In type 2 diabetic patients glucagon secretion becomes dysregulated under elevated glucose conditions worsening hyperglycemia. However, the mechanisms of glucose inhibition of glucagon secretion remain incompletely understood. Therefore, we sought to uncover the glucose dependent mechanisms that modulate pancreatic α-cell glucagon secretion. One mechanism that regulates α-cell Ca2+ influx in a glucose dependent manner is store-operated Ca2+ entry (SOCE). Therefore, in our studies we used a small molecule (AnCoA4) that inhibits the STIM1/Orai1 protein interaction and prevents store-operated Ca2+ channel activation. In whole mouse islet α-cells inhibition of SOCE with AnCoA4 reduced Ca2+ influx in 1 mM glucose (8.4% ± 1.1%). We went on to test the influence of SOCE on glucose modulation of glucagon secretion, in 1 mM glucose AnCoA4 reduced glucagon secretion in mouse pancreatic islets (53.5% ± 11%). However, there was no significant change in glucose inhibition of glucagon secretion by inhibition of SOCE at 11 mM glucose. To follow-up on this, we used transgenic mice without STIM1 in α-cells and showed that AnCoA4 does not influence Ca2+ fluctuations in knockout islet α-cells. This proves in our hands that AnCoA4 works selectively. Additionally, we used transgenic GCAMP3 mice without STIM1 in α-cells for whole islet confocal studies to measure SOCE in 1 mM and 11 mM glucose conditions. We found that in whole islet α-cells without functional STIM1, Ca2+ influx due to SOCE was reduced in 1 mM glucose. Next, we wanted to test this molecule in human islet calcium homeostasis studies. Human dispersed α-cells show inhibition of SOCE with AnCoA4 treatment in 1 mM glucose conditions. Thus, our findings identify that inhibition of STIM1/Orai1 reduces SOCE in low glucose conditions leading to decreased α-cell glucagon secretion.
M.K. Altman: None. P. Dadi: None. D. Jacobson: None.