Insulin secretion is mediated by pancreatic β-cells that are able to sense glucose levels in the blood. This involves glucose-induced activation of glycolysis, which in turn stimulates mitochondrial ATP synthesis, leading to a Ca2+ influx into the cell that then triggers insulin exocytosis. However, the exact role of Ca2+ in the process has been debated. On page 1929, Umberto De Marchi and co-workers therefore set out to clarify whether Ca2+ signalling and mitochondrial activation are a prerequisite for insulin secretion. To that end, they compare the effects of glucose and the mitochondrial substrate methylsuccinate to investigate the coupling between metabolism and secretion in insulinoma β-cells (INS-1E), which secrete insulin. Although both substrates induced insulin secretion, the underlying mechanisms are distinct, in that methylsuccinate failed to induce a significant rise in intracellular Ca2+ and insulin exocytosis proceeded independently of mitochondrial ATP synthesis. However, in the case of both substrates, Ca2+ was nevertheless required for exocytosis, as the addition of diazoxide, which prevents Ca2+ influx, inhibited secretion. Taken together, this work presents evidence for a new pathway downstream of mitochondrial activation that only requires a small increase in intracellular Ca2+ to mediate insulin secretion; this might also be important in pathological contexts such as type 2 diabetes.