Life-threatening hypoglycemia can complicate the use of beta blockers, which are commonly used for hypertension but also have a specialized use in the treatment of hemangiomasin in toddlers. These negative effects have occurred especially in individuals who have diminished food reserves, such as the very young and those with disease-related cachexia, or wasting. Though the sympathetic nervous system provides an important safeguard against low blood sugar by enhancing gluconeogenesis, specific individuals experience more severe hypoglycemia for unknown reasons. Mani and colleagues have now uncovered an important connection between the normal metabolic response to fasting and the sympathetic nervous system. As they report, this connection is mediated by the ghrelin-producing cells of the stomach.
Ghrelin is best known for its role as a hunger hormone. The plasma concentration rises during fasting and promotes food intake. At the same time, this rise in ghrelin protects against low blood sugar even in the absence of increased food intake. The investigators knocked out the beta-adrenergic receptor specifically in ghrelin-producing cells, the majority of which reside in the stomach. It was known that ghrelin-producing cells respond to sympathetic stimulation, although the physiologic consequence had not been tested. Elimination of their sensitivity to adrenergic stimulation led to an over fivefold reduction in production of active ghrelin during fasting. During subsequent calorie restriction, these mice suffered lower blood sugar and greater mortality. Last, treatment of very young mice at 3 weeks of age with the beta blocker atenolol reduced ghrelin production and significantly lowered fasting blood sugar.
These findings place ghrelin as a central player in integrating the response to hypoglycemia in the most susceptible individuals. Ghrelin likely augments the effects of the sympathetic response by enhancing growth hormone production, which will provide substrates from tissue breakdown needed to sustain hepatic glucose production. When these substrates are not readily mobilized, as in the very young or ill, ghrelin appears to be an important line of defense against the development of lethal hypoglycemia. These data suggest that approaches to enhance the ghrelin response, such as through a receptor agonist or allosteric modulator, may afford life-saving protection against hypoglycemia in specific clinical situations.
B. K. Mani et al., β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals. J. Clin. Invest. 10.1172/JCI86270 (2016). [Full Text]
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