In a series of animal experiments, the insulin concentration in the pancreatic veins is measured after the administration of various agents. Epinephrine administration is found to cause a decrease in insulin levels. However, after pretreatment with Drug A, epinephrine injection causes a paradoxical increase in insulin concentration. Which of the following receptors does Drug A most likely block?
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Pancreatic beta cell insulin secretion is influenced by serum glucose levels and other factors such as autonomic nervous system activity. Parasympathetic stimulation of muscarinic M3 receptors promotes insulin secretion and is induced by the smell and/or sight of food. In contrast, sympathetic stimulation is more complex, since both alpha-2 and beta-2 adrenergic receptors are present on pancreatic beta cells and exert opposite effects. Stimulation of beta-2 receptors promotes insulin secretion while stimulation of alpha-2 receptors inhibits insulin release. However, the alpha-2-mediated inhibitory effect is predominant, causing sympathetic stimulation to lead to overall inhibition of insulin secretion. Likewise, epinephrine administration activates both alpha-2 and beta-2 receptors, but the overriding inhibitory effect results in decreased insulin secretion. Following pretreatment with an alpha-2 receptor blocker (Drug A), epinephrine's effect on beta-2 receptors would become dominant, resulting in increased insulin secretion.
(Choice B) Stimulation of beta-2 adrenergic receptors results in increased insulin secretion; beta-2 receptor blockade would inhibit insulin release.
(Choice C) Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the intestinal L cells in response to food and acts on receptors found on pancreatic beta cells to potentiate glucose-induced insulin release. Blocking GLP-1 receptors reduces insulin release. GLP-1 receptor agonists (eg, exenatide, liraglutide) are commonly used to treat type 2 diabetes mellitus.
(Choice D) Histamine H2 receptor stimulation increases insulin secretion. Blocking these receptors would cause a decrease in insulin release.
(Choice E) Parasympathetic stimulation increases insulin secretion via M3 muscarinic receptors. Blocking these receptors would inhibit the release of insulin.
Educational objective:
Alpha-2 adrenergic receptors inhibit insulin secretion, and beta-2 adrenergic receptors stimulate insulin secretion. The alpha-2-mediated inhibitory effect is generally predominant, causing sympathetic stimulation to lead to overall inhibition of insulin secretion.