Pancreatic ß-cell death is a critical event in type 1 diabetes, type 2 diabetes and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca2+ stores activates calpain-10-dependent apoptosis in ß-cells. In the present study, we further characterized intracellular Ca2+ channel expression and function in human islets and the MIN6 ß-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these ER-channels were observed in close proximity to mitochondria. Blocking RyR channels, but not SERCA pumps, reduced the ATP:ADP ratio. Blocking Ca2+ flux through RyR or IP¬3R channels, but not SERCA pumps increased the expression of the hypoxia-inducible factor, HIF-1ß. Moreover, inhibition of RyR or IP3R channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1ß and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1ß, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signalling network in ß-cells. We demonstrate that this pathway is controlled by Ca2+ flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca2+ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.