Glucose Decouples Intracellular Ca2+ Activity from Glucagon Secretion in Mouse Pancreatic Islet Alpha-Cells

The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca2+]i) and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca2+]i and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on KATP channel activity but not on tetrodotoxin-sensitive Na+ channels. The use of glucagon secretagogues reveals a positive correlation between α-cell [Ca2+]i and secretion at low glucose levels. Glucose elevation suppresses glucagon secretion even after treatment with secretagogues. Importantly, this inhibition is not mediated by KATP channel activity or reduction in α-cell [Ca2+]i. Our results demonstrate that glucose uncouples the positive relationship between [Ca2+]i and secretory activity. We conclude that glucose suppression of glucagon secretion is not mediated by inactivation of calcium channels, but instead, it requires a calcium-independent inhibitory pathway.