The traditional role of glucagon was to reverse life-threatening hypoglycemia in patients with diabetes unable to receive dextrose in the outpatient setting. However, in medical toxicology, glucagon is used “off label” early in the management of β-adrenergic antagonist and calcium channel blocker toxicity to increase heart rate, contractility, and blood pressure by increasing myocardial cyclic adenosine monophosphate (cAMP) via a non–β-adrenergic receptor mechanism of action. The use of glucagon is based primarily on animal studies and as well as human case series and case reports. The effects of glucagon are often transient.
Glucagon was discovered in 1923, just 2 years after the discovery of insulin.10 The positive inotropic and chronotropic effects have been known since the 1960s.12,15
Glucagon is a polypeptide counterregulatory hormone with a molecular weight of 3500 Da, secreted by the α cells of the pancreas. Previously animal derived, and possibly contaminated with insulin, the form approved by the US Food and Drug Administration (FDA) has been synthesized by recombinant DNA technology since 1998; therefore, it no longer contains any insulin.25
In both animals and humans, glucagon receptors can be found in the heart, brain, and pancreas.22,33,64 Binding of glucagon to cardiac receptors is closely correlated with activation of cardiac adenylate cyclase (AC).52 A large number of glucagon binding sites are demonstrated, and as little as 10% occupancy produces near maximal stimulation of adenylate cyclase. Binding of glucagon to its receptor results in coupling with two isoforms of the Gs protein and catalyzes the exchange of guanosine triphosphate (GTP) for guanosine diphosphate on the α subunit of the Gs protein.21,51,69 One isoform is coupled to β agonists, while both isoforms are coupled to glucagon.69 The GTP-Gs units stimulate adenylate cyclase to convert adenosine triphosphate (ATP) to cAMP.32,40 In animal hearts, glucagon inhibits the phosphodiesterase PDE-3.5,43 Selective inhibition of PDE-4 potentiated the cAMP response to glucagon in adult rat ventricular myocytes.50 Glucagon, along with β2 agonists, histamine, and serotonin (but not β1 agonists), also activates Gi, which inhibits cAMP formation in human atrial heart tissue.27
Evidence now suggests an additional mechanism of action for glucagon, independent of cAMP, and dependent on arachidonic acid.57 Cardiac tissue metabolizes glucagon, liberating mini-glucagon, an apparently active smaller terminal fragment.57,66 Mini-glucagon stimulates phospholipase A2, releasing arachidonic acid. Arachidonic acid acts to increase cardiac contractility through an effect on calcium. The effect of arachidonic acid—and therefore of mini-glucagon—is synergistic with the effect of glucagon and cAMP.58
Stimulation of glucagon receptors in the liver and adipose tissue increases cAMP synthesis, resulting in ...