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U J Eriksson

Publications and source records attributed to U J Eriksson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Insulin treatment fails to abolish the teratogenic potential of serum from diabetic rats.

Maternal diabetes during pregnancy constitutes an increased risk for congenital malformations in the offspring. Previous studies have identified several serum components with teratogenic activity, e.g. glucose and beta-hydroxybutyrate, but have also suggested that the teratogenic influence of the diabetic environment on the developing embryo is multifactorial and may depend upon changed concentrations of several maternal metabolites. In the present investigation we aimed to assess the teratological impact of small, concomitant alterations in a series of metabolites, particularly those not previously identified as teratogens. We thus investigated the influence of a mild diabetic environment by culturing gestational day-9 rat embryos in serum from insulin-treated diabetic rats for 48 h in vitro, and compared the embryonic outcome with that obtained after culture in normal serum and in serum from manifestly diabetic rats without insulin treatment. The glucose concentration was adjusted to 10 or 30 mmol/l in the cultures, and the embryos were evaluated with respect to crown-rump length, protein and DNA content, number of somites and malformation score (comparing major, minor or no malformations). We found that increased glucose levels caused embryonic maldevelopment in both normal and diabetic serum, and that despite normalization of the diabetic state, the serum from the insulin-treated diabetic rats caused more growth retardation than the nondiabetic control serum. The normalized diabetic serum was also more teratogenic than the normal serum at the low glucose concentration, whereas the serum from the manifestly diabetic rats tended to cause more dysmorphogenesis at 30 mmol/l glucose than both the normal and normalized diabetic serum. The results suggest that the teratogenicity of maternal serum in diabetic pregnancy is not mediated exclusively by increased concentrations of glucose and ketone bodies. The efforts to diminish the teratogenic effects of a diabetic environment should therefore include normalization of a multitude of serum factors, including glucose and ketone bodies.

3-Hydroxybutyric Acid↗
PubMed1996

Pregnant diabetic rats fed the antioxidant butylated hydroxytoluene show decreased occurrence of malformations in offspring.

The increased incidence of congenital malformations in diabetic pregnancy may be associated with an excess of free oxygen radicals in the embryo. We have previously blocked the dysmorphogenesis of rat embryos exposed to high glucose and beta-hydroxybutyrate concentrations in vitro by increasing the antioxidant capacity of the conceptus. In the present study, we attempted to diminish the teratogenic process in vivo in a rat model of diabetic pregnancy. Thus, pregnant diabetic and normal rats were fed either a standard diet or a diet enriched with 1% of the antioxidant butylated hydroxytoluene (BHT). The fetuses of the diabetic rats were smaller than the fetuses of the normal rats (body weight 2.70 g vs. 3.68 g) when the mothers were fed a standard diet. The BHT diet increased the fetal weight in the offspring of diabetic rats (3.17 g), with no change in fetuses of the normal rats (3.65 g). The placentas of diabetic rats were heavier than the placentas of normal rats; this difference was not present in the BHT-fed rats. The BHT treatment had no effect on the rate of resorptions, which was increased in the diabetic rats compared with the normal rats. In contrast, the increased rate of congenital malformations in the offspring of diabetic rats (19%), compared with that in the normal rats (0%), was markedly decreased by the BHT diet (2.3%). No malformations were found in the normal rats treated with BHT. These data support the notion that an excess of free oxygen radicals in the embryo contributes to the teratogenic process of diabetic pregnancy and, thus, suggest an area for future preventive therapeutic treatment.

Animals↗
PubMed1996

Altered levels of scavenging enzymes in embryos subjected to a diabetic environment.

Maternal diabetes during pregnancy is associated with an increased rate of congenital malformations in the offspring. The exact molecular etiology of the disturbed embryogenesis is unknown, but an involvement of radical oxygen species in the teratological process has been suggested. Oxidative damage presupposes an imbalance between the activity of the free oxygen radicals and the antioxidant defence mechanisms on the cellular level. The aim of the present study was to investigate if maternal diabetes in vivo, or high glucose in vitro alters the expression of the free oxygen radical scavenging enzymes superoxide dismutase (CuZnSOD and MnSOD), catalase and glutathione peroxidase in rat embryos during late organogenesis. We studied offspring of normal and diabetic rats on gestational days 11 and 12, and also evaluated day-11 embryos after a 48 hour culture period in 10 mM or 50 mM glucose concentration. Both maternal diabetes and high glucose culture caused growth retardation and increased rate of congenital malformations in the embryos. The CuZnSOD and MnSOD enzymes were expressed on gestational day 11 and both CuZnSOD, MnSOD and catalase were expressed on day 12 with increased concentrations of MnSOD transcripts when challenged by a diabetic milieu. There was a good correlation between mRNA, protein, and activity levels, suggesting that the regulation of these enzymes occurs primarily at the pretranslational level. Maternal diabetes in vivo and high glucose concentration in vitro induced increased MnSOD expression, concomitant with increased total SOD activity, and a tentative decrease in catalase expression and activity in the embryos. These findings support the notion of enhanced oxidative stress in the embryo as an etiologic agent in diabetic teratogenesis.

Animals↗
PubMed1995

Altered mitochondrial morphology of rat embryos in diabetic pregnancy.

BACKGROUND: Previous studies in vivo and in vitro have suggested that the oxidative metabolism of the embryo may have a role in the teratogenicity of diabetic pregnancy. In particular, the production of reactive oxygen species by the embryonic mitochondria has been implicated in the teratological process. The induction of congenital malformations by the diabetic milieu occurs during the early embryonic development. The present study aimed to estimate the role of the embryonic mitochondria in the teratological process of diabetic pregnancy by studying mitochondrial morphology in the embryos exposed to a diabetic environment in vivo or in vitro during early organogenesis and late fetal development. METHODS: For studies in vivo embryos of control or streptozotocin-diabetic rats were taken at gestational days 9-11 and subjected to light and electron microscopical analysis. The brain, heart, and liver of day-15 fetuses were also observed. For studies in vitro day-9 embryos of normal rats were cultured in a whole-embryo culture system for 48 hours. The culture media were supplied with high concentration of diabetes-related substrates and metabolites, and their effect on structure of embryonic neuroepithelial cells determined. RESULTS: The light microscopical observations demonstrated numerous cytoplasmic vacuoles in the ectoderm of day-9 embryos and in the neuroepithelium and blood cells of day-10 and day-11 embryos of diabetic rats. Ultrastructurally, these vacuoles were found to be mitochondria undergoing large-amplitude swelling with loss of matrix density and disturbed cristae. In contrast, no mitochondrial differences were found in the brain, heart, and liver, when day-15 fetuses from normal and diabetic rats were compared. Ultrastructural analysis of day-9 embryos cultured for 48 hours in the presence of high concentrations of D-glucose, pyruvate, beta-hydroxybutyrate, and alpha-ketoisocaproate also showed high-amplitude mitochondrial swelling in the neuroepithelium. The mitochondrial swelling was, however, not found in embryos cultured in a high concentration of L-glucose, excluding simple osmotic effects of the diabetes-related substrates and metabolites. CONCLUSIONS: The mitochondrial morphological changes appeared in embryos subjected to a diabetic environment during a time period when the congenital malformations in diabetic pregnancy are induced. The results support the notion that embryonic mitochondria are involved in the teratological process of diabetic pregnancy.

Animals↗
PubMed1995

Prevention of diabetes-associated embryopathy by overexpression of the free radical scavenger copper zinc superoxide dismutase in transgenic mouse embryos.

OBJECTIVES: It has recently been suggested that oxygen free radicals are involved in the high incidence of fetal dysmorphogenesis that is associated with diabetic pregnancies. The purpose of the current investigation was to study the effect of copper zinc superoxide dismutase, a free radical scavenging enzyme, on the prevention of diabetes-associated embryopathy in mice. STUDY DESIGN: Mice used in this study were either transgenic, bearing the human copper zinc superoxide dismutase gene, or nontransgenic controls. Diabetes was generated by streptozotocin administration on days 6 and 7 of gestation. Hyperglycemia developed on day 8 and was maintained through day 10 (critical period of organogenesis). On day 10 fetuses were examined for external anomalies, and their crown-rump lengths and deoxyribonucleic acid content were determined. RESULTS: Induction of maternal diabetes produced a significant reduction in mean crown-rump length of control embryos (4.48 +/- 0.7 mm vs 3.65 +/- 0.6 mm, p = 0.0001), whereas transgenic embryos were not affected (4.72 +/- 0.6 mm vs 4.45 +/- 0.8 mm, p > 0.05). After induction of diabetes fetal loss and malformation rates were significantly higher in control embryos (6.0% vs 23.8% and 8.4% vs 16.5%, respectively). Transgenic embryos were practically unaffected by diabetes and showed fetal loss and malformation rates of 5.9% and 4.4%, respectively, after induction of diabetes. CONCLUSIONS: Elevated levels of copper zinc superoxide dismutase, a key enzyme in the metabolism of free oxygen radicals, elicit a protective effect against diabetes-associated embryopathy.

Analysis of Variance↗
PubMed1995

Correlations between maternal metabolism and deranged development in the offspring of normal and diabetic rats.

In an attempt to define the pathogenesis of congenital malformations in diabetic pregnancy, a number of serum factors were determined in normal and diabetic pregnant rats and correlated to the outcome of gestation with the aid of multivariate linear regression analysis. The animals were from two different lines of Sprague-Dawley rats with documented differences in rates of fetal dysmorphogenesis in diabetic pregnancy. The diabetic rats increased less in body weight than the normal rats, yet displayed increased liver and kidney weights. The serum concentrations of glucose, beta-hydroxybutyrate, triglycerides, the branched-chain amino acids, and asparagine, proline, alanine, citrulline, tyrosine, and ornithine were increased by diabetes. In contrast, IGF-I, glutamic acid, glutamine, cystine, and lysine were decreased in the serum of the diabetic pregnant rats. The maternal metabolic imbalance exerted profound effects on embryonic development. Thus, the embryos of the diabetic rats were smaller, had fewer somites, and contained less DNA and protein than the control embryos. In addition, the resorption and malformation rates were increased in the embryos of the diabetic rats. The regression analysis of the data revealed significant interrelationships between adverse embryonic outcome (rates of malformations and resorptions) and the maternal serum concentrations of glucose, triglycerides, beta-hydroxybutyrate, branched-chain amino acids, and creatinine. This suggests that the maternal metabolism of the three major classes of nutrients covariates with the embryonic development in diabetic rat pregnancy. The monitoring of only one of these maternal parameters, e.g. the serum glucose concentration, may therefore not adequately predict the developmental status of the offspring. Our results suggest that the pathogenesis of fetal malformations in diabetic pregnancy is multifactorial. Thus, maintaining metabolites from all nutrient classes at a normal level may be important in preventing adverse fetal outcome.

Animals↗
PubMed1995

Diabetes in pregnancy: uterine blood flow and embryonic development in the rat.

The uterine blood flow to individual implantation sites was evaluated in early normal and diabetic rat pregnancy, and related to maternal metabolic state, length of gestation, and embryonic outcome. The aim was to search for a possible coupling between the flow rate and embryonic development. We studied pregnant rats of a malformation-prone Sprague-Dawley strain on gestational d 9, 10, 11, and 12, a time period which roughly corresponds to postconception wk 3-6 in human gestation. The blood flow in the uterus was estimated with the aid of a microsphere technique, and the embryos were evaluated with respect to morphology and uterine position. We found increased blood flow in the uterine and decidual tissue of the pregnant diabetic animals compared with normal pregnant rats on all days studied. The blood perfusion peaked on gestational d 10, both in normal and diabetic pregnancy. The implantations tended to be fewer, whereas the resorption and malformation rates were higher, in the left horn than in the right horn. The blood flow in the uterine and decidual tissues was increased in the left horn in diabetic d 10 tissue, as well as d 12 tissues, thereby suggesting that compromised embryonic development is associated with increased rather than decreased supply of nutrients to the implantation site. These findings are in concert with previous in vitro results suggesting that enhanced oxidative stress due to increased substrate availability is an important factor in diabetic teratogenesis.

Animals↗
PubMed1994

Ornithine decarboxylase activity and concentrations of polyamines in embryos of diabetic rats.

Previous studies have demonstrated high concentrations of polyamines in neoplastic tissue and embryos and these compounds are therefore believed to play a role in cellular growth and embryonic development. Maternal diabetes causes embryonic dysmorphogenesis and alterations in embryonic polyamine concentrations may contribute to this process. In the present study we have measured the contents of DNA, putrescine, spermidine and spermine in embryos on days 10 and 11 of gestation in normal and diabetic rats. We also estimated the activity of ornithine decarboxylase (ODC) in embryos on days 9-11. We found that maternal diabetes causes delayed growth as reflected by decreased content of DNA on day 11 in the embryos of the diabetic group. Both the polyamine content and ODC activity were altered in the embryos of diabetic rats. Thus, the polyamines were increased on day 10 and decreased on day 11, and the ODC activity was decreased in a down-regulated manner in day-10 embryos of the diabetic rats. These findings suggest that polyamine metabolism is involved in the dysmorphogenesis of diabetic pregnancy.

Animals↗
PubMed1993

Increased lenticular aldose reductase activity and high incidence of congenital cataract in the offspring of diabetic rats.

In previous experimental studies we have found a 47% incidence of congenital cataracts among the fetuses of manifestly diabetic (MD) rats, and 4% of the offspring of normal (N) rats. The aim of the present study was to clarify the role of the sorbitol shunt in the pathogenesis of this congenital defect. Light microscopical evaluation of the fetal lenses revealed excessive formation of vacuoles in offspring of MD rats compared to N offspring. On gestational day 16 we found that aldose reductase (AR) activity was doubled in the lenses of fetuses of MD rats as compared to that of N fetuses. This difference as well as the net activity of AR declined in both groups during subsequent development. The sorbitol concentration was elevated more than ten-fold in the MD fetal lenses compared to N fetal lenses at all time points. The sorbitol concentration in both the MD and the N group decreased from day 16 to day 20 and increased again slightly on day 22. We conclude that the diabetic uterine milieu induces elevated AR activity and sorbitol formation in the fetal lens. This over-activity of the sorbitol shunt may produce metabolic and osmotic imbalances in the fetal lens, resulting in excessive vacuole formation and subsequent development of congenital cataract.

Aldehyde Reductase↗
PubMed1993

Diabetes in pregnancy: fetal macrosomia, hyperinsulinism, and islet hyperplasia in the offspring of rats subjected to temporary protein-energy malnutrition early in life.

The effect of temporary, severe protein-energy malnutrition in young female rats on the fetal and maternal outcome of subsequent pregnancy has been investigated. Female rats were fed a low-protein diet between 3 and 6 wk of age. During this period, growth was stunted, glucose tolerance impaired, and insulin secretory response to glucose almost absent. Upon refeeding normal diet, growth was resumed and glucose tolerance normalized, but a subnormal insulin secretory response to glucose and a reduced pancreatic B-cell mass persisted into adult life. During pregnancy, such rats had a glucose tolerance with wide excursions of the serum glucose concentrations and an exaggerated insulin secretory response compared with normal rats. The previously malnourished rats also expanded their B-cell mass during pregnancy to the level of normal rats. The incidence of fetal loss and malformations was not increased in the offspring of previously malnourished rats. At term, the viable offspring were heavier than those of normal rats and had an increased pancreatic insulin content and an increased pancreatic B-cell mass. It is concluded that temporary protein-energy malnutrition in young rats reduces the ability to increase insulin production to meet the needs of pregnancy. The capacity for glucose disposal is decreased and glucose and other nutrients are transferred to the fetus in increased amounts. This stimulates pancreatic B-cell growth and the development of macrosomia in the offspring, well recognized features of diabetic pregnancy. The long-term consequences of malnutrition are thus not restricted to the malnourished but may also be inflicted on subsequent generations.

Animals↗
PubMed1993

Diabetes and embryonic malformations. Role of substrate-induced free-oxygen radical production for dysmorphogenesis in cultured rat embryos.

The aim of this study was to evaluate the role of free-oxygen radicals in the embryonic maldevelopment of diabetic pregnancy. Rat embryos cultured in vitro during early organogenesis showed growth retardation and severe malformations after exposure to 50 mM glucose, 3 mM PYR, 10 mM HBT, or 3 mM KIC. Combinations of 25 mM glucose, 2.5 mM HBT, and 1 mM KIC also elicited embryonic growth retardation and malformations. The deleterious effects on embryonic development by all agents were alleviated by addition of SOD to the culture media, which yielded increased enzyme activity in the embryos and their membranes. The endogenous SOD activity also increased in embryos subjected to a high concentration of glucose or PYR in the culture medium. Addition of the mitochondrial PYR transport inhibitor CHC to the culture media blocked the dysmorphogenesis caused by glucose and PYR, but was without effect on the teratogenic actions of HBT and KIC. These findings implicate the embryonic mitochondria as a likely site for enhanced substrate-induced production of free-oxygen radicals mediating the teratogenic effect of a diabetic environment. In particular, the teratogenic process in diabetic pregnancy may depend on an increased production of free-oxygen radicals in immature embryonic mitochondria in response to a metabolic overload. This notion implies that every oxidative substrate entering the mitochondrial metabolism in excess may induce embryonic malformations and emphasizes the need for an extended metabolic surveillance of pregnant diabetic women. Consequently, optimal metabolic control should aim at normalizing the maternal serum concentrations of all possible oxidative substrates.

3-Hydroxybutyric Acid↗
PubMed1993

Maternal diabetes induces increased expression of extracellular matrix components in rat embryos.

The mechanisms responsible for the increased incidence of congenital malformations in offspring of diabetic mothers are poorly understood. Because the abnormal metabolic milieu of diabetes induces in the adult organism increased synthesis of basement membrane components, and these molecules play a prominent role in morphogenesis, we investigated whether maternal diabetes or high glucose levels disturb extracellular matrix synthesis in rat embryos. In gestational day 11 embryos, maternal diabetes induced a small but significant increase in laminin B1 (127 +/- 40% of control, mean +/- SD, P < 0.02) but not in fibronectin mRNA (101 +/- 26% of control). Day 12 embryos from diabetic mothers showed a larger increment in laminin B1 (179 +/- 91% of control, P < 0.02) and also an increase in fibronectin mRNA (172 +/- 73% of control, P < 0.02). A similar increase in the expression of fibronectin was observed in the kidneys and hearts of day 20 fetuses dissected from diabetic rats. High glucose levels mimicked in vitro the effects of maternal diabetes. Day 9 embryos cultured for 48 h in 50 mM D-glucose showed, akin to the day 11 embryos in vivo, an increase in laminin B1 mRNA (129 +/- 47% of control) and no changes in fibronectin mRNA (106 +/- 35% of control). The finding that maternal diabetes induces increased expression of extracellular matrix components in developing embryos establishes a link with the abnormalities occurring in the chronic complications of diabetes and proposes a new path of investigation for the mechanism of teratogenicity of the diabetic milieu.

Animals↗
PubMed1992

Development of rat embryos in culture media containing different concentrations of normal and diabetic rat serum.

In vitro culture of rodent embryos has been extensively used in the search for teratologic agents, with possible relevance to diabetic pregnancy. However, the high concentrations of rat serum added to the culture medium (approximately 75%) have raised concern that the teratogenic effects of some compounds may be attenuated or masked in this culture system and thereby forced the addition of pharmacological concentrations of the compounds (e.g., D-glucose and beta-hydroxybutyrate) to the medium. This issue has been examined in the present study where the effects of different concentrations of rat serum on growth and differentiation of rat embryos were recorded in cultures supplemented with increased concentrations of D-glucose and beta-hydroxybutyrate. The embryonic development was also evaluated after culture in medium supplied with serum from diabetic rats. Compared with normal rat serum, the diabetic serum had an elevated glucose concentration as well as markedly increased levels of triglycerides and branched amino acids, indicating a potentially rich supply of major nutrients for the cultured embryos. Lowering the serum concentration in the culture medium from 80% to 50% yielded progressively retarded embryonic growth but no increased rate of other morphological malformations. At 40% serum concentration, however, there was a sharp rise in the incidence of somatic malformations, in addition to the prevailing growth retardation. When the embryonic growth and development were compared at 50% and 80% serum concentrations, increased D-glucose or beta-hydroxybutyrate concentrations caused similar degrees of embryonic dysmorphogenesis. Also, the uptake of each compound by the embryos exposed to elevated levels of the two agents were similar in 50% and 80% serum cultures. There was, therefore, no protection against the teratogenic and growth-retarding effects of increased D-glucose or beta-hydroxybutyrate offered by high serum concentrations in the culture medium (i.e., 80% vs. 50%). Embryos cultured in 50% or 80% diabetic rat serum at 30 mmol/L or 50 mmol/L D-glucose concentration showed similar rates of somatic malformations as did embryos exposed to the same proportion of normal rat serum at similar glucose concentrations. By contrast, the diabetic rat serum amplified the general retarding effects of high D-glucose levels, yielding lower protein levels and somite numbers in embryos from diabetic serum culture than in embryos cultured in normal rat serum.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxybutyric Acid↗
PubMed1992

Regionally disturbed production of cartilage proteoglycans in malformed fetuses from diabetic rats.

Fetuses from normal and manifestly diabetic rats were obtained on pregnancy day 20. The fetuses from the diabetic rats were of normal or malformed morphology. Three tissue groups were dissected free; costal cartilage, the hard tissue of the rear, and of the frontal portion of the mandible. These tissues were maintained in vitro for 24 h during which time they were labelled with [35S]sulphate. After the culture period the tissues were extracted with guanidine HCl and the resulting residues were further extracted with alkali. The culture medium was saved and its macromolecular content was compared to that of the extracts. The proteoglycans recovered in all extracts eluted at two distinct positions after chromatography on a Sepharose CL-2B column (peak I: Kav approximately 0.4, and peak II: Kav approximately 0.8), but the elution patterns were markedly different in extracts from various tissues. Thus, in rib cartilage, the majority of the labelled proteoglycans were located in peak I (approximately 90%) with no difference between extracts of fetuses from normal and diabetic pregnancies. In extracts of mandibular cartilaginous tissue from normal rat offspring the peak I percentage (60-80%) was lower than in the rib cartilage extracts. In the extracts from the frontal portion of malformed mandibles of fetuses of diabetic rats, the peak I percentage (35 +/- 21%) was the lowest of all recorded and the only one to significantly differ from the other percentages in its (the frontal mandible) group. The results show an association between a congenital malformation, micrognathia, and a disturbance in the production of chondroitin sulphate proteoglycans in the malformed region.

Analysis of Variance↗
PubMed1992

A continuous 48-hour glucose infusion in rats causes both an acute and a persistent redistribution of the blood flow within the pancreas.

Male Sprague-Dawley rats were infused for 48 h at a rate of 1.8 ml/h with either a 30% solution of D-glucose or a 10% solution of D-mannitol. The blood perfusion of both the whole pancreas and the islets was measured with a microsphere technique either immediately after the infusion or 10 days later. Infusion of mannitol did not influence the serum glucose or the serum insulin concentration at any time point. Infusion of glucose, however, increased both the glucose and insulin concentrations during the infusion period, but 45 min after the infusion ended both the glucose and insulin concentrations had already returned toward the values found in the mannitol-infused rats. Intraperitoneal glucose tolerance tests were normal both immediately after the infusion and 8 days later. The glucose infusion caused a significant increase in whole pancreatic blood flow and islet blood flow when compared to mannitol-infused rats immediately after the infusion. The increase in blood perfusion of the islets was more marked than that to the whole pancreas since a larger fraction of the whole pancreatic blood flow was diverted through the islets. Ten days after the infusion there was still a marked increase in the fractional islet blood flow in the glucose-infused animals, whereas the absolute flow values for whole pancreatic or islet blood flow did not differ significantly between the groups. We conclude that continuous hyperglycemia for 48 h causes an acute increase in both whole pancreatic and islet blood flow, and that a redistribution of the blood flow within the gland is present 10 days after the infusion.

Analysis of Variance↗
PubMed1992

Glucose metabolism in embryos of normal and diabetic rats during organogenesis.

To investigate whether malformations in the offspring of diabetic rats are related to a disturbed embryonic glucose metabolism, lactate production, lactate content and glucose oxidation in embryos of normal and manifestly diabetic rats were measured in vitro during the period of organogenesis. The embryonic production and content of lactate decreased by 90% between gestational days 10 and 11. On both gestational days the embryos of diabetic rats showed increased lactate production and content compared to the embryos of normal rats. The embryonic oxidation of glucose decreased slightly from gestational day 10 to day 11, and the embryos of diabetic rats exhibited a lower glucose oxidation rate than those of normal rats on both days. The lactate production and content in the embryos increased with increasing concentrations of glucose in the incubation medium, whereas the oxidation of glucose was unaffected by the glucose concentration. The results suggest that the embryonic metabolism of glucose is only marginally affected by changes in the availability of glucose. The lactate production rate was higher and the glucose oxidation rate lower in the embryos of diabetic than in those of normal rats, even when the values for these metabolic variables were normalized to the embryonic DNA content. Thus, a causative role for a disturbance of the glucose metabolism in diabetes-induced embryonic dysmorphogenesis could be envisaged.

Animals↗
PubMed1991

Decreased activity of the heparan sulfate-modifying enzyme glucosaminyl N-deacetylase in hepatocytes from streptozotocin-diabetic rats.

N-Deacetylation is the initial polymer modification step in heparan sulfate biosynthesis and a prerequisite to subsequent N- and O-sulfation. It has previously been shown that the sulfation of liver heparan sulfate is lowered in diabetes (Kjellén, L., Bielefeld, D., and Höök, M. (1983) Diabetes 32, 337-342). To investigate whether the reduced sulfation is the result of a lowered N-deacetylase activity, we have assayed this enzyme in hepatocytes from streptozotocin-diabetic rats. In addition, the activity of the glucuronosyl C5-epimerase, which catalyzes a modification reaction subsequent to N-sulfation, was measured. The deacetylase activity, expressed per microgram of cell protein, was about 40% lower in diabetic hepatocytes as compared with control cells, whereas the epimerase activity was unaffected. Recently, a approximately 110-kDa glycoprotein that carries N-sulfotransferase activity was identified as one of at least two protein components required for N-deacetylation in mouse mastocytoma tissue (Pettersson, I., Kusche, M., Unger, E., Wlad, H., Nylund, L., Lindahl, U., and Kjellén, L. (1991) J. Biol. Chem. 266, 8044-8049). We therefore investigated if the lowered N-deacetylase activity in diabetes could be ascribed to a deficiency in either one of the corresponding rat components. The results indicated that (i) the glycoprotein component is present in limiting amounts in both control and diabetic cells, (ii) diabetes results in a lowered activity of this component, and (iii) excess amounts of the additional protein(s) needed for N-deacetylase activity are present in both control and diabetic cells.

Amidohydrolases↗