Factors Influencing Mitochondrial Function as a Key Mediator of Glucose-Induced Insulin Release: Highlighting Nicotinamide Nucleotide Transhydrogenase (original) (raw)
Related papers
Mitochondrial dysfunction in pancreatic β-cells
2012
In pancreatic b cells, mitochondria play a central role in coupling glucose metabolism to insulin exocytosis, thereby ensuring strict control of glucose-stimulated insulin secretion. Defects in mitochondrial function impair this metabolic coupling, and ultimately promote apoptosis and b cell death. Various factors have been identified that may contribute to mitochondrial dysfunction. In this review we address the emerging concept of complex links between these factors. We also discuss the role of the mitochondrial genome and mutations associated with diabetes, the effect of oxidative stress and reactive oxygen species, the sensitivity of mitochondria to lipotoxicity, and the adaptive dynamics of mitochondrial morphology. Better comprehension of the molecular mechanisms contributing to mitochondrial dysfunction will help drive the development of effective therapeutic approaches.
Beta-cell mitochondrial carriers and the diabetogenic stress response
Mitochondria play a central role in pancreatic beta-cells by coupling metabolism of the secretagogue glucose to distal events of regulated insulin exocytosis. This process requires transports of both metabolites and nucleotides in and out of the mitochondria. The molecular identification of mitochondrial carriers and their respective contribution to beta-cell function have been uncovered only recently. In type 2 diabetes, mitochondrial dysfunction is an early event and may precipitate beta-cell loss. Under diabetogenic conditions, characterized by glucotoxicity and lipotoxicity, the expression profile of mitochondrial carriers is selectively modified. This review describes the role of mitochondrial carriers in beta-cells and the selective changes in response to glucolipotoxicity. In particular , we discuss the importance of the transfer of metabolites (pyruvate, citrate, malate, and glutamate) and nucleotides (ATP, NADH, NADPH) for beta-cell function and dysfunction. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Jean-Claude Martinou.
Minireview: Implication of Mitochondria in Insulin Secretion and Action
Endocrinology, 2006
Mitochondria are essential for intermediary metabolism as well as energy production in the cell. Their aerobic metabolism permits oxidation of glucose and fatty acids for the generation of ATP and other intermediates that are exchanged with the cytoplasm for various biosynthetic and secretory processes. In the pancreatic -cell, glucose carbons are quantitatively funneled to the mitochondria, where signals for the initiation and potentiation of insulin secretion are generated. After mitochondrial activation, the plasma membrane is depolarized with ensuing cytosolic calcium transients and exocytosis of insulin. Calcium also acts in a feed-forward manner on mitochondrial metabolism, which contributes to sustained second phase insulin secretion. Patients with mitochondrial diabetes and a corresponding mouse model display defective glucose-stimulated insulin secretion and reduced -cell mass, leading to overt diabetes. Normal mitochondrial activity appears to be equally important in the action of insulin on its target tissues. The development of insulin resistance may involve impairment of glucose oxidation after short exposure to increased levels of circulating free fatty acids. Insulin resistance in the elderly and in relatives of type 2 diabetic patients has also been associated with mitochondrial dysfunction. Both prevention and treatment of type 2 diabetes should focus on mitochondrial targets for the improvement of nutrientstimulated insulin secretion and their utilization in peripheral tissues. (Endocrinology 147: 2643-2649, 2006) M ITOCHONDRIA NOT ONLY play a crucial role in cellular energy production, but also participate in intermediary metabolism, Ca 2ϩ handling, as well as apoptosis (1, 2). It is well established that -cell mitochondria are key determinants in glucose-stimulated insulin secretion and participate in the actions of insulin on its target tissues. Recently, particular interest has focused on mitochondria in -cells and target tissues in the development of type 2 diabetes (3), prompted by novel genetic findings in tissues from diabetic subjects. This article will highlight the implication of mitochondria in normal metabolism secretion coupling in the -cell and how the process may be impaired in the diabetic state. It will also briefly address certain aspects of mitochondrial function in insulin action in type 2 diabetes. Glucose Metabolism in the -Cell -Cells are designed to sense blood glucose and other secretagogues to adjust insulin secretion according to the needs of the organism. Rather than activating specific receptor molecules, glucose is metabolized to generate downstream signals that stimulate insulin secretion (4-6). Glucose enters -cells by facilitated diffusion through the glucose transporter (GLUT2 in rodents; mainly GLUT1 in humans)
Diabetologia
Aims/hypothesis In islets from individuals with type 2 diabetes and in islets exposed to chronic elevated glucose, mitochondrial energy metabolism is impaired. Here, we studied early metabolic changes and mitochondrial adaptations in human beta cells during chronic glucose stress. Methods Respiration and cytosolic ATP changes were measured in human islet cell clusters after culture for 4 days in 11.1 mmol/l glucose. Metabolomics was applied to analyse intracellular metabolite changes as a result of glucose stress conditions. Alterations in beta cell function were followed using insulin secretion assays or cytosolic calcium signalling after expression of the calcium probe YC3.6 specifically in beta cells of islet clusters. Results At early stages of glucose stress, mitochondrial energy metabolism was augmented in contrast to the previously described mitochondrial dysfunction in beta cells from islets of diabetic donors. Following chronic glucose stress, mitochondrial respiration incr...
Metabolism, 2013
The β-cell metabolism of glucose and of some other fuels (e.g. αketoisocaproate) generates signals triggering and acutely amplifying insulin secretion. As the pathway coupling metabolism with amplification is largely unknown, we aimed to narrow down the putative amplifying signals. Materials/Methods. An experimental design was used which previously prevented glucose-induced, but not α-ketoisocaproate-induced insulin secretion. Isolated mouse islets were pretreated for one hour with medium devoid of fuels and containing the sulfonylurea glipizide in high concentration which closed all ATP-sensitive K + channels. This concentration was also applied during the subsequent examination of fuel-induced effects. In perifused or incubated islets, insulin secretion and metabolic parameters were measured. Results. The pretreatment decreased the islet ATP/ADP ratio. Whereas glucose and αketoisovalerate were ineffective or weakly effective, respectively, when tested separately, their combination strongly enhanced the insulin secretion. Compared with glucose, the strong amplifier α-ketoisocaproate caused less increase in NAD(P)H-fluorescence and less mitochondrial hyperpolarization. Compared with α-ketoisovalerate, α-ketoisocaproate caused greater increase in NAD(P)H-fluorescence and greater mitochondrial hyperpolarization. Neither α-ketoacid anion enhanced the islet ATP/ADP ratio during onset of the insulin secretion. α-Ketoisocaproate induced a higher pyruvate content than glucose, slowly elevated the citrate content which was not changed by glucose and generated a much higher acetoacetate content than other fuels. α-Ketoisovalerate alone or in combination with glucose did not increase the citrate content. Conclusions. In β-cells, mitochondrial energy generation does not mediate acute metabolic amplification, but mitochondrial production of acetyl-CoA and supplemental acetoacetate supplies cytosolic metabolites which induce the generation of specific amplifying signals.
Diabetes, 1998
BSA, bovine serum albumin; [Ca 2 + ] i , intracellular free Ca 2 + c o n c e n t r a t i o n ; COX, cytochrome c oxidase; COX2, cytochrome c oxidase subunit II gene; COX4, cytochrome c oxidase subunit IV gene; EtBr, ethidium bromide; K AT P channel, AT Psensitive K + channel; KRH buffer, HEPES-balanced Krebs-Ringer bicarbonate buffer; MIN6 mt cells, mitochondrial DNA-depleted MIN6 cells; mtDNA, mitochondrial DNA; ND1, NADH dehydrogenase subunit 1; np, nucleotide position;
Cell Calcium, 2008
Mitochondria play an essential role in metabolism-secretion coupling in the pancreatic -cell. Dysfunction of the organelle leads to impaired glucose-stimulated insulin secretion, as exemplified by the rare disease mitochondrial diabetes, which is caused by mutations in the mitochondrial DNA. In the excitable -cell, mitochondria generate ATP and possibly other coupling factors that promote plasma membrane depolarization and calcium influx triggering insulin exocytosis. Cytosolic calcium signals are relayed into the mitochondria, where the ion potentiates oxidative metabolism. Hormones such as glucagon-like peptide 1 (GLP-1) or neurotransmitter secretagogues stimulate the -cell by activating different signal transduction pathways eventually also raising mitochondrial calcium. Likewise, pharmacological inhibition of the Na + /Ca 2+ exchanger of the inner mitochondrial membrane augments intraorganellar calcium and insulin secretion. Islets obtained after autopsy from type 2 diabetic patients have altered mitochondrial morphology impaired glucose oxidation and reduced ATP generation, explaining defective insulin secretion. We hypothesize that the improvement of glucose-stimulated insulin secretion by sulfonylurea compounds in type 2 diabetic patients is in part due to their capacity to raise mitochondrial calcium, which is beneficial for the generation of metabolic coupling factors.
Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Altern. Med. Rev
Alternative Medicine Review, 2002
A growing body of evidence has demonstrated a link between various disturbances in mitochondrial functioning and type 2 diabetes. This review focuses on a range of mitochondrial factors important in the pathogenesis of this disease. The mitochondrion is an integral part of the insulin system found in the islet cells of the pancreas. Because of the systemic complexity of mitochondrial functioning in terms of tissue and energetic thresholds, details of structure and function are reviewed. The expression of type 2 diabetes can be ascribed to a number of qualitative or quantitative changes in the mitochondria. Qualitative changes refer to genetic disturbances in mitochondrial DNA (mtDNA). Heteroplasmic as well as homoplasmic mutations of mtDNA can lead to the development of a number of genetic disorders that express the phenotype of type 2 diabetes. Quantitative decreases in mtDNA copy number have also been linked to the pathogenesis of diabetes. The study of the relationship of mtDNA t...
Antioxidants & Redox Signaling
Aims: Glucose-stimulated insulin secretion (GSIS) in pancreatic b cells was expected to enhance mitochondrial superoxide formation. Hence, we elucidated relevant redox equilibria. Results: Unexpectedly, INS-1E cells at transitions from 3 (11 mM; pancreatic islets from 5 mM) to 25 mM glucose decreased matrix superoxide release rates (MitoSOX Red monitoring validated by MitoB) and H 2 O 2 (mitoHyPer, subtracting mitoSypHer emission). Novel double-channel fluorescence lifetime imaging, approximating free mitochondrial matrix NADH F, indicated its *20% decrease. Matrix NAD + F increased on GSIS, indicated by the FAD-emission lifetime decrease, reflecting higher quenching of FAD by NAD + F. The participation of pyruvate/malate and pyruvate/citrate redox shuttles, elevating cytosolic NADPH F (iNAP1 fluorescence monitoring) at the expense of matrix NADH F , was indicated, using citrate (2-oxoglutarate) carrier inhibitors and cytosolic malic enzyme silencing: All changes vanished on these manipulations. 13 Cincorporation from 13 C-L-glutamine into 13 C-citrate reflected the pyruvate/isocitrate shuttle. Matrix NADPH F (iNAP3 monitored) decreased. With decreasing glucose, the suppressor of Complex III site Q electron leak (S3QEL) suppressor caused a higher Complex I I F site contribution, but a lower superoxide fraction ascribed to the Complex III site III Qo. Thus, the diminished matrix NADH F /NAD + F decreased Complex I flavin site I F superoxide formation on GSIS. Innovation: Mutually validated methods showed decreasing superoxide release into the mitochondrial matrix in pancreatic b cells on GSIS, due to the decreasing matrix NADH F /NAD + F (NADPH F /NADP + F) at increasing cytosolic NADPH F levels. The developed innovative methods enable real-time NADH/NAD + and NADPH/ NADP + monitoring in any distinct cell compartment. Conclusion: The export of reducing equivalents from mitochondria adjusts lower mitochondrial superoxide production on GSIS, but it does not prevent oxidative stress in pancreatic b cells. Antioxid. Redox Signal. 33, 789-815.
Insulin Signaling Regulates Mitochondrial Function in Pancreatic β-Cells
PLoS ONE, 2009
Insulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in bcells that included glucokinase (GK), and the pro-apoptotic protein, BAD S . Mitochondria isolated from b-cells derived from bcell specific insulin receptor knockout (bIRKO) mice exhibited reduced BAD S , GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in bIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BAD S . The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in bIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for b-cell dysfunction in type 2 diabetes.