Pancreatic α-cells are functionally heterogeneous and sex-dependently regulated by neighboring endocrine cells

Glucose and paracrine regulation on -cells, particularly with respect to sex differences, remains unclear. Hence, we imaged islets of GluCre:GCaMP6ffl/fl mice in pancreatic slices, additionally loaded with a red Ca{superscript 2} dye, to precisely interrogate Ca{superscript 2} dynamics in -cells and the adjacent {beta}- and {delta}-cells. During a glucose ramp (1.8-10.8mM), -cell Ca{superscript 2} oscillations were heterogeneous, antiphasic to {beta}-cells, and inversely correlated with {delta}-cells. Selective inhibition of insulin receptor (InsR) and somatostatin receptor subtypes-2 and 3 (SSTR2/3) shifted the majority of -cells to hyperactivity, delayed the decline of -cell activity and onset of synchronized {beta}-cell Ca{superscript 2} oscillations during the ramp. While female -cells exhibited greater sensitivity to SSTR2/3 inhibition, male -cells were more responsive to InsR blockade. Under complete SSTR2/3 and InsR antagonism, -cells exhibited elevated Ca{superscript 2} oscillations but remained glucose-dependent. We conclude that intra-islet coordination fine-tunes -cell glucose responses, with sex-specific paracrine signaling potentially shaping glucagon profiles in metabolic disease.