Objective
The dawn phenomenon is a transient rise in blood glucose between 4 and 6 am that is attributed to the pulsatile release of pituitary growth hormone (GH). In pregnancy, GH is suppressed by placental GH. Hence, we hypothesize that there is no evidence for the dawn phenomenon in late pregnancy in healthy women.
Study Design
Twenty glucose-tolerant women with singleton gestations between 28 weeks and 36 weeks 6 days’ gestation were recruited. The women were admitted overnight to the Clinical Research Unit and had continuous glucose monitoring. Insulin and GH were measured at 2-hour intervals from 8 pm to 8 am . GH was grouped into times 1A (8-10 pm ), 2A (12-2 am ), and 3A (4-8 am ) for changes over time. Further analysis was performed with time 1B (8 pm to 2 am ) and 2B (4-8 am ). Insulin was measured between 4 and 8 am .
Results
Plasma glucose decreased over time ( P < .001). There were no significant changes in GH among times 1A, 2A, and 3A ( P = .45) or times 1B and 2B ( P = .12). Insulin concentrations increased after meals, but there were no changes from 4 am (8.5 ± 1.4 μU/mL) through 8 am (8.6 ± 1.1 μU/mL; P = .98).
Conclusion
Glucose and insulin concentrations show no increase from 4-8 am ; although there is variability in GH, there is no evidence for the dawn phenomenon in late pregnancy in healthy women.
The dawn phenomenon is defined as a transient rise in blood glucose concentration that occurs overnight between 4 and 6 am . This transient hyperglycemia has been attributed to the pulsatile release of growth hormone (GH) overnight. GH is released by the anterior pituitary in a pulsatile and diurnal fashion and is central in the balance between metabolic and catabolic states. Pituitary GH functions include stimulation of linear growth, lipolysis, protein synthesis, and antagonism of insulin. There are significant alterations in GH metabolism during pregnancy. GH is inhibited by somatostatin, insulin-like growth factor-I, hyperglycemia, and leptin in the normal patient.
In the pregnant patient, however, GH is inhibited by placental GH, which is synthesized by the syncytiotrophoblasts of the placenta and is released directly into maternal circulation. Placental GH secretion is modified by Glut1, the major glucose transporter in the placenta, in response to maternal blood glucose levels. The inhibition of GH during pregnancy dominates other stimulatory factors, including estrogen. As placental GH concentrations increase, the GH concentrations decrease. By 15-20 weeks’ gestation, placental GH is the dominant GH, with the GH virtually undetectable. This dominance continues until parturition, after which 75% of the placental GH can be cleared as soon as 30 minutes after delivery.
In the treatment of people with diabetes mellitus, insulin management must take into account the hyperglycemic effects of the dawn phenomenon. Management of diabetes mellitus is particularly important in the pregnant patient, for whom normalization of glucose is the priority. Because placental GH functionally replaces GH during pregnancy, we hypothesize that there is no dawn phenomenon during late pregnancy. Hence, the primary aim of this study was to document the relationship between blood glucose, insulin, and placental GH levels during pregnancy.
Materials and Methods
Twenty healthy glucose-tolerant women in the third trimester of pregnancy (28 weeks to 36 weeks 6 days gestation) were recruited prospectively. All participants signed a consent form that was approved by the Institutional Review Board at MetroHealth Medical Center/Case Western Reserve University. The protocol was reviewed and approved by the MetroHealth Scientific Review Committee of the Clinical Research Unit of the Case Western Reserve University Clinical and Translational Science Collaborative. Women with a normal 1-hr 50-g glucose challenge test and a nonanomalous singleton gestation were eligible for participation. Women were excluded from participation if their pregnancy was complicated by intrauterine growth restriction, preterm labor, premature rupture of membranes, abnormal placentation, hypertension, preexisting diabetes mellitus, gestational diabetes mellitus, autoimmune disorders, illicit drug use, or chronic steroid use. Each woman completed 2 visits at the Clinical Research Unit. The first visit included body composition estimates with the use of air displacement plethysmography (Bod Pod; COSMED, Rome, Italy). The women also met with the Clinical Research Unit research nutritionist to review and discuss components of their current diet.
The second visit entailed an overnight admission to the Clinical Research Unit. Women were admitted at 6 pm . Weight, blood pressure, and fetal heart tones were recorded. The Continuous Glucose Monitoring System (CGMS) iPro sensor (Medtronic Inc, Northridge, CA) and an intravenous catheter were placed on admission. The CGMS obtained glucose values every 5 minutes over a 12-hour period for a total of 145 values per subject. The iPro sensor was placed in the suprailiac region and was calibrated with serum glucose measurements that were obtained at each scheduled blood draw on each subject. Eighty-eight percent of values were obtained and available for analysis. Peripheral intravenous access was obtained for repeated blood draws overnight to obtain samples without awakening the women. Women received a standard 2000-2200 calorie/day diet for dinner (75-80 g carbohydrates) and a bedtime snack (30 g carbohydrates) then received nothing by mouth overnight. GH and insulin values were obtained every 2 hours overnight for a total of 7 values. A fasting lipid profile and hemoglobin A1c level were also obtained the next morning. A fasting lipid panel was obtained in addition to the HbA1c, body mass index, and percent body fat to obtain a representation of the metabolic state of our study population and to confirm that there were no underlying disturbances in lipid metabolism.
There are currently no assays specific for placental GH available for research purposes in the United States. Plasma human GH was assayed by enzyme-linked immunosorbent assay (Quantikine Human Growth Hormone Immunoassay DGH00; R&D Systems, Inc, Minneapolis, MN). The antibody does not differentiate between pituitary and placental GH.
Glucose values for all the women were analyzed with time series analysis. The median blood glucose, GH, and insulin levels were analyzed with Kruskal-Wallis 1-way analysis of variance based on ranks between different epochs overnight. We also used repeated measures analysis of variance, 1-way analysis of variance, regression analysis, and time series analysis to study the changes over time. Considering a paired sample size of 20 patients, a coefficient of variation of 0.04, and a correlation between measurements of 0.30, we were able to detect a 20% increase from baseline at the .05 significance level with 90% power. Analyses were performed with SPSS software (version 20; SPSS Inc, Chicago, IL) and Statistix software (version 9; Analytical Software, Tallahassee, FL).
Results
Cohort characteristics are depicted in Table 1 . Most of the women were African American, multiparous, and evenly represented by normal, overweight, and obese prepregnancy body mass index measurements. The mean percentage of body fat was 38%. Metabolic data are presented in Table 2 . The mean 1-hr 50-g glucose challenge test was 102.2 mg/dL; the hemoglobin A1c level was 5.5%. Fasting lipid profiles were consistent with late gestation. The mean glucose value during the 12 hour acquisition was 85.4 ± 0.49 mg/dL.
| Characteristic | Measure |
|---|---|
| Age, y a | 27.2 ± 4.7 |
| Gestational age at first visit, wk/d a | 30/4 ± 12 d |
| Parity >1, n (%) | 15 (75) |
| Ethnicity, n (%) | |
| White | 7 (35.0) |
| African American | 11 (55.0) |
| Hispanic | 1 (5.0) |
| Other | 1 (5.0) |
| Prepregnancy body mass index, n (%) | |
| Normal | 6 (30) |
| Overweight | 6 (30) |
| Obese | 8 (40) |
| Body mass index at first visit, kg/m 2 a | 31.1 ± 5.2 |
| Weight gain at first visit, kg a | 7.0 ± 7.1 |
| Body fat, % a | 37.8 ± 5.8 |
| Variable | Mean ± SD |
|---|---|
| Hemoglobin A1c, % | 5.5 ± 0.6 |
| Cholesterol, mg/dL | 238.0 ± 50.2 |
| Triglycerides, mg/dL | 165.0 ± 58.0 |
| High-density lipoprotein, mg/dL | 59.6 ± 12.8 |
| Low-density lipoprotein, mg/dL | 154.6 ± 42.6 |
| Very low-density lipoprotein, mg/dL | 26.4 ± 9.3 |
| Glucose, mg/dL | 85.4 ± 0.49 |
| 1-hour glucose tolerance test, mg/dL | 102.2 ± 18.4 |
Longitudinal variations in plasma glucose that was obtained from the CGMS are shown in Figure 1 . A time series analysis identified the auto regressive integrated moving average time series model (1,0,1) to be the best fit model for forecasting plasma glucose level during the study period. Auto regressive integrated moving average (1,0,1) means auto regressive and moving average of order 1 without differencing. Mean glucose values decreased over time ( P < .001). Insulin levels peaked by 10 pm then gradually decrease through 8 am . There were no significant differences in insulin levels over time with 8.5 ± 1.4, 8.7 ± 1.0, and 8.6 ± 1.1 μU/mL, respectively, at 4, 6, and 8 am ( P = .84; Figure 2 ). GH levels were compared among 3 time periods (1A, 1B, and 1C; Figure 3 ). There were no significant differences (108 ± 25, 125.8 ± 23.9, and 143.9 ± 30.6 pg/mL at 8-10 pm , 12-2 am , and 4-6 am , respectively; P = .45). Similar results were noted when made the comparisons over the 2 time periods 8 pm to 2 am and 4-8 am (116.9 ± 23.7 and 143.9 ± 30.6 pg/mL, respectively; P = .74). These results were confirmed with the use of the repeated measures analysis of variance and 1-way analysis of variance.
