Awakening to the Dawn Phenomenon in Diabetes

The “dawn phenomenon” (DP) describes a pattern in which episodes of hyperglycemia are experienced by patients with diabetes or prediabetes during the early morning hours (usually between 3:00 and 8:00 AM). It typically occurs in the absence of prior nocturnal hypoglycemia.
The term was first coined by Schmidt and colleagues in 1981 to refer to a rise in morning fasting glucose in patients with type 1 diabetes (T1D). It has since been identified in patients with type 2 diabetes (T2D) — both insulin and non-insulin dependent. If hyperglycemia persists into later morning hours, it is sometimes referred to as the “extended dawn phenomenon.” 
The DP is quite common, affecting 54% of individuals with T1D, 55% of individuals with T2D, and approximately 30% of individuals with prediabetes or insulin resistance.
Research suggests that patients with diabetes with the DP have poorer outcomes and higher rates of all-cause mortality than those without the DP. In particular, the DP can worsen overall glycemic control in T2D leading to an increase in A1c levels as high as 0.4%. One study of 3642 patients with T2D found that every 1% reduction in A1c was associated with a mean 14% lower risk for myocardial infarction (8%-21%; P < .0001) and 37% lower risk for microvascular complications (33%-41%, P < .0001). Therefore, tackling the DP can potentially have a beneficial impact in mortality reduction.
Pathophysiology of DP
“The dawn phenomenon is likely due to a number of hormones that rise close to the morning hours,” Marc-Andre Cornier, MD, professor of medicine, and James A. Keating, Endowed Chair in Diabetes, Medical University of South Carolina, Charleston, South Carolina, told Medscape Medical News.
Throughout the day, hepatic glucose metabolism fluctuates, with an increase in glycogenolysis and gluconeogenesis during the early morning hours. In people without diabetes, plasma insulin tends to remain stable and consistent during the night, with a slight, transient increase in insulin secretion just before dawn. This increase in insulin suppresses hepatic glucose production, thereby preventing hyperglycemia. But in the absence of sufficient insulin, this transient increase in hepatic glucose production can lead to hyperglycemia. 
Additionally, cortisol and growth hormone rise during the night, especially toward the morning, explained Cornier, who is also the director of the Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. “This is normal and happens in everyone, and for most people, the body takes care of it.”
Kevin Peterson, MD, MPH, vice president of primary care, American Diabetes Association, described the DP as a “dynamic change caused by a healthy body preparing to wake up.” But in those with insulin resistance, prediabetes, or diabetes, the body can’t compensate for the spike in hormones, leading to a surge in blood glucose and hyperglycemia.
Disruption of the molecular circadian clock is associated with DP in T2D. Research from Huang and colleagues suggests that the DP is closely associated with poor sleep quality. Additionally, a genetic component may mediate the association: mRNA expression of circadian clock genes is “dampened” in the peripheral leukocytes of patients with diabetes and poor sleep quality — particularly the BMAL1 and the PER1 genes.
The study authors suggest that these findings “may help to recognize a new pathophysiological mechanism of DP and find a new target for management and treatment of T2D.” 
Another study found an altered temporal expression of the rev-erbα and rev-erbβ genes may explain the DP, also pointing to a potential future target for intervention.
Assessing the DP
Peterson noted the DP “may not cause any symptoms, although sometimes the side effects of a high blood glucose level may be noticed.” 
It can be detected using “traditional ambulatory glucose monitors,” he said. In fact, it was first identified and described before continuous glucose monitoring (CGM) was introduced in 1999. Detecting DP is most effectively accomplished through the use of CGM, but an alternative is using intermittent glucose monitoring to assess the magnitude of the DP, wherein there is a correlation between premeal glucose values and the change brought by the DP.
Monnier and colleagues proposed a formula that can be used to calculate the magnitude of early morning hyperglycemia, even without CGM: Three measurements of blood glucose at the pre-breakfast, pre-lunch, and pre-dinner time points and the subsequent calculation of differences between the pre-breakfast glucose and the average of the pre-lunch and pre-dinner glucose values, can inform prediction of the absence/presence of DP with a “satisfactory balance between sensitivity (71%) and specificity (68%).”
Monnier and colleagues also suggested a calculation to assess the clinical significance of these findings and how to utilize it to adjust treat-to-target strategies designed to lower the pre-breakfast glucose value to < 100 mg/dL without risking overnight hypoglycemia. 
In assessing early morning hyperglycemia, it is important to distinguish it from the Somogyi effect (SE), which Peterson defined as “rebound hyperglycemia caused by hypoglycemia, usually triggered by a medication.” For example, excess or incorrectly timed insulin or inadequate caloric intake can trigger the SE.
The SE can be detected by using CGM. If this is not available, a glucose reading in the middle of the night should disclose hypoglycemia and establish the diagnosis. Additionally, an A1c level that falls within the reference range or is low, despite an elevated fasting glucose level, may be a helpful clue.
It is also important to distinguish the DP from other causes of morning hyperglycemia, such as overnight deficiency in basal insulin and medication interactions, Peterson said.
Pharmacologic Approaches to the DP
Pharmacotherapy for treating the DP can be challenging because increasing the bedtime doses of medications that counteract hyperglycemia might be associated with undesirable nocturnal hypoglycemia.
Oral agents typically don’t adequately control the DP, even when given in combination. The drawback of sulfonylureas is that they carry the risk for potential hypoglycemia in the afternoon or evening when the dose is increased to counteract the hyperglycemia of the DP. Incretins improve blood glucose during postprandial periods but not during fasting periods. However, a recent study found that compared with sulfonylurea, acarbose helped with treating DP.
Optimal insulin therapy is critical and must be individualized to each patient, with the DP playing a role in choosing the type of insulin and mechanism of delivery. Continuous insulin infusion seems to be superior to long-acting insulin formulations because it can provide a bolus during the early morning hours. Administration of basal insulin can eliminate the DP by “restraining hepatic glucose production and lipolysis” and is an “effective treatment as it mimics the physiology of glucose homeostasis in normal, nondiabetic subjects.”
A study examined the pathophysiology of the DP by monitoring the effects of changes in blood glucose levels from late night to early morning in patients taking the insulin glargine U-100 biosimilar (insulin glargine BS injection) and glargine U-300 (Lantus XR). The mean blood glucose was significantly lower in the BS vs XR group, (P < .0001). The BS group also had significantly higher adrenocorticotropic hormone and cortisol levels than the XR group (P = .0215 and P = .0491, respectively).
“These results suggest that XR may be a better choice for long-acting insulin since it is less likely to induce cortisol secretion” and that “appropriate basal insulin replacement therapy is a beneficial treatment for the dawn phenomenon,” the authors wrote.
The Role of Nonpharmacologic Interventions in Managing DP
Research suggests that dietary interventions can be helpful in minimizing the DP. For example, a higher protein-to-carbohydrate ratio during the evening meal and eating breakfast regularly decreases the secretion of insulin-antagonistic hormones.
The time of eating also makes a difference, according to Cornier. Eating a large dinner later at night means going to bed with already higher glucose levels and will “accentuate the DP — especially if the patient is not receiving adequate medical therapy.” On the other hand, eating a smaller meal earlier in the evening or having adequate treatment to counterbalance that meal means that the natural rise in blood glucose will start at a lower point.
Because of the early morning surge in hormones, the body tends to be more resistant to insulin. Breakfast content is important as well, Cornier said.
“Typically, we would recommend a breakfast lower in carbohydrates and sugar in those with the dawn phenomenon,” he said. “Cereal, oatmeal, and orange juice are traditional breakfast foods but probably not the best choice for people with an impaired glucose mechanism, which is accentuated by the dawn phenomenon.”
Physical exercise can also be useful in managing the DP. “It probably helps to exercise before breakfast because that can utilize some of the circulating glucose,” Cornier said. “It also enhances people’s sensitivity to insulin.” However, exercising after a meal “helps burn glucose” and is also valuable.
Cornier noted that research has been mixed regarding whether it’s better for people with diabetes to exercise in the morning or in the afternoon. For example, a study by Zheng and colleagues found that acute moderate-intensity aerobic exercise before breakfast reduced the morning rise of blood glucose in patients with T2D, partially counterbalancing DP, and also significantly reduced blood glucose fluctuations and improved blood glucose control throughout the day. Other studies have suggested that evening exercise may improve glycemia and reduce the DP. Exercising prior to overnight fasting may help improve hepatic insulin sensitivity, resulting in an attenuation of the early morning rise in endogenous glucose production responsible for DP.
Cornier said the most important thing is simply for those with diabetes to engage in physical exercise. “Do it whenever you can and pick a time that makes sense for you in your daily life.”
Managing the DP is an important component of overall diabetes management.
A multidisciplinary team approach incorporating diabetes nurse educators, dieticians, and clinicians is likely to yield the best outcomes. Communication between team members is important for coordinating strategies that include lifestyle changes, self-monitoring of the disease, and medication adjustment.
Cornier reported having served as a consultant for Novo Nordisk. Peterson reported no relevant financial relationships.
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
 
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