scholarly journals Essential Roles for the Non-Canonical IκB Kinases in Linking Inflammation to Cancer, Obesity, and Diabetes

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 178 ◽  
Author(s):  
Chong Shin ◽  
Doo-Sup Choi
Keyword(s):  
Innate Immunity ◽  
Recent Work ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Current Data ◽  
Cell Regeneration ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Obesity And Diabetes

Non-canonical IκB kinases (IKKs) TBK1 and IKKε have essential roles as regulators of innate immunity and cancer. Recent work has also implicated these kinases in distinctively controlling glucose homeostasis and repressing adaptive thermogenic and mitochondrial biogenic response upon obesity-induced inflammation. Additionally, TBK1 and IKKε regulate pancreatic β-cell regeneration. In this review, we summarize current data on the functions and molecular mechanisms of TBK1 and IKKε in orchestrating inflammation to cancer, obesity, and diabetes.

Pancreatic β‐cell regeneration: From molecular mechanisms to therapy

2019 ◽  
Vol 120 (9) ◽  
pp. 14189-14200
Author(s):  
Roozbeh Akbari Motlagh ◽  
Shabnam Mohebbi ◽  
Maryam Moslemi ◽  
Parnia Jabbari ◽  
Arezoo Alizadeh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Regeneration ◽  
Pancreatic Β Cell ◽  
Β Cell

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

Effects of lipotoxicity on a novel insulin-secreting human pancreatic β-cell line, 1.1B4

2013 ◽  
Vol 394 (7) ◽  
pp. 909-918 ◽  
Author(s):  
Srividya Vasu ◽  
Neville H. McClenaghan ◽  
Jane T. McCluskey ◽  
Peter R. Flatt
Keyword(s):  
Mrna Expression ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Endoplasmic Reticulum Stress Response ◽  
Future Research ◽  
The Novel ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Expression Of Genes ◽  
Cellular Ca

Abstract The novel insulin-secreting human pancreatic β-cell line, 1.1B4, demonstrates stability in culture and many of the secretory functional attributes of human pancreatic β-cells. This study investigated the cellular responses of 1.1B4 cells to lipotoxicity. Chronic 18-h exposure of 1.1B4 cells to 0.5 mm palmitate resulted in decreased cell viability and insulin content. Secretory responses to classical insulinotropic agents and cellular Ca2+ handling were also impaired. Palmitate decreased glucokinase activity and mRNA expression of genes involved in secretory function but up-regulated mRNA expression of HSPA5, EIF2A, and EIF2AK3, implicating activation of the endoplasmic reticulum stress response. Palmitate also induced DNA damage and apoptosis of 1.1B4 cells. These responses were accompanied by increased gene expression of the antioxidant enzymes SOD1, SOD2, CAT and GPX1. This study details molecular mechanisms underlying lipotoxicity in 1.1B4 cells and indicates the potential value of the novel β-cell line for future research.

scholarly journals Programming effects of metformin exposure during gestation on offspring pancreatic β‐cell mass and glucose homeostasis (910.5)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Brigid Gregg ◽  
Emilyn Alejandro ◽  
Michelle Smith ◽  
Lynda Elghazi ◽  
Deena El‐Gabri ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell

Insulin Vesicle Release: Walk, Kiss, Pause … Then Run

Physiology ◽  
2006 ◽  
Vol 21 (3) ◽  
pp. 189-196 ◽  
Author(s):  
Guy A. Rutter ◽  
Elaine V. Hill
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Secretory Vesicles ◽  
Pancreatic Β Cell ◽  
Current Interest ◽  
Contributing Factors ◽  
Β Cell ◽  
Vesicle Release ◽  
Reversible Process

The mechanisms by which insulin-containing dense core secretory vesicles approach and finally fuse with the plasma membrane are of considerable current interest: defects in these processes may be one of the contributing factors to Type 2 diabetes. In this review, we discuss the molecular mechanisms involved in vesicle trafficking within the pancreatic β-cell and the mechanisms whereby these may be regulated. We then go on to describe recent evidence that suggests that vesicle fusion at the plasma membrane is a partly reversible process (“kiss and run” or “cavity recapture”). We propose that vesicles may participate in a exo-endocytotic cycle in which a proportion of those that have already undergone an interaction with the plasma membrane may exchange exocytotic machinery with maturing vesicles.

scholarly journals The Constitutive Lack of α7 Nicotinic Receptor Leads to Metabolic Disorders in Mouse

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1057
Author(s):  
Blandine Gausserès ◽  
Junjun Liu ◽  
Ewout Foppen ◽  
Cécile Tourrel-Cuzin ◽  
Ana Rodriguez Sanchez-Archidona ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
Metabolic Disorders ◽  
Late Onset ◽  
Cell Mass ◽  
Chow Diet ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Α7 Nachr ◽  
Old Mice

Objective: Type 2 diabetes (T2D) occurs by deterioration in pancreatic β-cell function and/or progressive loss of pancreatic β-cell mass under the context of insulin resistance. α7 nicotinic acetylcholine receptor (nAChR) may contribute to insulin sensitivity but its role in the pathogenesis of T2D remains undefined. We investigated whether the systemic lack of α7 nAChR was sufficient to impair glucose homeostasis. Methods: We used an α7 nAChR knock-out (α7−/−) mouse model fed a standard chow diet. The effects of the lack of α7 nAChR on islet mass, insulin secretion, glucose and insulin tolerance, body composition, and food behaviour were assessed in vivo and ex vivo experiments. Results: Young α7−/− mice display a chronic mild high glycemia combined with an impaired glucose tolerance and a marked deficit in β-cell mass. In addition to these metabolic disorders, old mice developed adipose tissue inflammation, elevated plasma free fatty acid concentrations and presented glycolytic muscle insulin resistance in old mice. Finally, α7−/− mice, fed a chow diet, exhibited a late-onset excessive gain in body weight through increased fat mass associated with higher food intake. Conclusion: Our work highlights the important role of α7 nAChR in glucose homeostasis. The constitutive lack of α7 nAChR suggests a novel pathway influencing the pathogenesis of T2D.

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