Glucose and paracrine regulation on α-cells, particularly with respect to sex differences, remains unclear. Hence, we imaged islets of GluCre:GCaMP6f^fl/fl mice in pancreatic slices, additionally loaded with a red Ca2+ dye, to precisely interrogate Ca2+ dynamics in α-cells and the adjacent β- and δ-cells. During a glucose ramp (1.8-10.8mM), α-cell Ca2+ oscillations were heterogeneous, antiphasic to β-cells, and inversely correlated with δ-cells. Selective inhibition of insulin receptor (InsR) and somatostatin receptor subtypes-2 and 3 (SSTR2/3) shifted the majority of α-cells to hyperactivity, delayed the decline of α-cell activity and onset of synchronized β-cell Ca2+ oscillations during the ramp. While female α-cells exhibited greater sensitivity to SSTR2/3 inhibition, male α-cells were more responsive to InsR blockade. Under complete SSTR2/3 and InsR antagonism, α-cells exhibited elevated Ca2+ oscillations but remained glucose-dependent. We conclude that intra-islet coordination fine-tunes α-cell glucose responses, with sex-specific paracrine signaling potentially shaping glucagon profiles in metabolic disease. ### Competing Interest Statement The authors have declared no competing interest.

Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse, Elizabeth Selvin, David A. D’Alessio; NIDDK at 75 Years of Age: Great Triumphs but Concerns for Its Lon

Podcast Episode · Diabetes Insights - Breakthroughs and Innovators · 2025-02-21 · 10m

Monogenic diabetes, formerly called Maturity-Onset Diabetes of the Young (MODY), involves single-gene mutations, typically with dominant inheritance, and has been associated with variants in 14 genes....