Fig. 6. Schematic representation of the consequences of presenilin-1 mediated ER Ca²⁺ leak on pancreatic islets and pancreatic β-cells. The presenilin-1-mediated ER Ca²⁺ leak is directly sequestered by mitochondria, leading to increased basal matrix Ca²⁺ levels that yields enhanced resting activity of mitochondria in the pancreatic β-cells due to pre-stimulation the Ca²⁺-dependent dehydrogenases of the citric acid cycle. Upon elevation of glucose, glucose is metabolized and the pre-activated citric cycle in the mitochondria efficiently converts glucose metabolism to activation of the respiratory chain (OXPHOS) and, subsequently, fast ATP production, thus, ensuring a fast, initial insulin secretion within 10 minutes of exposure to elevated glucose.