of pregnancy, while in women with LDM it was realized through all the period of pregnancy. The heterozygosity of women for MD proved not to be pathogenic for the progeny. Possible mechanisms realizing the effect of heterozygosity of women for the abovementioned recessive genes during pregnancy are discussed.

One hundred ninety-nine gravida with gestational diabetes mellitus (GDM) defined as "carbohydrate intolerance of varying severity with onset or first recognition during pregnancy" have been stratified into subgroups on the basis of fasting plasma glucose and evaluated for further phenotypic and genotypic heterogeneity. A significantly greater proportion of the women in all our groups were older and heavier than in a "control" population of 148 consecutive gravida with documented normal oral glucose tolerance. After correction for age and weight by covariate analysis, absolute insulinopenia in response to oral glucose could be demonstrated in all GDM groups, although exceptions were present in each. The incidence of diabetes in the mothers of our patients with GDM was 8-fold greater than in controls; the incidence in fathers did not deviate from control patterns. HLA-DR3 and DR4 antigens were more frequently present in GDM and the increase was statistically significant in blacks. At the time of diagnosis, cytoplasmic islet cell antibodies (ICA) were significantly more common in GDM associated with elevated fasting plasma glucose than in controls; the frequency of ICA was 18.4% (7/38) in women with fasting plasma glucose greater than or equal to 130 mg/dl. Our findings indicate that GDM entails genotypic as well as phenotypic diversity and may include patients with slowly-evolving Type I diabetes mellitus, as well as patients with Type II diabetes mellitus, and women with asymptomatic diabetes which antedated the pregnancy (i.e. pregestational diabetes mellitus). Appreciation of this heterogeneity should be incorporated into any evaluation of intervention strategies for women with GDM or into prognoses concerning their postpartum metabolic status.

Islet hyperplasia and B-cell degranulation were found in the fetuses of the third generation from mothers (second generation) born to a diabetic mother (first generation) regardless of the origin of the father, while pancreatic islets were normal in fetuses from control mothers, even when the father was an offspring of a diabetic mother. These data support the hypothesis that in our experimental model overstimulation of the fetal endocrine pancreas results in long-term consequences to the third generation.

Haemoglobin D Punjab was detected in a slightly overweight, but otherwise healthy pregnant woman when she was tested for gestational diabetes within the framework of a screening programme. Chromatographic evaluation of the haemolysate by high-pressure liquid chromatography (HPLC) revealed an unusual "splitting" of the A1 peak into two minor peaks. A diabetes-independent haemoglobin variant was suspected and further investigations, including electrophoresis, purification and sequential analysis of the tryptic peptide, identified the abnormal haemoglobin as haemoglobin D Punjab (beta 121 Glu-Gln). This is the first report of this haemoglobin variant in Austria. Various possible modes of geographical spreading of the gene from Punjab (India) are discussed, the land-route via Turkey being the most favourable hypothesis in this case. An investigation of 6 out of 7 living members of the family was undertaken. In 3 instances haemoglobin D Punjab was confirmed by HPLC and electrophoresis. The investigation of the family is currently being expanded to include a total of five generations.

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.

Glucose-stimulated insulin secretion was assessed in relation to the DNA polymorphism flanking the insulin gene in 16 women who had had gestational diabetes. When not pregnant they were studied by a Constant Glucose Infusion for 1 hr with Model Assessment (CIGMA). The patients with either heterozygous 1/3 alleles or homozygous 1/1 or 3/3 alleles in the 5' flanking region of the insulin gene had similar plasma insulin and C-peptide concentrations and similar estimates of beta-cell function. This suggests that the large DNA insert (Class 3 allele) near the insulin gene does not directly affect insulin secretion. The association of polymorphisms with Type 2 diabetes may be due to linkage disequilibrium with other disease-related alleles.

We evaluated glucose tolerance during the first year postpartum in 113 women with gestational diabetes mellitus (GDM) diagnosed according to the criteria of the First International Workshop-Conference on GDM and the National Diabetes Data Group. The high incidence of abnormal postpartum glucose tolerance (38% "diabetes mellitus" plus 19% "impaired glucose tolerance") was correlated with certain of the heterogeneous characteristics of the population at the time of antepartum diagnosis. Virtually all women with antepartum fasting plasma glucose (FPG) greater than or equal to 130 mg/dl (GDM class B1) remained abnormal postpartum (21/22 [95%]), which suggests that this group may include women with preexisting glucose intolerance unrecognized before pregnancy. In the remainder, those with FPG greater than or equal to 105-129 mg/dl (GDM class A2) were more likely to be abnormal postpartum than those with FPG less than 105 mg/dl (GDM class A1). Within the A1 and A2 groups, increasing maternal age, relative insulinopenia, and hyperglycemia at 2 h during antepartum OGTT were also associated with a greater likelihood of abnormal glucose tolerance postpartum. The presence of HLA-DR3 and/or -DR4 antigens was not predictive of the status of glucose tolerance during the first year postpartum, although the increased frequency of cytoplasmic islet cell antibodies in A2 and B1 subjects was associated with a high incidence of abnormal postpartum glucoregulation. The high incidence of abnormal postpartum glucose tolerance in all GDM classes makes a compelling case for careful, early, and continuing follow-up of all women with a diagnosis of GDM.(ABSTRACT TRUNCATED AT 250 WORDS)

An intensive screening programme for potential diabetics in pregnancy was conducted in the University Department of Obstetrics and Gynaecology, Kandang Kerbau Hospital, Singapore, from June 1978 to December 1980. All patients with one or more risk factors for potential diabetes underwent an oral glucose tolerance tests (OGTT) with 50 g glucose loads. An abnormal OGTT was defined as one in which the second hour venous plasma glucose value was 7.8 mmol/1 (140 mg%) or more. In a group of 789 Chinese patients aged between 20 and 40 years, the overall detection rate of abnormal OGTTs was 15.5%. A significantly high proportion of abnormal OGTTs was found in patients with a direct family history of diabetes associated with random glycosuria during pregnancy and those with a previous history of 2 or more consecutive spontaneous abortions. However, in view of the relatively low detection rate of abnormal OGTTs in pregnant potential diabetics, a preliminary blood screening test would be useful to select those patients who require full OGTTs.

Fetal growth and development are dependent upon the growth and development of the placenta. Control of placental growth and development is little understood. Immunoreactive insulin-like growth factor-I and -II (IGF-I and IGF-II) have been shown to be released by human placental tissue and human placental membranes have been observed to contain specific receptors for these growth factors. Furthermore, we have demonstrated the presence of IGF-II mRNA transcripts in the developing human placenta and at gestational term in placentae of diabetics. Thus, the IGFs may have a regulatory role in the growth and development of the placenta via autocrine and/or paracrine mechanism(s) of action. In this report we demonstrate the presence of four differing size species of placental poly(A)+ RNA which specifically hybridize to an IGF-I probe originally isolated from an adult human liver cDNA library and localize IGF-I and IGF-II mRNA to syncytiotrophoblasts and fibroblasts, respectively, of the placenta by in situ hybridization. The major transcript is 7500 bases in size and the remaining three transcripts are 5000, 1100, and 900 bases in length with no apparent changes from these sizes throughout gestation and at term in diabetics. Quantification by densitometry of placental IGF-I mRNA detected by dot blot hybridization indicated that first and second trimester placentae each express more IGF-I mRNA relative to that expressed in placenta at term. These results suggest that there are developmental changes in the relative amount of IGF-I mRNA expressed in the human placenta. IGF-I is, therefore, most likely important early in gestation as a placental growth factor. This time period is critical for fetal development and growth, when embryonic induction, organogenesis, and rapid cell proliferation occur.

We have examined gravida with gestational diabetes mellitus (GDM), as defined by the National Diabetes Data Group (Diabetes 1979; 28:1039), for phenotypic and genotypic heterogeneity. Fasting plasma glucose (FPG) at diagnosis was used for further stratification of GDM according to putative metabolic severity into class A1 (FPG less than 105 mg/dl [N = 129]), class A2 (FPG 105-129 mg/dl [N = 47]), and class B1 (FPG greater than or equal to 130 mg/dl [N = 23]). All GDM classes tended to be older and heavier than consecutive gravida with documented normal glucose tolerance (controls, N = 148). Subdivision into "lean" and "obese" indicated that plasma immunoreactive insulin (IRI) was greater after overnight fast in the obese of all groups except B1. However, absolute increases in IRI above fasting levels in response to glucose during OGTT were significantly enhanced by obesity only in class A2 gravida. Adjustment for the effects of age and weight by covariate analysis indicated that the IRI response to glycemic stimulation is usually attenuated in all forms of GDM. Mean values for increases in IRI above fasting values during the first 15 min and IRI increments relative to the increases in plasma glucose throughout the 180-min OGTT were below control values in all GDM groups and progressively so, i.e., A1 less than A2 less than B1. The absolute insulinopenia was not invariable; a small number of gravida from all GDM groups displayed well-preserved IRI responses to oral glucose. Genotypic evaluation of the GDM population disclosed an increased occurrence of "markers" known to be associated with type I diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Restriction fragment length polymorphisms in the insulin gene hypervariable region are compared among 93 women with gestational onset diabetes mellitus and 146 women with normal glucose tolerance during pregnancy. No significant differences in gene or genotype frequencies were observed in the overall sample (p greater than 0.50). However, an increased frequency of one allele (class 1) was observed among nonoverweight patients with gestational onset diabetes mellitus with elevated fasting plasma glucose levels compared with age-, race-, and parity-matched control subjects (p = 0.061). These data suggest that gestational onset diabetes mellitus is a heterogeneous disorder with respect to both genotypic and phenotypic characteristics, and that restriction fragment length polymorphisms near the insulin gene may serve as a molecular marker for susceptibility to gestational onset diabetes mellitus only in some women.