Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Abstract

In previous lectures, Claude Bernard's many scientific contributions have been highlighted. Among others he suggested in 1850 that the liver stores glucose and 7 years later, in 1857, he finally isolated glycogen [2]. Before that, in 1849, Claude Bernard reported his ªPiqßre sucrØeº to the SociØtØ de Biologie, Paris [3]. In analogy to his experiments in which stimulation of the fifth cranial nerve caused saliva secretion, he assumed that stimulation of the vagus nerve would elicit glucose secretion from the liver. In unanaesthetised rabbits and dogs, the pricking of the bottom of the fourth ventricle resulted in pronounced hyperglycaemia and glucosuria within 20 min. The ªdiabetesº was transient and disappeared after a few hours. He later showed that this effect was mediated, not by the vagus, but by sympathetic nerves. His discovery of glycogen made Claude Bernard the true father of Diabetologia (2000) AbstractInsulin 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 Ca 2+ influx, which raises cytosolic Ca 2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca 2+ 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-1a (HNF-1a) 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. [Diabetologia (2000) 43: 265±277]

Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet

“…An important role for beta cell mitochondria, besides generation of ATP, the coupling signal which triggers insulin secretion, is to generate additional coupling factors that sustain secretion. Thus, a number of metabolic intermediates from the tricarboxylic acid cycle may couple beta cell metabolism to exocytosis [7,9,10]. If these processes fail, insulin secretion will be perturbed.…”

“…The importance of mitochondrial metabolism in insulin secretion has been apparent for some time [7]. Many glycolytic and mitochondrial intermediates as well as some amino acids can readily stimulate insulin secretion [8].…”

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

“…That mitochondrial ATP production is a pre-requisite for fuel-stimulated insulin secretion is well established (Henquin, 2000;Muoio and Newgard, 2008;Wollheim, 2000). Oxidative phosphorylation and ATP production occur in a system consisting of five multiprotein complexes with 90 known protein subunits (Scarpulla, 2008).…”

“…Other factors, such as circulating hormones, paracrine and autocrine mechanisms, and neuronal (autonomic and sensory) control, all combine to modulate insulin secretion elicited by β-cell metabolism (Ahrén, 2000). In this process, mitochondria play a key role (Wollheim, 2000). Here, oxidation of most cellular fuels produces reducing equivalents, which drive the respiratory chain and subsequently ATP production via oxidative phosphorylation (OXPHOS).…”

Sp1 Is Required for Glucose-Induced Transcriptional Regulation of Mouse Vesicular Glutamate Transporter 2 Gene

“…In a consensus model of glucose-induced insulin secretion, the metabolism of glucose by oxidative glycolysis increases the ATP/ADP ratio, and subsequently promotes the closure of ATP-sensitive K + channels and depolarization of the plasma membrane. As a consequence, the concentration of free cytoplasmic Ca 2+ is raised by the opening of voltage-dependent Ca 2+ channel and the increased cytoplasmic Ca 2+ triggers the exocytosis of insulin containing granules [2][3][4] . However, the triggering action of cytoplasmic Ca 2+ does not completely explain the stimulation of insulin secretion by glucose.…”