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The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca 2+ ]  i  ) and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca 2+ ]  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 K ATP  channel activity but not on tetrodotoxin-sensitive Na +  channels. The use of glucagon secretagogues reveals a positive correlation between α-cell [Ca 2+ ]  i   and secretion at low glucose levels. Glucose elevation suppresses glucagon secretion even after treatment with secretagogues. Importantly, this inhibition is not mediated by K ATP  channel activity or reduction in α-cell [Ca 2+ ]  i  . Our results demonstrate that glucose uncouples the positive relationship between [Ca 2+ ]  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.

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