Glucose Regulates the Release of Orexin-A From the Endocrine Pancreas

Abstract

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. Diabetes 52: 111-117, 2003 O rexins (hypocretins) are novel neuropeptides that play a role in arousal and the regulation of energy balances (1-3). Orexin-A (OXA) and -B are 33-and 28-residue peptides, respectively, that are isolated from the rat hypothalamus and named for their ability to stimulate feeding when injected into the brain (2). Their common precursor, prepro-orexin, is expressed in a specific population of neurons in and around the lateral hypothalamic area (LHA) (2), a region classically implicated in the control of mammalian feeding behavior (4). The LHA contains glucosensitive neurons that are stimulated by falls in circulating glucose (5) and inhibited by prandial signals, such as the presence of food in the gut and/or a rise in portal glucose concentration (4). Previous studies have suggested that orexin neurons might correspond to this neuronal population, since orexin neurons are activated by hypoglycemia (6) and increased hypothalamic prepro-orexin mRNA levels are observed in response to fasting (1,7); however, glucosensitive neurons do not contain OXA (8). They are excited by the peptide (8), implying that orexin acts as a neuromodulator at glucosensitive cells, stimulating them under conditions of hunger.Glucosensitive neurons are also found in regions outside the hypothalamus, including the nucleus of the solitary tract (NTS) (9) and enteric nervous system (ENS) (10). The NTS relays visceral afferent signals to the LHA (8). Orexin fibers are distributed extensively in the NTS (11), and glucosensitive neurons are activated by the same conditions that stimulate orexin neurons in the LHA (6). The ENS participates in the regulation of food intake by directly sensing, integrating, and reg...

Impact of Porcine Orexin a on Glucagon Plasma Concentrations in Pigs

“…This explanation possibly gives priority to the paracrine regulatory pathways, which are potentially involved in regulating the secretion of glucagon in the experimental pattern of this study, as well as to the existence of the enteroinsular axis with a leading role (20,29,64).…”

“…A considerable increase in glucagon values (p<0.05) was seen when the quantity of Orexin A was lowered to 80 nmol/I, while there was no change in glucagon plasma concentrations when the quantity of Orexin A ranged from I to 50nmol/l. The same researchers re-administered Orexin A to rats intravenously (100 pmol-Kg' -rnirr ' for 20 min) and found that it caused a significant increase (p<0.05) in plasma glucagon levels (from 33.25± 2.14 to 53.5±6.5 pg/ml, n=4) (29).…”

“…In addition, the selection of glucagon was made after thinking that the pancreas is probably the main target-organ for the actions of the neuropeptide, Orexin A (29).…”

“…In addition, other studies examined the intravenous (IV) injection of Orexin A and its effect on blood glucagon in rats (25)(26)(27)(28). Besides, other authors examined the effect of Orexin A on isolated pancreatic islets of rats (29).…”

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

“…Accumulating evidence supports the peripheral role of neuropeptides controlling feeding behavior such as neuropeptide Y, orexins, ghrelin, corticotropin-releasing factor, or apelin in the regulation of glucose homeostasis (14)(15)(16)(17)(18), coining the new concept that hypothalamic neuropeptides may serve as a link between energy and glucose homeostasis and identifying them therefore as potential therapeutic targets for the treatment of diabetes and obesity (19,20).…”