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Article ; Online: Targeting protein misfolding to protect pancreatic beta-cells in type 2 diabetes.

Costes, Safia

2018 Volume 43, Page(s) 104–110

Abstract: The islet in type 2 diabetes is characterized by beta-cell dysfunction and deficit, increased beta-cell apoptosis and amyloid deposits that derived from islet amyloid polypeptide (IAPP). In species such as humans that are vulnerable to developing type 2 ... ...

Abstract	The islet in type 2 diabetes is characterized by beta-cell dysfunction and deficit, increased beta-cell apoptosis and amyloid deposits that derived from islet amyloid polypeptide (IAPP). In species such as humans that are vulnerable to developing type 2 diabetes, IAPP has the propensity to form toxic oligomers that contribute to beta-cell dysfunction and apoptosis, defining type 2 diabetes as a protein misfolding disorder. In this report, we review mechanisms known to contribute to protein misfolding and formation of toxic oligomers, and the deleterious consequences of these oligomers on beta-cell function and survival. Finally, we will consider approaches to prevent protein misfolding and formation of toxic oligomers as potential novel therapeutic targets for type 2 diabetes and other protein misfolding diseases.
MeSH term(s)	Animals ; Biomarkers/blood ; Blood Glucose/drug effects ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/pathology ; Diffusion of Innovation ; Drug Design ; Humans ; Hypoglycemic Agents/adverse effects ; Hypoglycemic Agents/therapeutic use ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Molecular Targeted Therapy ; Protein Folding/drug effects ; Proteostasis Deficiencies/blood ; Proteostasis Deficiencies/drug therapy ; Proteostasis Deficiencies/pathology ; Signal Transduction/drug effects
Chemical Substances	Biomarkers ; Blood Glucose ; Hypoglycemic Agents
Language	English
Publishing date	2018-09-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2018.08.016
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Article ; Online: Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies.

Costes, Safia / Bertrand, Gyslaine / Ravier, Magalie A

International journal of molecular sciences

2021 Volume 22, Issue 10

Abstract: Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a ... ...

Abstract	Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.
MeSH term(s)	Animals ; Apoptosis/physiology ; Cells, Cultured ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Disease Models, Animal ; Glucagon-Like Peptide 1/metabolism ; Glucagon-Like Peptide 1/pharmacology ; Glucagon-Like Peptide 1/physiology ; Glucose/metabolism ; Humans ; Hyperglycemia/metabolism ; Insulin/metabolism ; Insulin Resistance/physiology ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/physiology ; Islets of Langerhans/metabolism ; Signal Transduction
Chemical Substances	Insulin ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-05-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22105303
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Article ; Online: GLP-1 and GIP receptors signal through distinct β-arrestin 2-dependent pathways to regulate pancreatic β cell function.

Zaïmia, Nour / Obeid, Joelle / Varrault, Annie / Sabatier, Julia / Broca, Christophe / Gilon, Patrick / Costes, Safia / Bertrand, Gyslaine / Ravier, Magalie A

Cell reports

2023 Volume 42, Issue 11, Page(s) 113326

Abstract: Glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR) receptors are G-protein-coupled receptors involved in glucose homeostasis. Diabetogenic conditions decrease β-arrestin 2 (ARRB2) levels in human islets. In mouse β ... ...

Abstract	Glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR) receptors are G-protein-coupled receptors involved in glucose homeostasis. Diabetogenic conditions decrease β-arrestin 2 (ARRB2) levels in human islets. In mouse β cells, ARRB2 dampens insulin secretion by partially uncoupling cyclic AMP (cAMP)/protein kinase A (PKA) signaling at physiological doses of GLP-1, whereas at pharmacological doses, the activation of extracellular signal-related kinase (ERK)/cAMP-responsive element-binding protein (CREB) requires ARRB2. In contrast, GIP-potentiated insulin secretion needs ARRB2 in mouse and human islets. The GIPR-ARRB2 axis is not involved in cAMP/PKA or ERK signaling but does mediate GIP-induced F-actin depolymerization. Finally, the dual GLP-1/GIP agonist tirzepatide does not require ARRB2 for the potentiation of insulin secretion. Thus, ARRB2 plays distinct roles in regulating GLP-1R and GIPR signaling, and we highlight (1) its role in the physiological context and the possible functional consequences of its decreased expression in pathological situations such as diabetes and (2) the importance of assessing the signaling pathways engaged by the agonists (biased/dual) for therapeutic purposes.
MeSH term(s)	Mice ; Humans ; Animals ; Insulin-Secreting Cells/metabolism ; Glucagon-Like Peptide 1/metabolism ; Insulin/metabolism ; beta-Arrestin 2/metabolism ; beta-Arrestin 1/metabolism ; Glucose/metabolism
Chemical Substances	Glucagon-Like Peptide 1 (89750-14-1) ; Insulin ; beta-Arrestin 2 ; beta-Arrestin 1 ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113326
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Article ; Online: Erratum. β-Cell Dysfunctional ERAD/Ubiquitin/Proteasome System in Type 2 Diabetes Mediated by Islet Amyloid Polypeptide-Induced UCH-L1 Deficiency. Diabetes 2011;60:227-238.

Costes, Safia / Huang, Chang-Jiang / Gurlo, Tatyana / Daval, Marie / Matveyenko, Aleksey V / Rizza, Robert A / Butler, Alexandra E / Butler, Peter C

Diabetes

2023 Volume 72, Issue 12, Page(s) 1881

Language	English
Publishing date	2023-09-04
Publishing country	United States
Document type	Published Erratum
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db23-er12
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Article ; Online: Methods to Study Roles of β-Arrestins in the Regulation of Pancreatic β-Cell Function.

Dalle, Stéphane / Costes, Safia / Bertrand, Gyslaine / Ravier, Magalie A

Methods in molecular biology (Clifton, N.J.)

2019 Volume 1957, Page(s) 345–364

Abstract: Novel findings reveal important functional roles for β-arrestin 1 and β-arrestin 2 in the regulation of insulin secretion, β-cell survival, and β-cell mass plasticity not only by glucose but also by G-protein-coupled receptors, such as the glucagon-like ... ...

Abstract	Novel findings reveal important functional roles for β-arrestin 1 and β-arrestin 2 in the regulation of insulin secretion, β-cell survival, and β-cell mass plasticity not only by glucose but also by G-protein-coupled receptors, such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors or GPR40, or tyrosine kinase receptors, such as the insulin receptor. Here, we describe experimental protocols to knock down β-arrestins by small interference RNA, to follow subcellular localization of β-arrestins in the cytosol and nucleus of the insulinoma INS-1E rat pancreatic β-cell line, and to analyze β-arrestin protein expression by Western blot using INS-1E cells and isolated mouse or human pancreatic islets. We also provide details on how to genotype β-arrestin 2 knockout (Arrb2
MeSH term(s)	Animals ; Cytoplasm/metabolism ; Gene Knockdown Techniques ; Genotype ; Insulin-Secreting Cells/metabolism ; Mice, Knockout ; Molecular Biology/methods ; Nuclear Proteins/metabolism ; RNA, Small Interfering/metabolism ; beta-Arrestins/metabolism
Chemical Substances	Nuclear Proteins ; RNA, Small Interfering ; beta-Arrestins
Language	English
Publishing date	2019-03-27
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9158-7_22
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Article ; Online: Insulin-degrading enzyme inhibition, a novel therapy for type 2 diabetes?

Costes, Safia / Butler, Peter C

Cell metabolism

2014 Volume 20, Issue 2, Page(s) 201–203

Abstract: The insulin-degrading enzyme (IDE) has been identified as a type 2 diabetes and Alzheimer's disease susceptibility gene, though its physiological function remains unclear. Maianti et al. (2014) now propose that an IDE inhibitor may be a promising ... ...

Abstract	The insulin-degrading enzyme (IDE) has been identified as a type 2 diabetes and Alzheimer's disease susceptibility gene, though its physiological function remains unclear. Maianti et al. (2014) now propose that an IDE inhibitor may be a promising therapeutic strategy for type 2 diabetes.
MeSH term(s)	Animals ; Glucagon/metabolism ; Hypoglycemic Agents/pharmacology ; Insulin/metabolism ; Insulysin/antagonists & inhibitors ; Islet Amyloid Polypeptide/metabolism ; Macrocyclic Compounds/pharmacology ; Male
Chemical Substances	Hypoglycemic Agents ; Insulin ; Islet Amyloid Polypeptide ; Macrocyclic Compounds ; Glucagon (9007-92-5) ; Insulysin (EC 3.4.24.56)
Language	English
Publishing date	2014-08-07
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2014.07.016
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Zs.A 6169: Show issues

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Article ; Online: The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.

Brown, Matthew R / Laouteouet, Damien / Delobel, Morgane / Villard, Orianne / Broca, Christophe / Bertrand, Gyslaine / Wojtusciszyn, Anne / Dalle, Stéphane / Ravier, Magalie A / Matveyenko, Aleksey V / Costes, Safia

Cell death & disease

2022 Volume 13, Issue 4, Page(s) 353

Abstract: Pancreatic β-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls β-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the ... ...

Abstract	Pancreatic β-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls β-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM β-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERBα as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERBα-mediated inhibition of autophagy contributes to the β-cell failure in T2DM. Our study provides evidence that common diabetogenic stressors (e.g., glucotoxicity and cytokine-mediated inflammation) augment β-cell REV-ERBα expression and impair β-cell autophagy and survival. Notably, pharmacological activation of REV-ERBα was shown to phenocopy effects of diabetogenic stressors on the β-cell through inhibition of autophagic flux, survival, and insulin secretion. In contrast, negative modulation of REV-ERBα was shown to provide partial protection from inflammation and glucotoxicity-induced β-cell failure. Finally, using bioinformatic approaches, we provide further supporting evidence for augmented REV-ERBα activity in T2DM human islets associated with impaired transcriptional regulation of autophagy and protein degradation pathways. In conclusion, our study reveals a previously unexplored causative relationship between REV-ERBα expression, inhibition of autophagy, and β-cell failure in T2DM.
MeSH term(s)	Autophagy/genetics ; Circadian Clocks ; Circadian Rhythm/physiology ; Diabetes Mellitus, Type 2/genetics ; Humans ; Inflammation ; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics ; Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism
Chemical Substances	Nuclear Receptor Subfamily 1, Group D, Member 1
Language	English
Publishing date	2022-04-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-022-04767-z
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Article ; Online: Activation of Melatonin Signaling Promotes β-Cell Survival and Function.

Costes, Safia / Boss, Marti / Thomas, Anthony P / Matveyenko, Aleksey V

Molecular endocrinology (Baltimore, Md.)

2015 Volume 29, Issue 5, Page(s) 682–692

Abstract: Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin ... ...

Abstract	Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of β-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced β-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Survival ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Insulin-Secreting Cells/physiology ; Melatonin/physiology ; Rats ; Receptors, Melatonin/metabolism ; Signal Transduction
Chemical Substances	Receptors, Melatonin ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2015-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639167-9
ISSN	1944-9917 ; 0888-8809
ISSN (online)	1944-9917
ISSN	0888-8809
DOI	10.1210/me.2014-1293
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Zs.A 2261: Show issues

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Article ; Online: UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in β-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy.

Costes, Safia / Gurlo, Tatyana / Rivera, Jacqueline F / Butler, Peter C

Autophagy

2014 Volume 10, Issue 6, Page(s) 1004–1014

Abstract: The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cells and increased β-cell apoptosis attributable at least in part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). β-cells of individuals with T2DM are ... ...

Abstract	The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cells and increased β-cell apoptosis attributable at least in part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). β-cells of individuals with T2DM are also characterized by accumulation of polyubiquitinated proteins and deficiency in the deubiquitinating enzyme UCHL1 (ubiquitin carboxyl-terminal esterase L1 [ubiquitin thiolesterase]), accounting for a dysfunctional ubiquitin/proteasome system. In the present study, we used mouse genetics to elucidate in vivo whether a partial deficit in UCHL1 enhances the vulnerability of β-cells to human-IAPP (hIAPP) toxicity, and thus accelerates diabetes onset. We further investigated whether a genetically induced deficit in UCHL1 function in β-cells exacerbates hIAPP-induced alteration of the autophagy pathway in vivo. We report that a deficit in UCHL1 accelerated the onset of diabetes in hIAPP transgenic mice, due to a decrease in β-cell mass caused by increased β-cell apoptosis. We report that UCHL1 dysfunction aggravated the hIAPP-induced defect in the autophagy/lysosomal pathway, illustrated by the marked accumulation of autophagosomes and cytoplasmic inclusions positive for SQSTM1/p62 and polyubiquitinated proteins with lysine 63-specific ubiquitin chains. Collectively, this study shows that defective UCHL1 function may be an early contributor to vulnerability of pancreatic β-cells for protein misfolding and proteotoxicity, hallmark defects in islets of T2DM. Also, given that deficiency in UCHL1 exacerbated the defective autophagy/lysosomal degradation characteristic of hIAPP proteotoxicity, we demonstrate a previously unrecognized role of UCHL1 in the function of the autophagy/lysosomal pathway in β-cells.
MeSH term(s)	Animals ; Apoptosis ; Autophagy/genetics ; Autophagy/physiology ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Humans ; Insulin Resistance ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Islet Amyloid Polypeptide/genetics ; Islet Amyloid Polypeptide/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mice, Transgenic ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin Thiolesterase/deficiency ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism
Chemical Substances	Islet Amyloid Polypeptide ; Mutant Proteins ; Recombinant Proteins ; Ubiquitin ; Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2014-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.28478
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Article: β

Gurlo, Tatyana / Costes, Safia / Hoang, Jonathan D / Rivera, Jacqueline F / Butler, Alexandra E / Butler, Peter C

JCI insight

2016 Volume 1, Issue 18, Page(s) e89590

Abstract: The islet in type 2 diabetes (T2D) shares many features of the brain in protein misfolding diseases. There is a deficit of β cells with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed with insulin. Small intracellular ... ...

Abstract	The islet in type 2 diabetes (T2D) shares many features of the brain in protein misfolding diseases. There is a deficit of β cells with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed with insulin. Small intracellular membrane-permeant oligomers, the most toxic form of IAPP, are more frequent in β cells of patients with T2D and rodents expressing human IAPP. β Cells in T2D, and affected cells in neurodegenerative diseases, share a comparable pattern of molecular pathology, including endoplasmic reticulum stress, mitochondrial dysfunction, attenuation of autophagy, and calpain hyperactivation. While this adverse functional cascade in response to toxic oligomers is well described, the sequence of events and how best to intervene is unknown. We hypothesized that calpain hyperactivation is a proximal event and tested this in vivo by β cell-specific suppression of calpain hyperactivation with calpastatin overexpression in human IAPP transgenic mice. β Cell-specific calpastatin overexpression was remarkably protective against β cell dysfunction and loss and diabetes onset. The critical autophagy/lysosomal pathway for β cell viability was protected with calpain suppression, consistent with findings in models of neurodegenerative diseases. We conclude that suppression of calpain hyperactivation is a potentially beneficial disease-modifying strategy for protein misfolding diseases, including T2D.
MeSH term(s)	Animals ; Calcium-Binding Proteins/metabolism ; Calpain/metabolism ; Diabetes Mellitus, Type 2/chemically induced ; Diabetes Mellitus, Type 2/prevention & control ; Female ; Humans ; Insulin-Secreting Cells/metabolism ; Islet Amyloid Polypeptide/adverse effects ; Male ; Mice ; Mice, Transgenic
Chemical Substances	Calcium-Binding Proteins ; Islet Amyloid Polypeptide ; calpastatin (79079-11-1) ; Calpain (EC 3.4.22.-)
Language	English
Publishing date	2016-11-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN	2379-3708
DOI	10.1172/jci.insight.89590
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