Biomedical subjects

U J Eriksson

Publications and source records attributed to U J Eriksson.

At least 73 records · Page 4Linked to original sources

PubMed1991

In vitro effects of glucose and growth factors on limb bud and mandibular arch chondrocytes maintained at various serum concentrations.

In human and experimental diabetic pregnancy there is an increased risk of congenital malformation in the offspring. Some malformations involve growth retardation and altered chondrocyte differentiation, suggesting that a diabetic milieu may modify embryonic cell replication and the development of (pre)chondrocytes. The aim of the present work was to study the effects of a diabetes-like environment in vitro on the growth and differentiation of rat chondrocytes in the presence of specific growth factors and different concentrations of serum. This was performed with a modified micromass culture system of embryonic (pre)chondrocytes from the limb bud and mandibular arch areas using medium supplemented with different glucose concentrations and with serum from diabetic rats. An elevated ambient glucose concentration inhibited the growth of mature chondrocytes in vitro, and this effect was diminished in a serum-rich culture milieu. The (pre)chondrocytes exhibited a marked dependence on the serum level in the culture medium for optimal in vitro development. Diabetic rat serum had the lowest stimulatory capacity of the three different types tested (at similar glucose concentrations), suggesting a deficiency of growth-stimulating factor(s) rather than the presence of inhibiting factor(s) in this type of serum. One of the deficient factor(s) in diabetic rat serum may be similar to IGF-II, but a combined deficiency of several growth-stimulating agents is likely to be present. Chondrocytes originating from the mandibular arch in general appeared more sensitive to MSA and IGF-II than those from the limb buds. The present observations support the notion that while diabetes-induced hyperglycemia in the conceptus contributes to severe growth retardation of the mandibular arch, additional factors also play a role.

Animals↗

PubMed1991

Influence of severe diabetes mellitus early in pregnancy in the rat: effects on insulin sensitivity and insulin secretion in the offspring.

We studied the influence of severe diabetes early in pregnancy on insulin sensitivity and insulin secretion in the offspring. Diabetes (blood glucose greater than 20 mmol/l) was induced in female Sprague-Dawley rats before mating. Diabetic dams were insulin treated during the second half of pregnancy (mean blood glucose 10.6 mmol/l). The offspring were reared by foster mothers. Offspring of both sexes were insulin resistant at four and seven months of age as evidenced by normal glucose tolerance after glucose (2 g/kg body weight intraperitoneally) concomitant with higher than normal rises in insulin levels. Regardless of fetal environment the male rats had higher glucose and insulin levels than the female rats. Insulin responses to glucose (27 mmol/l) in vitro in perfused pancreases were not increased by maternal diabetes, male gender or higher age. Conversely responses to 3-isobutyl-1-methylxanthine (1.0 mmol/l) were enhanced by all three conditions. The pancreatic content of insulin was only marginally affected by maternal diabetes. We conclude that severe diabetes during early pregnancy affects glucose homeostasis in the offspring primarily by diminishing insulin sensitivity and that susceptibility to this effect is not sex- or age-dependent.

Aging↗

PubMed1991

Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro.

This study addresses the possibility that the teratogenic effects of a diabetic pregnancy are associated with increased embryonic activities of free oxygen radicals. Rat embryos were cultured in 50 mmol/l glucose for 48 h and subsequently showed pronounced growth retardation and severe malformations. The enzyme inducer citiolone and the free oxygen radical scavenging enzymes superoxide dismutase, catalase and glutathione peroxidase protected against the disturbed growth and development of the embryos at 50 mmol/l glucose when added to the culture media. Enzymatic measurements indicated that citiolone induced an increased activity of superoxide dismutase in the embryonic tissues and that the added enzymes were taken up by both the yolk sac and the embryo proper. The protection against embryonic maldevelopment was thus conferred by agents that increased the free oxygen radical scavenging capacity of the embryonic tissues. The results suggest that a high glucose concentration in vitro causes embryonic dysmorphogenesis by generation of free oxygen radicals. An enhanced production of such radicals in embryonic tissues may be directly related to the increased risk of congenital malformations in diabetic pregnancy.

Abnormalities, Drug-Induced↗

PubMed1991

Effect of insulin on the altered production of proteoglycans in rib cartilage of experimentally diabetic rats.

Costal cartilage from experimentally diabetic rats, labeled in vivo or in vitro with [35S]sulfate, was shown to incorporate less label into proteoglycans than cartilage from nondiabetic rats. Analyses of guanidine HCl cartilage extracts by gel chromatography on Sepharose CL-2B showed two major peaks at Kav approximately 0.4 and 0.8 (peaks I and II, respectively). Cartilage extracts from the diabetic rats contained predominantly peak II proteoglycans, while 60 and 55%, respectively, of the total 35S-labeled proteoglycans extracted from control cartilage labeled in vivo and in vitro with [35S]sulfate were present in peak I. After insulin treatment of the diabetic rats, the relative amount of peak I 35S-labeled proteoglycans synthesized in vivo was increased to 70%. The overall in vivo incorporation of [35S]sulfate into proteoglycans was also stimulated in diabetic rats treated with insulin to levels above those found for control rats. Thus, diabetes-induced changes in the biosynthesis of rat costal cartilage proteoglycans may be alleviated by normalization of the diabetic state by insulin treatment. However, addition of insulin (10(-5)-10(-9) M) to the culture medium did not affect the amount of 35S-labeled proteoglycans synthesized in vitro or the relative amounts of peak I proteoglycans produced by control or diabetic cartilage, suggesting that insulin does not have a direct effect on proteoglycan production. Moreover, no decrease in the amount of 35S-labeled proteoglycans produced was found when glucose at high concentrations was present in the culture medium. However, the presence of rat serum resulted in an increase in the amount of 35S-labeled proteoglycans produced by both control and diabetic cartilage, demonstrating that the cartilage explants were metabolically responsive to stimulatory factors.

Animals↗

PubMed1991

Behavioral effects of an intrauterine or neonatal diabetic environment in the rat.

Maternal diabetes during pregnancy may cause lasting effects on the psychoneurological development in the offspring. The aim of the present study was to investigate possible effects of an intrauterine or neonatal exposure to a diabetic environment on behavior during infancy and adulthood. On days 4 and 6 of age, offspring of streptozotocin-diabetic rats emitted higher numbers of ultrasound calls compared to control offspring. Neonatally streptozotocin-treated rats explored their environment by diminished sniffing and rearing intensity compared to control rats. However, in adult life neither of these rat groups displayed behavioral differences compared to their respective control group. The results suggest that development of basic behavioral patterns in the rat proceed almost normally despite exposure to a diabetic environment in the early embryonic period or in early infancy.

Animals↗

PubMed1991

Effects of maternal diabetes or in vitro hyperglycemia on uptake of palmitic and arachidonic acid by rat embryos.

Altered transfer of nutrients from mother to conceptus may be involved in the pathogenesis of the developmental disturbances in offspring of diabetic mothers. In our study, the embryonic uptake of a saturated (palmitic acid) and a nonsaturated (arachidonic acid) fatty acid was evaluated in a normal and a diabetes-like environment under in vivo and in vitro conditions that yield growth retardation and somatic malformations in the embryos. The palmitic acid uptake in embryos from diabetic rats and in embryos cultured in vitro in 30 mmol/L D-glucose did not differ from the respective controls. Only embryos cultured in the highest D-glucose concentration (60 mmol/L) showed slightly increased uptake, which suggests that alterations in palmitic acid transfer have no role in the processes of embryonic maldevelopment in diabetic pregnancy. In contrast, the results showed that a diabetes-like environment both in vivo and in vitro causes increased embryonic uptake of arachidonic acid. Consequently, if the teratogenic mechanisms of diabetic pregnancy involve decreased embryonic levels of arachidonic acid, as has been suggested, this would not be the effect of a decreased uptake per se, but rather of an altered intracellular metabolism or decreased extracellular availability of this fatty acid.

Animals↗

PubMed1991

Inhibition of N-acetylheparosan deacetylase in diabetic rats.

The effects on N-acetylheparosan deacetylase (N-deacetylase) activity exerted by poorly and well-regulated diabetes and variation of genetic background were investigated in insulin-treated streptozocin-induced diabetic rats of two different strains (H and U). N-deacetylase plays a key role in heparan sulfate biosynthesis, because N-deacetylation is a prerequisite for N- and further O-sulfation. Specific activity of the enzyme was reduced by 50% in poorly regulated diabetic rats compared with nondiabetic rats (P less than 0.001). The decrease in specific activity was accompanied by a reduction in the estimated KM from 34 +/- 3 to 27 +/- 4 mg/L (P less than 0.001). Optimal insulin treatment, leading to near normalization of blood glucose, prevented reduction in N-deacetylase activity. In rat strain U, however, a 20% reduction was found despite optimal insulin treatment (P = 0.01), and the nondiabetic animals of this strain had reduced N-deacetylase activity compared with nondiabetic rats from the H strain. This might suggest a genetic difference between the rat strains in the regulation of the enzyme activity. The diabetes-induced inhibition of N-deacetylase may have an important role in the pathogenesis of nephropathy and vascular complications in human diabetes mellitus.

Amidohydrolases↗

PubMed1991

Diabetic embryopathy. Studies with animal and in vitro models.

Diabetic pregnancy is associated with an increased risk for fetal maldevelopment for a largely unknown reason. A decade ago, Norbert Freinkel suggested that the altered fuel mixture offered to the growing conceptus may be the key to most of the changes in the embryogenesis of diabetic pregnancy. He coined the term fuel-mediated teratogenesis. During early pregnancy, periods of maternal hyper- and hypoglycemia may cause marked changes in the availability of glucose to the conceptus. Also, increased concentrations of lipids, notably ketone bodies, and branched-chain amino acids in the maternal circulation contribute to a changed fuel mixture for the embryo. In a recent experimental study of diabetic rats, it was found that the maternal metabolism of all three major classes of nutrients and maternal somatic growth during gestation covaried with the development of the embryo. Consequently, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy. In vitro, a high glucose concentration causes embryonic dysmorphogenesis by generation of free oxygen radicals. An enhanced production of such radicals in embryonic tissues may be directly related to an increased risk of congenital malformations in diabetic pregnancy. Thus, the notion that alterations in the net transfer of cellular fuels from the diabetic mother to her offspring may cause embryonic dysmorphogenesis, which suggests that combustion of the fuel may produce compounds that impair embryonic development, has obtained experimental support. If this is also true for human diabetic pregnancy, it has therapeutic implications.

Animals↗

PubMed1990

Effects of D-glucose and beta-hydroxybutyric acid on the in vitro development of (pre)chondrocytes from embryos of normal and diabetic rats.

In order to elucidate cellular mechanisms causing skeletal malformations in offspring of diabetic rats we studied the incorporation of thymidine and sulphate into embryonic (pre)chondrocytes exposed to increased levels of D-glucose and beta-hydroxybutyric acid for six days in vitro. The (pre)chondrocytes were prepared from embryos of normal or diabetic rats of a malformation-prone strain or from embryos of normal rats of a non-malformation-prone strain. Diabetic female rats of the former strain are known to produce a high proportion of offspring with mandibular and lumbosacral malformations. Increased beta-hydroxybutyric acid caused decreased thymidine incorporation in all types of chondrocytes, and decreased sulphate incorporation in limb bud cells from embryos of normal rats from both strains. Elevated D-glucose levels yielded a slight decrease in thymidine incorporation in mandibular arch cells from embryos of normal rats of the malformation-prone strain, and a marked decrease of both sulphate and thymidine incorporation in mandibular arch cells from embryos of diabetic rats of this strain. The observations suggest that elevated levels of D-glucose or beta-hydroxybutyric acid are able to inhibit the differentiation and growth of (pre)-chondrocytes and illustrate a selective sensitivity of mandibular arch (pre)chondrocytes to a diabetic environment. The data are compatible with the view that both D-glucose and beta-hydroxybutyric acid may cause aberrations in the development of rat mandibular arch chondrocytes, suggesting a role for these compounds in diabetic teratogenesis.

3-Hydroxybutyric Acid↗

PubMed1990

Effects of maternal diabetes on placental transfer of glucose in rats.

In situ perfusion of the fetal side of the anesthetized rat placenta was used to monitor glucose fluxes in nondiabetic, streptozocin-induced diabetic (STZ-D), acutely hyperglycemic nondiabetic, and acutely normoglycemic STZ-D rats. STZ-D resulted in increased accumulation of glucose in the perfusate during a single passage through the fetal vasculature compared with nondiabetic rats, and this increase was maintained in normoglycemic STZ-D rats, indicating glucose release from placental stores. The fractional clearance of 3-O-[14C]methylglucose, a nonmetabolizable glucose analogue, across the placenta was decreased in both STZ-D groups compared with nondiabetic rats but unchanged in hyperglycemic nondiabetic rats, implying a reduction in glucose transporters in diabetic placentas. The difference between the transfer of D-[3H]glucose and 3-O-[14C]methylglucose indicated that 17% of the glucose was retained while traversing the placenta of nondiabetic rats, whereas a smaller percentage (8%) but a larger absolute amount (9 vs. 6 mumol/h) of glucose was retained by the placentas of the severely STZ-D rats. This retention was markedly enhanced in hyperglycemic nondiabetic rats and STZ-D rats when rendered normoglycemic. The net accumulation of perfusate glucose was less than that predicted from radiolabeled transfer data, indicating that glucose is also back transferred from the perfusate to the mother's placenta. We conclude that maternal diabetes markedly affects placental glucose flux.

Animals↗

PubMed1990

Metabolism in vitro of cartilage proteoglycans in rat (pre)chondrocytes from different embryonic regions.

Diabetes in the mother may cause disturbances in the chondrocyte development in the embryo. A rat model was used to investigate whether this was reflected in the production of proteoglycans by cells from two embryonic regions. One of these regions is resistant (limb bud) and the other susceptible (mandibular arch) to malformation in diabetic pregnancy. Chondroitin sulphate proteoglycans from cultures of day-12 rat embryo limb bud and mandibular arch chondrocytes were extracted with guanidine-HCl and analyzed by gel chromatography after in vitro 35S-sulphate-labeling. Two sizes of proteoglycans (Kav 0.26 and 0.66 on CL-2B Sepharose) were found in both types of chondrocytes and in all media. The polysaccharide chain length was the same (Kav 0.36 on CL-6B Sepharose) for both proteoglycans. Elevated levels of D-glucose or beta-hydroxybutyric acid had no effect on either proteoglycan size or proportion, nor on polysaccharide chain length. However, there were differences (in all culture conditions) between limb bud and mandibular arch cultures in that the larger proteoglycan accounted for 80% of total radioactivity in the limb bud cultures, 53% in the mandibular arch cultures, and only 25-29% in the media from both types of cultures. Furthermore, different ratios between radioactive proteoglycans in medium and matrix suggested markedly different efficiencies for matrix formation in the two cell types. These findings indicate differences in the metabolism of the proteoglycans in these two cell types which may be related to the induction of mandibular malformation in diabetic pregnancy.

Animals↗

PubMed1990

Perinatal hypoadrenalism in the rat does not alter glucose tolerance and insulin secretory response to glucose.

Fetal and neonatal hypoadrenalism was induced by treating rat mothers with metyrapone from day 12 of pregnancy to day 7 postnatally. Hypoadrenalism in the neonates was indicated by a slight reduction in body weight, adrenal hyperplasia and a tendency towards reduced adrenal corticosterone concentration. An intraperitoneal glucose tolerance test on the 7-day old neonates did not show any disturbancies of glucose disposal or insulin secretory response to glucose. The data suggest that adrenal corticosteroids are not essential for the perinatal development of the B-cell secretory response to glucose.

Adrenal Insufficiency↗

PubMed1989

Sorbitol metabolism in retina studied in vitro.

A new method is described which allows study of the retinal sorbitol metabolism in vitro. Bovine retinal tissue was incubated in tissue culture medium for 24 h and after this time showed only small morphological changes. The sorbitol content doubled at a glucose level of 5.5 mM compared with freshly prepared noncultured retina. Increasing glucose concentrations led to a gradual increase of the sorbitol content. Supplementation of the culture medium with fructose likewise enhanced the retinal sorbitol accumulation. An aldose reductase inhibitor (ICI 128436; Statil) significantly decreased the sorbitol content.

Animals↗

PubMed1989

Timed interruption of insulin therapy in diabetic BB/E rat pregnancy: effect on maternal metabolism and fetal outcome.

Experimental and clinical studies have suggested that periods of poor metabolic control in early diabetic pregnancy have an adverse effect on the developing embryo, but the precise nature and mechanism of this damaging influence have not been defined. In this study the effect of withdrawing treatment with insulin for 2 days at various times during early gestation on maternal metabolism and fetal outcome has been investigated in the spontaneously diabetic BB/E rat. Non-diabetic BB/E rats and diabetic BB/E rats treated continuously with insulin throughout pregnancy served as controls. Continuously treated diabetic rats had a higher rate of fetal resorption and bigger placentae and their offspring had fewer ossification centres, lower extractable pancreatic insulin content, larger hearts, and smaller kidneys and lungs than the offspring of non-diabetic rats. Interruption of treatment with insulin further aggravated the adverse effect of diabetes on the outcome of pregnancy by resulting in a further increase in the rate of fetal resorption, a rise in the neonatal death rate, a reduction in fetal body weight, and retardation of skeletal development. These effects were more apparent when interruption of treatment with insulin occurred during the period of organogenesis, i.e. during gestational days 8 and 9, and 10 and 11. Two severe malformations were seen, both in litters originating from mothers whose treatment with insulin was interrupted during and immediately before fetal organogenesis. We conclude that a period of disturbed maternal metabolism during fetal organogenesis is capable of affecting the survival, growth, and organ development of the fetus and that the spontaneously diabetic insulin-dependent BB rat appears to be a good model for studies of the effect of diabetes and its treatment on the outcome of pregnancy.

Animals↗

PubMed1989

Effects of interrupted insulin treatment on fetal outcome of pregnant diabetic rats.

Streptozocin-induced diabetic female rats became normoglycemic after subcutaneous insertion of insulin-releasing osmotic minipumps. These female rats were mated with normal males from the same Sprague-Dawley substrain. In this substrain, the offspring of diabetic rats show a markedly increased congenital malformation rate compared with fetuses of nondiabetic rats. The pregnant diabetic rats were subjected to removal and insertion of pumps at defined gestational days that marked the beginning or end of a 2- or 4-day period of insulin withdrawal. Evaluation of the offspring on day 20 of pregnancy included fetal/placental weights, estimated number of implants, resorptions, and morphological assessment of congenital malformations. Resorptions occurred in all interruption groups, but malformations were found only in animals with insulin withdrawal on gestational days 4-8, 6-8, 6-10, 8-10, and 8-12. The highest resorption (42%) and malformation (17%) rates were found in the rats subjected to insulin withdrawal during gestational days 6-10. Because manifestly diabetic rats with no insulin treatment showed similar resorption (39%) and malformation (17%) rates, this study suggests that a teratogenic period in diabetic rat pregnancy occurs during gestational days 6-10, a period corresponding to postconceptional wk 2-4 in human pregnancy. Interruption of insulin treatment induced similar maternal weight loss and similar maternal serum concentrations of D-glucose, cholesterol, urea, and creatinine in rats with and without malformed offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Influence of sorbitol accumulation on growth and development of embryos cultured in elevated levels of glucose and fructose.

Day-9 rat embryos, cultured for 48 hours in 67 mmol/l D-glucose, showed impaired growth, increased malformation rate and elevated concentration of sorbitol compared to embryos cultured in medium without additional glucose supplement. Supplementing the high-glucose cultures with an aldose reductase inhibitor markedly decreased the sorbitol levels without affecting the malformations or the retarded growth of the embryos. Since embryos cultured in 6.6 mmol/l D-fructose showed normal growth and morphology despite increased accumulation of sorbitol, this study suggests a dissociation between raised sorbitol levels and glucose-induced maldevelopment in rat embryos.

Abnormalities, Drug-Induced↗

PubMed1988

Importance of genetic predisposition and maternal environment for the occurrence of congenital malformations in offspring of diabetic rats.

Previous experimental studies have implicated a genetic component in the induction of malformations in the offspring of diabetic rats. We have compared the outcome of diabetic pregnancy in two outbred (sub)strains of Sprague-Dawley rats (with low incidence [H] and high incidence [U] of skeletal malformations in the offspring) and hybrids between them. The fetuses of diabetic H mothers had no skeletal malformations and the lowest frequency of resorptions (8-9%), regardless of embryo type (H/H or H/U). When the diabetic mother was U or from the hybrid strain (H/U) and the offspring were of the mixed H/U type, we found increased resorption (16-21%) and skeletal malformation (3-5%) rates. If instead the embryos contained a major U genome [either U/U or U/(H/U)], further increased resorptions (23-30%) and skeletal malformations (17-19%) resulted. The H/H and U/U embryonic susceptibility to defined teratogens (3-6 mg/ml D-glucose, 4-8 mM B-hydroxy-butyrate) were compared in whole embryo culture and found to be similar, suggesting that the malformations occurring in vivo may have a different etiology than those found in vitro. In the rat model studied, diabetes in the mother appears to cause a disturbance of early stages of embryogenesis in genetically predisposed embryos. This early disturbance results in skeletal malformations and seems to require inducing factor(s) in addition to increased levels of D-glucose and B-hydroxybutyrate. The findings are in concert with the notion of a mixed genetic-environmental etiology of malformations in (diabetic) pregnancy.

Animals↗

PubMed1988

Sorbitol metabolism in the retina, optic nerve, and sural nerve of diabetic rats treated with an aldose reductase inhibitor.

Sorbitol concentration has been measured in retina, optic, and sural nerve of normal, diabetic, and aldose reductase inhibitor-treated diabetic rats. The sural nerve displayed significantly higher sorbitol content than the retina and the optic nerve both in control animals and in diabetic animals. In the sural nerve the response to treatment with an aldose reductase inhibitor was more marked than in the two other tissues. The activities of aldose reductase and sorbitol dehydrogenase were not influenced by diabetes. It is suggested that aldose reductase inhibition may be of greater use for alleviating peripheral nervous system accumulation of sorbitol than for hindering CNS accumulation of the polyol.

Aldehyde Reductase↗