Monitoring the severity of metabolic disturbances and effectiveness of management of gestational diabetes mellitus.

To monitor the severity of metabolic disturbances during gestational diabetes mellitus (GDM), some risk factors existing at the time of diagnosis must be considered, including age of the pregnant women, early gestational age at diagnosis, high fasting blood glucose level, high HbA1c or fructosamine levels, or high amniotic fluid insulin level. The degree of OGTT abnormality will also influence the therapeutic approach, although the insulin response to the glucose challenge seems to be of little discriminating value. Effectiveness of the treatment can be appreciated by self-monitoring of blood glucose, although the practical precision of these measures and their necessary repetitions will limit clear-cut evaluation of borderline cases. HbA1c and fructosamine are of little help because of lack of sensitivity and time delay between changes in blood glucose and associated glycosylated protein changes. Whether other parameters such as amino acids, growth factors, or related compounds are more specifically linked to the physiopathology of GDM complications remains to be established but would help in monitoring GDM metabolic disturbances in the future. Meanwhile, prophylactic insulin treatment may still constitute a pragmatic approach, taking into account possible and poorly appreciated drawbacks from overtreatment, e.g., maternal hyperinsulinism and chronic hypoglycemia.

Increased synthesis of tumor necrosis factor-alpha in uterine explants from pregnant diabetic rats and in primary cultures of uterine cells in high glucose.

The production of tumor necrosis factor-alpha (TNF-alpha) was investigated in uterine explants from normal, diabetic, or insulin-treated diabetic pregnant rats. Explants from diabetic rats released more soluble TNF-alpha than did those in the other groups. The extent of this secretion was correlated with blood glucose concentration at the time of explantation. The concentration of cell membrane-associated TNF-alpha in the explants was not altered by diabetes. Daily insulin administration failed to normalize uterine TNF-alpha secretion despite correction of glycemia in the diabetic rats. Explants from normal pregnant rats cultured in vitro with increasing concentrations of D-glucose showed a dose-dependent increase in TNF-alpha secretion. The production of TNF-alpha in high glucose was also tested in primary cultures of uterine cells isolated from either immature or adult rats. TNF-alpha secretion was increased in high D-glucose but not in iso-osmolar concentrations of L-glucose, D-raffinose, D-galactose, or mannitol. Cell membrane-associated TNF-alpha was not influenced by high D-glucose. Semiquantitative reverse transcription-amplification of RNA extracted from primary cultures of uterine cells showed that the steady-state level of TNF-alpha transcripts was increased by high D-glucose but not by high L-glucose. The results are consistent with the hypothesis that hyperglycemia is instrumental in the overexpression of TNF-alpha in the diabetic uterus. Because TNF-alpha has a demonstrated negative impact on embryonic growth, enhanced TNF-alpha synthesis in the pregnant uterus may contribute to the embryopathy associated with maternal diabetes.

Glucose tolerance in a Saharan nomad population--the Broayas, from the Toubou ethnic group.

Oral plucose tolerance was studied in the Toubou Broayas living in northeaster Niger. Mean fasting plasma level of glucose was 64 +/- 22 (S.D.) mg./100 ml. Two hours after oral administration of 100 gm. glucose, the level was 74 +/- 26 mg./100 ml. Plasma insulin levels were, respectively, 18 +/- 13 and 36 +/- 24 muU./ml. There was no sex difference. Older subjects had higher glucose levels and heavier females had higher insulin levels two hours after glucose administration. In six subjects (4 per cent) the plasma glucose level exceeded either 110 or 130 mg./100 ml. in the fasting state or after glucose administration, respectively, without, however, exceeding 150 mg./100 ml. in any of them. The low prevalence of glucose intolerance in this population is discussed with regard to their nutritional conditions (80 per cent carbohydrates) and their physical activity (nomadism). The Broaya group, in whom obesity is unknown, appears to be well adapted to its extreme environment.

Decreased inner cell mass proportion in blastocysts from diabetic rats.

Late morulae and blastocysts were recovered from streptozocin-induced diabetic pregnant rats and individually examined for numbers of inner cell mass (ICM) cells and trophectoderm (TE) cells. Compared with embryos collected from control rats, exposure to maternal diabetes significantly decreased mean ICM cell number of blastocysts recovered on day 5 of gestation, but the TE population of these embryos remained unaffected. The mean ICM proportion was therefore significantly lower than that of control embryos. These differences were not observed between the two groups of morulae collected on day 5, suggesting that the distinctive susceptibility of the ICM was expressed after blastocyst formation. On day 6, a significant inhibitory effect of diabetes was observed on the growth of both ICM and TE cells, but because the reduction was more severe in the ICM than in the TE, the mean ICM proportion of these blastocysts was again significantly lower than in control embryos. A linear quadratic relationship was obtained between the numbers of ICM cells of individual blastocysts and their respective numbers of TE cells in each of the two experimental groups. However, the slope of the curve was slower in the diabetic group than the control group. The disturbed ICM cell growth in the blastocysts from diabetic rats was found to be associated with a significantly increased incidence of cell death predominantly located in the ICM. Because it is known that excessive reduction of the ICM is incompatible with normal embryogenesis after implantation, our results suggest that the differential sensitivity of ICM and TE cells in preimplantation blastocysts may contribute to the pattern of postimplantation defects described in diabetic pregnancies.

Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro.

The effect of glucose and insulin on the in vitro development of the rat preimplantation embryo was studied by incubating rat blastocysts recovered on days 5 or 6 of pregnancy in the absence or presence of increasing levels of glucose and/or insulin for 24 or 48 h. A differential cell-staining method allowed the separate counting of inner cell mass (ICM) and trophectoderm (TE) cells at the end of the incubation period. In a high-glucose medium (17 mM), ICM and, to a lesser extent, TE developments were significantly and irreversibly inhibited. Low insulin concentrations (3 pM) stimulated ICM and TE development in the presence of 1.1 or 6 mM glucose. Higher insulin levels (30-600 pM) in a 6-mM glucose medium, resulted in a dose-dependent inhibition of ICM and, to a lesser extent, TE development after both 24 and 48 h. This insulin-induced inhibition was reversible if insulin was removed from the medium after 24 h. In the absence of glucose in the medium, insulin was neither stimulatory nor inhibitory on ICM growth. Dead-cell occurrence in ICM after a 48-h incubation increased with increasing glucose concentration in the medium. Insulin alone did not increase dead-cell number but enhanced the effect of glucose. These results show that, in the presence of glucose, insulin might be stimulatory (at low concentrations) or inhibitory (at higher concentrations) on ICM development. A high glucose level was also inhibitory and increased dead-cell occurrence. The data suggest that insulin and glucose might interact and modulate blastocyst development as a function of their respective concentrations.

Possible role for TNF-alpha in early embryopathy associated with maternal diabetes in the rat.

Tumor necrosis factor (TNF) bioactivity was assessed in culture media conditioned with uterine cells collected from control or diabetic rats on days 5 and 8 of pregnancy. On both days, diabetic uterine cells released significantly more biologically active TNF than did control cells, and this activity was significantly decreased by the addition of anti-TNF-alpha antibodies but not by the addition of normal IgG when WEHI 164 cells were used as a target. When uterine tissues from day 5 or day 8 pregnant diabetic rats were tested by Northern blot analysis, TNF-alpha mRNAs were twofold more abundant than in control samples, but the difference was not statistically significant (P = 0.086 and 0.100, respectively). Immunohistochemical analysis of diabetic day 5 uterine sections revealed that most of the TNF-alpha synthesis occurs in the epithelium lining the uterine lumen. Finally, the growth of day-5 embryos in culture medium conditioned with day-5 diabetic uterine cells was significantly reduced when compared with that of embryos in medium conditioned with control cells. Embryonic development was markedly improved when anti-TNF-alpha antibodies were added to the diabetic-cell conditioned medium. Our data support the hypothesis that TNF-alpha may be implicated in the developmental deficiencies observed in preimplantation embryos from pregnant diabetic rats.

Expression and role of Bcl-2 in rat blastocysts exposed to high D-glucose.

Bcl-2 mRNA expression was detected in rat blastocysts by in situ hybridization. The distribution of mRNA expression was rather heterogenous, with approximately 2% of high-expressing cells. In vitro exposure to 28 mmol/l D-glucose for 24 h resulted in a significant increase in the proportion of these cells compared with control embryos in either 6 mmol/l D-glucose or 28 mmol/l D+L-glucose. Heterogeneity in the expression of Bcl-2 was also observed at the protein level by immunocytochemistry. Exposure to 28 mmol/l D-glucose significantly increased the incidence of chromatin degradation (karyolysis) and nuclear fragmentation (karyorhexis), two nuclear markers of apoptosis in rat blastocysts. When two different antisense oligodeoxynucleotides designed to block Bcl-2 expression were added to 28 mmol/1 D-glucose, the incidence of karyolysis (but not karyorhexis) was increased compared with embryos in 28 mmol/l D-glucose alone. These data suggest that Bcl-2 is involved in the protective response against the induction of karyolysis in blastocysts on their exposure to high concentrations of D-glucose in vitro, whereas karyorhexis appears to result from the activation of an intracellular pathway that is independent of Bcl-2.

Normalization of estradiol receptor kinetics and hormonal activity in uterus of streptozotocin-induced diabetic rats treated with insulin.

In response to ip 17 beta-estradiol injection, ovariectomized streptozotocin-induced diabetic rats showed a decreased early and late stimulation of uterine protein synthesis as compared to nondiabetic controls. An early nuclear loss of estradiol-receptor complex and an accelerated estradiol clearance from the circulating blood were also observed in these animals. To establish whether these alterations in hormone kinetics and activity were related to the diabetic state, further investigation was done by treating diabetic animals with insulin, during 18 consecutive days after 3 to 8 months of long standing diabetes (type I treatment) or during 10 weeks starting immediately at the onset of the streptozotocin-induced disease (type II treatment). Both types of treatment either restored (type I) or preserved (type II) a normal body weight, low glycemia, and absence of glycosuria. Both types of treatment also restored a normal hormonal clearance so that higher plasma levels of estradiol at 30 and 90 min were noted after ip injection when compared to untreated diabetics. Nuclear retention of the estradiol-receptor complex was significantly higher in treated diabetics at 210 min as compared to the nondiabetic controls. Finally, stimulation of early protein synthesis at 90 min was normalized after both types of treatment. From the above observations it is concluded that insulin treatment restored a normal estrogen metabolism in diabetics, resulting in a prolonged retention of the estradiol-receptor complex in the uterine nuclei; the latter event in turn elicited a normal hormonal activity on protein synthesis. A direct influence of the diabetic state and of insulin treatment on the receptor kinetics and/or on the tissue response to the hormonal stimulus may however not be excluded.

Expression of tumor necrosis factor-alpha (TNF alpha) receptors and selective effect of TNF alpha on the inner cell mass in mouse blastocysts.

The presence of tumor necrosis factor-alpha (TNF alpha) receptors was demonstrated at the cell surface of mouse blastocysts by indirect immunofluorescence. Amplification of total cDNA from these embryos indicated that only the p60 form of the TNF alpha receptor was expressed. Amplification of the p80 form remained negative. Blastocysts were cultured with 0.5, 5.0, or 50 ng/ml TNF alpha and examined for their morphology and cell proliferation rate. Doses of 5.0 and 50 ng/ml delayed the morphological development after 24 h, but this effect was no longer detected after 48 h. Overall cell proliferation was decreased by 15% with 50 ng/ml TNF alpha after 24 h and with all three concentrations after 48 h. Differential staining of the two embryonic cell lineages revealed that the reduction in cell number was at the expense of the inner cell mass, the cell group responsible for forming the fetal layers after implantation. This inhibition was not mediated by cytotoxicity, as the proportion of dead ICM cells remained low in the presence of TNF alpha. Our data indicate that the expression of TNF alpha receptors is developmentally regulated before implantation, and that preimplantation embryos are responsive to TNF alpha.

Estrogen and progestogen receptors in the implantation sites and interembryonic segments of rat uterus endometrium and myometrium.

Estrogens play a central role in the mechanism of blastocyst implantation. Whether the blastocyst itself contributes to this hormonal effect by locally releasing estrogens at the site of implantation remains debatable. Indirect evidence of estrogen production by the embryo could be obtained if specific estrogenic effects were found to a greater extent at the implantation sites, when compared to the interembryonic segments. Six-day pregnant rats were injected in the morning with Evans' blue, and the uterine blue stripes revealing the implantation sites were separated from the interembryonic segments. Endometrial and myometrial portions of the two sites were separately pooled and analyzed for protein, estradiol receptor (E2R) and progesterone receptor (Prog.R) contents, in cytosol and nuclear fractions. The present results show a significantly higher protein concentration in cytosol of endometrium (20 +/- 6.2 vs. 12 +/- 7.6) (means +/- SD) and, to a lesser extent, in the cytosol of myometrium (10 +/- 2.5 vs. 8.1 +/- 2.2 mg/mg DNA) at the implantation sites as compared to interembryonic segments. Protein levels were slightly higher in nuclei of endometrium only (8.3 +/- 3.4 vs. 6.4 +/- 4.5 mg/mg DNA). E2R concentrations were significantly lower in cytosol of endometrium from implantation sites (3.5 +/- 1.4 vs. 5.0 +/- 2.6 pmol/mg DNA), whereas nuclear levels were higher (0.63 +/- 0.38 vs. 0.47 +/- 0.24 pmol/mg DNA); nuclei-cytosol ratios were significantly higher in endometrium from implantation sites (16 +/- 7 vs. 9.7 +/- 5%). In myometrium no differences were observed between the two sites. Prog.R were higher both in cytosol (3.3 +/- 1.0 vs. 2.0 +/- 0.3) and in nuclei (3.0 +/- 1.2 vs. 1.4 +/- 0.7 pmol/mg DNA) of endometrium from implantation sites; nuclei-cytosol ratios were also higher (97 +/- 32 vs. 71 +/- 34%). In myometrium, differences between the sites were minimal. Our results show higher protein concentration in endometrium from implantation sites, mostly in cytosol and to a lesser extent in nuclei; lower cytosol but higher nuclear E2R concentrations, and both higher cytosol and nuclear Prog.R concentrations in endometrium from implantations sites, and strongly suggest a local estrogenic effect on tissues in close vicinity of the blastocyst. Thus they favor the hypothesis of estrogen release by the embryo itself.

Ontogeny of liver somatotropic and lactogenic binding sites in male and female rats.

Developmental changes in liver somatotropic (GH) and lactogenic (PRL) binding sites were evaluated in male and female rats from birth to sexual maturity, and compared with growth velocity, plasma GH, PRL, testosterone, and estrogens. The affinity (Ka) and the concentration of these sites were determined from the analysis of equilibrium saturation curves with [125I]bovine GH and [125I]ovine PRL, incubated with liver homogenates. GH receptors rose from 6.4 fmol/mg protein at 8 days of age to 30.3 fmol/mg protein in males and 39.4 fmol/mg protein in females at 28 days. This surge occurred concomitant with the fall of plasma GH observed after birth. It preceded by about 1 week the acceleration of growth velocity and the increase of plasma GH seen at puberty. After the peak of growth velocity (42 days), GH receptors increased steadily until 120 days in females (63.8 fmol/mg protein), whereas in males they reached a concentration of 33.5 fmol/mg protein after a transient decrease to a nadir of 13.3 fmol/mg protein a day 50. From day 8 to day 35, PRL receptors in males remained at a constant level of 10.3 fmol/mg protein, whereas in females they increased progressively from 4.8 to 21.5 fmol/mg protein. Thereafter, in most pubertal males, they became undetectable, whereas plasma testosterone was rising. In contrast, PRL receptors in females increased 3-fold between day 42 (18.9 fmol/protein) and day 50 (50.2 fmol/mg protein). Between days 8 and 120, the Ka of GH and PRL receptors showed no significant changes with age and sex (GH: 0.66 X 10(9) M-1; PRL: 0.97 X 10(9) M-1). In conclusion, the rise of liver GH receptors occurring before puberty in male and female rats may be of importance for the initiation of the pubertal growth spurt. The inverse relationship between plasma testosterone and liver PRL receptors in pubertal male rats suggests that physiological concentrations of testosterone may inhibit PRL receptors. In contrast, in female rats an opposite change of PRL receptors is observed during puberty.

Quantitative determination of sex hormone-binding globulin capacity in the plasma of normal and diabetic pregnancies.

Sex hormone-binding globulin (SHBG) capacity was measured in a longitudinal study in plasma samples from normal subjects, diabetics, and gestational diabetics and throughout pregnancy, together with unconjugated plasma estradiol. In normal women SHBG capacity (expressed in ng DHT bound per ml of plasma) increased from 23.7 +/- 13.7 (SD) in the 5-8th week period, to 74.5 +/- 20.7 in the 17-20th week period, and to 102 +/- 24 in the 37-40th week period. In diabetics the SHBG capacity for the same periods of time were respectively: 25.3 +/- 17.2, 83.1 +/- 29.1, and 111.6 +/- 22.6. Plasma levels of unconjugated estradiol were 55% higher in the diabetics than in the normal subjects in the second half of gestation, as reported in detail in another publication. From the imbalance between the close to normal SHBG capacity and the higher plasma levels of unconjugated estradiol in the diabetics, it is suggested that the unbound, i.e., metabolically active, fraction of plasma estradiol reaches higher levels in diabetics than in normal subjects in the second half of gestation.

Angiotensin-II stimulates estradiol secretion from human placental explants through AT1 receptor activation.

A complete renin-angiotensin system has been shown to be present in human placenta, but its physiological role is poorly known. To investigate the implication of this system in the regulation of steroid hormone secretion, we studied the effect of angiotensin-II on the release of estradiol and progesterone from human placental explants. Our experiments showed that angiotensin-II stimulated estradiol secretion from term placental explants in a dose- and time-dependent fashion, although progesterone release was unaffected. Estradiol release induced by angiotensin-II (0.2 mumol/L) was blocked by angiotensin AT1 receptor antagonist losartan in a dose-dependent manner, suggesting the involvement of the AT1 receptor subtype in the process. On the contrary, the angiotensin AT2 receptor antagonist PD123319 (1 mumol/L) or the angiotensin AT2 receptor agonist CGP42112A (1 mumol/L) had no effect. Analysis of the amount of steroid hormones in the placental tissues incubated for 12 h showed that angiotensin-II increased estradiol production by 34% compared with the unstimulated explants, whereas the total levels of the estrogen precursor androstenedione and testosterone were decreased by 30-45% in the presence of the peptide, suggesting a stimulatory effect on the aromatization step. This hypothesis was reinforced by the absence of effect of angiotensin-II on both estradiol and testosterone concentrations in the placental explants pretreated with the aromatase inhibitor 4-hydroxyandrostenedione (25 mumol/L). Progesterone synthesis was not affected by angiotensin-II. The present study indicates that angiotensin-II induces the secretion of estradiol from human placenta through the angiotensin AT1 receptor subtype activation, and this effect seems to be linked to the stimulation of local androgen aromatization.

Down-regulation of angiotensin AT1 receptor by progesterone in human placenta.

Regulation of the angiotensin AT1 receptor in human placenta is poorly understood. In this study, we analyzed the time course of angiotensin AT1 receptor expression, internalization, and recycling by human trophoblast cells. We also studied the effects of estradiol, progesterone, and chloroquine on regulation of the angiotensin AT1 receptor in 48-h cell culture. The angiotensin II receptor expression increased with the time of incubation, reaching a level at 48 h of culture that was about 120% above the initial value. A large majority of angiotensin II receptors was of the AT1 subtype, as it was completely inhibited by losartan (1 mumol/L). The internalization of [125]angiotensin II binding and the angiotensin AT1 receptor recycling were also time dependent, with t1/2 values of 12 and 21 min, respectively. In human trophoblast cells exposed to progesterone (10 mumol/L) for 48 h, angiotensin AT1 receptor density was decreased by 49%, whereas estradiol (10 mumol/L) or chloroquine (100 mumol/L) treatment was ineffective. In the freshly isolated trophoblast cells initially treated with unlabeled angiotensin II (200 nmol/L) for 30 min, chloroquine was shown to decrease angiotensin AT1 receptor recycling by 73%, whereas estradiol and progesterone had no effect. These findings indicate that progesterone induces a down-regulation of the angiotensin AT1 receptor in human placenta and that the recycling of this receptor can be delayed by chloroquine.

Feminizing testicular Leydig cell tumor: hormonal profile before and after unilateral orchidectomy.

The effect of chronic hyperestrogenism on gonadal function was studied in three men who had estrogen-secreting Leydig cell tumors before unilateral orchidectomy and for 11-43 months after surgery. All three men had low plasma gonadotropin and testosterone levels and increased estradiol levels. Impairment of testicular steroidogenesis was also suggested by increased progesterone to 17-hydroxyprogesterone and 17-hydroxyprogesterone to androstenedione ratios in both spermatic venous plasma and the medium of Leydig tumor cells from one patient incubated in vitro. Before surgery, spermatogenesis was abnormal in two men. Testicular endocrine function and spermatogenesis did not return to normal after surgery. During the follow-up period, plasma gonadotropin levels were high in all three men, and testosterone was low normal. Estradiol levels decreased to normal immediately after surgery and then returned to the upper normal limit. The response to hCG stimulation in one man was subnormal. We conclude that chronic hyperestrogenism produced hypothalamo-pituitary inhibition as well as direct steroidogenic blockade at the testicular level. Long term impairment of both endocrine and exocrine testicular functions may be secondary to slowly reversible (or irreversible) estrogen-induced damage to tubular and Leydig cells.

Secretion rates of LH and FSH during infusion of LH-FSH/RH in normal women and in patients with secondary amenorrhea: suggestive evidence for two pools of LH and FSH.

Normal women in the early follicular phase and in the luteal phase of the cycle, and patients with secondary amenorrhea received on consecutive days a rapid intravenous injection (50 mug) and a two or four-hour infusion (25 mug/h) of synthetic LH-FSH/RH. The responses of LH and FSH were evaluated by the measured plasma concentrations, as well as by the calculated pituitary secretion rates and by the amounts of hormone released. To estimate these pituitary secretion rates of LH and FSH, a simplified mathematical model is proposed. During an infusion of LH-FSH/RH the secretion rates of both LH and FSH increased in the three groups of women in a biphasic way with a dip after 1 to 2h of infusion, suggesting that besides the pool mobilized by a rapid intravenous injection of LH-FSH/RH there is a second pool of (stored) gonadotropins. For LH the increase above baseline concentrations was higher in group II (luteal phase) than in group I (follicular phase) or in group III (amenorrhea) and this both after a bolus injection and during infusion of LH-FSH/RH. For FSH a similar pattern of response prevailed during an infusion of LH-FSH/RH. After a bolus administration, however, the FSH release was relatively higher in group III (amenorrhea) than in both groups of normal women in which the increases were about the same. The latter finding suggests that the first pool of FSH is released by a different mechanism than the second pool.

Particle counting immunoassay of choriogonadotropin using monoclonal antibodies.

A latex particle immunoassay has been developed for the quantification of choriogonadotropin in human serum using two monoclonal antibodies specific for the beta-chain of the hormone. The assay, based on optical counting of monomeric particles, was achieved in 40 min and the calibration curve was linear between 10 and 200 IU/l. Intra- and interassay precisions at three different levels of the curve varied between 3.3 and 10.9%. The method was validated by comparison with two different radioimmunoassays and correlation coefficients of 0.97-0.99 were obtained.

Angiotensin II and its different receptor subtypes in placenta and fetal membranes.

The recent discovery of a local renin-angiotensin system in trophoblastic tissues has raised many questions regarding its role in the physiology of normal gestation and its implications in the pathophysiology of hypertension during pregnancy. In this article, the authors first review the most interesting aspects of the chorioplacental renin-angiotensin system, dwelling on the tissue distribution of angiotensin II and its receptor subtypes in the placenta and fetal membranes of different species. The relationship between angiotensin II and other locally synthesized chorioplacental substances is also analysed and the therapeutic implications of phenomena observed in pregnancy-associated hypertension are discussed.

The Pattern of Plasma Insulin Response to Glucose in Patients with a Previous Myocardial Infarction-The Respective Effects of Age and Disease.

Plasma insulin and blood sugar variations were investigated during oral (OGTT) and intravenous (IVGTT) glucose tolerance tests in 10 patients aged 32 to 41 and 10 Patients aged 48 to 60 who had suffered a myocardial infarction at least three months previously. The results obtained in each group of patients were compared with those of ten normal subjects of corresponding age. The respective influences of age and cardio-vascular disease on the pattern of the plasma insulin and blood sugar responses to the glucose load were dissociated on the basis of analysis of variance.-Advancing age was associated with a rise in the mean blood sugar level during OGTT and a lowering of the glucose assimilation coefficient during IVGTT, but it was not accompanied by a significant change in the plasma insulin levels during either of the two tests.-Cardiovascular disease was associated with an augmentation of the mean blood sugar level during OGTT, but also with a prolonged and excessive response in plasma insulin. During IVGTT the glucose assimilation coefficient and the plasma insulin variations were not statistically different in the patients with a previous myocardial infarction and in the normal subjects.-The previous occurrence of a myocardial infarction is thus associated with a hyperinsulinism during OGTT, but not after a rapid stimulation as realized during IVGTT. The nature of the gastrointestinal factors involved in the genesis of this hyperinsulinism remains a matter of conjecture.

Down regulation of the angiotensin II receptor subtype AT2 in human myometrium during pregnancy.

Samples of human myometrium have been collected during pregnancy and from non-pregnant women. Binding studies revealed the presence of a 50-fold higher density of angiotensin II AT2 receptor in the non-pregnant state than during gestation. Low levels of the AT1 receptor subtype (approx. 20 fmol/mg protein) were detected in both pregnant and non-pregnant myometrium. Outside pregnancy, the AT2 receptor accounted for greater than 95% of all angiotensin receptors, whereas during pregnancy the value dropped to about 40%. The down regulation of the human myometrial AT2 receptor during pregnancy may be related to the high hormonal content of the environment induced by gestation. The mechanism by which the AT2 receptor is regulated appears to be different to that of the AT1 receptor.