Suppressed tonic glucagon, depleted substrate and attenuated warning: hypoglycaemia risk with incretin receptor agonists outside diabetes

Descrição para o Zenodo: Narrative review examining a gap in the hypoglycaemia safety evidence for incretin receptor agonists in users without diabetes. The safety of this class rests on hyperinsulinaemic hypoglycaemic clamp studies showing that the acute counterregulatory response is preserved. This review argues that several variables have been treated as one: the acute counterregulatory response, tonic glucagon tone, the gluconeogenic substrate reserve, hepatic sensitivity to glucagon, and the symptomatic warning that reaches the patient. Only the first has been a primary endpoint under pharmacological agonism, and it was measured in the one nutritional state in which the others do not matter. In the pivotal tirzepatide clamp study the acute glucagon response was preserved, but absolute glucagon concentrations were lower at every plateau except the nadir; adrenaline and noradrenaline responses at the 63 mg/dL alerting threshold were reduced by approximately 70%, converging with placebo at the nadir; autonomic symptom scores at nadir were lower; and eight of nine spontaneous hypoglycaemic events were asymptomatic. All participants were fed, metabolically replete and supervised. Published cases of hypoglycaemia and ketoacidosis in non-diabetic users share a different antecedent: days of vomiting and negligible intake, with hypoglycaemia and ketosis occurring together. Hepatic glycogen is exhausted within 24 hours of fasting, after which glucose output depends on gluconeogenesis from skeletal-muscle amino acids — a reserve reduced by 5.6 kg in the SURMOUNT-1 body-composition substudy. The review then draws on a human model that has not previously been connected to this literature. After gastric bypass, endogenous glucose production during insulin-induced hypoglycaemia is blunted despite higher prandial glucagon, indicating reduced hepatic sensitivity to glucagon; blockade of the GLP-1 receptor with exendin-(9-39) restores the response. Exogenous GLP-1 infusion lowers endogenous glucose production in humans directly. The hepatic step is therefore a demonstrated site at which GLP-1 receptor signalling degrades counterregulation, and no clamp study of a pharmacological agonist has measured it. On this account hypoglycaemia, starvation ketoacidosis and lean-mass loss are not three independent safety signals but three expressions of one nutritional mechanism, with attenuated warning determining how late the patient becomes aware of it. Four studies that would resolve the question are specified, together with the findings that would falsify the account. This version substantially expands the previous deposit, adding the hepatic glucagon-resistance evidence from bariatric surgery, a section on ketone kinetics during fasting, a methods statement and a limitations section. Preprint. Not yet submitted to a journal.