The Effect of Melatonin on Early Signs of Hypertension in Teenagers With Diabetes Mellitus Type 1

Premature and extensive atherosclerosis and the increased risk for cardio-vascular disease (CVD) are the major causes of morbidity and mortality in patients with type 1 diabetes (T1DM), with an up to 20 fold increase in mortality from CVD . Most subjects with diabetes will develop hypertension which is a major determinant of both microvascular and cardiovascular complications.

The pediatric population is much less studied but nevertheless sufficient data suggest that the risk for CVD emerges during childhood. Up to 16% of adolescents with T1DM have hypertension, and studies using 24 hour ambulatory blood pressure monitoring (ABPM) in normotensive adolescents with T1DM have identified loss of diurnal systolic rhythm and nocturnal hypertension . Moreover, many normotensive patients, may have a loss of the physiologic drop in BP during the night ("non-dippers") and this too correlates with early vascular changes. This early change frequently leads to frank hypertension later on. The prevalence of CVD in this population points to the importance of early identification of known CVD risk factors and early intervention. Data from the Pathological Determinant in Youth (PDAY) study have shown that early changes leading to atherosclerosis exist in adolescence . These data stress the importance of identifying asymptomatic patients at the early stages of vascular changes.

Sleep and Hypertension:

During adolescence, total sleep duration changes and sleep/wake times shift such that teenagers go to bed late and wake up even later. The circadian timing system responsible for this phase delay in sleep is influenced by hormonal changes during puberty, specifically a delay in melatonin secretion . Only 20% of adolescents meet recommendations for hours of sleep during the week (9-9.25 h) , and adolescents frequently overcompensate on weekends with delayed awakening times . There is only limited data describing sleep patterns in type T1DM patients. Altered sleep may be of greater relevance in adolescents with T1DM, because disrupted sleep architecture occurs in children with diabetes, and sleep depravation does impair insulin sensitivity in diabetic subjects . We previously published a study comparing sleeping habits in diabetic and non-diabetic adolescents, showing that despite the intensive treatment they require which involves eating and injecting insulin at certain times, including in early morning, the diabetic adolescents did not make adjustments to their sleeping habits compared to healthy adolescents10. It has previously been reported that in certain situations where disrupted sleep occurs, including night shift workers, there is a loss of the "nocturnal dip" in blood pressure.11 In a preliminary observational study we performed in the diabetes clinic at Safra children's hospital we were able to identify more than 50% of adolescents with T1DM as "non-dippers" when measuring continuous BP using ABPM. More than 20% of diabetic adolescents had frank hypertension above the 95th %ile for age and height compared to 0% in the control group, and despite being normotensive during clinic visits12. In addition, a significant increase in hypertension load was seen in the diabetics compared to health controls only during sleep, and not wake hours.

All the information described above, points towards the hypothesis that adolescents with T1DM are at risk for developing nocturnal hypertension while still remaining normotensive when assessed during clinic visits.