Chapter A20: Glucagon

INTRODUCTION

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 clinical toxicology, glucagon is used 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 as well as human case series and case reports. The effects of glucagon are often transient.

HISTORY

Glucagon was discovered in 1922, the year after insulin’s discovery, when acetone precipitates of pancreatic extracts were found to produce “a distinctly hyperglycemic effect” in animals.³⁴ Originally viewed as a mere contaminant in insulin products, glucagon was eventually attributed to pancreatic α-cells and sequenced in 1957.^7,22 The positive inotropic and chronotropic effects of glucagon were recognized in the 1960s.^18,20 Clinical use in human poisonings began in 1971.³⁹

PHARMACOLOGY

Chemistry and Preparation

Glucagon is a single-chain polypeptide counterregulatory hormone with a molecular weight of 3,500 Da that is secreted by the α-cells of the pancreas. The previously animal-derived product was possibly contaminated with insulin; the form approved in 1998 by the US Food and Drug Administration (FDA) is synthesized by recombinant DNA technology and thus is free of insulin and the prior phenol preservative.^31,57

Mechanism of Action

In both animals and humans, glucagon receptors are found in the heart, brain, and pancreas.^26,42,90 Binding of glucagon to cardiac receptors is closely correlated with activation of cardiac adenylate cyclase.⁶⁸ 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 G_s protein and catalyzes the exchange of guanosine triphosphate (GTP) for guanosine diphosphate on the α subunit of the G_s protein.^25,67,95 One isoform is coupled to β-adrenergic agonists, and both isoforms are coupled to glucagon.⁹⁵ The GTP-G_s units stimulate adenylate cyclase to convert adenosine triphosphate (ATP) to cAMP.^41,51 In animal hearts, glucagon inhibits the phosphodiesterase PDE₃.^6,56 Selective inhibition of PDE₄ potentiated the cAMP response to glucagon in adult rat ventricular myocytes.⁶⁶ Glucagon, along with β₂-adrenergic agonists (not β₁-adrenergic agonists), histamine, and serotonin, also activates G_i, which inhibits cAMP formation in human atrial heart tissue.³³

Evidence suggests an additional mechanism of action for glucagon independent of cAMP and dependent on arachidonic acid.⁷⁶ Cardiac tissue metabolizes glucagon, liberating mini-glucagon, an active smaller terminal fragment.^76...