Barriers to achieving targets, risks of hyperglycemia and hypoglycemia in children

Traditionally, clinicians have focused on hypoglycemia as the main barrier preventing patients from achieving target HbA1c levels. There is, however, an increasing body of evidence that hyperglycemia may beget further hyperglycemia through neurobehavioral pathways, and that hyperglycemia can be associated with anatomic as well as cognitive alterations in central nervous system morphology and function.

Recent data from pediatric cohorts yet to achieve neuromaturation showed that chronic hyperglycemia is associated with morphologic, biochemical and functional changes to the central nervous system. These changes may be exacerbated by associated hypoglycemia, aptly described by the so-called “diathesis hypothesis” or glycemic variation.

Fergus J. Cameron

Timothy W. Jones

In addition, neuronal injury in the developing brain has been shown to be associated with changes in cognition — with hyperglycemia having demonstrable acute and chronic effects on cognitive testing. Hyperglycemia has also been shown to be associated with levels of externalizing behaviors in young children with established diabetes. A U.S. study of children with type 1 diabetes, aged 8 to 18 years, found an association between glycemia and academic performance and behavior. In addition, behavioral status at the time of diagnosis of type 1 diabetes in children has been shown to be highly predictive of mental health outcomes in late adolescence, with growing evidence that behavioral status in late adolescence is highly predictive of metabolic status in mid-adulthood. Depression is also a common comorbidity in adolescents and young adults with type 1 diabetes and poor glycemic control. It appears that “diabetes distress,” described as negative emotions toward diabetes and its treatment, is an important mediator in terms of its impact upon glycemic status.

Finally, some early and intriguing data showed that impaired cognitive performance in Danish conscripts born to diabetic mothers raises the possibility that hyperglycemia impacts neural ontogeny via glycemic memory and/or programming. The implications of this model are that normoglycemia and glycemic stability are highly desirable from a neurodevelopmental point of view and that medical interventions should be optimized with this in mind.

It is recommended that all children with diabetes have neuropsychologic testing shortly after diabetes diagnosis and engage in early initiation of educational, cognitive and behavior modifying interventions in order to address maladaptive behaviors. This intervention may provide a synergistic therapeutic effect in breaking the cycle of hyperglycemia leading to further hyperglycemia.

Risks of hypoglycemia

The Diabetes Control and Complications Trial (DCCT) established the value of systematically monitoring hypoglycemia outcomes both in research studies and in routine clinic care. Important outcomes from DCCT monitoring were the demonstration of the increased risk of hypoglycemia that was associated with tight glycemic control and the novel observation that adolescence is an independent risk factor for severe hypoglycemia.

In children, severe hypoglycemia remains prevalent, but there is early evidence that the frequency of severe events has fallen recently and that the relationship between glycemic control and rates of severe events may not be as strong as in previous studies. Newer insulins, improvements in insulin delivery and blood glucose monitoring may be responsible.

Still, impaired awareness of hypoglycemic symptoms may be present in up to 30% of youth with type 1 diabetes. A recent report from the Direct Net group suggests that counter-regulatory hormone responses may be reduced in a similar proportion of children. Impaired hypoglycemia awareness is associated with a high risk for severe hypoglycemia and it is important to identify in routine clinical care. Careful avoidance of hypoglycemia may reverse impaired adrenergic responses to hypoglycemia and the use of continuous glucose monitoring (CGM) systems in a pilot study was found to be a useful clinical tool.

Care must be taken when comparing studies, however, as the definition of severe events is different in adult and pediatric studies as well as between studies. Most studies in adults define a severe event as one that requires assistance to treat, but this is clearly a problematic definition in a young child. Studies in pediatric patients often use a more stringent definition for severe hypoglycemia as an event that results in coma or convulsion.

The patient’s perspective of hypoglycemia also encompasses more than severe events. Hypoglycemic symptoms are uncomfortable, potentially embarrassing, impair cognitive function and are associated with a fear of the unknown and of death. This fear of hypoglycemia is a major barrier to achieving blood glucose goals and can limit attempts to tighten diabetes control. Early studies suggest that real-time CGM systems may help alleviate the fear associated with hypoglycemia.

The majority of severe events occur at night. Excess insulin, defective counter-regulation during sleep and the delayed effects of exercise all contribute to the risk of nocturnal hypoglycemia. CGM has confirmed a high prevalence of prolonged asymptomatic nocturnal hypoglycemia, particularly in the young.

There is recent anecdotal evidence that seizures follow prolonged periods of hypoglycemia. This offers the potential to prevent events through CGM systems and algorithms based on CGM data that suspend insulin delivery if hypoglycemia is predicted.

Exercise is also associated with a risk for hypoglycemia both at the time of the exercise and 8 to 12 hours later. For afternoon exercise, delayed hypoglycemia may occur during sleep and is prevented through reduced overnight insulin and a bedtime snack.

It is important to identify those at greater risk, such as those with hypoglycemia unawareness, recently improved glycemic control, younger age groups, and those situations with a greater risk, including lack of sleep, physical inactivity and alcohol use, in order to mitigate the impact of hypoglycemia.

Patient education to recognize hypoglycemia early and to identify situations that hold higher risk along with effective preventive strategies is critical. Counseling to reduce inappropriate responses to the fear of hypoglycemia may be needed. The more widespread use of real time CGM may be effective in the future at reducing the adverse impact of hypoglycemia on attempts to achieve glycemic targets.

Fergus J. Cameron, MD, is head of diabetes services at Royal Children’s Hospital, Melbourne, Australia. Timothy W. Jones, MD, is head of the department of diabetes and endocrinology at Princess Margaret Hospital for Children and clinical professor at the Institute for Child Health Research at University of Western Australia.

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