Fetal Insulin Levels Research Articles

Effect of maternal diabetes upon fetal rat myocardial and skeletal muscle glucose transporters.

We investigated the effect of streptozotocin-induced short-term maternal diabetes upon fetal rat myocardial and skeletal muscle glucose transporter Glut 1 (basal form) and Glut 4 (insulin-responsive form) protein concentrations by Western blot analysis. In the severely diabetic group (SEVERE-D, n = 17), a 3-fold increase in maternal and fetal glucose concentrations (p < 0.01) was associated with a 3-fold decline in maternal (p < 0.01) with no change in fetal insulin levels when compared with the streptozotocin-treated nondiabetic (n = 10) and vehicle-treated control (control, n = 14) groups. These changes in the SEVERE-D group when compared with controls were associated with a 30 and 65% decline, respectively, in fetal myocardial and skeletal muscle (forelimb and hind limb) Glut 1 protein concentrations. The fetal myocardium also demonstrated a 45% decline in Glut 4 protein levels. Fetal skeletal muscle Glut 4 protein, which was expressed only at very low levels in controls showed no change in SEVERE-D. Immunohistochemical analysis revealed a myocyte-plasma membrane association of Glut 1 and an intracellular Glut 4 distribution in the fetal myocardium and skeletal muscle. No Glut 1 immunoreactivity was noted in either the fetal myocardial or skeletal muscle perineural sheaths, blood vessels, or the entrapped fetal red blood cells. This subcellular localization pattern was unaltered in all three treatment groups. We conclude that maternal diabetes causing fetal hyperglycemia with normoinsulinemia suppresses fetal myocardial Glut 1 and Glut 4 and fetal skeletal muscle Glut 1. The decline in the plasma membrane associated Glut 1 concentrations may serve a protective function by reducing the glucose transport rate into fetal myocardial and skeletal muscle cells, which otherwise could be vulnerable to high circulating glucose. The in-utero maternal diabetes induced decrease in fetal myocardial intracellular-Glut 4 concentration could herald the emergence of insulin resistance.

925-39 Prenatal Hypertrophic Cardiomyopathy and its Association with Amniotic Fluid Insulin in Fetuses of Diabetic Mothers

The frequent presence of a disproportionate hypertrophic ventricular septum in infants of diabetic mothers, as well as its benign course, has been widely reported. This phenomenon has also been demonstrated in the fetus. The most accepted hypothesis to explain this disorder, yet to be proved in the prenatal period, is fetal hyperinsulinism due to inadequate control of maternal diabetes. This prospective controlled tra nsversal study was carried out to test the hypothesis that hypertrophic cardiomyopathy during prenatal life in diabetic pregnancies is related to fetal hyperinsulinism as assessed by amniotic fluid insulin levels. Sixty-five fetuses (37 of diabetic mothers and 28 of hypertensive mothers) were studied sequentially and non-intentionally. A comprehensive M-mode and cross-sectional Doppler echocardiogram, with color flow mapping, was performed within one week of the amniocentesis in every case. Fetal insulin levels and interventricular septum thickness were considered abnormal when their values were above 2 standard deviations, according to local nomograms. Statistical analysis utilized Student's “t” test, Fisher's exact test, ANOVA and Kruskal-Wallis test. The mean gestational age at the time of examination was 32.3 ± 3.5 weeks (24 – 39 weeks) in the gestational diabetes group, 28.5 ± 2.7 weeks (23 – 33 weeks) in the previous diabetes group and 30.6 ± 3.1 weeks (25 – 36 weeks) in the control group. Mean septal thickness was 3.7 (2.2 to 6.3 mm) in the group of diabetic mothers and 3.0 (2.0 to 4.3 mm) in the control group (p &lt; 0.01). Mean fetal insulin levels was 14.7 ± 16.8 microlU/ml (3.2 to 75.3 microlU/ml) in the group with diabetes and 6.4 ± 3.3 microlU/ml (3.1 to 17 microlU/ml) in the control group (p &lt; 0.01) Median insulin levels were 8.7 and 5.5 microlU/ml in the diabetes and in the control group, respectively. Ten out of 37 fetuses of the diabetic group were considered to have hypertrophic cardiomyopathy (27%). while none of the fetuses of the control group showed increase in the septal thickness (p &lt; 0.01). A significant association between prenatal hypertrophic cardiomyopathy and fetal hyperinsulinism was demonstrated (p &lt; 0007). We conclude that there is association between the presence of hypertrophic cardiomyopathy during prenatal life and high levels of fetal insulin in diabetic mothers, thus justifying efforts to improve the glucemic control in pregnancies with this frequent complication.

Expression of genes involved in placental glucose uptake and transport in the nonobese diabetic mouse pregnancy

Maternal diabetes alters placental glucose metabolism and maternofetal glucose transport. The purpose of this study was to determine whether genes involved in placental glucose uptake and transport were concomitantly altered, resulting in the observed changes in the state of maternal diabetes. By means of the nonobese diabetic pregnant mouse we examined the expression of placental glucose transporters, hexokinase I, glycogen content, glycogen-regulating enzyme activities in control animals (blood glucose 8.5 +/- 0.2 mmol/L, n = 25), moderate maternal diabetes (blood glucose 10 to 13.9 mmol/L, n = 16), and severe maternal diabetes (blood glucose > 16.7 mmol/L, n = 12). Comparisons by the analysis of variance and the Newman-Keuls test were performed. Although changes in placental glucose transporters and hexokinase I messenger ribonucleic acid levels occurred, neither state of diabetes altered the corresponding protein levels. Changes in placental deoxyribonucleic acid (p < 0.05) and glycogen content (p < 0.01), fetal insulin levels (p < 0.02), and fetal size (p < 0.05) occurred in the moderately diabetic group, and changes in placental weight (p < 0.05) and fetal glucose levels (p < 0.02) were observed in the severely diabetic group. Placental glucose transporting and phosphorylating protein levels by themselves do not regulate diabetes-induced fetoplacental alterations. The lack of a protective decline in these proteins may account for the observed fetoplacental adaptations to excess glucose.

Carbohydrate metabolism in fetuses with Rh alloimmunization.

Glucose, insulin, glucagon and fructosamine were measured in the plasma of control (n = 34) and of Rh fetuses (n = 22) before the first and subsequent transfusion. Prior to treatment, Rh fetuses, compared to controls, had raised concentrations of glucose (p = 0.01), glucagon (p = 0.04) and fructosamine (p = 0.004). Fetal insulin levels were not significantly different. Before subsequent transfusion, despite correction of anemia, Rh fetuses were clearly hyperinsulinemic even after correction for gestation (p = 0.002) and had low glucagon concentrations (p = 0.01) when compared with values at the first transfusion. This metabolic milieu appears similar to that of fetuses of diabetic mothers which have increased plasma glucose and insulin during most of the last third of gestation.

The nutritional regulation of circulating placental lactogen in fetal sheep.

Maternal and fetal plasma ovine placental lactogen (oPL), insulin, and IGF-I levels were measured in response to the starvation and refeeding of pregnant sheep on two defined planes of nutrition. Chronically catheterized pregnant ewes were placed on either a high plane (n = 5) or low plane (n = 5) of nutrition at least 1 wk before the experiment. At 125 to 135 d gestation, the ewes were starved for 72 h and then an i.v. infusion of 10% glucose was administered over 4 h, followed by refeeding at the designated nutritional plane. Plasma oPL levels of fetuses whose mothers had been on a high plane of nutrition were significantly higher during starvation (p less than 0.05) than those of fetuses whose mothers had been on a low plane (high + 0.54 +/- 0.17 and low -0.02 +/- 0.17 nmol/L from mean control levels). Intravenous glucose infusion to the ewes at the end of starvation caused a marked rise in fetal plasma oPL levels in both groups (increments of 2.61 +/- 1.4 nmol/L in the high group and 2.81 +/- 1.16 nmol/L in the low group). Maternal oPL levels did not differ significantly between the two nutritional groups during starvation and did not change during glucose infusion. Fetal and maternal plasma IGF-I levels both fell during starvation. Maternal IGF-I levels fell faster in the high group (-17.9 +/- 4.5 at 24 h versus -4.7 +/- 7.2 nmol/L in the low group), but the groups were not different at the end of starvation.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolic clearance rate of epinephrine in the fetus of the diabetic ewe

Delayed organ maturation is a characteristic of the fetus of the diabetic mother with poor glucose control. We hypothesized that the ovine fetal catecholamine maturation sequence would be delayed in the fetus of the diabetic ewe. Twelve pregnant ewes were rendered glucose intolerant by the administration of streptozocin at 85 to 95 days' gestation. Maternal diabetic status was verified with fasting blood glucose assessments. The fetal metabolic clearance rate of epinephrine was determined at 126 to 140 days' gestation by the constant infusion of 0.1 μg epinephrine per kilogram estimated fetal weight per minute. Fetal arterial blood gas values, lactate, glucose, and insulin levels were measured before infusion; after 20, 30, and 40 minutes of epinephrine infusion; and 15, 30, and 60 minutes after cessation of infusion. Fetal plasma glucose rose significantly from a control level of 42.1 ± 8.2 to 64.6 ± 5.9 mg/dl during the epinephrine infusion (p < 0.05). Fetal insulin levels increased from a baseline of 9.2 ± 2.6 μIU/ml to 32.4 ± 18.0 in the recovery period (p < 0.05), and lactate levels similarly rose from 36.4 ± 4.8 to 52.2 ± 8.2 mg/dl (p < 0.05). The plasma epinephrine production rates did not vary significantly between fetuses <135 and τ135 days' gestation (15.4 ± 1.5 vs 13.9 ± 2.0 ng/min, p τ 0.5). The fetal metabolic clearance rate of epinephrine at early gestations (< 135 days) was similar to that of the fetus of the nondiabetic ewe (35.3 ± 3.4 vs 28.0 ± 4.3 ml/min/kg, p τ 0.2). However, at later gestations (τ135 days) the fetus of the diabetic ewe did not have the increase in the metabolic clearance rate previously published for the control fetus (32.0 ± 4.6 vs 133.7 ± 41.7 ml/min/kg, p < 0.05). These data appear to indicate an absence in the maturation of the metabolic clearance rate of epinephrine in the fetus of the diabetic ewe. The observed alteration in the metabolic clearance rate of epinephrine of the fetus of the diabetic ewe could potentially impair the response to stress. (AM J OBSTET GYNECOL 1991;165:1655-60.)

Fetal catecholamine responses to maternal hypoglycemia

The present studies were designed to determine the fetal catecholamine and metabolic responses to insulin-induced maternal hypoglycemia. Maternal hypoglycemia was induced by a primed constant infusion of insulin and glucose administered to pregnant ewes to maintain maternal glucose at 20-25 mg/dl. Maternal and fetal samples for measurement of catecholamine, glucose, and free fatty acid levels and arterial blood gas analysis were collected before insulin infusion and at intervals thereafter for 6 h. Maternal and fetal plasma catecholamine levels increased significantly in response to hypoglycemia (analysis of variance, P less than 0.01). Fetal insulin and glucagon levels did not change despite a 50% reduction in fetal whole blood glucose concentration. Fetal free fatty acid levels increased significantly during hypoglycemia (P less than 0.05). There were no significant changes in maternal or fetal heart rate, blood pressure, or arterial blood gases during hypoglycemia. These results suggest that the fetus is capable of responding to hypoglycemia with an increase in catecholamine and free fatty acid levels. These results are consistent with the interpretation that the fetus is able to mobilize alternative energy substrates in response to maternal insulin-induced hypoglycemia.

Endocrine Regulation of Tissue Glucose-6-Phosphatase Activity in the Fetal Sheep during Late Gestation*

Endocrine regulation of tissue glucose-6-phosphatase activity in utero was examined by measuring enzyme levels in liver and kidneys of fetal sheep during the second half of gestation and after experimental manipulation of fetal plasma cortisol and insulin levels. Tissue glucose-6-phosphatase activities increased toward term in parallel with the rise in fetal plasma cortisol. At birth, the activities were significantly higher than in utero, but significantly less than in adult nonpregnant sheep. Fetal hypophysectomy lowered fetal plasma cortisol and reduced hepatic and renal glucose-6-phosphatase activities compared with those in intact fetuses near term. Conversely, intrafetal cortisol infusion raised fetal plasma cortisol and significantly increased tissue glucose-6-phosphatase activity to values similar to those in older fetuses. When the data from these groups of fetuses and the newborn lambs were combined, there was a significant positive correlation between the plasma cortisol level and the glucose-6-phosphatase activity in both liver and kidney. Fetal hypoinsulinemia was induced by fasting the ewe for 48 h and by fetal pancreatectomy. Fetal hepatic and renal glucose-6-phosphatase activities were higher in fasted than in fed animals, while pancreatectomy had little apparent effect on enzyme activity in either tissue. However, when differences in plasma cortisol were taken into account, hepatic, but not renal, glucose-6-phosphatase activities were higher in both groups of hypoinsulinemic fetuses than would have been observed in normoinsulinemic animals with a similar plasma cortisol level. Partial correlation analysis of the data showed that plasma insulin and cortisol were both significant influences on hepatic glucose-6-phosphatase activity in utero, but plasma cortisol had the more pronounced effect. Cortisol, therefore, appears to be a physiological regulator of tissue glucose-6-phosphatase activity in utero and enhances the glucogenic capacity of the sheep fetus during late gestation.

The effects of insulin on the growth rate of the sheep fetus during late gestation.

The effects of insulin on fetal growth rates were investigated by measuring crown-rump length (CRL) chronically in sheep fetuses before and after pancreatectomy, sham operation or pancreatectomy accompanied by insulin-replacement treatment. Pancreatectomy of the fetus produced hypoinsulinaemia and reduced the daily and total increments in CRL by 40-50% over the last 20-30 days of gestation. The growth rate fell immediately after pancreatectomy and remained low throughout the rest of gestation. In contrast to the sham-operated fetus no pre-partum decline in the growth rate was observed in the pancreatectomized animal. The body weight, limb lengths and actual CRL at delivery were also significantly less after pancreatectomy than in the sham-operated animals. When fetal insulin levels were maintained after pancreatectomy by exogenous insulin infusion, the daily and total increments in CRL and the body size at delivery were restored to their normal values. Raising insulin levels above normal in the pancreatectomized fetus did not lead to additional fetal growth. When the data from all the fetuses were combined irrespective of treatment, there were significant positive correlations between the plasma insulin concentration in utero and the mean daily increment in CRL after treatment and between the former value and the body weight at delivery. These observations demonstrate that insulin is a major determinant of the growth rate in utero and that it is required throughout late gestation for the normal growth and development of the sheep fetus. They also indicate that insulin deficiency is probably the primary cause of the growth retardation observed after fetal pancreatectomy.

Oxygen consumption and guanosine diphosphate binding by fetal brown adipose tissue in diabetic pregnancy

Oxygen consumption and 3H-guanosine diphosphate (GDP) binding were determined in brown adipocytes and mitochondria from 28-day gestation fetuses of alloxan-diabetic rabbit does and saline-injected controls. Maternal diabetes was classified as severe or mild determined by whether maternal blood glucose values were greater or less than 200 mg/dL, respectively, at death. Basal oxygen consumption and adipocyte diameters did not vary among groups. A significant reduction in maximal norepinephrine (NE) stimulated O 2 consumption by fetal brown adipose tissue (BAT) cells was seen in offspring of severely diabetic pregnancies when compared with control values ( 248 ± 53 ± v 482 ± 32 μ L O 2 10 6 cells/h ; P < .005 ). In contrast, a significant increase in maximal NE-stimulated O 2 consumption by fetal BAT cells occurred in offspring of mild diabetic pregnacies (807 ± 60, P < .001 v controls). A highly significant inverse correlation between serum glucose levels and maximal O 2 consumption by fetal BAT was observed in fetuses from mild and severe diabetic pregnancies ( r = −.98, P < .005), and there was no correlation between these two parameters in offspring of normal pregnancies. A significant inverse correlation was observed between maximal O 2 consumption by fetal BAT cells and serum insulin levels in offspring of both control and diabetic pregnancy ( r = −.74; P < .02). Tissue cytochrome oxidase activity was lower in offspring of severely affected diabetic does, indicating a reduction in BAT mitochondrial content compared with controls. BAT mitochondria from fetuses of severely diabetic does exhibited reduced 3H-GDP capacity, which was 2.5-fold lower than controls. These studies show that brown adipocytes obtained from offspring of severely diabetic pregnancies exhibit reduced NE-stimulated oxygen consumption. Reduced thermogenin content, indicated by lower GDP binding, is the most likely cause of the impaired oxygen consumption offspring of severely affected diabetic pregnancies.

Chronic hyperglycemia and insulin concentrations in fetal lambs

Insulin concentrations were measured in 20 chronically instrumented fetuses of 10 sheep with alloxan-induced chronic hyperglycemia and 10 control sheep to examine if the hyperglycemia resulted in high fetal insulin concentrations. Additionally, in six neonatal lambs of three chronically hyperglycemic ewes and three control sheep, insulin concentrations were measured after intravenous glucose injection. After a 2-month period of significant maternal hyperglycemia, no relationship between concentrations of fetal glucose and insulin could be detected. The mean fetal glucose concentration was 3.5 ± 0.5 mmol/L in the hyperglycemic group and 0.6 ± 0.1 mmol/L in the control group. Mean fetal insulin levels were 12.5 ± 1.4 and 10.7 ± 1.3 μU/ml, respectively. The neonatal lambs of the hyperglycemic and control ewes showed comparable concentrations of glucose and insulin after infusion of glucose. It is presumed that persistent high glucose levels depress the insulin secreting capacity of the fetal pancreas.

Effects of glucose infusion on surfactant and glycogen regulation in fetal lamb lung.

To investigate the increased incidence of respiratory distress syndrome (RDS) that occurs in infants of diabetic mothers (IDM) with poor maternal glucose homeostasis, we infused glucose intravenously at a rate of 14 +/- 2 (SD) mg.kg-1.min-1 into eight twin and four singleton chronically catheterized fetal lambs from 112 days (0.77) gestation onward. Twelve catheterized and seven uncatheterized fetuses served as controls, including the eight twins of the glucose-treated fetuses. Glucose infusion resulted in a twofold elevation in fetal serum glucose levels and a 2.2-fold elevation in fetal serum insulin levels. Before 113 days (0.9) gestation, pulmonary disaturated phosphatidylcholine (DSPC) content was 1.5-fold higher in the glucose-infused fetuses than in the controls. However, after 0.9 gestation, pulmonary DSPC content increased 2.2-fold in the controls but did not increase significantly in the glucose-infused fetuses. In addition, the DSPC content of lung lavage was 5.0-fold higher in the controls and lung stability to air inflation was 2.0-fold greater and to deflation was 2.2-fold greater than in the glucose-infused fetuses. Pulmonary adenosine 3',5'-cyclic monophosphate-dependent protein kinase activity was also 1.5-fold higher, and pulmonary protein kinase C activity was 1.3-fold higher in the controls than in the glucose-infused fetuses. In contrast, glucose infusion was associated with a 1.8-fold increase in pulmonary glycogen content and with increased activities of glycogen phosphorylase kinase and glycogen phosphorylase. We conclude that the effects of chronic glucose infusion on fetal lamb lung DSPC and lung stability are compatible with a predisposition of the fetus to develop RDS.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the dynamics of insulin secretion and the regulatory mechanism of insulin receptor in fetal rats

In order to clarify the onset of insulin secretion and the regulatory mechanism of its receptor induction in fetus, blood glucose, serum insulin and its hepatic receptor in situ in fetal rats (D18-D21) were measured and the changes of the levels of insulin and its receptor after the direct injection of glucose (1g/kg) to fetal rats in utero were investigated. In fetal rats (D18-D21), both serum insulin and glucose levels increased as pregnancy progresses and specific binding of insulin in fetal liver microsomal membranes increased on D21 of gestation, mainly due to the increase in binding affinity rather than binding capacity. After the direct injection of glucose to the fetus in utero, the rapid increase in serum insulin and the rapid decrease in insulin specific binding to liver microsomal membranes were observed in a part of D20 and all of D21 fetal rats, which was mainly due to the decrease of binding capacity. This suggests that the acute elevation of endogenous insulin level followed by the decrease of insulin specific binding in fetal rat liver is based on the down regulation mechanism of insulin receptor, because the amounts of insulin separated from liver microsomal membranes were less than one twentieth of the insulin concentration which are enough to decrease the binding capacity of hepatic receptor theoretically. In addition, the dissociation of 125I-insulin from liver microsomal membranes of glucose-treated rats were indistinguishable from that of control. From these results, it can be concluded that the onset of glucose-stimulated insulin secretion appears in fetal rats on D20 of gestation and the elevation of endogeneous insulin rapidly down-regulates the number of hepatic insulin receptor in fetal rats.

Fetal plasma insulin and thyroid hormone levels during acute in utero ethanol exposure in a maternal-fetal sheep model.

The effects of acute in utero ethanol (ETOH) treatment on basal and stimulated thyroid and insulin levels in fetal plasma were studied in chronically cannulated fetal sheep. In test situations, pregnant ewes (0.78-0.88 gestation) which were chronically cannulated received 2 g/kg ETOH [25% (vol/vol) in isotonic saline] for 2 h; this was followed by a maintenance iv infusion of 0.13 g/kg ETOH. Control animals received isovolemic infusions of isotonic saline. Fetal arterial plasma samples were obtained after the 2-h infusion, and basal levels of T3, T4, glucose, and insulin were measured. The 2-h ETOH infusion did not influence fetal basal plasma T3, T4, insulin, or glucose. Fetal thyroid responses to an intraarterial injection of 0.01, 0.10, 1.00, or 10.00 micrograms/kg TRH or of 5 mU/kg TSH through the fetal catheters were studied in the presence or absence of high plasma ETOH concentrations. Fetal T4 or T3 levels during the 4 h following any of these stimuli were not significantly different in ethanol-treated and control animals. The effects of acute ETOH exposure on insulin responses to a glucose challenge were studied in six chronically cannulated ewes and their fetuses using a cross-over experimental design. After the 2-h ETOH infusion, ewes received a bolus injection of 600 mg/kg 50% glucose, followed by a 1-h infusion of 624 mg/kg 50% glucose and 0.13 g/kg ETOH. In control situations, ewes received saline plus glucose. Acute ETOH treatment did not influence maternal or fetal plasma glucose levels at any time, but enhanced both maternal and fetal insulin responses to glucose. Total insulin release, as measured by the area under the insulin response curve, was greater during ETOH exposure in both mother (ETOH, 4740 +/- 1475 microU/ml X min; control, 2807 +/- 766 microU/ml X min; P = 0.05) and fetus (ETOH, 562 +/- 94 microU/ml X min; control, 363 +/- 46 microU/ml X min; P less than 0.05). Thus acute in utero ETOH exposure does not diminish plasma levels of either thyroid hormones or insulin, two important hormones for fetal growth and development. However, ethanol exposure enhances the insulin response to increases in blood glucose in both mother and fetus.

Multihormonal control of tyrosine aminotransferase activity in developing rat liver.

Tyrosine aminotransferase (TAT) enzymatic activity was undetectable in fetal rat liver until 1 day before birth (21 days). In utero injection of (Bu)2cAMP induced both catalytic and mRNA activity. By contrast, in utero injection of hydrocortisone acetate did not elicit the appearance of TAT enzyme or its functional mRNA. Injection of both the steroid hormone and the cyclic nucleotide elicited the appearance of nearly adult levels of the enzyme and its mRNA. By 24 h after injection of (Bu)2cAMP alone or in combination with hydrocortisone acetate, enzymatic activity had returned to basal levels. Functional TAT mRNA levels, however, remained elevated. The role of insulin as a potential repressor of TAT activity in utero was examined. Reducing circulating fetal insulin levels by injection of streptozotocin was not sufficient to induce TAT enzyme activity. In vitro, either (Bu)2cAMP or hydrocortisone acetate alone induced TAT enzymatic activity in liver explants from fetuses as early as the 16th day of gestation. Explants from fetuses in the 20th day of gestation were able to maintain induced levels of TAT enzymatic activity 48 h after removal from medium containing hydrocortisone.

Chronic Hyperinsulinemia in the Fetal Rhesus Monkey: Effects of Physiologic Hyperinsulinemia on Fetal Growth and Composition

One of the hallmarks of the hyperglycemic-hyperinsulinemic infant of the diabetic mother (IDM) is macrosomia and selective organomegaly. Primary hyperinsulinemia, with insulin levels similar to those observed in human IDMs at delivery, was produced in the fetal rhesus monkey during the last third of gestation. The effects of this physiologically relevant hyperinsulinemia, in the absence of hyperglycemia, on fetal growth were studied. Fetal macrosomia, with a 23% increase in total body weight, was observed in physiologically hyperinsulinemic fetuses. A similar 27% increase in weight was produced by fetal insulin levels that were 10 times higher. A logarithmic correlation was observed between fetal birth weight ratio and fetal plasma insulin concentration. In contrast to this increase in weight, skeletal growth, as measured by crown-heel length and head circumference, was not affected by hyperinsulinemia. Only cardiomegaly was found in the low-dose hyperinsulinemic fetuses, whereas cardiomegaly, hepatomegaly, and splenomegaly were produced by hyperinsulinemia in which insulin levels were in the highest range. Compositional analysis of heart and skeletal muscle indicated no differences in the protein, RNA and DNA concentration, or in the protein-to-DNA ratio in hyperinsulinemic fetuses. We interpret these data as indicating that fetal insulin plays the predominant role in controlling the normal, as well as the augmented, fetal weight characteristic of the human infant of the diabetic mother.

A NOVEL MODEL OF MATERNAL HYPOAMINOACIDEMIA

Chronic hyperglucagonemia produces persistent hypoaminoacidemia (HA). Glucagon does not cross the placenta; therefore, the effects of low maternal amino acids on the fetus could be studied. Alzet pumps delivered glucagon (0.25 mg/d) s.c. in 8 rats fed ad lib from d. 14 to 20 of gestation. Ten controls were sham-operated. Blood was obtained prior to implantation, at d. 3, and before delivery for total amino acids (α-amino nitrogen), glucose, and insulin. Four dams (HA-A) had weight gain and caloric intake comparable to controls; the other 4 (HA-B) gained no weight and had 1/3 lower caloric intake. Glucose cone. declined comparably from d. 14 to 20 in all groups. Insulin was unaffected in HA-A, but decreased in HA-B.Fetal weight on day 20 was 4.01±0.37 g in controls (n=102), 3.90±0.51 in HA-A (45), but 3.05±0.27 in HA-B (48). Fetal glucose and insulin levels were similar as were fetal amino acid levels. The latter resulted in higher feto-maternal ratios in both HA groups (p <0.001). Thus, hypoaminoacidemia in mothers with normal weight gain did not affect fetal weight due to the ability of the conceptus to maintain total amino acid levels.

Increased fetal insulin receptors and changes in membrane fluidity and lipid composition.

Fetal tissues exposed to hyperinsulinemia in utero have significantly greater numbers of insulin receptors than do those of controls. We have studied this upregulation phenomenon using crude microsomal membranes from fetal rabbit litters exposed to varying degrees of hyperinsulinemia in diabetic pregnant rabbits. We have observed that insulin binding capacity of membranes increased directly with the severity of maternal diabetes, ranging from 8.5 ng in controls to 44.6 ng insulin/mg membrane protein in offspring of severely diabetic animals and related directly with increasing fetal insulin levels (r = 0.77, P less than 0.005). Lipid analyses of fetal lung membranes showed that reduction of phospholipid to protein ratios occurred in the presence of maternal diabetes. Membrane cholesterol-to-phospholipid ratios were also altered in the presence of maternal diabetes. Significantly, increases in plasma membrane microviscosity were noted in the membranes from diabetic offspring. The data suggest that reduction of membrane fluidity is associated with increases in fetal membrane insulin receptors in severely diabetic pregnancies.

Continuous maternal glucose measurements and fetal glucose and insulin levels after administration of terbutaline in term labor.

Maternal blood glucose and fetal blood glucose and insulin levels were studied in 16 women at full-term labor after administration of terbutaline 250 microgram i.v. The maternal blood glucose level was registered by a continuous blood glucose monitoring unit. In all patients studied, the terbutaline injection was followed by a rise in maternal blood glucose within 15 min, lasting for at least one hour. The fetal glucose levels paralleled those of the mothers, but on a lower level. None of the infants demonstrated hypoglycemia during the first 90 min after birth. We conclude that terbutaline administrated in this way has a direct effect on the maternal blood glucose release, and report that no harmful effects on fetal carbohydrate metabolism could be demonstrated.

3,5-Dimethyl-3'-isopropyl-l-thyronine therapy in diabetic pregnancy: stimulation of rabbit fetal lung phospholipids.

Diabetes mellitus in pregnancy is associated with neonatal respiratory distress syndrome due to impaired synthesis of fetal lung surfactant. Pharmacologic agents that promote fetal lung maturity are diabetogenic and have limited use in the management of diabetic pregnancy for prevention of respiratory distress syndrome. Maternal administration of a thyroid analog 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) results in significant enhancement of fetal lung phospholipid synthesis and accelerated lung maturity. We therefore studied the effects of DIMIT (0.5 mg/kg per d, s.c.) administration to pregnant alloxan-diabetic rabbits on days 25 and 26 of gestation. DIMIT treatment of diabetic maternal rabbits (DD) was associated with reduction of maternal blood glucose (115 +/- 13 vs. 275 +/- 72 mg/dl, P less than 0.05) and fetal glucose (64 +/- 6 vs. 274 +/- 47 mg/dl, P less than 0.001) compared with saline-injected diabetic (D) mothers. Reduction of fetal insulin levels was also associated with maternal DIMIT therapy in diabetic rabbits (56 +/- 5 (D) vs. 24 +/- 4 microunits/ml, P less than 0.001). Maternal diabetes resulted in significant reduction of fetal lung weight (370 +/- 20 vs. 520 +/- 30 mg, P less than 0.005) and lung protein content (6.5 +/- 0.7 vs. 8.7 +/- 0.7 mg/gm, P less than 0.005), which were restored to normal in offspring of DIMIT-treated diabetic rabbits. Maternal DIMIT administration caused significant reduction in fetal lung glycogen content in control (62 +/- 5.8 vs. 25 +/- 5.9 micrograms/mg protein, P less than 0.001) and diabetic (56 +/- 7 vs. 34 +/- 5 micrograms/mg protein, P less than 0.02) offspring. Whereas maternal diabetes was associated with reduction of all major phospholipid species in fetal lung-comprising surfactant, these were restored with DIMIT therapy. The results demonstrate that short-term maternal administration of DIMIT in pregnant diabetic rabbits not only promotes fetal lung phospholipid synthesis, but also appears to ameliorate maternal hyperglycemia. Thus, DIMIT is of potential benefit in the management of diabetic pregnancy.