Hypothalamo–pituitary–adrenal axis, glucose metabolism and TNF‐α in narcolepsy

Abstract

SUMMARYNarcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case-control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults underwent an oral glucose tolerance test, and dexamethasone suppression/corticotropin-releasing hormone stimulation test. The average age of patients and controls was 35.1 AE 13.2 and 41.0 AE 2.9 years, respectively, body mass index was 28.1 AE 6.6 and 25.5 AE 4.7 kg m À2. We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in patients with narcolepsy. After hypothalamo-pituitary-adrenal axis suppression, the number of non-suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethasone suppression was significantly lower in patients with narcolepsy, suggesting a slight basal downregulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following corticotropin-releasing hormone stimulation, there were no significant differences in levels of adrenocorticotropic hormone or cortisol, and in adrenocortical responsivity to adrenocorticotropic hormone. Finally, patients with narcolepsy displayed significantly higher plasma levels of tumour necrosis factor alpha, soluble tumour necrosis factor receptor p55, soluble tumour necrosis factor receptor p75 and interleukin 6 after adjustment for body mass index. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic hypothalamo-pituitary-adrenal system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced. IN TROD UCTI ONNarcolepsy is a rare, chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Low cerebral spinal fluid hypocretin/orexin levels, caused by selective loss of hypocretin-producing neurons in the prefornical hypothalamus, due to possible autoimmune mechanisms, are reported in 95% of patients with narcolepsy with cataplexy (NC) (Baumann and Bassetti, 2005).In addition to their crucial role as regulators of sleep and wakefulness, hypocretin neurons have been shown to play an important role in energy homeostasis. For example, hypocretins increase food intake, and are involved in glucose metabolism and insulin sensitivity. Furthermore, they have a stimulatory role on the major stress system and can activate

Reduced Numbers of Corticotropin‐Releasing Hormone Neurons in Narcolepsy Type 1

“…Our study indicates that besides hypocretin deficiency, there is also a marked loss of CRH‐positive neurons selectively in the PVN. This may explain earlier findings, such as a 60% reduction in the basal secretion of ACTH in patients with NT1, 19 and lower plasma levels of cortisol after dexamethasone suppression 20 . The unaffected number of AVP neurons in the biological clock may explain the normal circadian rhythm of adrenocorticotropic hormone 19 .…”

“…This may explain earlier findings, such as a 60% reduction in the basal secretion of ACTH in patients with NT1, 19 and lower plasma levels of cortisol after dexamethasone suppression. 20 The unaffected number of AVP neurons in the biological clock may explain the normal circadian rhythm of adrenocorticotropic hormone. 19 The marked loss of CRH‐positive neurons in the PVN may provide a novel target for diagnostics and therapeutic interventions, and for identifying the target of the presumed auto‐immune cause of narcolepsy.…”

Impact of Serum Cytokine Levels on EEG-Measured Arousal Regulation in Patients with Major Depressive Disorder and Healthy Controls

“…Subjects suffering from inflammation frequently exhibit tiredness or sleepiness mediated by the increased production of proinflammatory cytokines in the setting of ‘sickness behavior', which resembles depressive symptoms [4,7]. Narcolepsy, a disorder with increased daytime sleepiness, was found to be associated with specific markers of the HLA system and increased production of proinflammatory cytokines [21,42,43]. Cytokines not only influence wakefulness regulation, but their concentrations also change depending on sleep characteristics or following sleep deprivation [44,45,46].…”

Roles of Microglial Phagocytosis and Inflammatory Mediators in the Pathophysiology of Sleep Disorders

“…Clinical studies have also revealed that narcolepsy patients have subtly dysregulated cytokine levels in their serum and CSF consistent with markers of microglial reactivity (Okun et al, 2004 ; Dauvilliers et al, 2014 ; Maurovich-Horvat et al, 2014 ; Tanaka et al, 2014 ). Multiple independent studies that include different ethnic populations showed a preponderant increase in IL-6 and TNFα expression in sera or plasma from patients with narcolepsy (Okun et al, 2004 ; Maurovich-Horvat et al, 2014 ; Tanaka et al, 2014 ). Other studies have identified changes in IL-4 (Dauvilliers et al, 2014 ) or IL-8 (Tanaka et al, 2014 ) levels.…”