["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Amino acids attenuate somatostatin‐mediated inhibition of islet hormone secretion in humans. Schematic illustration of study design and principal findings. In healthy participants (n = 15) intravenous amino acid infusion increased plasma glucagon and insulin concentrations compared with saline. Despite concurrent somatostatin exposure amino acids were associated with increases in glucagon and C‐Peptide levels, indicating partial preservation of α‐ and β‐cell secretion. Overall amino acids may overcome somatostatin‐induced suppression of pancreatic hormone secretion in healthy individuals.\n\n\n\n\n\n\n\n\n\nAbstract\nHyperaminoacidaemia and hyperglucagonaemia are hallmarks of metabolic dysfunction–associated liver disease and type 2 diabetes. Amino acids potently stimulate glucagon secretion and can stimulate insulin secretion, although less potently than glucose. Endogenous somatostatin released from pancreatic δ‐cells inhibits islet hormone output. It remains uncertain whether amino acid–induced stimulation can dominate pharmacological somatostatin receptor (SSTR) activation in humans. To address this we examined hormonal responses to intravenous amino acid infusion (Vamin) with and without concomitant infusion of the somatostatin analogue octreotide in 15 healthy individuals. Plasma glucagon, insulin and C‐Peptide were measured during 45 min of amino acid infusion alone, during amino acid infusion combined with a 240‑min octreotide infusion and during octreotide infusion without amino acids. Octreotide alone suppressed glucagon and insulin concentrations by greater than 90% and reduced C‑Peptide by greater than 65%. In contrast amino acids alone significantly increased all three peptides. When amino acids and octreotide were co‑infused, the amino acid–driven elevations in glucagon, insulin and C‑Peptide were reduced to 49%, 43% and 78% of the levels achieved by amino acids alone. These findings demonstrate robust α‑ and β‑cell secretion during SSTR‐2‑biased agonism despite profound baseline suppression, indicating partial ‘breakthrough’ secretion and suggesting that amino acid–driven stimulation can, in part, counteract SSTR‑mediated inhibition in humans.\n\n\n\n\n\n\n\n\n\nKey points\n\nAmino acids strongly stimulate glucagon secretion in humans, whereas somatostatin receptor (SSTR) activation potently inhibits basal islet hormone release.\nDuring near‐maximal suppression with the somatostatin analogue octreotide, amino acid infusion induced substantial ‘breakthrough’ secretion of glucagon, insulin and C‐Peptide.\nCo‐infusion of amino acids and octreotide reduced amino acid–stimulated responses to 49% (glucagon), 47% (insulin) and 78% (C‐Peptide) of amino acids alone.\nBreakthrough secretion was not specific to α‐cells, indicating that strong secretagogue stimulation can partially escape somatostatin‐mediated inhibition for both α‐ and β‐cells.\nThese in vivo human data support a balance‐of‐signals model in which elevated amino acids can counteract, but not fully overcome, inhibitory SSTR activation.\n\n\n\nHighlights\n\nWe performed this study to determine why hyperglucagonaemia persists in metabolic diseases despite somatostatin's inhibitory role.\nWe specifically evaluated whether amino acid–induced glucagon secretion can persist during pharmacological somatostatin receptor (SSTR) activation (octreotide) in humans.\nWe found that amino acids strongly stimulated glucagon, insulin and C‐Peptide secretion even during somatostatin infusion, reducing but not eliminating the hormonal responses.\nThese findings imply that amino acid–driven stimulation can partially bypass inhibitory signalling downstream of SSTR activation, helping explain persistent glucagon elevation in metabolic disorders.\n\n\n"]