Abstract
ObjectiveDisturbances in the activity of the hypothalamus-pituitary-adrenal axis could lead to functional alterations in the brain of diabetes patients. In a later perspective of investigating the link between the activity of the hypothalamus-pituitary-adrenal axis and the developing brain in children with diabetes, we assessed here nocturnal cortisol metabolism in prepubertal children with type 1 diabetes mellitus (T1DM).MethodsPrepubertal patients (aged 6–12 years) diagnosed with T1DM at least 1 year previously were recruited, along with matched controls. Nocturnal urine samples were collected, with saliva samples taken at awakening and 30 minutes after awakening. All samples were collected at home over 5 consecutive days with no detectable nocturnal hypoglycaemia. The State-Trait Anxiety Inventory (trait scale only) and Child Depression Inventory were also completed. Glucocorticoid metabolites in the urine, salivary cortisol (sF) and cortisone (sE) were measured by liquid chromatography–tandem mass spectrometry. Metabolic data were analysed by logistic regression, adjusting for sex, age, BMI and trait anxiety score.ResultsUrine glucocorticoid metabolites were significantly lower in T1DM patients compared to controls. 11β-hydroxysteroid dehydrogenase type 1 activity was significantly higher, while 11β-hydroxysteroid dehydrogenase type 2, 5(α+β)-reductase and 5α-reductase levels were all lower, in T1DM patients compared to controls. There was a significant group difference in delta sE level but not in delta sF level between the time of awakening and 30 minutes thereafter.ConclusionsOur findings suggest that altered nocturnal cortisol metabolism and morning HPA axis hyperactivity in children with T1DM leads to greater cortisol bioavailability and lower cortisol production as a compensatory effect. This altered nocturnal glucocorticoid metabolism when cortisol production is physiologically reduced and this HPA axis hyperactivity question their impact on brain functioning.
Highlights
It is well established that type 1 diabetes mellitus (T1DM) in children can have a significant impact on the developing brain, as reflected in high prevalence of depression [1] and poor performance on certain cognitive tasks [2] along with structural and functional changes [3]
We showed that glucocorticoid levels and 11b-HSD1 activity were elevated in diabetic rats not treated with insulin
We showed that insulin treatment partially rescued several hippocampus-dependent behavioural and structural changes in early onset insulin-deficient diabetic rats, as well as 11b-HSD1 activity in the hippocampus [12] indicating that the elevated bioavailability of glucocorticoids may be involved in the diabetes cognitive dysfunctions
Summary
It is well established that type 1 diabetes mellitus (T1DM) in children can have a significant impact on the developing brain, as reflected in high prevalence of depression [1] and poor performance on certain cognitive tasks [2] along with structural and functional changes [3]. In children with diabetes, sustained dysregulation of blood glucose is currently considered the cause of cognitive dysfunction. The extent to which acute hypoglycaemia, chronic hyperglycaemia and/or blood sugar variations directly and indirectly affect brain function has yet to be clarified [2]. In addition to chronic hyperglycaemia and relative insulin insufficiency, disturbances in the activity of the hypothalamus-pituitary-adrenal (HPA) axis, often implicated in autoimmune or pharmacological models of diabetes mellitus, could participate in brain alterations [5, 6]. Dysregulated glucocorticoids are well known to lead to depression [7] or mnesic dysfunctions [8]
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