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Article ; Online: A role for Glucagon-Like Peptide-1 in the regulation of β-cell autophagy.

Arden, Catherine

2018 Volume 100, Page(s) 85–93

Abstract: Autophagy is a highly conserved intracellular recycling pathway that serves to recycle damaged organelles/proteins or superfluous nutrients during times of nutritional stress to provide energy to maintain intracellular homeostasis and sustain core ... ...

Abstract	Autophagy is a highly conserved intracellular recycling pathway that serves to recycle damaged organelles/proteins or superfluous nutrients during times of nutritional stress to provide energy to maintain intracellular homeostasis and sustain core metabolic functions. Under these conditions, autophagy functions as a cell survival mechanism but impairment of this pathway can lead to pro-death stimuli. Due to their role in synthesising and secreting insulin, pancreatic β-cells have a high requirement for robust degradation pathways. Recent research suggests that functional autophagy is required to maintain β-cell survival and function in response to high fat diet suggesting a pro-survival role. However, a role for autophagy has also been implicated in the pathogenesis of type 2 diabetes. Thus, the pro-survival vs pro-death role of autophagy in regulating β-cell mass requires discussion. Emerging evidence suggests that Glucagon-Like Peptide-1 (GLP-1) may exert beneficial effects on glucose homeostasis via autophagy-dependent pathways both in pancreatic β-cells and in other cell types. The aim of the current review is to: i) summarise the literature surrounding β-cell autophagy and its pro-death vs pro-survival role in regulating β-cell mass; ii) review the literature describing the impact of GLP-1 on β-cell autophagy and in other cell types; iii) discuss the potential underlying mechanisms.
MeSH term(s)	Autophagy/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Glucagon-Like Peptide 1/genetics ; Glucose/metabolism ; Homeostasis ; Humans ; Insulin/metabolism ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Signal Transduction/genetics
Chemical Substances	Insulin ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2018-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2017.12.002
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Article: Upregulation of Anti-Angiogenic miR-106b-3p Correlates Negatively with IGF-1 and Vascular Health Parameters in a Model of Subclinical Cardiovascular Disease: Study with Metformin Therapy.

Bakhashab, Sherin / O'Neill, Josie / Barber, Rosie / Arden, Catherine / Weaver, Jolanta U

Biomedicines

2024 Volume 12, Issue 1

Abstract: Well-controlled type 1 diabetes mellitus (T1DM) is regarded as a model of subclinical cardiovascular disease (CVD), characterized by inflammation and adverse vascular health. However, the underlying mechanisms are not fully understood. We investigated ... ...

Abstract	Well-controlled type 1 diabetes mellitus (T1DM) is regarded as a model of subclinical cardiovascular disease (CVD), characterized by inflammation and adverse vascular health. However, the underlying mechanisms are not fully understood. We investigated insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, their correlation to miR-106b-3p expression in a subclinical CVD model, and the cardioprotective effect of metformin. A total of 20 controls and 29 well-controlled T1DM subjects were studied. Plasma IGF-1, IGFBP-3 levels, and miR-106b-3p expression in colony-forming unit-Hills were analyzed and compared with vascular markers. miR-106b-3p was upregulated in T1DM (
Language	English
Publishing date	2024-01-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines12010171
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Article ; Online: Creative approaches towards protecting the planet in clinical skills and simulation in nursing education.

Arden, Catherine / Taylor-Rollings, Hannah / Tremayne, Penny / Padley, Wendy / Hinsliff-Smith, Kathryn

Nurse education in practice

2024 Volume 76, Page(s) 103941

MeSH term(s)	Humans ; Clinical Competence ; Planets ; Education, Nursing ; Thinking ; Students, Nursing ; Education, Nursing, Baccalaureate
Language	English
Publishing date	2024-03-12
Publishing country	Scotland
Document type	Editorial
ZDB-ID	2058575-5
ISSN	1873-5223 ; 1471-5953
ISSN (online)	1873-5223
ISSN	1471-5953
DOI	10.1016/j.nepr.2024.103941
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Zs.A 5492: Show issues

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Article ; Online: Differential routing and disposition of the long-chain saturated fatty acid palmitate in rodent vs human beta-cells.

Thomas, Patricia / Arden, Catherine / Corcoran, Jenna / Hacker, Christian / Welters, Hannah J / Morgan, Noel G

Nutrition & diabetes

2022 Volume 12, Issue 1, Page(s) 22

Abstract: Background: Rodent and human β-cells are differentially susceptible to the "lipotoxic" effects of long-chain saturated fatty acids (LC-SFA) but the factors accounting for this are unclear. Here, we have studied the intracellular disposition of the LC- ... ...

Abstract	Background: Rodent and human β-cells are differentially susceptible to the "lipotoxic" effects of long-chain saturated fatty acids (LC-SFA) but the factors accounting for this are unclear. Here, we have studied the intracellular disposition of the LC-SFA palmitate in human vs rodent β-cells and present data that reveal new insights into the factors regulating β-cell lipotoxicity. Methods: The subcellular distribution of the LC-SFA palmitate was studied in rodent (INS-1E and INS-1 823/13 cells) and human (EndoC-βH1) β-cells using confocal fluorescence and electron microscopy (EM). Protein expression was assessed by Western blotting and cell viability, by vital dye staining. Results: Exposure of INS-1 cells to palmitate for 24 h led to loss of viability, whereas EndoC-βH1 cells remained viable even after 72 h of treatment with a high concentration (1 mM) of palmitate. Use of the fluorescent palmitate analogue BODIPY FL C Conclusion: In rodent β-cells, palmitate accumulates in the Golgi apparatus at early time points whereas, in EndoC- βH1 cells, it is routed preferentially into lipid droplets. This may account for the differential sensitivity of rodent vs human β-cells to "lipotoxicity" since manoeuvres leading to the incorporation of palmitate into lipid droplets is associated with the maintenance of cell viability in both cell types.
MeSH term(s)	Animals ; Fatty Acids/metabolism ; Humans ; Insulin-Secreting Cells/metabolism ; Oleic Acid/metabolism ; Palmitates/metabolism ; Palmitates/pharmacology ; Rodentia/metabolism
Chemical Substances	Fatty Acids ; Palmitates ; Oleic Acid (2UMI9U37CP)
Language	English
Publishing date	2022-04-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609314-5
ISSN	2044-4052 ; 2044-4052
ISSN (online)	2044-4052
ISSN	2044-4052
DOI	10.1038/s41387-022-00199-y
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Article ; Online: Pseudoislet Aggregation of Pancreatic β-Cells Improves Glucose Stimulated Insulin Secretion by Altering Glucose Metabolism and Increasing ATP Production.

Cornell, Deborah / Miwa, Satomi / Georgiou, Merilin / Anderson, Scott James / Honkanen-Scott, Minna / Shaw, James A M / Arden, Catherine

Cells

2022 Volume 11, Issue 15

Abstract: Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The ... ...

Abstract	Appropriate glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells is an essential component of blood glucose homeostasis. Configuration of β-cells as 3D pseudoislets (PI) improves the GSIS response compared to 2D monolayer (ML) culture. The aim of this study was to determine the underlying mechanisms. MIN6 β-cells were grown as ML or PI for 5 days. Human islets were isolated from patients without diabetes. Function was assessed by GSIS and metabolic capacity using the Seahorse bioanalyser. Connexin 36 was downregulated using inducible shRNA. Culturing MIN6 as PI improved GSIS. MIN6 PI showed higher glucose-stimulated oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Further analysis showed the higher ECAR was, at least in part, a consequence of increased glycolysis. Intact human islets also showed glucose-stimulated increases in both OCR and ECAR rates, although the latter was smaller in magnitude compared to MIN6 PI. The higher rates of glucose-stimulated ATP production in MIN6 PI were consistent with increased enzyme activity of key glycolytic and TCA cycle enzymes. There was no impact of connexin 36 knockdown on GSIS or ATP production. Configuration of β-cells as PI improves GSIS by increasing the metabolic capacity of the cells, allowing higher ATP production in response to glucose.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Glucose/metabolism ; Glucose/pharmacology ; Humans ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism
Chemical Substances	Insulin ; Adenosine Triphosphate (8L70Q75FXE) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-07-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11152330
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Article ; Online: Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation.

Yu, Xuefei / Arden, Catherine / Berlinguer-Palmini, Rolando / Chen, Chun / Bradshaw, Carla / Smith, Anna Lm / Whitehall, Julia / White, Michael / Anderson, Scott / Kattner, Nicole / Shaw, James / Turnbull, Doug / Greaves, Laura C / Walker, Mark

Molecular metabolism

2022 Volume 60, Page(s) 101489

Abstract: Objective: There is strong evidence that mitochondrial DNA mutations and mitochondrial dysfunction play a role in diabetes pathogenesis. The homozygous knock-in mtDNA mutator mouse is a model of premature aging due to the accumulation of mitochondrial ... ...

Abstract	Objective: There is strong evidence that mitochondrial DNA mutations and mitochondrial dysfunction play a role in diabetes pathogenesis. The homozygous knock-in mtDNA mutator mouse is a model of premature aging due to the accumulation of mitochondrial DNA mutations. We used this mouse model to investigate the relationship between mitochondrial subunit expression and pancreatic islet cell composition. Methods: Quadruple immunofluorescence was used to quantify mitochondrial subunit expression (complex I and IV) and cell composition in pancreatic islets from mitochondrial DNA mutator mice (PolgA Results: Mitochondrial complex I subunit expression was decreased in islets from 12 week PolgA Conclusion: Complex I deficiency promotes α-cell proliferation and alters islet cell composition.
MeSH term(s)	Animals ; Cell Proliferation ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Electron Transport Complex I/deficiency ; Mice ; Mice, Inbred C57BL ; Mitochondrial Diseases
Chemical Substances	DNA, Mitochondrial ; Electron Transport Complex I (EC 7.1.1.2)
Language	English
Publishing date	2022-04-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2022.101489
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Article ; Online: Differential effects of saturated and unsaturated fatty acids on autophagy in pancreatic β-cells.

Dhayal, Shalinee / Zummo, Francesco P / Anderson, Matthew W / Thomas, Patricia / Welters, Hannah J / Arden, Catherine / Morgan, Noel G

Journal of molecular endocrinology

2019 Volume 63, Issue 4, Page(s) 285–296

Abstract: Long-chain saturated fatty acids are lipotoxic to pancreatic β-cells, whereas most unsaturates are better tolerated and some may even be cytoprotective. Fatty acids alter autophagy in β-cells and there is increasing evidence that such alterations can ... ...

Abstract	Long-chain saturated fatty acids are lipotoxic to pancreatic β-cells, whereas most unsaturates are better tolerated and some may even be cytoprotective. Fatty acids alter autophagy in β-cells and there is increasing evidence that such alterations can impact directly on the regulation of viability. Accordingly, we have compared the effects of palmitate (C16:0) and palmitoleate (C16:1) on autophagy in cultured β-cells and human islets. Treatment of BRIN-BD11 β-cells with palmitate led to enhanced autophagic activity, as judged by cleavage of microtubule-associated protein 1 light chain 3-I (LC3-I) and this correlated with a marked loss of cell viability in the cells. In addition, transfection of these cells with an mCherry-YFP-LC3 reporter construct revealed the accumulation of autophagosomes in palmitate-treated cells, indicating an impairment of autophagosome-lysosome fusion. This was also seen upon addition of the vacuolar ATPase inhibitor, bafilomycin A1. Exposure of BRIN-BD11 cells to palmitoleate (C16:1) did not lead directly to changes in autophagic activity or flux, but it antagonised the actions of palmitate. In parallel, palmitoleate also improved the viability of palmitate-treated BRIN-BD11 cells. Equivalent responses were observed in INS-1E cells and in isolated human islets. Taken together, these data suggest that palmitate may cause an impairment of autophagosome-lysosome fusion. These effects were not reproduced by palmitoleate which, instead, antagonised the responses mediated by palmitate suggesting that attenuation of β-cell stress may contribute to the improvement in cell viability caused by the mono-unsaturated fatty acid.
MeSH term(s)	Cell Survival/drug effects ; Cells, Cultured ; Cytoprotection ; Endoplasmic Reticulum Stress/drug effects ; Fatty Acids/metabolism ; Fatty Acids/pharmacology ; Fatty Acids, Unsaturated/metabolism ; Fatty Acids, Unsaturated/pharmacology ; Humans ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/cytology ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Microtubule-Associated Proteins/metabolism ; Palmitates/pharmacology ; Proteolysis
Chemical Substances	Fatty Acids ; Fatty Acids, Unsaturated ; MAP1LC3B protein, human ; Microtubule-Associated Proteins ; Palmitates
Language	English
Publishing date	2019-10-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645012-x
ISSN	1479-6813 ; 0952-5041
ISSN (online)	1479-6813
ISSN	0952-5041
DOI	10.1530/JME-19-0096
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Zs.A 2406: Show issues

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Article ; Online: Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca

Zummo, Francesco P / Krishnanda, Stanislaus I / Georgiou, Merilin / O'Harte, Finbarr Pm / Parthsarathy, Vadivel / Cullen, Kirsty S / Honkanen-Scott, Minna / Shaw, James Am / Lovat, Penny E / Arden, Catherine

Autophagy

2021 Volume 18, Issue 4, Page(s) 799–815

Abstract: Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R ( ... ...

Abstract	Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R (glucagon like peptide 1 receptor) agonist exendin-4 stimulates autophagic flux in a setting of chronic nutrient excess. The aim of this study was to identify the underlying pathways contributing to enhanced autophagic flux.Pancreatic β-cells (INS-1E),mouse and human islets were treated with glucolipotoxic stress (0.5 mM palmitate and 25 mM glucose) in the presence of exendin-4. Consistent with our previous work, exendin-4 stimulated autophagic flux. Using chemical inhibitors and siRNA knockdown, we identified RAPGEF4/EPAC2 (Rap guanine nucleotide exchange factor 4) and downstream calcium signaling to be essential for regulation of autophagic flux by exendin-4. This pathway was independent of AMPK and MTOR signaling. Further analysis identified PPP3/calcineurin and its downstream regulator TFEB (transcription factor EB) as key proteins mediating exendin-4 induced autophagy. Importantly, inhibition of this pathway prevented exendin-4-mediated cell survival and overexpression of TFEB mimicked the cell protective effects of exendin-4 in INS-1E and human islets. Moreover, treatment of
MeSH term(s)	AMP-Activated Protein Kinases ; Animals ; Autophagy ; Calcineurin/metabolism ; Calcium/metabolism ; Diabetes Mellitus, Type 2 ; Exenatide/pharmacology ; Glucagon-Like Peptide-1 Receptor ; Guanine Nucleotide Exchange Factors ; Mice ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Epac protein, mouse ; Glucagon-Like Peptide-1 Receptor ; Guanine Nucleotide Exchange Factors ; Exenatide (9P1872D4OL) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Calcineurin (EC 3.1.3.16) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2021.1956123
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Zs.A 6741: Show issues

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Article ; Online: Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation.

Moonira, Tabassum / Chachra, Shruti S / Ford, Brian E / Marin, Silvia / Alshawi, Ahmed / Adam-Primus, Natasha S / Arden, Catherine / Al-Oanzi, Ziad H / Foretz, Marc / Viollet, Benoit / Cascante, Marta / Agius, Loranne

The Journal of biological chemistry

2020 Volume 295, Issue 10, Page(s) 3330–3346

Abstract: The chronic effects of metformin on liver gluconeogenesis involve repression of ... ...

Abstract	The chronic effects of metformin on liver gluconeogenesis involve repression of the
MeSH term(s)	AMP-Activated Protein Kinases/deficiency ; AMP-Activated Protein Kinases/genetics ; Adenosine Triphosphate/metabolism ; Animals ; Dihydroxyacetone/pharmacology ; Gluconeogenesis/drug effects ; Glucose/metabolism ; Glucose/pharmacology ; Glucose-6-Phosphate/metabolism ; Glycerolphosphate Dehydrogenase/genetics ; Glycerolphosphate Dehydrogenase/metabolism ; Glycolysis/drug effects ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Male ; Metformin/metabolism ; Metformin/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphofructokinase-1/antagonists & inhibitors ; Phosphofructokinase-1/metabolism ; Phosphorylation/drug effects ; Rats ; Rats, Wistar ; Rotenone/pharmacology
Chemical Substances	Rotenone (03L9OT429T) ; Glucose-6-Phosphate (56-73-5) ; Adenosine Triphosphate (8L70Q75FXE) ; Metformin (9100L32L2N) ; Glycerolphosphate Dehydrogenase (EC 1.1.-) ; Phosphofructokinase-1 (EC 2.7.1.11) ; AMPK alpha1 subunit, mouse (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Glucose (IY9XDZ35W2) ; Dihydroxyacetone (O10DDW6JOO)
Language	English
Publishing date	2020-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.012533
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Article ; Online: Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function.

Zummo, Francesco P / Cullen, Kirsty S / Honkanen-Scott, Minna / Shaw, James A M / Lovat, Penny E / Arden, Catherine

Diabetes

2017 Volume 66, Issue 5, Page(s) 1272–1285

Abstract: Studies in animal models of type 2 diabetes have shown that glucagon-like peptide 1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown. In this study, we ... ...

Abstract	Studies in animal models of type 2 diabetes have shown that glucagon-like peptide 1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown. In this study, we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5 mmol/L palmitate and 25 mmol/L glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilization and release of cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Cotreatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. Small interfering RNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4. Collectively, our data highlight lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy/lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signaling pathway as a potential focus.
MeSH term(s)	Adult ; Animals ; Apoptosis ; Autophagy/drug effects ; Blotting, Western ; Case-Control Studies ; Cathepsin D/drug effects ; Cathepsin D/metabolism ; Cell Line ; Cell Survival/drug effects ; Diabetes Mellitus, Type 2/metabolism ; Exenatide ; Glucagon-Like Peptide 1/metabolism ; Glucose/pharmacology ; Humans ; Immunohistochemistry ; Incretins/pharmacology ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Lysosomes/drug effects ; Lysosomes/metabolism ; Mice ; Microtubule-Associated Proteins/drug effects ; Microtubule-Associated Proteins/metabolism ; Middle Aged ; Palmitates/pharmacology ; Peptides/pharmacology ; RNA, Small Interfering ; Rats ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Venoms/pharmacology
Chemical Substances	Incretins ; LC3 protein, rat ; MAP1LC3A protein, human ; Map1lc3b protein, mouse ; Microtubule-Associated Proteins ; Palmitates ; Peptides ; RNA, Small Interfering ; Venoms ; Glucagon-Like Peptide 1 (89750-14-1) ; Exenatide (9P1872D4OL) ; Cathepsin D (EC 3.4.23.5) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2017-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db16-1009
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