β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade

“…Unless otherwise specified, samples were collected between 10:00 and 11:30 a.m. by quick superficial temporal vein bleed into EDTA-coated microtubes containing p -hydroxymercuribenzoic acid (final concentration 1 mmol/L; Sigma-Aldrich, St. Louis, MO) kept on ice and HCl was added to the plasma after centrifugation to achieve a final concentration of 0.1 nmol/L, as described (20). Blood glucose levels were measured using a Bayer CONTOUR Blood Glucose Monitoring System.…”

“…Notably, ghrelin administration or transgenic overexpression raises blood glucose levels, whereas genetic deletion or pharmacologic blockage of key elements of the ghrelin system lowers blood glucose levels (13–15,17–19). Indeed, mice lacking the usual ghrelin response to marked caloric restriction develop severe hypoglycemia and experience increased mortality (12,16,20). Interestingly, plasma ghrelin levels also are negatively regulated by blood glucose, presumably because of effects on ghrelin secretion (21–23).…”

Ghrelin as a Survival Hormone

“…Also of note, the increase in plasma ghrelin associated with both short-term and more chronic caloric restriction requires sympathetic activation of the highly-expressed β 1 -adrenergic receptors on ghrelin cells [32]. Other settings associated with high ghrelin include exposure to psychosocial stress [40] and Prader-Willi Syndrome, although in Prader-Willi Syndrome, it is unclear how much of this represents unprocessed ghrelin [13, 41].…”

“…Not only do mice with ghrelin cell-selective deletion of β 1 -adrenergic receptors fail to appropriately increase ghrelin secretion in response to the chronic 60% caloric restriction protocol, but also they too experience hypoglycemia and a 36% mortality rate [32]. These findings were unlike another group’s experience with ghrl −/− , ghsr −/− or double ghrl −/− / ghsr −/− mice [80], albeit differences in their protocol [they used older mice that had a higher starting fat mass and were group-housed (which may have prevented equivalent extremes of caloric restriction in all mice)] may have influenced those results.…”

“…The significance of the ghrelin system in defending against hypoglycemia depends not only on the severity/duration of the caloric restriction, but also on the age of the animal and the availability of other counterregulatory hormones. For instance, hypoglycemia is induced in 24 h-fasted 3 week-old mice, but not in 24 h-fasted adult mice upon blockade of ghrelin secretion with a β-blocker, suggesting that neonates and infants may be more dependent on the blood glucose protective actions of ghrelin than adults [32]. Regarding the availability of other counterregulatory hormones, whereas glucagon receptor genetic deletion prevents the hyperglycemia induced by STZ, the concomitant increase in plasma ghrelin acts in that setting to block the development of hypoglycemia, as administration of a GHSR antagonist further reduces blood glucose levels into the markedly hypoglycemic range in overnight-fasted, STZ-treated glucagon receptor-knockout mice [78].…”