Dorothy R. Hollingsworth

The 24-hour excursion and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy☆☆☆

Abstract A longitudinal study to quantitate the progressive effects of the second and third trimesters of normal pregnancy on the levels of plasma glucose, immunoreactive insulin (IRI), and C-peptide (C-P) at hourly intervals throughout the 24-hour “metabolic clock” was made. Identical studies were conducted in each subject at 6 to 11 weeks post partum and these data were used as nonpregnant control values. Data analyses were made to determine the role of meal-activity-sleep cycles as physiologic modifiers. A diurnal rhythm of plasma glucose, IRI, and C-P was demonstrated in all study periods. During meals anabolic values of plasma glucose (increments above the 24-hour mean) in response to meal intake were remarkably small, ranging between 30 and 35 mg/100 ml in the postpartum state, and were not significantly modified by pregnancy. The corresponding IRI levels were similarly small with a mean increase on only 31% in pregnancy. However, during the third but not the second trimester of pregnancy, the peak anabolic values for both plasma glucose and IRI were significantly (p a.m. ) plasma glucose and 24-hour integrated glucose levels. This relative nocturnal hypoglycemia was associated with synchronous IRI values but without concomitant reduction of absolute IRI levels. Consequently, the fasting, premeal, and 24-hour IRI/glucose ratios were increased. Thus, basal insulin secretion is significantly augmented relative to levels of plasma glucose, but a quantitative increase in insulin secretion following food intake is relatively small during pregnancy. These observations together with the finding of a marked diurnal rhythm of plasma glucose and relative nocturnal hypoglycemia provide important insights for the formulation of guidelines for the timing, amount, and mode of delivery of exogenous insulin necessary for the management of diabetic patients during pregnancy.

Qualitative and quantitative assessment of the circadian rhythm of cortisol in pregnancy.

The effect of pregnancy on the circadian rhythm and diurnal excursion of plasma cortisol and urinary free corticoids was examined in a sequential study during the second and third trimester and 6 to 12 weeks post partum. Hourly blood samples from six subjects and 8-hour urine collections from eight subjects were obtained around the clock. While the circadian rhythm was maintained during gestation, plasma cortisol levels (24-hour mean, nadir, peak, and nadir-peak excursion) increased. The relative excursion of plasma cortisol (expressed as the percentage of deviation from the 24-hour mean) exhibited remarkable blunting compared with postpartum values. This pregnancy-associated blunting of plasma cortisol excursion was indicated by a significant reduction in the: (1) mean peak and nadir excursion, (2) integrated area between the percent deviation curve and the 24-hour mean, and (3) mean slope of the major incremental and decremental segments of the percent deviation curve. The circadian rhythm and diurnal excursion of plasma cortisol were reflected in urinary free corticoid values. Mean 24-hour urinary free corticoid concentrations increased 180% during gestation over nonpregnant levels. Nadir concentrations of urinary free corticoids in pregnancy exceeded peak nonpregnant levels. The gestational rise of metabolically active free cortisol and adrenocorticotropin (ACTH), and the pregnancy-associated blunting of the excursion of plasma cortisol may be explained by an autonomous source of ACTH during gestation.

Alterations of maternal metabolism in normal and diabetic pregnancies: Differences in insulin-dependent, non-insulin-dependent, and gestational diabetes

In normal and diabetic pregnancies, the placenta functions as a complex endocrine gland that modulates all classes of maternal nutrients to the fetus. The metabolic alterations of normal pregnancy are diabetogenic and associated with modest resistance to endogenous insulin. Pregnant women with carbohydrate intolerance represent three metabolically heterogeneous groups: type I (insulin-dependent), type II (non-insulin-dependent), and gestational diabetes. Patients with type I diabetes are at risk for ketosis and require replacement therapy because of a deficient production of insulin. They have decreased 24-hour, around-the-clock levels of C-peptide and glucagon, and lower nocturnal cortisol values and higher 24-hour prolactin levels than those of women with type II diabetes. Type II pregnant diabetic patients are not prone to ketosis and are more resistant to endogenous and exogenous insulin. They have higher fasting and meal-stimulated levels of C-peptide, accentuated fasting hypertriglyceridemia, and significantly lower high-density lipoprotein cholesterol levels than those of normal or type I women. In gestational diabetes, the metabolic stress of pregnancy evokes reversible hyperglycemia which may be associated with either a surfeit or a deficiency of insulin. These metabolic differences among diabetic pregnant women could have implications for placental structure and function that might influence fetal growth.

Pregnancy-associated Hypertriglyceridemia in Normal and Diabetic Women: Differences in Insulin-dependent, Non-insulin-dependent, and Gestational Diabetes

In this study longitudinal observations of plasma lipo-proteins were made in pregnant diabetic women classified according to the National Diabetes Data Group. Sequential measurements at second trimester (25–27 wk), third trimester (34–37 wk), and 3 mo postpartum (control period) were carried out in 18 diabetic and 6 normal women. In 15 diabetic and 4 normal women from this group, 24-h plasma glucose, serum C-peptide levels, and HbA1c concentrations were measured. Another group of 15 normal and 18 diabetic women underwent determinations of fasting plasma lipoproteine and other parameters at one or more of the test periods. Insulin-dependent diabetic patients (IDDM, type I) as a group did not differ from normal controls in mean plasma levels of total cholesterol (CHOL), triglyceride (TG), very-low-density lipoprotein triglyceride (VLDL TG), low-density lipoprotein cholesterol (LDL CHOL), high-density lipoprotein cholesterol (HDL CHOL), or ratios of TG:CHOL in LDL or HDL during mid or late pregnancy or 3 mo postpartum. In marked contrast, non-insulin-dependent diabetics (NIDDM, type II) had significantly higher total fasting TG at second trimester (P < 0.005), third trimester (P < 0.03), and postpartum (P < 0.01). VLDL TG levels at the second trimester, third trimester, and postpartum also were higher than in women with IDDM or normals. In NIDDM subjects the accentuated hypertriglyceridemia during second and third trimesters was also apparent in elevated LDL TG:CHOL and HDL TG:CHOL ratios. These differences were not correlated with prepregnancy weight, weight gain during gestation, or diabetic control. Women with gestational diabetes (GDM) also had significantly higher TG levels at second trimester and postpartum. Mean HDL CHOL levels were significantly lower in patients with NIDDM and GDM than in controls and IDDM patients throughout pregnancy and 3 mo postpartum. Two of 21 normals and one woman with IDDM diabetes had spontaneously reversible pregnancy-evoked hypertriglyceridemia. These results indicate that women with IDDM diabetes do not differ from normal women with respect to pregnancy-associated changes in lipid metabolism. On the other hand, women with NIDDM and GDM exhibit a pregnancy-associated hypertriglyceridemia.

Glycosylated hemoglobin as a screening test for carbohydrate intolerance in pregnancy

The usefulness of glycosylated hemoglobin as a prenatal screening test for carbohydrate intolerance was studied in 806 consecutive subjects by correlating glycosylated hemoglobin to 1-hour post-50 gm Glucola plasma glucose (1 degree G) levels, and 3-hour oral glucose tolerance tests (3 degrees GTT). Sixty-seven subjects whose 1 degree G greater than or equal to 150 mg/100 ml received a 3 degrees GTT; 12 were diagnostic of carbohydrate intolerance. Compared to carbohydrate-tolerant controls, carbohydrate-intolerant gravid patients had higher 1 degree G (p less than 0.001) and glycosylated hemoglobin (p less than 0.05) levels. Linear regression analysis of 1 degree G and glycosylated hemoglobin demonstrated r = 0.35 (p less than 0.0001). Compared to the glycosylated hemoglobin test, the 1 degree G screening test has greater specificity, sensitivity, and predictive value for a positive diagnosis. Consequently, the 1 degree G is a better routine screening test for carbohydrate intolerance than is glycosylated hemoglobin.

Decreased Insulin Requirement and Improved Control of Diabetes in Pregnant Women Given a High-Carbohydrate, High-Fiber, Low-Fat Diet

Five quantitative measures of diabetic control [HbA1c determinations, mean 24-h plasma glucose values, mean amplitude of glycemic excursions (MAGE), mean 24-h urinary loss of glucose, and daily exogenous insulin requirement] were compared in 20 pregnant women who were randomly assigned to either a high-carbohydrate, high-fiber diet (HCF) that was low in fat or to a control diet commonly prescribed for pregnancy. Eleven women followed the HCF diet and nine subjects, the control diet, from baseline entry into the study until delivery. Dietary compliance was excellent, with 78% of the women in each group rated good or acceptable. HbA1c values were similar in both groups at baseline (HCF: 11.0 ± 0.5% versus control: 10.2 ± 0.6%), with no different predelivery values (8.6 ± 0.4%). Mean 24-h plasma glucose levels improved in patients on both diets, with lower values noted in the HCF group at predelivery. MAGE values and standard deviations did not differ significantly in the two groups. Glycosuria decreased markedly in both dietary groups, but differences between groups were not significant. Improved control of diabetes on the HCF diet was achieved with significantly lower increments in insulin dose during gestation (HCF baseline: 32 ± 8 U/24 h to 66 ± 10 U/24 h versus control baseline: 27 ± 9 U/24 h to 108 ± 12 U/24 h, P < 0.03). Outcome of pregnancy did not differ in the two groups of patients, but women on the HCF diet gained less weight than those on the control diet (26 ± 3 lb versus 35 ± 5 lb, P < 0.05). Mean newborn gestational age was similar in the two groups (HCF: 37.2 ± 0.7 wk versus control: 36.5 ± 0.7 wk). Mean birth weight in infants of HCF mothers ± was 3809 ± 248 g versus 3313 ± 278 g in infants of control mothers (P < 0.05). We conclude that although marked improvement of diabetic control occurred on both regimens, patients on the HCF diet achieved better control of diabetes with significantly lower increments in exogenous insulin.

Postprandial walking exercise in pregnant insulin-dependent (type I) diabetic women: Reduction of plasma lipid levels but absence of a significant effect on glycemic control

In this study 42 pregnant women with type I diabetes and 28 nondiabetic controls were recruited to participate in a postprandial walking exercise program. Exercise patients were instructed to walk 20 minutes (1 mile) after each meal and were divided into two groups: group 1 were normal nondiabetic controls and group 2 were women with type I diabetes. There were two nonexercise comparison groups: group 3, nondiabetic controls, and group 4, women with type I diabetes. Diabetic women were followed weekly in an intensive perinatal program. Glycemic control was assessed by serial hemoglobin A1 concentration measurements, home blood glucose monitoring, 24-hour glucose profiles, and 24-hour quantitative urinary glucose loss. Glycemic control was modestly but not significantly superior in the diabetic exercise group 2 compared with the diabetic nonexercise group 4. Exercise was associated with lower fasting cholesterol and triglyceride values in both controls and diabetic women, with significantly lower fasting plasma triglyceride levels in the diabetic exercise group (p less than 0.02). There were no adverse effects of postprandial walking exercise in mothers or infants.

Psychosocial aspects of Mexican-American, white, and black teenage pregnancy

This study assesses whether pregnant Mexican-American adolescents have psychosocial characteristics different from their pregnant white or black peers. The study population consisted of 199 consecutive Mexican-American, white, and black pregnant adolescents, ages 11-19 years, followed prospectively at the University of California San Diego Medical Center Teen Obstetric Clinic from 1978 to 1981 (79 whites, 76 Mexican-Americans, and 44 blacks). Although all three groups had the same chronologic age (X = 16.4 +/- 1.4 years), and the same number of years of schooling, pregnant black adolescents were more likely to be in school at the time of registration for prenatal care (p less than 0.01). Mexican-American teens were more likely to be married at conception and/or delivery (p less than 0.001), and to breastfeed their infants (p less than 0.05). The fathers of the Mexican-American babies were more likely than other fathers to be full-time students or employed (p less than 0.001). Although pregnant Mexican-American teens came from the largest families (p less than 0.001), black teenagers most frequently reported a good mother-daughter relationship (p less than 0.05). White pregnant teens most frequently reported a family history of psychiatric illness (p less than 0.01), parental death (p less than 0.05), or runaway behavior (p less than 0.01). These data suggest that pregnant teenagers from these three racial/ethnic backgrounds have different psychosocial profiles and hence different psychosocial problems and needs.

Teenage pregnancy: A multiracial sociologic problem

Teenage pregnancy is not an epidemic in the United States. Because this is an emotional topic that receives high-decibel publicity in the press and on television, we wish to present the most recent factual information available on the subject and a more balanced perspective of the problem for physicians and other health professionals who care for women at the youngest age of the reproductive spectrum. Pregnancy during adolescence is a multiethnic sociologic problem that crosses all socioeconomic, ethnic, cultural, and geographic boundaries. Pregnancies in teenagers are decreasing (except in teenagers under age 15), not accelerating. New approaches for premature adolescent pregnancy and childbearing focus on adolescent peer pressure for behavior modification, prevention of pregnancy at a younger age, continuation of secondary education, and job training for both adolescent fathers and mothers.

Diabetes in pregnancy in Mexican Americans

Diabetes in pregnant Mexican-American women is a serious and expensive health problem. At the University of California, San Diego Medical Center, 44% of pregnant women are Mexican American. In the Diabetes in Pregnancy Clinic, only 7% of women with insulin-dependent diabetes are in this ethnic group compared with 66% of non-insulin-dependent diabetic patients and 51% of those with gestational diabetes mellitus (GDM). GDM is the most common complication of pregnancy in Mexican Americans with a prevalence approximately three times higher than that of whites (4.5 vs. 1.5%). Mexican-American obese GDM subjects had more frequent cesarean sections and were more likely to have complications of premature rupture of membranes and preterm labor (NS). Polycythemia and sepsis also occurred more often in their infants. Anthropometric measurements in infants of both lean and obese GDM subjects differed from those of infants of mothers without GDM. Infants of lean mothers with GDM were heavier and longer than those of lean mothers without GDM. In addition, they had increased waist-hip ratio and triceps and subscapular skin folds. Infants of obese mothers with GDM were heavier than those of lean mothers with GDM. Moreover, they were longer (P < 0.04); had a higher body mass index (P < 0.04); and larger waist and hip circumferences (P < 0.03) and buccal (P < 0.01), subscapular (P < 0.01), and sum of skin-fold measurements (P < 0.03). Our observations indicate that pregnant diabetic Mexican-American women have predominantly GDM and non-insulin-dependent diabetes. They represent a major public health problem because of increased maternal and neonatal morbidity.