Orexins (hypocretins) are novel neuropeptides that appear to play a role in the regulation of energy balances. Orexin-A (OXA) increases food intake in rodents, and fasting activates OXA neurons in both the lateral hypothalamic area and gut. OXA is also found in the endocrine pancreas; however, little is known about its release or functional significance. In this study, we show that depolarizing stimuli evoke the release of OXA from rat pancreatic islets in a calcium-dependent manner. Moreover, OXA release is stimulated by low glucose (2.8 mmol/l), similar to glucagon secretion, and inhibited by high glucose (16.7 mmol/l). Fasting increases plasma OXA, supporting the idea that orexin is released in response to hypoglycemia. Cells that secrete glucagon and insulin contain OXA and both cell types express orexin receptors. OXA increases glucagon secretion and decreases glucose-stimulated insulin release from isolated islets. OXA infusion increases plasma glucagon and glucose levels and decreases plasma insulin in fasted rats. We conclude that orexin-containing islet cells, like those in the brain and gut, are glucosensitive and part of a network of glucose “sensing” cells that becomes activated when blood glucose levels fall. OXA may modulate islet hormone secretion to maintain blood glucose levels during fasting.
Address correspondence and reprint requests to Dr. Annette Kirchgessner, Neurology and GI CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW. E-mail:.
Received for publication 19 June 2002 and accepted in revised form 9 October 2002.
A.L.K. is employed by and holds stock in GlaxoSmithKline.
EIA, enzyme immunoassay; ENS, enteric nervous system; FITC, fluorescein isothiocyanate; HPLC, high-performance liquid chromatography; IR-OXA, immunoreactive Orexin-A; LHA, lateral hypothalamic area; NTS, nucleus of the solitary tract; OXA, Orexin-A; OXR1, orexin receptor 1; TFA, trifluoroacetic acid; TTX, tetrodotoxin.