Glucagon in Endocrine and Metabolic Practice: A Critical Narrative Review of Stimulation Testing, Diagnostic Cut-points and Therapeutic Use in Children, Adolescents and Adults

Abstract

Glucagon occupies an unusual position in clinical endocrinology. The same 29-amino-acid peptide serves as a provocative agent for pituitary function testing, as an emergency treatment for severe hypoglycaemia, as a continuous infusion in hyperinsulinaemic states of infancy, and, through receptor co-agonism, as a component of the newest generation of cardiometabolic drugs. These applications have developed in parallel, largely within separate literatures, and the assumptions that underpin them have rarely been examined together. This review evaluates the evidence accumulated over approximately a quarter of a century on the glucagon stimulation test and on therapeutic glucagon across the paediatric and adult lifespan, with particular attention to the derivation, transportability and validity of diagnostic cut-points. Evidence was identified through structured searching of biomedical and bibliographic sources and appraised for design adequacy, reference-standard quality, sample size, assay dependence and generalisability. Three findings dominate the synthesis. First, the growth hormone cut-point for the glucagon stimulation test is not a fixed biological threshold but a function of dose regimen, adiposity, glucose tolerance, age and assay calibration; the widely used threshold of 3 µg/L overdiagnoses deficiency in overweight adults, and the proposed alternative of 1 µg/L rests on small validation cohorts. Second, the corticotroph read-out from the same test performs considerably less well than the somatotroph read-out, and several independent series show a broad indeterminate zone in which the test cannot classify patients reliably. Third, therapeutic glucagon has been transformed by stable ready-to-use formulations and by the analogue dasiglucagon, with randomised evidence in severe hypoglycaemia, congenital hyperinsulinism and post-bariatric hypoglycaemia, although comparative effectiveness data and long-term paediatric safety data remain sparse. Priorities include multicentre cut-point validation stratified by body mass index and assay platform, harmonised cortisol thresholds, and adequately powered comparisons between glucagon formulations in real-world hypoglycaemia.