Search

Glucotoxicity-induced β-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in β-cells is still largely unknown, and their implication in glucotoxicity-associated β-cell dysfunction remains to be defined. Here, we report that acute glucose treatment stimulated ER-mitochondria interactions and calcium (Ca2+) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS and concomitantly reduced ER Ca2+ store, increased basal mitochondrial Ca2+, and reduced ATP-stimulated ER-mitochondria Ca2+ exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca2+ signaling are associated with ER stress, altered mitochondrial respiration, and mitochondria fragmentation, and these organelle stresses may participate in increased organelle tethering as a protective mechanism. Last, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca2+ exchange, induced mitochondrial fission, and altered GSIS. Therefore, dynamic organelle coupling participates in GSIS in β-cells, and over time, disruption of organelle Ca2+ exchange might be a novel mechanism contributing to glucotoxicity-induced β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a complex polygenic disease. Several genes are activated and/or inactivated by environmental factors. Here, we have analyzed the patterns of gene expression in prediabetic and newly-diagnosed patients to address the question of the critical events associated with beta cell failure. Samples were collected in PAXgene tubes from 10 prediabetic children presenting auto-antibodies, 10 children immediately after the onset of clinical type 1 diabetes and 10 age- and sex-matched healthy controls. A pangenomic study was performed using the Affymetrix HG-U 133 Plus 2.0 oligonucleotide arrays. Based on gene expression, a global view from the multidimensional scaling approach showed the possibility to distinguish prediabetic subjects, diabetic patients and healthy controls. The univariate statistical analysis, Significant Analysis of Microarrays (SAM), underlined 299 genes differently expressed between these three groups. Five major gene expression profiles were characterized, including immune response genes such as antiviral response and additional genes involved in biosynthesis and apoptosis pathways, illustrating pathophysiological changes between healthy controls, prediabetes and type 1 diabetes. Finally, our observations revealed the presence of functional modifications associated with type 1 diabetes which could help understanding and diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Glucotoxicity-induced β-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in β-cells is still largely unknown, and their implication in glucotoxicity-associated β-cell dysfunction remains to be defined. Here, we report that acute glucose treatment stimulated ER-mitochondria interactions and calcium (Ca 2+ ) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS and concomitantly reduced ER Ca 2+ store, increased basal mitochondrial Ca 2+ , and reduced ATP-stimulated ER-mitochondria Ca 2+ exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca 2+ signaling are associated with ER stress, altered mitochondrial respiration, and mitochondria fragmentation, and these organelle stresses may participate in increased organelle tethering as a protective mechanism. Last, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca 2+ exchange, induced mitochondrial fission, and altered GSIS. Therefore, dynamic organelle coupling participates in GSIS in β-cells, and over time, disruption of organelle Ca 2+ exchange might be a novel mechanism contributing to glucotoxicity-induced β-cell dysfunction., (© 2019 by the American Diabetes Association.)