Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell

Glucose-induced insulin secretion is determined by signals generated in the mitochondria. The elevation of ATP is necessary for the membrane-dependent increase in cytosolic Ca2+, the main trigger of insulin exocytosis. Beta c ells depleted of mitochondrial DNA fail to respond to glucose while still s ecreting insulin in response to membrane depolarisation. This cell model re sembles the situation of defective insulin secretion in patients with mitoc hondrial diabetes. On the other hand, infants with activating mutations in the mitochondrial enzyme glutamate dehydrogenase are characterised by hyper insulinism and hypoglycaemia. We have recently proposed that glutamate, gen erated by this enzyme, participates in insulin secretion as a glucose-deriv ed metabolic messenger. In this model, glutamate acts downstream of the mit ochondria by sensitising the exocytotic process to Ca2+. The evidence in fa vour of such a role for glutamate is discussed in the present review.