Impaired insulin receptor binding and postbinding defects of adipocytes from normal and diabetic pregnant women.

To evaluate the relative contribution of insulin binding and postbinding defects of glucose utilization in peripheral tissue during normal and diabetic pregnancy, we have studied the in vitro insulin action of isolated adipocytes from eight nondiabetic pregnant women and nine pregnant women with insulin-dependent diabetes mellitus who were undergoing cesarian section. The pregnant women were compared with a matched group of normal nonpregnant women undergoing gynecologic surgery. Insulin binding to adipocytes measured at tracer insulin concentration was reduced by 45% (P less than 0.01) in normal pregnant women and by 30% (P less than 0.02) in pregnant women with diabetes. In contrast, no changes were found between the three groups in insulin binding to pure monocytes and erythrocytes. The glucose transport system in fat cells from both groups of pregnant women was characterized by impaired maximal (P less than 0.05) and half-maximal (P less than 0.05) response to insulin. When fat cell glucose metabolism was studied, pregnant diabetic women exhibited decreased basal lipogenesis (P less than 0.05) and decreased maximal responses of lipogenesis and glucose oxidation to insulin stimulation (P less than 0.05). Similar but less pronounced abnormalities were seen in glucose metabolism of adipocytes from nondiabetic pregnant women. In conclusion, both in late normal and diabetic pregnancy, insulin binding to adipocytes is significantly reduced and accompanied by decreased insulin sensitivity and reduced maximal insulin responsiveness of glucose transport and by impaired basal and maximally insulin-stimulated glucose metabolism.

Phosphorylated insulin-like growth factor binding protein 1 is increased in pregnant diabetic subjects.

During pregnancy, IGFs and their binding proteins (IGFBPs) are important for the growth of fetal and maternal tissues. IGFBP-1 normally circulates as a single, highly phosphorylated species (hpIGFBP-1). However, in pregnancy there are lesser phosphorylated isoforms (lpIGFBP-1) with decreased affinity for IGF-I, allowing for increased IGF bioavailability. Because regulation of IGFBP-1 is abnormal in type 1 diabetes, we examined the impact of this on IGFBP-1 and its phosphorylation status in diabetic pregnancy. We assessed IGFBP-1 in relation to birth weight, maternal weight gain, duration of diabetes, glycemic control, and the presence or absence of retinopathy in 44 diabetic and 11 nondiabetic subjects. We found that in type 1 diabetic patients there was a significant negative relationship between hpIGFBP-1 and birth weight (r = -0.42, P < 0.01) and between the ratio of hpIGFBP-1 to lpIGFBP-1 and birth weight (r = -0.38, P = 0.02) by week 18 of gestation. Multiple regression analysis confirmed that hpIGFBP-1 was the best single predictor of birth weight (R2 = 0.3, P = 0.001) in diabetic subjects using models including other parameters known to influence fetal size. In contrast to hpIGFBP-1 levels, lpIGFBP-1 levels were not associated with birth weight, but were significantly related to initial maternal BMI and maternal weight throughout gestation in diabetic subjects (r = -0.57, P < 0.001). hpIGFBP-1 levels were positively related to duration of diabetes (r = 0.38, P < 0.01). Diabetic subjects had significantly higher hpIGFBP-1 and lpIGFBP-1 levels than nondiabetic subjects (hpIGFBP-1: 215 +/- 21 vs. 108 +/- 13 microg/l, P = 0.01; lpIGFBP-1: 139 +/- 12 vs. 66 +/- 5 microg/l, P < 0.001), but the ratio of hpIGFBP-1 to lpIGFBP-1 was similar in both groups (2.1 +/- 0.3 [diabetic] vs. 1.7 +/- 0.2 [nondiabetic], NS). In summary, maternal IGFBP-1 levels were higher in diabetic than in normal pregnancies. Diabetic subjects with prolonged duration of diabetes and retinopathy had higher total IGFBP-1 levels than those with shorter disease duration. Thus hpIGFBP-1 in diabetic pregnancy is positively related to the duration of diabetes and inversely related to fetal growth, with lpIGFBP-1 being related to maternal weight and BMI. The ratio of hpIGFBP-1 to lpIGFBP-1 may be a more robust indicator of fetal outcome, since it was consistent between diabetic and nondiabetic subjects. Measurement of the different phosphorylated isoforms of IGFBP-1 may increase the usefulness of IGFBP-1 as a predictor of fetal growth in both normal and diabetic pregnancy.

Insulin receptors in the pregnant diabetic and her newborn.

To ascertain if changes in the diabetic state during pregnancy were mediated by alterations in insulin receptors, we studied insulin receptors on monocytes and erythrocytes from 18 pregnant women with insulin-dependent diabetes (IDD) during the first and third trimesters. In the first trimester, insulin binding to both cell types was similar to that in normal nonpregnant women. Moreover, insulin receptor binding remained unchanged during the third trimester even in the face of the significantly increased insulin requirement and concomitant hyperinsulinemia. Our findings suggest that changes in insulin receptors are not primarily involved in alterations of diabetic control during pregnancy. Newborns of mothers with IDD have the appearance of fetal gigantism and often suffer from neonatal hypoglycemia. To determine whether altered insulin receptor binding might contribute to these phenomena, we studied insulin receptors on monocytes and erythrocytes in infants of normal mothers (n = 21) and mothers with IDD (n = 14). Compared to adults, insulin binding to both cell types from both categories of infants was significantly increased and to the same extent. The combination of fetal hyperinsulinemia and increased receptor binding in the presence of hyperglycemia may account, at least in part, for the accelerated growth of fetuses born of diabetic mothers. Finally, the enhanced neonatal glucose tolerance of these babies may be related not only to the hyperinsulinemia but also to increased insulin sensitivity mediated, in part, by the increased insulin receptor binding.

Decreased insulin binding to monocytes from normal pregnant women.

To ascertain whether the decrease of glucose tolerance in pregnancy might be mediated by changes in insulin receptors, we have studied insulin binding to monocytes in 12 normal women during late pregnancy and 14 healthy, young, normal weight, nonpregnant female controls. The pregnant women had significantly higher fasting insulin concentrations in plasma than the controsl (18 +/- 3.5 vs. 8 +/- 1.1 microU/ml; P less than 0.01). Fasting concentrations of glucose and ketone bodies in plasma were not significantly different in the two groups. Insulin binding to monocytes from pregnant women was about 35% lower at each insulin concentration tested compared to the nonpregnant controls (P less than 0.01 at tracer insulin concentrations). Changes in cellular insulin binding were due to changes of the receptor number per cell, whereas the receptor affinity was unaffected. Insulin binding was not significantly correlated with the fasting plasma insulin in either of the two groups (P less than 0.1). Our results suggest that the deterioration of glucose tolerance in normal late pregnancy might be explained by a decrease of insulin sensitivity caused by a reduction of the number of insulin receptors.

Increased levels of serum fibroblast growth factor-2 in diabetic pregnant women with retinopathy.

Fibroblast growth factor-2 (FGF-2) is a potent mitogen and angiogenic factor normally absent from the adult circulation. We have previously shown that it appears in normal maternal serum and that circulating FGF-2 levels are elevated in pregnancies complicated by diabetes. This study was performed to determine whether serum FGF-2 is more abundant in pregnant diabetic women with retinopathy than in those without. Serum was collected monthly between 14-30 weeks gestation and every 2 weeks from then until delivery (35-38 weeks) from 36 women with type 1 diabetes. FGF-2 was extracted by heparin-Sepharose affinity chromatography and quantified by specific RIA. Patients were divided according to the White classification of diabetes. In 17 women without retinopathy (White groups B, C, and D0), immunoreactive FGF-2 was detectable at 14 weeks (mean +/- SEM, 154 +/- 39 pmol/L), was maximal after 26 weeks (306 +/- 38 pmol/L), after which values steadily declined to term (212 +/- 48 pmol/L). In 19 women with simplex or proliferative retinopathy (White groups D+ and R), circulating levels of FGF-2 were significantly greater between 22-32 weeks gestation (22 weeks, 480 +/- 102 vs. 239 +/- 38 pmol/L; P < 0.05). Serum FGF-2 was significantly correlated with hemoglobin A1c levels at 22, 30, and 34 weeks gestation. The mean birth weight of the infants did not significantly differ between groups. Macroalbuminuria was absent in all patients, and creatinine clearance and blood pressure did not significantly differ between the two groups. The results suggest that serum FGF-2 is substantially elevated in pregnant diabetic women with retinopathy in second and early third trimesters. It is unlikely that in these patients this was primarily due to altered FGF-2 clearance, but may relate to excessive production by the utero-placental compartment. The high circulating levels of FGF-2 may be causally related to the development of diabetic retinopathy.

Growth and maturation of villi in placentae from well-controlled diabetic women.

Placentae from controls and two groups of diabetic women (one White classes A, B, C and the other classes D, F/R) were collected at 37-42 weeks of gestation. Tissue sections were analysed using stereological methods in order to quantify the growth and maturational status of villi. Birth and placental weights were recorded and placentae sampled in a systematic manner. Fields of view on formalin-fixed, paraffin-embedded sections were analysed to obtain estimates of volumes, surface areas, lengths and diffusion (harmonic mean) distances. Comparisons were drawn using three-way analyses of variance with group, mode of delivery and sex of newborn as the principal effects. Mean weights were similar in controls and diabetic groups. Diabetic placentae had a more voluminous fetal capillary bed of greater length, diameter and surface area. In addition, the diffusion distances across fetal plasma (erythrocyte to endothelium) were shorter. Stromal diffusion distance and villous diameter were greater in vaginal deliveries. Interaction effects influenced also villous capillarization, capillary volume, capillary diameter, trophoblast thickness and stromal thickness. Our results emphasize the importance of adaptations on the fetal side of the diabetic placenta. They show that changes can affect the placentae of appropriate-for-age as well as large-for-age babies and provide no evidence that they increase with the severity and duration of diabetes.

Macrosomia associated with maternal serum insulin-like growth factor-I and -II in diabetic pregnancy.

OBJECTIVE: To determine the possible relation between maternal serum insulin-like growth factor I and II (IGF-I and IGF-II) in women with insulin-dependent diabetes mellitus and fetal macrosomia. METHODS: This was a prospective, observational study of 45 pregnant women with insulin-dependent diabetes mellitus without overt nephropathy, examined in an outpatient, antenatal diabetic clinic. Maternal venous serum samples were collected from week 14 every fourth week until week 30, and every other week until delivery. Levels of IGF-I and -II were measured in maternal serum by immunoassays. The repeated measurements were tested with two-way analysis of variance. The outcome measures were birth weight and serum IGF-I, IGF-II, IGF binding protein (BP)-3, and IGFBP-3 proteases. Before the study, minimum sampling size was calculated as 14 subjects in each group if a difference in IGF-I of 50 microg/L was to be detected with an estimated standard deviation of 40, a two-sided P value (alpha) of.05, and a power of 90 (beta =.1). RESULTS: Increasing levels of IGF-I and -II were significantly associated with the birth-weight groups: The higher the birth-weight ratio, the higher the levels of IGF-I and -II (P <.01). CONCLUSION: Macrosomia in diabetic pregnancy is associated with high levels of maternal IGF-I and -II.

Effect of a high monounsaturated fatty acid diet on blood pressure and glucose metabolism in women with gestational diabetes mellitus.

OBJECTIVE: The effect of a diet rich in monounsaturated fatty acids (MUFA) on blood pressure, glycemic control, lipids and insulin sensitivity was evaluated in women with gestational diabetes mellitus. DESIGN AND METHODS: A randomized, unpaired diet intervention was performed in 27 women with gestational diabetes mellitus in an outpatient clinic. After randomization the women received either a high-carbohydrate diet (H-CHO) or a high-MUFA diet (H-MUFA) from the 33rd gestational week of pregnancy. Outcome measures were 24 h ambulatory blood pressure, blood lipids, glycemic control and insulin sensitivity estimated by an intravenous glucose tolerance test. RESULTS: The 24 h diastolic blood pressure increased more in the H-CHO group than in the H-MUFA group (P<0.04). CONCLUSIONS: After 5 weeks of treatment with a MUFA-enriched diet, no increase in 24 h diastolic blood pressure and no adverse effects on blood lipids were seen. The favorable effect on the blood pressure by the MUFA diet is a possible non-medication treatment. The H-MUFA diet had no advantage to the H-CHO diet in ameliorating the decline of insulin sensitivity in third term of pregnancy in GDM.

Renal growth during pregnancy in insulin-dependent diabetic women. A prospective study of renal volume and clinical variables.

Kidney volume was measured during pregnancy in insulin-dependent diabetic women by an ultrasound technique and prognostic value of these measurements evaluated. A prospective study was performed on 87 pregnant women with insulin-dependent diabetes attending the maternity clinic of Aarhus Kommunehospital. Patients with proliferative retinopathy alone, hydronephrosis, or nephrotic syndrome were excluded. The patients were grouped according to onset and duration of diabetes and to vascular lesions; group I (n = 35, White class B+C), group II (n = 11, White class D0), group III (n = 26, White class D+), and group IV (n = 15, White class F+F/R). The patients visited the hospital every 2 weeks during pregnancy for general obstetric and glycaemic control and blood sampling. The volume of both kidneys was measured by a computerized nephrosonograph during the three terms of pregnancy, the puerperium and 4 months postpartum. The kidney volume increased significantly in all four groups from first to third trimester. In the third trimester the kidney volumes were 375 +/- 68 ml (I), 341 +/- 50 ml (II), 362 +/- 63 ml (III), and 343 +/- 54 ml (IV). The kidney volume in the third trimester was positively correlated with creatinine clearance (r = 0.33, P < 0.01) and inversely correlated with creatinine in serum (r = -0.27, P = < 0.02). Total kidney volume decrease (in percent) defined as the difference of maximal volume and value at 4 months postpartum was inversely correlated to albuminuria in the third trimester (r = -0.25, P < 0.05) and vascular lesions of the patients: (mean +/- SEM) 37 +/- 4% (I), 25 +/- 7% (II), 19 +/- 5% (III), and 11 +/- 7% (IV), P < 0.01. In the puerperium, kidney volume decreased significantly from third trimester in groups I, II, and III, whereas we observed no change in group IV. Six of 15 women in groups II and III with kidney volume < 300 ml and normoalbuminuria in the first trimester developed persistent microalbuminuria after pregnancy (P < 0.02). The renal volume in insulin-dependent diabetic women increases significantly during pregnancy and is inversely related to the vascular lesions of the patients. The decrease in renal volume after pregnancy is related to the albuminuria at the end of pregnancy. Women with longstanding diabetes, White class D (= groups II+III), and kidney volume < 300 ml in the first trimester have a high risk of developing permanent microalbuminuria after pregnancy.

Intravascular "mulberry-like" bodies: morphological, immunohistochemical, and ultrastructural observations of an incidental finding caused by autolysis?

Intravascular "mulberry-like" bodies in a stillborn female infant with moderate maceration are reported. The histogenesis of these structures is discussed based on light-microscopic, immunohistochemical and ultrastructural findings. No demonstrable causal relation between the intravascular lesions and fetal death was found, the cause of death being attributed to intrauterine asphyxia. It is concluded, that intravascular "mulberry-bodies" most likely represent artifacts due to red blood cell autolysis.

[Changes in glucose metabolism in gestational diabetes mellitus during and after pregnancy]. / Forandringer i glukosestofskiftet ved gestationel diabetes mellitus under og efter graviditet.

Twenty-nine pregnant women with gestational diabetes mellitus (GDM) diagnosed before the 34th gestational week had three intravenous glucose tolerance tests (IVGTT) performed during pregnancy and a follow-up with OGTT post partum. The women with a normal OGTT post partum had a significant decrease in fasting serum glucose from the 33rd to the 38th week in pregnancy (4.8-->4.0 mmol/l, p < 0.05). However, the women with a diabetic/borderline OGTT showed no decrease in fasting serum glucose during the same period (5.1-->5.0 mmol/l). The K-value (the diminution rate of blood glucose) of the IVGTT in week 38 was significantly lower in women with puerperal diabetic/borderline OGTT compared with women with a normal post partum OGTT (1.05 +/- 0.07 vs. 1.32 +/- 0.08 -10(2) x mmol/l x min-1, respectively, p < 0.05). Diabetic or borderline diabetic OGTT in the first week post partum was significantly associated with a decrease in the K-value from week 33 to 38 (p < 0.05). Early diagnosis of GDM was found to be associated with a pathological OGTT post partum (p < 0.05). Five of 22 women (23%) with previous GDM had a diabetic and one (5%) a borderline OGTT at follow-up four to thirteen months post partum. High fasting serum glucose levels during the last trimester in GDM can identify the women at risk of diabetic/borderline OGTT post partum.

Self-monitoring of blood glucose in pregnant diabetics. A comparative study of the blood glucose level and course of pregnancy in pregnant diabetics on an out-patient regime before and after the introduction of methods for home analysis of blood glucose.

Sixty-one pregnant patients with insulin-dependent diabetes mellitus completed a self-monitoring program consisting of five daily blood glucose tests at least twice weekly during the ambulatory periods of their pregnancies. Either a reflectometer method, Eyetone, glucometer--reflectometer, or Haemoglucotest 1-44 test strips were used. Of 1 834 glucose profiles, 45% were optimal, with all blood glucose values between 3.9 and 8.3 mmol/l. The 61 pregnancies were compared with 62 pregnancies where the diabetic control and therapy principles were identical, but where self-monitoring blood glucose methods were not employed. The self-monitoring regime resulted in a significant drop in mean blood glucose levels, from 7.8 +/- 1.3 to 6.4 +/- 1.0 mmol/l, compared with the period before the self-monitoring program was introduced. Furthermore, a decline in the number of diabetes-conditioned extra hospitalizations during pregnancy in the self-test group could be registered.

Rupture of the spleen during delivery.

A case of traumatic rupture of a normal spleen in a complicated delivery is presented. The etiology of splenic rupture and therapeutic aspects of this unusual occurrence are discussed. It is pointed out that a violent expression of the fetus might be dangerous for the mother.

Birthweight in women with potential gestational diabetes mellitus--an effect of obesity rather than glucose intolerance?

BACKGROUND: The purpose was to compare the influence of varying levels of glycemia on the perinatal outcome. METHODS: The data charts of 383 women screened for gestational diabetes mellitus with an oral glucose tolerance test during two birthyears were retrospectively evaluated. In 55 women gestational diabetes mellitus was diagnosed and treated with diet. The non-diabetic women (n=328) were subdivided into a borderline diabetes group (n=74) and a normal group (n= 254) on the basis of the oral glucose tolerance test result. The birth registry of 8196 singleton pregnancies from The Perinatal Research Unit at Skejby University Hospital served as the background population. RESULTS: Birthweight was highest in the borderline group. Weight increase during pregnancy was larger in the non-diabetic than the gestational diabetic women (15 vs. 8 kg p<0.01). The women with less increase of body weight delivered neonates with lower birthweight than those with higher increase. Birthweight was associated with maternal weight during pregnancy (p<0.01). Birthweight ratio increased with increasing glucose intolerance. Vaginal delivery rate was less and cesarean section rate higher in women with gestational diabetes mellitus compared to the non-diabetic women. No significant difference was found in the incidence of hypertensive disorders during pregnancy or neonatal morbidity. CONCLUSIONS: Even minor hyperglycemia is associated with increasing birthweight. Birthweight is reduced in GDM when dietary treatment is instituted and effect on weight gain is achieved.