Absence of Dawn Phenomenon in Normal Children ... - Diabetes Care

Absence of Dawn Phenomenon in Normal Children and Adolescents

The dawn phenomenon consists of a rise in plasma glucose levels or insulin requirements in the early morning. This phenomenon has been observed in normal adults and in patients with diabetes mellitus. To determine whether this phenomenon also occurs in normal children and adolescents, we evaluated plasma glucose, insulin, C-peptide, and growth hormone levels during the early morning in 31 normal children between the ages of 8 and 18 yr. Blood samples were obtained through an indwelling catheter every 20 min for growth hormone and hourly for glucose, insulin, and C-peptide from 2100 to 0900 h. Glucose levels decreased slowly overnight from 2100 to 0900 h, despite increases in growth hormone levels. No significant rise in insulin or C-peptide levels was detected in the early morning in these normal subjects. There were no signficant differences between prepubertal and pubertal children. We conclude that glucose, insulin, and C-peptide levels remain stable overnight, suggesting that the dawn phenomenon is not observed in normal children. Diabetes Care 11:393-96,1988

he dawn phenomenon is characterized by increases in plasma glucose levels or insulin requirements in the early morning (1). This phenomenon has been described in patients with insulin-dependent diabetes mellitus as well as in patients with non-insulin-dependent diabetes mellitus (2). The dawn phenomenon has been demonstrated in normal adult subjects by studies of insulin secretion and

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From the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Dr. Gabriela Marin, Building 10, Room 10 N 262, NIH, Bethesda, MD 20892.

DIABETES CARE, VOL. 11, NO. 5, MAY 1988

Gabriela Marin, MD Susan R. Rose, MD Maral Kibarian, BA Kevin Barnes, BS Fernando Cassorla, MD

glucose production and utilization (3,4). However, it does not appear to occur in elderly subjects (5). The dawn phenomenon has not been studied in children and adolescents. Children have a different ratio of brain-to-body glucose consumption and are more susceptible to changes in plasma glucose levels (6). In addition, nocturnal growth hormone levels increase during pubertal development and may affect glucose metabolism (7,8). We studied the dawn phenomenon in normal children and adolescents by serially measuring the plasma levels of glucose, insulin, C-peptide, and growth hormone during the night.

MATERIALS AND METHODS Subjects. The subjects were 17 males and 14 females, aged 8 to 18 yr. All were Caucasian and had normal blood glucose, insulin, and C-peptide levels as well as normal glycosylated hemoglobin. We evaluated pubertal development in each patient according to the criteria of Marshall and Tanner (9,10). We studied 8 prepubertal and 23 pubertal children. Their clinical characteristics are shown in Table 1. Children of both sexes were studied at each Marshall and Tanner stage. Protocol. The study was approved by the Clinical Research Committee of the National Institute of Child Health and Human Development. The parents gave informed consent, and the children gave assent. We measured baseline serum chemistries, complete blood count, glycosylated hemoglobin, and serum C-peptide. Six weeks later, the patients were admitted to the Clinical Center at the National Institutes of Health. Glucose, insulin, and C-peptide levels were measured through an indwelling venous catheter at hourly intervals from 2100

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ABSENCE OF DAWN PHENOMENON IN NORMAL SUBJECTS

GLUCOSE

INSUUN

2100

2300

0100

2100

2300

0100

0300

0600

0700

0900

0300 0800 Tim* (hour*)

0700

0900

110

100 -

0 2100

2300

0100

0900 Tin* (hows)

FIG. 1. Blood glucose, insulin, C-peptide, and growth hormone concentrations (mean ± SE) at night in normal children. Prepubertal (•) and pubertal (A) subjects are shown separately. O, All patients.

to 0900 h. Growth hormone was measured every 20 min during this period. Subjects were encouraged to maintain their usual diet and ambulatory (not strenuous) activity during their hospital stay. Each subject was given a bedtime snack between 2000 and 2200 h. Bedtime varied between 2100 and 2300 h depending on the age of the child. Serum samples were stored at -20°C until assayed. Glucose was measured by the glucose oxidase method. Insulin and growth hormone were measured by radioimmunoassay (11,12), and C-peptide was measured by radioimmunoassay at Endocrine Sciences (Tarzana, CA). Statistical analysis. Multivariate repeated-measures analysis of variance was used to determine whether glucose, insulin, or C-peptide levels varied significantly over time (13). The same analysis was used to evaluate the correlation between growth hormone and glucose, insulin, or C-peptide levels.

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RESULTS Results are shown in Fig. 1. Plasma glucose levels increased from 2200 to 0100 h and decreased slowly thereafter, reaching a nadir at 0800 h. Glucose levels were significantly lower at 0600 and 0700 h than at 0200 h (P< .001). Plasma insulin levels decreased slowly from 2100 h, reaching a nadir at 0600 h. Insulin levels were significantly lower at 0600 than at 0200 h (P < .005). Plasma C-peptide levels decreased slowly from 2100 h, reaching a nadir at 0900 h. These differences, however, were not statistically significant. There were no differences in glucose, insulin, and C-peptide levels between males and females or between patient groups according to pubertal stage. Plasma growth hormone levels increased from 2100 h, reaching a peak at 2420 h, then decreased


G. MARIN AND ASSOCIATES

GROWTH HORMONE

C-PEPTIDE

0 2100

0300

2300

0600

0700

2100

2300

0100

Tims (hours)

0300

0500

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0900

0600

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0900

Tim* (hours)

10

0

2100

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FIG. 1—Continued

between 0300 and 0340 h (P < .005), increased again at 0500 h (P < .005), and then remained stable from 0500 until 0900 h. Growth hormone levels were higher in the pubertal group (P < .005) than in the prepubertal group.

period. This is in accord with the studies of Meneilly et al. (5) and Levy et al. (16), who could not demonstrate this phenomenon in normal adults. The mechanisms responsible for the dawn phenomenon remain controversial (17). In diabetic individuals, the dawn phenomenon may be a variant of the glucose circadian rhythm, with glucose reaching a nadir in the

DISCUSSION The dawn phenomenon is defined as a rise in plasma glucose levels or insulin requirements during the early morning (1). It has been described in diabetic patients and in normal adult subjects (2-4,14,15). However, it has not been studied in normal children. Our results indicate that the dawn phenomenon does not occur in normal children and adolescents. Plasma glucose levels remained stable during the early morning, a time when insulin and C-peptide levels decreased slowly, suggesting that insulin requirements did not increase during this


TABLE 1 Clinical characteristics of subjects Pubertal stage*

I

Age (yr, mean ± SE)

9 ±

1.5

n (male/female)

3/5

II

10 ± 2

4/2

III

12.5 ± 2

6/2

IV

13 ± 1

2/1

V

16 ± 1

2/4

*From Marshall and Tanner (9,10).

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ABSENCE OF DAWN PHENOMENON IN NORMAL SUBJECTS

evening and a peak in the morning (2). This phenomenon might also be related to the early-morning increase in cortisol levels observed physiologically. However, adrenal suppression does not prevent the dawn phenomenon in diabetic patients (18-20). Nocturnal surges in growth hormone have been reported as another possible cause of the dawn phenomenon (21,22). Growth hormone stimulates glucose production by the liver and limits glucose transport into cells. In our study, plasma glucose levels remained stable during the early morning despite nocturnal surges in growth hormone. Although the pubertal children in our study had higher growth hormone levels than prepubertal children, there were no significant differences in glucose, insulin, and C-peptide levels between the two groups. The variations in insulin levels that are associated with stable glucose levels may be explained by changes in tissue sensitivity to insulin. Thus, the stable glucose levels and decreased insulin concentrations that we observed would be consistent with an increase in insulinreceptor affinity as hypothesized by Levy et al. (16). Further studies are needed to clarify this issue.

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