Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes.
Insulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca2+ influx, which raises cytosolic Ca2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca2+ concentration in the mitochondrial matrix activating Ca(2+)-sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca(2+)-stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca(2+)-induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1 alpha (HNF-1 alpha) also displayed deletion of glucose-induced but not Ca(2+)-induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease.
Wollheim
C B
CB
Department of Internal Medicine, University Medical Centre, Geneva, Switzerland.
D002118:Calcium / Q000378:metabolism / Q000502:physiology; D004272:DNA, Mitochondrial / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological
D004272:DNA, Mitochondrial; D007328:Insulin; D002118:Calcium