GCK monogenic diabetes and gestational diabetes: possible diagnosis on clinical grounds.

AIM: To determine if the previously published clinical criteria for identifying glucokinase monogenic diabetes [GCK gene mutation in maturity-onset diabetes of the young (GCK-MODY)], an elevated antenatal fasting blood glucose of 5.5-8.0 mmol/l, an increment of < 4.6 mmol/l at 2 h in an oral glucose tolerance test and slim are applicable in a large multi-ethnic cohort of women with gestational diabetes. METHODS: We analysed de-identified data from all women with gestational diabetes, diagnosed using the Australasian Diabetes in Pregnancy Society (1998) Australian criteria at our institution between 1993 and 2013, making comparisons among those with complete antenatal data including: diagnostic oral glucose tolerance test results meeting the above criteria; pregestational BMI; birth outcomes; and postpartum oral glucose tolerance test data. We categorized these women into two groups: Group A1 had a BMI ≤ 21 kg/m(2) and Group A2 had a BMI > 21 kg/m(2) and < 25 kg/m(2). RESULTS: Of the 302 women meeting the study entry criteria, we had complete data including a postpartum oral glucose tolerance test result for 171 women: 54 in Group A1 and 117 in Group A2. Ethnicity was significantly different between the groups. The oral glucose tolerance test and postpartum HbA1c results identified few women ( < 14%) in Group A1 and Group A2 who still had 'possible GCK-MODY'. CONCLUSIONS: Our findings indicate that previously recommended clinical criteria for the identification of women likely to have GCK-MODY lack specificity in a cohort of women with multi-ethnic backgrounds. Using these criteria to select women for testing for GCK-MODY in pregnancy would therefore be costly and is likely to yield few women positive for this condition.

Does the presence of thyroid antibodies affect the course and outcome of pregnancy in type 1 diabetic women?

OBJECTIVE: The aim of the study was to evaluate the significance of the presence of thyroid peroxidase autoantibodies (anti-TPO Abs) in type 1 diabetes mellitus (DM1) pregnant women relative to the course of pregnancy and, especially, with regard to metabolic control, thyroid function, maternal complications and neonatal outcome. METHODS: In a prospective observational study of 91 DM1 women with singleton pregnancies, anti-TPO, anti-thyroglobulin, thyroid-stimulating hormone (TSH), and free thyroxine index (T4/thyroid binding capacity) were measured in each trimester. At each visit, HbA1c, body mass index, and units of insulin per kilogram were recorded, as were complications and pregnancy outcome. RESULTS: Twenty-one (27%) of the 78 women who met the inclusion criteria presented with positive anti-TPO Abs. There were no differences regarding glycemic control (HbA1c) or insulin dose. First-trimester TSH levels were significantly higher in the anti-TPO-positive group than in the anti-TPO-negative group. Finally, no differences were observed regarding diabetic or obstetric complications and neonatal outcome. CONCLUSION: One fourth of DM1 pregnant women presented with positive anti-TPO Abs. However, the presence of anti-TPO Abs does not seem to be related with worse metabolic control or adverse pregnancy outcome. Further investigation is needed; meanwhile, the effort for early treatment of thyroid dysfunction and strict metabolic control in all DM1 women should be continued.

Glucokinase Deficit Prevalence in Women With Diabetes in Pregnancy: A Matter of Screening Selection.

Introduction: The prevalence among pregnant women with diabetes of monogenic diabetes due to glucokinase deficit (GCK-MODY) varies from 0 to 80% in different studies, based on the chosen selection criteria for genetic test. New pregnancy-specific Screening Criteria (NSC), validated on an Anglo-Celtic pregnant cohort, have been proposed and include pre-pregnancy BMI <25 kg/m2 and fasting glycemia >99 mg/dl. Our aim was to estimate the prevalence of GCK-MODY and to evaluate the diagnostic performance of NSC in our population of women with diabetes in pregnancy. Patients and Methods: We retrospectively selected from our database of 468 diabetic pregnant patients in Sant'Andrea Hospital, in Rome, from 2010 to 2018, all the women who received a genetic test for GCK deficit because of specific clinical features. We estimated the prevalence of GCK-MODY among tested women and the minimum prevalence in our entire population with non-autoimmune diabetes. We evaluated diagnostic performance of NSC on the tested cohort and estimated the eligibility to genetic test based on NSC in the entire population. Results: A total of 409 patients had diabetes in pregnancy, excluding those with autoimmune diabetes; 21 patients have been tested for GCK-MODY, 8 have been positive and 13 have been negative (2 of them had HNF1-alfa mutations and 1 had HNF4-alfa mutation). We found no significant differences in clinical features between positive and negative groups except for fasting glycemia, which was higher in the positive group. The minimum prevalence of monogenic diabetes in our population was 2.4%. The minimum prevalence of GCK-MODY was 1.95%. In the tested cohort, the prevalence of GCK-MODY was 38%. In this group, NSC sensitivity is 87% and specificity is 30%, positive predictive value is 43%, and negative predictive value is 80%. Applying NSC on the entire population of women with non-autoimmune diabetes in pregnancy, 41 patients (10%) would be eligible for genetic test; considering a fasting glycemia >92 mg/dl, 85 patients (20.7%) would be eligible. Discussion: In our population, NSC have good sensitivity but low specificity, probably because there are many GDM with GCK-MODY like features. It is mandatory to define selective criteria with a good diagnostic performance on Italian population, to avoid unnecessary genetic tests.

Caspase-8: a key role in the pathogenesis of diabetic embryopathy.

Maternal diabetes causes neural tube defects in embryos, which are associated with increased apoptosis in the neuroepithelium. Many factors, including effector caspases, have been shown to be involved in the events. However, the key regulators have not been identified and the underlying mechanisms remain to be addressed. Caspase-8, an initiator caspase, has been shown to be altered in diabetic embryopathy, suggesting a role as an upstream apoptotic regulator. Using mouse embryos as a model system, this study demonstrates that caspase-8 is required for the production of hyperglycemia-associated embryonic malformations. Caspase-8 was shown to be expressed in the developing neural tube. Its activity, as evidenced by enhanced cleavage, was increased by hyperglycemia. These changes were associated with increased formation of the active cleavage of Bid. Inhibition of caspase-8 activity in high glucose-challenged embryos reduced the rate of embryonic malformation and this was associated with decreased apoptosis in the neuroepithelium of the neural tube. Inhibition of caspase-8 activity also reduced hyperglycemia-induced Bid activation and caspase-9 cleavage. These data suggest that caspase-8 may control diabetic embryopathy-associated apoptosis via regulation of the Bid-stimulated mitochondrion/caspase-9 pathway.

Diabetic pregnancy in rats leads to impaired glucose metabolism in offspring involving tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 expression.

Population-based studies have shown that the offspring of diabetic mothers have an increased risk of developing obesity, insulin resistance, type 2 diabetes and hypertension in later life. To investigate mechanism for the high incidence of metabolic diseases in the offspring of diabetic mothers, we focused on the tissue-specific glucocorticoid regulation by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and studied offspring born to streptozotocin-induced diabetic rats. The body weights of newborn rats from diabetic mothers were heavier than those from control mothers. Offspring born to diabetic mothers demonstrated insulin resistance and mild glucose intolerance after glucose loading at 10 weeks and showed significantly increased 11beta-HSD1 mRNA and enzyme activity in adipose tissue at 12 weeks of age without obvious obesity. Hepatic 11beta-HSD1 mRNA was also elevated. We propose that the 11beta-HSD1 in adipose tissue and liver may play a key role in the development of metabolic syndrome in the offspring of diabetic mothers. Tissue-specific glucocorticoid dysregulation provides a candidate mechanism for the high incidence of metabolic diseases in the offspring of diabetic mothers. Therefore early analyses before apparent obesity are needed to elucidate the molecular mechanisms that may be programmed during the fetal period.

[Selenium and glutathion peroxidase enzyme levels in diabetic patients with early spontaneous abortions].

UNLABELLED: The incidence of spontaneous abortions in women with type 1 diabetes mellitus varies between 10-30%. The etiology of this is still unclear despite numerous experimental studies. Pregnancy is a condition of increased oxidative stress due to impaired balance between pro- and antioxidants. Glutathion and related enzymes perform the best antioxidant protection. Some authors point to a possible correlation between spontaneous abortions and low plasma Se levels as well as low intracellular activity of glutathion peroxidase enzyme. Others report that Hb A1-c, values over 1SD above normal increase the risk of spontaneous abortions with 3% and Hb A1-C values between 10-12% are critically high for the occurrence of spontaneous abortions. The purpose of the study was to evaluate the levels of Se and glutathion peroxidase enzyme (Gl-Px) in pregnant women with type 1 diabetes mellitus in the first trimester of pregnancy and to find out is there a correlation between glycemic control of diabetes and the incidence of spontaneous abortions. DESCRIPTION OF PROJECT: 75 pregnant women enrolled in an- 1 year prospective study divided in 3 groups according to pregnancy outcome: gr. 1 - n = 30 with type diabetes mellitus, no abortions, gr.2 - n = 16 with type diabetes mellitus with first trimester spontaneous abortion and gr. 3 - n = 29 healthy pregnant women. Women with type 1 diabetes mellitus were divided into three subgr. according to glycemic control - subgr. 1 - n = 12 (Hb A1-c < 7%), subgr.2 - n = 18 (Hb A1-c > 7< 8%), subgr.3 - n = 16 (Hb A1-c > 8%). Gl-Px activity was determined in Er hemolisate with test reagents of Randox Ransel, with ref.values 27.5 - 73 U/g Hb. Selen concentration was determined in whole blood sample by atomic absorption spectrophotometry with ref. values 0.12-1.1 micromol/l. HbA 1-C was measured by affinity chromatography with ref. values 4.5-6.3%. Statistical methods used were: dispersion, correlation analysis - SPSS package version 11.01.01. RESULTS: Basic Se levels were low in all pregnant women in early pregnancy. The metabolic control level did not influence the levels of Se in pregnant women with diabetes mellitus type1. Gl -Px activity was within the normal limits in all women. There was no correlation between Se levels and Gl -Px activity in pregnant diabetics with and without abortions. There was a correlation between Se levels and Gl -Px activity only in healthy pregnant women. Pregnant women with poor glycemic control had higher incidence of spontaneous abortions. CONCLUSIONS: We could not support the hypothesis of reduced antioxidant protection (low Se and Gl-Px levels) as a causative factor in the pathogenesis of spontaneous abortions in diabetic patients. Our study results showed that poor metabolic control of diabetes (high Hb A1-c) in the first trimester of pregnancy had a primary role in the occurrence of early abortions. We could speculate that the early hyperglycemic maternal-fetal environment most probably plays a role of an additional stress to the developing embryo.

Placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes: The effect of vitamin C and E supplementation.

AIM: In view of the increased rates of pre-eclampsia observed in diabetic pregnancy and the lack of ex vivo data on placental biomarkers of oxidative stress in T1 diabetic pregnancy, the aim of the current investigation was to examine placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes. A further objective of the study was to investigate the putative impact of vitamin C and E supplementation on antioxidant enzyme activity and lipid peroxidation in type 1 diabetic placentae. METHODS: The current study measured levels of antioxidant enzyme [glutathione peroxidase (Gpx), glutathione reductase (Gred), superoxide dismutase (SOD) and catalase] activity and degree of lipid peroxidation (aqueous phase hydroperoxides and 8-iso-prostaglandin F2α) in matched central and peripheral samples from placentae of DAPIT (n=57) participants. Levels of vitamin C and E were assessed in placentae and cord blood. RESULTS: Peripheral placentae demonstrated significant increases in Gpx and Gred activities in pre-eclamptic in comparison to non-pre-eclamptic women. Vitamin C and E supplementation had no significant effect on cord blood or placental levels of these vitamins, nor on placental antioxidant enzyme activity or degree of lipid peroxidation in comparison to placebo-supplementation. CONCLUSION: The finding that maternal supplementation with vitamin C/E does not augment cord or placental levels of these vitamins is likely to explain the lack of effect of such supplementation on placental indices including antioxidant enzymes or markers of lipid peroxidation.

Effects of maternal diabetes on the levels, synthetic rates and activities of synthetic enzymes of surface-active phospholipids in perinatal rat lung.

Streptozotocin-induced maternal diabetes in the rat has been found to reduce selectively the content and synthetic rates of disaturated phosphatidylcholine and lysophosphatidylcholine in the lungs of term fetuses. Furthermore, the elevations in these parameters which occur during normal pulmonary maturation between the final gestational day and the first neonatal day are abolished or markedly curtailed, resulting in significantly reduced levels and synthetic rates of surfactant and its immediate precursor in the neonatal lung. In addition, complete or partial inhibition of the perinatal developmental rise in the activities of key enzymes catalyzing de novo phosphatidylcholine synthesis in the lung, viz., cholinephosphate cytidylyltransferase and cholinephosphotransferase, and of enzymes catalyzing reacylation of unsaturated to disaturated phospholipid, viz., lysophosphatidic acid and lysophosphatidylcholine acyltransferases, has been observed, resulting in reduced activities of these enzymes in the neonate. The observed reductions in surface-active phospholipid synthesis in the lungs of offspring of diabetic mothers may be related to these lowered enzyme activities, as well as to deficiencies in carbohydrate precursors available for phospholipid synthesis, as reported in previous studies. It is suggested that the hyperinsulinemia manifested in fetuses of diabetic mothers opposes the tendency of corticosteroids to enhance surface-active phospholipid synthesis, resulting in pulmonary surfactant deficiency and thus the propensity for neonatal respiratory distress.

Placental alkaline phosphatase (PLAP) study in diabetic human placental villi infected with Trypanosoma cruzi.

Previous work has demonstrated that PLAP activity decreases in serum and placental villi from term chagasic and diabetic pregnant women. In vitro, T. cruzi induces changes in human syncytiotrophoblast's PLAP. Our aim was to determine if infection with T. cruzi induces changes in PLAP activity in diabetic and chagasic women's placenta, in order to elucidate if PLAP plays a role in the mechanisms of interaction between placenta and T. cruzi, and whether hyperglycemic conditions could worsen the placental infection. Using zymogrammes, Western blot, biochemical and immunohistological techniques, PLAP activity was determined in placental villi from diabetic and chagasic women, and in normal placentas cultured under hyperglycemic conditions with or without trypomastigotes. A significant reduction of PLAP expression was immunologically detected in infected diabetic and normal placental villi cultured under hyperglycemic conditions of 71 and 81%, respectively, compared with controls. A significant decrease of PLAP specific activity was registered in homogenates and in the culture media from both infected diabetic and normal placentas under hyperglycemic conditions (of about 50-70%), and in chagasic ones (of about 87%), when compared with controls. Thus, PLAP might be involved in parasite invasion and diabetic and hyperglycemic placentas could be more susceptible to T. cruzi infection.

Oxidative stress promotes the increase of matrix metalloproteinases-2 and -9 activities in the feto-placental unit of diabetic rats.

Maternal diabetes increases the risk of congenital malformations, placental dysfunction and diseases in both the neonate and the offspring's later life. Oxidative stress has been involved in the etiology of these abnormalities. Matrix metalloproteases (MMPs), involved in multiple developmental pathways, are increased in the fetus and placenta from diabetic experimental models. As oxidants could be involved in the activation of latent MMPs, we investigated a putative relationship between MMPs activities and oxidative stress in the feto-placental unit of diabetic rats at midgestation. We found that H2O2 enhanced and that superoxide dismutase (SOD) reduced MMPs activities in the maternal side of the placenta and in the fetuses from control and diabetic rats. MMPs were not modified by oxidative status in the fetal side of the placenta. Lipid peroxidation was enhanced in the maternal and fetal sides of the placenta and in the fetus from diabetic rats when compared to controls, and gradually decreased from the maternal placental side to the fetus in diabetic animals. The activities of the antioxidant enzymes SOD and catalase were decreased in the maternal placental side, catalase activity was enhanced in the fetal placental side and both enzymes were increased in the fetuses from diabetic rats when compared to controls. Our data demonstrate changes in the oxidative balance and capability of oxidants to upregulate MMPs activity in the feto-placental unit from diabetic rats, a basis to elucidate links between oxidative stress and alterations in the developmental pathways in which MMPs are involved.

[Effect of lipid peroxidation and antioxidant defence system on the development of hemorrhagic complications in neonates of mothers with diabetes mellitus].

217 postmortem protocols of autopsies have been analyzed to study percentage of hemorrhagic complications. The analyzes allowed to determine frequency and localization hemorrhages happened in children bourn by mothers suffering from diabetes mellitus. The most detected localizations of hemorrhages are follows: ependyma (38.8%), ventricles of brain (30.8%), parenchyma of brain (30.8%) as well as frequently have been observed pleura, epicardium and adrenal glands hemorrhages.

S6K1 controls pancreatic ß cell size independently of intrauterine growth restriction.

Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of ß cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased ß cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic ß cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore ß cell size or insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic ß cell lesion. Consistent with this hypothesis, reexpression of S6K1 in ß cells of S6K1-/- mice restored embryonic ß cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic ß cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced ß cell growth and eventual development of T2DM later in life.

Alteration of phosphotyrosine phosphatase activity in tissues from diabetic and pregnant rats.

Membrane-associated tyrosine phosphatase activities were studied in two distinct states of insulin resistance: diabetes and pregnancy. Using a novel immunoenzymatic assay with intact insulin-like growth factor-I (IGF-I) and insulin receptors as substrates, we show that phosphotyrosine-protein phosphatases (PTP-ases) from normal rat tissues induce a decrease in tyrosine phosphorylation of both receptors. Membrane fractions from kidney, brain, and liver contain the highest PTP-ase activity toward the insulin receptor. After 20-day streptozotocin-induced diabetes, PTP-ase activities are increased by 70% in the placenta, reduced by 40-50% in liver and skeletal muscle, and remained unchanged in the nonclassical insulin target tissues, kidney and brain. In general, the dephosphorylation of IGF-I receptor follows a pattern similar to that of insulin receptor except in red skeletal muscle in which it is not modified. Pregnancy also induces alterations of liver PTP-ases similar to those elicited by diabetes with a 50% reduction of insulin and IGF-I receptor dephosphorylation. This effect of pregnancy is further potentiated by diabetes. The alterations in the activity of hepatic PTP-ases from diabetic and pregnant rats are associated with a decreased autophosphorylation of the insulin receptor, suggesting that the diminution of phosphatase activity might be associated to the state of receptor phosphorylation and activation. Our data demonstrate that alterations of PTP-ases in insulin target tissues are found in two insulin-resistant states, one characterized by hyperinsulinemia, pregnancy and one by insulinopenia, streptozotocin-diabetes. These observations suggest a possible relationship between the defective activity of receptor tyrosine kinases and membrane-associated phosphatases from insulin responsive tissues.

Na(+)/K(+)-ATPase activity and expression in syncytiotrophoblast plasma membranes in pregnancies complicated by diabetes.

Many of the transport processes across the syncytiotrophoblast (ST), such as amino acid transport, are Na(+)-coupled. The maintenance of a low intracellular Na(+) concentration by Na(+)/K(+)-ATPase is therefore crucial for placental transport of nutrients and consequently, foetal growth. In pregnancies complicated by diabetes foetal growth is often accelerated despite rigorous glycemic control of the mother, however the underlying mechanisms are not fully understood. We tested the hypothesis that Na(+)/K(+)-ATPase in ST plasma membranes is up-regulated in diabetic pregnancies associated with accelerated growth. ST microvillous (MVM) and basal (BM) plasma membranes were purified from term placentas of normal pregnancies (control, n=13) and pregnancies complicated by insulin-dependent diabetes mellitus (n=7) or gestational diabetes (n=6). All mothers with diabetes gave birth to large for gestational age babies. The Na(+)/K(+)-ATPase alpha(1)-subunit protein expression (Western blot) in MVM and BM was unaltered by diabetes. Na(+)/K(+)-ATPase activity (K(+)-stimulated, ouabain-sensitive phosphatase activity) in ST plasma membranes was not affected by diabetes. This is the first study of Na(+)/K(+)-ATPase in ST membranes of the human placenta in diabetes. Our data show that accelerated foetal growth in diabetic pregnancies is not associated with elevated ST Na(+)/K(+)-ATPase protein expression or activity.

ATP dependent Ca2+ transport across basal membrane of human syncytiotrophoblast in pregnancies complicated by intrauterine growth restriction or diabetes.

Neonates born after pregnancies complicated by diabetes or intrauterine growth restriction (IUGR) have increased incidence of hypocalcaemia. Furthermore, IUGR is associated with reduced bone mineralization in infancy and osteoporosis in adult life. We tested the hypothesis that placental calcium transport is altered in these pregnancy complications. Transport of calcium into syncytiotrophoblast basal plasma membrane (BM) vesicles was studied by rapid filtration and protein expression of Ca(2+) ATPase by Western blot. In IUGR Ca(2+) ATPase activity was increased by 48 per cent (n=13; P< 0.05) whereas protein expression was 15 per cent lower (n=13; P< 0.05) than in controls (n=16). Basal membrane ATP dependent calcium transport was unaltered in gestational diabetes (GDM) but increased by 54 per cent in insulin dependent diabetes (IDDM) compared to controls (P< 0.05; n =14). Diabetes did not affect Ca(2+) ATPase expression in BM. We have previously shown that the mid-molecular fragment of parathyroid hormone related peptide (PTHrP midmolecule) stimulates BM Ca(2+) ATPase in vitro. PTHrP midmolecule concentrations in umbilical cord plasma were measured using radioimmunoassay. The concentrations in umbilical cord plasma were increased in IUGR, but unaltered in diabetes. In conclusion, placental calcium pump is activated in IUGR and IDDM, which may be secondary to increased foetal calcium demand. We speculate that PTHrP midmolecule may be one mechanism for activating BM Ca(2+) ATPase in IUGR.

Hexokinase isoenzymes in the rat placenta.

The phosphorylation of glucose to glucose-6-phosphate, the first enzymatic step for glucose utilization is catalysed by a family of four hexokinase isoenzymes (HKI-IV) which display a tissue-specific distribution. The expression of HK isoenzymes was investigated in the rat placenta. High levels of HKI and HKII mRNA were found in the junctional and the labyrinthine zones. HKIII mRNA was present at low levels in the junctional zone and glucokinase (HKIV) mRNA was not detected, indicating that HKI and HKII are the two major placental HK isoenzymes. HKII activity was increased in placenta of insulinopenic diabetic rats. This regulation is likely to support the increase in glucose utilization and storage characteristics of the enlarged placentae of diabetic rats.

Changes in activity of enzymes related to glycolysis, gluconeogenesis and lipogenesis in placentae from diabetic women.

The activity of enzymes with a regulatory function in the pathways of glycolysis, gluconeogenesis and NADP-generation was investigated in 50 placentae from normal pregnancies and deliveries, 23 placentae from women with gestational diabetes, and 12 placentae from insulin-dependent patients. In placentae from the gestational diabetic group, the activity of pyruvate kinase and of NADPH-generating enzymes was raised and the activity of enzymes connected to glucogenesis was unchanged. These alterations were attributed to the oversupply of glucose and insulin to morphologically normal and well-oxygenated placental tissue. In the placentae from the insulin-dependent group, the activity of pyruvate kinase was reduced, the activity of NADPH-generating enzymes was enhanced and the activity of those related to the gluconeogenesis was unchanged. It is suggested that this pattern of enzyme changes reflects a reduction in the glycolytic capacity in these placentae, which may be due to inhibition by products of enhanced fatty acid oxidation in diabetes, amino acids and/or by long-term anoxia as a result of uteroplacental circulatory disturbances. The possible relation of reduced energy-forming capacity of the placenta in diabetes to its transport function is discussed.

Further studies on acid phosphatase in obese subjects.

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.

Phosphotyrosine-protein-phosphatase and diabetic disorders. Further studies on the relationship between low molecular weight acid phosphatase genotype and degree of glycemic control.

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.

Increased neutrophil activation in diabetic pregnancy and in nonpregnant diabetic women.

Human neutrophil elastase may be a mediator of vascular damage, and enhanced neutrophil reactivity could contribute to the susceptibility of pregnant diabetic women to vascular complications. Elevated plasma levels of neutrophil elastase will reflect neutrophil activation in vivo. The aim of this study was to determine whether neutrophil activation occurs in uncomplicated diabetic pregnancy. We studied 30 normal nonpregnant women, 20 nonpregnant diabetic women, 32 nondiabetic women with normal pregnancies, and 17 insulin-requiring pregnant diabetic patients. Plasma neutrophil elastase was measured by radioimmunoassay. There was a significantly higher concentration of plasma neutrophil elastase in normal pregnant women compared with the nonpregnant group (P less than .001). The nonpregnant diabetic group had significantly higher concentrations than the normal nonpregnant group (P less than .002). The pregnant diabetic group had significantly higher concentrations than the nonpregnant diabetic group (P less than .001) and the normal pregnant group (P less than .05). The high concentrations of plasma neutrophil elastase may contribute to the greater sensitivity of pregnant diabetic patients to vascular complications.