Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

In adults with insulin-treated diabetes, hypoglycemia-associated autonomic failure (HAAF) is described as a syndrome that includes counterregulatory hormonal deficiencies and impaired symptomatic awareness in response to severe hypoglycemia (1). It is thought to result from failure of the central autonomic response to acute neuroglycopenia and is associated with recurrent exposure to hypoglycemia and increasing duration of diabetes. It is not known whether this syndrome occurs in children with type 1 diabetes, but the Diabetes Research in Children Network (DirecNet) Study Group has claimed that HAAF was present in at least a third of their participants with type 1 diabetes (2). Examination of the study design and methodology raises doubts as to whether this conclusion is justified.

In this study, the mean glucose nadir achieved was 60 mg/dl (3.3 mmol/l). When blood glucose was >60 mg/dl, only 11 (39%) subjects generated an epinephrine response with 9 (32%) of these mounting a response when blood glucose was <60 mg/dl. No response was identified in eight (29%). Only 29% of parents indicated that their children appeared to be hypoglycemic, whereas adolescents were better able to detect the symptoms of hypoglycemia, albeit with poor specificity.

The quality of glycemic control modifies the blood glucose threshold for the generation of symptoms and counterregulatory responses; poor glycemic control resets these thresholds upward (3). A previous study in Edinburgh examined the symptomatic and hormonal responses to hypoglycemia in 27 children and adolescents (age 9–16.6 years) with type 1 diabetes (4). An acute autonomic response (rapid increments in heart rate and pulse pressure) was demonstrated at a mean blood glucose of 40 mg/dl (2.2 mmol/l) despite a higher median A1C of 8.5% (compared with a mean A1C of 7.65% in the DirecNet study). Symptom onset was concurrent with objective evidence of the acute autonomic response, as noted by observers. Blood glucose thresholds for counterregulatory hormone secretion in nondiabetic adults are widely distributed (5), with many being below the blood glucose nadir reached in the DirecNet study. Thus, the depth of hypoglycemia obtained in the DirecNet study may have been insufficient to trigger the typical hormonal and symptomatic responses associated with hypoglycemia in their well-controlled pediatric cohort. A failure to mount a hormonal or symptomatic response to an inadequate hypoglycemic stimulus would not equate with the presence of HAAF.

Young children undoubtedly have difficulty recognizing the onset of hypoglycemia, but we do not accept that this necessarily demonstrates the existence of HAAF. Recognition of hypoglycemia is a consequence of a complex interplay of many factors, including concurrent mental and physical activities, psychological factors, behavioral patterns, emotional and physical maturity, plus the prevailing level of glycemic control and exposure to antecedent hypoglycemia. Although we appreciate that the authors may have been restricted by ethical constraints to lowering blood glucose to <60 mg/dl, the apparent deficient responses that were observed may be a consequence of the modest hypoglycemic stimulus imposed, and not to the presence of a syndrome that usually takes several years to develop (1).

• © 2010 by the American Diabetes Association.