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Biomedical subjects

N Freinkel

Publications and source records attributed to N Freinkel.

At least 37 records · Page 2Linked to original sources
PubMed1986

Effect of hyperglycemia on sorbitol and myo-inositol content of cultured rat conceptus: failure of aldose reductase inhibitors to modify myo-inositol depletion and dysmorphogenesis.

Growth retardation and dysmorphogenesis were seen in the rat conceptus following culture from day 9.5 to 11.5 of development in the presence of increased amounts of glucose. Sorbitol accumulated in the conceptus during the hyperglycemia whereas total protein, DNA, and free myo-inositol decreased. Similar glucose-related compositional changes were present in separated embryos and extra-embryonic membranes suggesting that all portions of the conceptus participate in the alterations. The aldose reductase inhibitors Sorbinil and Statil obtunded the rises in sorbitol but did not modify the increased incidence of malformations and the fall in DNA, protein and myo-inositol. Thus, the aldose reductase pathway may function in the early post-implantation rat conceptus but the resultant accumulation of sorbitol does not appear to contribute to the growth-retarding, dysmorphogenic, and myo-inositol-depleting effects of hyperglycemia.

Aldehyde Reductase↗
PubMed1986

Changes in diabetic retinopathy during pregnancy. Correlations with regulation of hyperglycemia.

Thirty-eight pregnancies in 35 women with insulin-dependent diabetes mellitus were monitored for changes in diabetic retinopathy during the institution of "tight" metabolic control by intensive medical management. Eye findings were scored on paired sets of retinal photographs obtained when enrolled in this study and shortly after delivery. These findings were then correlated with measurements of diabetic regulation. Intensive therapy for the diabetes mellitus resulted in improved glucose control by the time of delivery. However, retinal abnormalities worsened as gestation proceeded in 55% of the pregnancies. Deterioration of background retinopathy correlated significantly with the levels of plasma glucose at entry and with the magnitude of improvement in glycemia achieved during the first six to 14 weeks after entry (ie, "early changes") and by the final week before delivery (ie, "overall changes"). Our findings indicate that the changing retinopathy during pregnancy cannot be interpreted without assessment of concurrent changes in the regulation of maternal diabetes and that the abrupt institution of improved diabetic control during pregnancy may be one factor in the deterioration of background retinopathy sometimes seen during pregnancy.

Adult↗
PubMed1986

Gestational diabetes mellitus: a syndrome with phenotypic and genotypic heterogeneity.

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.

Adult↗
PubMed1986

The 1986 McCollum award lecture. Fuel-mediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture.

Whole rat embryos were explanted at head-fold, late pre-somite stage (day 9.5 of gestation) and cultured in rat sera varyingly supplemented with glucose (3, 6, 9, or 12 mg/mL), D,L sodium beta-hydroxybutyrate (2, 4, 8, or 16 mM), or both (6 mg/mL D-glucose plus 8 mM beta-hydroxybutyrate). During 48 h culture, increasing glucose alone or beta-hydroxybutyrate alone effected growth retardation and faulty neural and extraneural organogenesis in dose-dependent fashion. Synergistic dysmorphogenic effects occurred when minimally teratogenic concentrations of glucose and beta-hydroxybutyrate were combined. Sera from diabetic animals containing somatomedin inhibitor bioactivity were also able to produce growth retardation and major developmental lesions in presence of amounts of glucose and ketones which of themselves were not teratogenic. Thus, aberrant fuels and fuel-related products can impair growth and organogenesis in early post-implantation embryo. Such fuel-mediated teratogenesis may be multifactorial and include possibilities for synergistic and additive interactions.

3-Hydroxybutyric Acid↗
PubMed1986

Embryotoxic effects of brief maternal insulin-hypoglycemia during organogenesis in the rat.

To test whether maternal hypoglycemia can impair organogenesis, we induced brief glucopenia with insulin in conscious pregnant rats during either the headfold stage or the early neural tube closure stage of embryogenesis. At each time, 10 pairs of animals received identical insulin infusions for 1 h. Half the animals were maintained at euglycemia during the infusions, while the others were allowed to become hypoglycemic. Euglycemia was maintained or restored in all animals immediately after the insulin was stopped. Spontaneous activity was diminished during the hypoglycemia but consciousness was preserved. Embryos were removed from mothers and examined 2 d later. This examination revealed that embryos from the hypoglycemic mothers were growth-retarded and displayed a small but significant incidence of gross developmental anomalies compared with embryos from the insulin-infused euglycemic mothers. Thus, brief, mild maternal hypoglycemia during early organogenesis can disrupt normal embryo development in the rat. The effect is due to the hypoglycemia per se rather than to the insulin employed for its induction.

Animals↗
PubMed1986

Relationships between glucose and mannose during late gestation in normal pregnancy and pregnancy complicated by diabetes mellitus: concurrent concentrations in maternal plasma and amniotic fluid.

Enzymatic assays were modified to permit sensitive and highly reproducible simultaneous measurements of D-mannose and D-glucose in biological fluids during weeks 34-40 of human pregnancy. Plasma mannose and glucose averaged 9.8 +/- 0.4 (+/- SEM) and 790 +/- 16 micrograms/ml, respectively, after an overnight fast in pregnant women (n = 22) with normal carbohydrate metabolism. Significantly higher plasma mannose levels were found, despite only minor increases in plasma glucose, in pregnant women with relatively well controlled diabetes mellitus after an overnight fast (16.9 +/- 0.6 micrograms/ml mannose; 883 +/- 29 micrograms/ml glucose; n = 31) or 3-4 h after breakfast (15.7 +/- 1.2 micrograms/ml mannose; 1159 +/- 101 micrograms/ml glucose; n = 19). Plasma mannose correlated significantly with plasma glucose in the women with diabetes mellitus, particularly after an overnight fast. Samples of amniotic fluid were also obtained from the gravida with diabetes mellitus to provide some index of simultaneous relationships in utero. Amniotic fluid mannose and glucose averaged 5.9 +/- 0.4 and 302 +/- 24 micrograms/ml, respectively, after an overnight fast and 6.7 +/- 1.3 and 459 +/- 84 micrograms/ml 3-4 h after breakfast. In amniotic fluid, as in plasma, the concurrent levels of mannose and glucose conformed to relatively fixed relationships. Thus, both fetus and mother appear to be exposed to readily demonstrable amounts of mannose during late gestation and the absolute as well as relative abundance of mannose may be increased coincident with faulty maternal glucoregulation. However, since mannose did not exceed 3% of the concurrent concentration of glucose in any instance, it does not seem likely that endogenous levels of circulating mannose can modify glucose utilization appreciably by competing with glucose for phosphorylation via hexokinase and subsequent intracellular processing.

Adolescent↗
PubMed1986

Insulin receptors in embryo and extraembryonic membranes of early somite rat conceptus.

Intact rat conceptuses were cultured from day 9.5 of gestation on. Individual components of the conceptus, including the embryo and the extraembryonic membranes (consisting of yolk sac, amnion, and allantoic placenta), were isolated and examined for insulin receptors at two time points during organogenesis: day 10.4 of gestation (approximately 10-12 somites) when the yolk sac had become vascularized and just before closure of the anterior neuropore and day 11.6 (approximately 27-31 somites) when vascularization of the chorioallantoic placenta had been established and the neural tube was closed completely. The studies were designed to provide inferential insights about the possible role of insulin in embryogenesis during different phases of nutrient delivery. Active insulin degradation occurred with embryo as well as membrane homogenates during incubation at 37 degrees C. Degradation was markedly reduced at 4 degrees C, and binding of 125I-labeled insulin by embryo or membrane homogenates prepared on day 10.4 or 11.6, respectively, of gestation approached equilibrium after a 20-h incubation at this temperature. Values for the specific binding of tracer (0.4 ng/ml) or carrier (10.4 ng/ml) insulin by embryo and membrane homogenates were the same on days 10.4 and 11.6; specific binding was significantly greater with preparations of membranes than embryo at both time points. Full binding curves on day 11.6 showed similar affinities for insulin by embryo and membranes (Ke = 1.2 X 10(8)/M and 4.6 X 10(8)/M, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Allantois↗
PubMed1985

A new method for the simultaneous estimation of phosphate efflux and influx during glucose stimulation of isolated pancreatic islets.

Isolated rat pancreatic islets were prelabeled with [33Pi] and then incubated with basal (2.8 mM) or stimulatory (16.7 mM) glucose in the presence of [32Pi]. Subsequent changes in islet [33P] and [32P] were utilized as respective indices of net efflux and influx. During the initial eight min, (the period usually spanning the first phase of stimulated insulin secretion) efflux was significantly greater with 16.7 than 2.8 mM glucose whereas the lesser amount of phosphate influx did not differ in the two systems. During the subsequent seven min (a time usually associated with the onset of the second phase of stimulated insulin secretion), efflux was dampened in the presence of 16.7 mM glucose and Pi influx significantly exceeded the 2.8 mM glucose values. Thus, acute stimulation with glucose effects an initial phosphate depletion in pancreatic islets as efflux exceeds influx and repletion occurs thereafter as efflux is attenuated and influx is enhanced. These oscillations in islet phosphate may contribute to the biphasic pattern of glucose-stimulated insulin release.

Animals↗
PubMed1985

Frequency of diabetes mellitus in mothers of probands with gestational diabetes: possible maternal influence on the predisposition to gestational diabetes.

Interviews for genetic histories were conducted prior to delivery in 166 pregnant diabetic probands and 83 control gravidas with normal carbohydrate metabolism throughout gestation. A significant association was observed between parental diabetic phenotypes and type of diabetes in the probands (chi 2(12)) = 32.413; p less than 0.001). In particular a higher than expected number of mothers with diabetes was encountered in 91 probands with gestational diabetes mellitus. The findings are examined in relationship to the hypothesis that vulnerability to gestational diabetes may be increased by exposure to an abnormal environment during intrauterine development.

Adult↗
PubMed1985

Fuel-mediated teratogenesis. Use of D-mannose to modify organogenesis in the rat embryo in vivo.

The unique embryotoxic properties of D-mannose have been used as the basis for a new technique to secure precise temporal correlations between metabolic perturbations during organogenesis and subsequent dysmorphogenesis. Conscious, pregnant rats were infused with D-mannose or equimolar amounts of D-glucose by "square wave" delivery during the interval in which the neural plate is established and early fusion of neural folds takes place, that is, days 9.5-10.0 of gestation. Infusions of mannose to maternal plasma levels of 150-200 mg/dl did not elicit any toxicity in the mothers: motor activity, eating behavior, and serum components (electrolytes, osmolality, bilirubin) did not differ in glucose- vis-à-vis mannose-infused dams. Embryos were excised by hysterotomy on day 11.6 for evaluation of development. Examination with a dissecting microscope did not disclose developmental abnormalities in any of the 136 embryos from glucose-infused mothers or in 62 additional embryos from mothers that had not received any infusions. By contrast, dysmorphic changes were seen in 17 of 191 embryos (8.9%) from mannose-infused mothers. 14 of the 17 had abnormal brain or neural tube development with incomplete neural tube closure in 9 instances. Abnormal axial rotation was present in 8 of the 191 embryos (4.2%) and lesions of the heart or optic vesicles were seen in 4 (2.1%) and 3 (1.6%), respectively. Embryos from mannose-infused mothers displayed significant retardations in somite number, crown-rump length, and total protein and DNA content. These stigmata of growth retardation were more marked in the 17 dysmorphic embryos. The experiments indicate that D-mannose may be employed in model systems with rodents for precisely timed interruptions of organogenesis in vivo. Initial applications are consistent with our earlier suggestion that multiple dysmorphic changes may supervene after interference with communally observed metabolic dependencies during organogenesis. The studies do not identify the vulnerable site(s) within the conceptus (e.g., investing membranes, embryos, or both). However, the findings suggest that dysmorphic events are manifest most markedly in a general setting of embryo growth retardation.

Abnormalities, Drug-Induced↗
PubMed1985

Gestational diabetes mellitus. Heterogeneity of maternal age, weight, insulin secretion, HLA antigens, and islet cell antibodies and the impact of maternal metabolism on pancreatic B-cell and somatic development in the offspring.

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)

Adult↗
PubMed1985

Gestational diabetes mellitus. Correlations between the phenotypic and genotypic characteristics of the mother and abnormal glucose tolerance during the first year postpartum.

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)

Adult↗
PubMed1984

The honeybee syndrome - implications of the teratogenicity of mannose in rat-embryo culture.

Lethal effects of D-mannose in the honeybee have been recognized for more than a half a century. We observed another toxic effect of D- mannose during culture of rat embryos from the early head-fold stage to the 26-to-29-somite stage (Days 9-1/2 through 11-1 of gestation). The addition to culture mediums of 1.5 mg of D-mannose per milliliter caused growth retardation and faulty neural-tube closure in approximately two thirds of the embryos. Mannose effects occurred during the first 24 hours of culture and were attended by modes inhibition of the glycolysis that constitutes the principal energy pathway at this stage of development. Adding more glucose to preserve glycolytic flux or increasing atmospheric oxygen to promote oxidative metabolism offset the mannose teratogenesis. Our findings highlight the metabolic vulnerabilities that exist during early organogenesis, before oxidative flexibility is established. They may serve as a model to explain the teratogenicity of many other seemingly unrelated agents that could act by perturbing glycolysis at this vulnerable stage.

Abnormalities, Drug-Induced↗
PubMed1984

Differential effects of age versus glycemic stimulation on the maturation of insulin stimulus-secretion coupling during culture of fetal rat islets.

We have cultured islets from 21.5-day-old fetal rats for 1-7 days in RMPI 1640/10% fetal calf serum containing 2.8 or 11.1 mM glucose to evaluate the differential effects of age vis-à-vis glycemic stimulation on the maturation of selected components of stimulus-secretion coupling. After 1 day of culture in either media, acute stimulation with 3.0 mg/ml glucose during basal perifusion with 0.5 mg/ml glucose elicited only a small first phase of stimulated insulin secretion and no second phase. The acute exposure to 3.0 mg/ml glucose produced no change in the prevailing high rates of oxygen consumption (QO2) and caused only minor increments in phosphate efflux (i.e., peak values for phosphate flush of 126 +/- 16% of baseline for islets that had been cultured in 11.1 mM glucose and 162 +/- 30% for islets cultured in 2.8 mM glucose). After 7 days of culture in 11.1 mM glucose, acute stimulation with 3.0 mg/ml glucose increased Qo2 (as in adult islets) and effected acute increases in the AT32P and GT32P content of prelabeled islets. The 3.0 mg/ml glucose also triggered phosphate flush to 599 +/- 45% of baseline and elicited first as well as early second phases of stimulated insulin secretion that replicated the performance of adult islets. By contrast, after 7 days of culture in 2.8 mM glucose, similar acute exposures of fetal islets to 3.0 mg/ml glucose effected only a small first phase and a negligible second phase of stimulated insulin secretion despite the occurrence of the same increments in Qo2 as after culture in 11.1 mM glucose, highly significant increases in AT32P and GT32P, and phosphate flushes that peaked at 306 +/- 16% of basal values. Thus, the ontogeny of individual components of stimulus-secretion coupling may occur in asynchronous fashion and varying require glycemic stimulation in addition to aging per se. The capacities to augment efflux of orthophosphate, enhance respiration, and heighten nucleotide turnover in response to acute stimulation with glucose seem to mature in large measure in time-dependent fashion, whereas some chronic exposure to ambient glucose in excess of basal levels may be required to establish and/or maintain the other coupled components that underlie biphasic stimulated insulin release. However, we did not achieve full exocytotic maturation even after 7 days of culture with 11.1 mM glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1984

Growth retardation during early organogenesis in embryos of experimentally diabetic rats.

Embryos from rats rendered diabetic with streptozotocin for 1 wk or more before conception were examined on day 11.5 of gestation (i.e., at the 26-29-somite stage of normal rat embryonic development). The studies were designed to assess whether poorly regulated maternal diabetes is associated with demonstrable abnormalities even during this early phase of embryogenesis. We found that manifest retardations in growth and development were invariably present as judged by significant reductions in crown-rump length and somite number, respectively. Total protein and DNA content of the embryos were also reduced, although not symmetrically, so that protein/DNA ratios were increased. Gross dysmorphogenic lesions in neural tissue disproportional to the overall growth retardation at 11.5 days could not be demonstrated. The findings suggest that maternal diabetes can compromise intra-uterine growth and development during the period preceding and coinciding with the establishment of circulation in the allantoic placenta. The possible multifactorial determinants remain to be elucidated. It also remains to be established whether the early embryotoxicity provides a setting conducive to the increased dysmorphogenesis that is traditionally recognized during the later stages of pregnancy complicated by diabetes.

Animals↗
PubMed1983

Biphasic changes in hemoglobin A1c concentrations during normal human pregnancy.

Analyses of hemoglobin A1c concentrations were performed throughout gestation in 377 nondiabetic women. We observed significant biphasic changes in hemoglobin A1c concentrations, with an initial gradual decline to a nadir level at 24 weeks, followed by a subsequent slow reascension to peak near term. All these changes fell within the usual range of normal values for hemoglobin A1c. Values for plasma glucose estimated 1 hour after a 50 gm oral glucose load in 1,756 normal gravid women showed similar biphasic excursions, with the nadir occurring 4 weeks earlier, i.e., at 20 weeks' gestation. We conclude that the small but significant changes in hemoglobin A1c during the course of normal gestation reflect, with an appropriate displacement in time, the biphasic alterations in mean blood sugar that characterize the sequential changes in glucoregulation during normal pregnancy.

Blood Glucose↗