scholarly journals In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets

2018 ◽  
Author(s):  
Francesca Sacco ◽  
Anett Seelig ◽  
Sean J. Humphrey ◽  
Natalie Krahmer ◽  
Francesco Volta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Drug Targets ◽  
High Sensitivity ◽  
Glucose Stimulated Insulin Secretion

SUMMARYProgressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic isletsin vivoremain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.

The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo

Diabetologia ◽  
2014 ◽  
Vol 57 (7) ◽  
pp. 1410-1419 ◽  
Author(s):  
Arne A. Ittner ◽  
Josefine Bertz ◽  
Tse Yan Becky Chan ◽  
Janet van Eersel ◽  
Patsie Polly ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Nucleotide Exchange Factor ◽  
Glucose Stimulated Insulin Secretion

Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes

Diabetes ◽  
1999 ◽  
Vol 48 (4) ◽  
pp. 927-932 ◽  
Author(s):  
Y. Ihara ◽  
S. Toyokuni ◽  
K. Uchida ◽  
H. Odaka ◽  
T. Tanaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Gk Rats

scholarly journals Disruption of Beta-Cell Mitochondrial Networks by the Orphan Nuclear Receptor Nor1/Nr4a3

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 168 ◽  
Author(s):  
Anne-Françoise Close ◽  
Nidheesh Dadheech ◽  
Hélène Lemieux ◽  
Qian Wang ◽  
Jean Buteau
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Nuclear Receptor ◽  
Pancreatic Beta Cells ◽  
Orphan Nuclear Receptor ◽  
Atp Production ◽  
Human Beta Cells ◽  
Glucose Stimulated Insulin Secretion ◽  
Mitochondrial Networks

Nor1, the third member of the Nr4a subfamily of nuclear receptor, is garnering increased interest in view of its role in the regulation of glucose homeostasis. Our previous study highlighted a proapoptotic role of Nor1 in pancreatic beta cells and showed that Nor1 expression was increased in islets isolated from type 2 diabetic individuals, suggesting that Nor1 could mediate the deterioration of islet function in type 2 diabetes. However, the mechanism remains incompletely understood. We herein investigated the subcellular localization of Nor1 in INS832/13 cells and dispersed human beta cells. We also examined the consequences of Nor1 overexpression on mitochondrial function and morphology. Our results show that, surprisingly, Nor1 is mostly cytoplasmic in beta cells and undergoes mitochondrial translocation upon activation by proinflammatory cytokines. Mitochondrial localization of Nor1 reduced glucose oxidation, lowered ATP production rates, and inhibited glucose-stimulated insulin secretion. Western blot and microscopy images revealed that Nor1 could provoke mitochondrial fragmentation via mitophagy. Our study unveils a new mode of action for Nor1, which affects beta-cell viability and function by disrupting mitochondrial networks.

scholarly journals Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

Diabetologia ◽  
2020 ◽  
Vol 63 (10) ◽  
pp. 1990-1998 ◽  
Author(s):  
Guy A. Rutter ◽  
Eleni Georgiadou ◽  
Aida Martinez-Sanchez ◽  
Timothy J. Pullen
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Beta Cell ◽  
Beta Cells ◽  
Mitochondrial Metabolism ◽  
Monocarboxylate Transporter ◽  
Genome Wide Association Studies ◽  
Monocarboxylate Transporter 1

Abstract All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed (‘disallowed’) in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1–7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell–beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion.

scholarly journals Precise expression of Fis1 is important for glucose responsiveness of beta cells

2016 ◽  
Vol 230 (1) ◽  
pp. 81-91 ◽  
Author(s):  
Julia Schultz ◽  
Rica Waterstradt ◽  
Tobias Kantowski ◽  
Annekatrin Rickmann ◽  
Florian Reinhardt ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Mitochondrial Network ◽  
Primary Mouse ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucose Responsiveness ◽  
Precise Expression

Mitochondrial network functionality is vital for glucose-stimulated insulin secretion in pancreatic beta cells. Altered mitochondrial dynamics in pancreatic beta cells are thought to trigger the development of type 2 diabetes mellitus. Fission protein 1 (Fis1) might be a key player in this process. Thus, the aim of this study was to investigate mitochondrial morphology in dependence of beta cell function, after knockdown and overexpression of Fis1. We demonstrate that glucose-unresponsive cells with impaired glucose-stimulated insulin secretion (INS1-832/2) showed decreased mitochondrial dynamics compared with glucose-responsive cells (INS1-832/13). Accordingly, mitochondrial morphology visualised using MitoTracker staining differed between the two cell lines. INS1-832/2 cells formed elongated and clustered mitochondria, whereas INS1-832/13 cells showed a homogenous mitochondrial network. Fis1 overexpression using lentiviral transduction significantly improved glucose-stimulated insulin secretion and mitochondrial network homogeneity in glucose-unresponsive cells. Conversely, Fis1 downregulation by shRNA, both in primary mouse beta cells and glucose-responsive INS1-832/13 cells, caused unresponsiveness and significantly greater numbers of elongated mitochondria. Overexpression of FIS1 in primary mouse beta cells indicated an upper limit at which higher FIS1 expression reduced glucose-stimulated insulin secretion. Thus, FIS1 was overexpressed stepwise up to a high concentration in RINm5F cells using the RheoSwitch system. Moderate FIS1 expression improved glucose-stimulated insulin secretion, whereas high expression resulted in loss of glucose responsiveness and in mitochondrial artificial loop structures and clustering. Our data confirm that FIS1 is a key regulator in pancreatic beta cells, because both glucose-stimulated insulin secretion and mitochondrial dynamics were clearly adapted to precise expression levels of this fission protein.

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