Untangling narcolepsy and diabetes: Pathomechanisms with eyes on therapeutic options

Narcolepsy (NA) is a primary sleep disorder characterized by loss of hypocretinergic/orexinergic neurons. NA is associated with an increased risk for metabolic disorders such as diabetes mellitus (DM). Proposed mechanisms for this association are alterations in food intake, disruption of energy balance, glucose tolerance, and insulin sensitivity, as well as inflammation and genetic factors. Orexin deficiency, is associated with increased food intake and reduced basal metabolic rate (BMR) both leading to obesity. The anti-apoptotic effect of orexin on pancreatic beta-cells, increase in peripheral insulin sensitivity, and reduced lipolysis in the adipose tissue, together confer an increased risk for obesity and type 2 DM (T2DM) in NA patients. The main pathomechanisms relating type 1 DM (T1DM) to NA involve autoimmunity and inflammation. HLA genes that confer a risk for NA, such as DQB1*0602 are protective against T1DM, while catepsin gene (CTSH) mutations are a risk factor for both NA and T1DM. Gestational DM (GDM) is associated with obesity which is a potential outcome of narcolepsy. GDM patients have lower serum orexin expression which is associated with increased fasting glucose and decreased fasting insulin. Ongoing research on the use of orexin receptor (OXR) antagonists in sleep disorders has opened a window to the pathomechanisms of NA and the potentials for OXR modulation in eating disorders and obesity. Understanding the common pathophysiological mechanisms of NA, DM and obesity could guide us in designing life-style modification programs, genetic consultations, and targeted therapies, such as immunotherapy, for obesity in NA.