scholarly journals Spatiotemporal Correlation Spectroscopy Reveals a Protective Effect of Peptide-Based GLP-1 Receptor Agonism against Lipotoxicity on Insulin Granule Dynamics in Primary Human β-Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1403
Author(s):  
Gianmarco Ferri ◽  
Marta Tesi ◽  
Luca Pesce ◽  
Marco Bugliani ◽  
Francesca Grano ◽  
...  
Keyword(s):  
Mean Square Displacement ◽  
Metabolic Stress ◽  
Human Islets ◽  
Correlation Spectroscopy ◽  
Β Cells ◽  
Glucose Stimulation ◽  
Structural Dynamic ◽  
Beneficial Effects ◽  
Spatiotemporal Correlation ◽  
In Cells

Glucagon-like peptide-1 receptor (GLP-1R) agonists are being used for the treatment of type 2 diabetes (T2D) and may have beneficial effects on the pancreatic β-cells. Here, we evaluated the effects of GLP-1R agonism on insulin secretory granule (ISG) dynamics in primary β-cells isolated from human islets exposed to palmitate-induced lipotoxic stress. Islets cells were exposed for 48 h to 0.5 mM palmitate (hereafter, ‘Palm’) with or without the addition of a GLP-1 agonist, namely 10 nM exendin-4 (hereafter, ‘Ex-4′). Dissociated cells were first transfected with syncollin-EGFP in order to fluorescently mark the ISGs. Then, by applying a recently established spatiotemporal correlation spectroscopy technique, the average structural (i.e., size) and dynamic (i.e., the local diffusivity and mode of motion) properties of ISGs are extracted from a calculated imaging-derived Mean Square Displacement (iMSD) trace. Besides defining the structural/dynamic fingerprint of ISGs in human cells for the first time, iMSD analysis allowed to probe fingerprint variations under selected conditions: namely, it was shown that Palm affects ISGs dynamics in response to acute glucose stimulation by abolishing the ISGs mobilization typically imparted by glucose and, concomitantly, by reducing the extent of ISGs active/directed intracellular movement. By contrast, co-treatment with Ex-4 normalizes ISG dynamics, i.e., re-establish ISG mobilization and ability to perform active transport in response to glucose stimulation. These observations were correlated with standard glucose-stimulated insulin secretion (GSIS), which resulted in being reduced in cells exposed to Palm but preserved in cells concomitantly exposed to 10 nM Ex-4. Our data support the idea that GLP-1R agonism may exert its beneficial effect on human β-cells under metabolic stress by maintaining ISGs’ proper intracellular dynamics.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

scholarly journals Mature and immature β-cells both contribute to islet function and insulin release

2020 ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas Fine ◽  
Fiona Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Ionic Fluxes ◽  
Signalling Network ◽  
Transcriptomic Level ◽  
Adult Islet

Abstract Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that differences in β-cell maturity, defined using PDX1 and MAFA expression, are required for proper islet operation. Functional mapping of rodent and human islets containing proportionally more mature β-cells revealed defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of mature β-cells led to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, the islet signalling network was found to contribute to differences in maturity across β-cells. During metabolic stress, islet function could be restored by redressing the balance between immature and mature β-cells. Thus, preserving a balance between immature and mature β-cells might be important for islet engineering efforts and more broadly the treatment of type 1 and type 2 diabetes.

scholarly journals Perilipin Is Present in Islets of Langerhans and Protects against Lipotoxicity When Overexpressed in the β-Cell Line INS-1

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3049-3057 ◽  
Author(s):  
Jörgen Borg ◽  
Cecilia Klint ◽  
Nils Wierup ◽  
Kristoffer Ström ◽  
Sara Larsson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Line ◽  
Islets Of Langerhans ◽  
Prolonged Exposure ◽  
Human Islets ◽  
Lipid Storage ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
In Cells

Lipids have been shown to play a dual role in pancreatic β-cells: a lipid-derived signal appears to be necessary for glucose-stimulated insulin secretion, whereas lipid accumulation causes impaired insulin secretion and apoptosis. The ability of the protein perilipin to regulate lipolysis prompted an investigation of the presence of perilipin in the islets of Langerhans. In this study evidence is presented for perilipin expression in rat, mouse, and human islets of Langerhans as well as the rat clonal β-cell line INS-1. In rat and mouse islets, perilipin was verified to be present in β-cells. To examine whether the development of lipotoxicity could be prevented by manipulating the conditions for lipid storage in the β-cell, INS-1 cells with adenoviral-mediated overexpression of perilipin were exposed to lipotoxic conditions for 72 h. In cells exposed to palmitate, perilipin overexpression caused increased accumulation of triacylglycerols and decreased lipolysis compared with control cells. Whereas glucose-stimulated insulin secretion was retained after palmitate exposure in cells overexpressing perilipin, it was completely abolished in control β-cells. Thus, overexpression of perilipin appears to confer protection against the development of β-cell dysfunction after prolonged exposure to palmitate by promoting lipid storage and limiting lipolysis.

scholarly journals Metabolic Stress Induces Caspase-3 Mediated Degradation and Inactivation of Farnesyl and Geranylgeranyl Transferase Activities in Pancreatic β-Cells

2016 ◽  
Vol 39 (6) ◽  
pp. 2110-2120 ◽  
Author(s):  
Rajakrishnan Veluthakal ◽  
Daleep K. Arora ◽  
Marc L. Goalstone ◽  
Renu A. Kowluru ◽  
Anjaneyulu Kowluru
Keyword(s):  
G Proteins ◽  
Caspase 3 ◽  
Metabolic Stress ◽  
Human Islets ◽  
Protein Prenylation ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Α Subunit ◽  
Zdf Rat ◽  
The Impact

Background/Aims: At least 300 prenylated proteins are identified in the human genome; the majority of which partake in a variety of cellular processes including growth, differentiation, cytoskeletal organization/dynamics and vesicle trafficking. Aberrant prenylation of proteins is implicated in human pathologies including cancer; neurodegenerative diseases, retinitis pigmentosa, and premature ageing syndromes. Original observations from our laboratory have demonstrated that prenylation of proteins [small G-proteins and γ-subunits of trimeric G-proteins] is requisite for physiological insulin secretion. Herein, we assessed the impact of metabolic stress [gluco-, lipotoxicity and ER-stress] on the functional status of protein prenylation pathway in pancreatic β-cells. Methods: Farnesyltransferase [FTase] and geranylgeranyltransferase [GGTase] activities were quantified by radioisotopic methods. Caspase-3 activation and FTase/GGTase-α subunit degradation were determined by Western blotting. Results: We observed that metabolic stress activates caspase-3 and induces degradation of the common α-subunit of FTase and GGTase-I in INS-1 832/13 cells, normal rodent islets and human islets leading to functional defects [inactivation] in FTase and GGTase activities. Caspase-3 activation and FTase/GGTase-α degradation were also seen in islets from the Zucker diabetic fatty [ZDF] rat, a model for Type 2 diabetes. Consequential to defects in FTase/GGTase-α signaling, we observed significant accumulation of unprenylated proteins [Rap1] in β-cells exposed to glucotoxic conditions. These findings were replicated in β-cells following pharmacological inhibition of generation of prenylpyrophosphate substrates [Simvastatin] or catalytic activity of prenylating enzymes [GGTI-2147]. Conclusions: Our findings provide the first evidence to suggest that metabolic stress induced dysfunction of the islet β-cell may, in part, be due to defective protein prenylation signaling pathway.

scholarly journals Regulation and functional effects of ZNT8 in human pancreatic islets

2012 ◽  
Vol 214 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Bruno Lefebvre ◽  
Brigitte Vandewalle ◽  
Anne-Sophie Balavoine ◽  
Gurvan Queniat ◽  
Ericka Moerman ◽  
...  
Keyword(s):  
Cell Death ◽  
Insulin Secretion ◽  
Metabolic Stress ◽  
Human Islets ◽  
Β Cells ◽  
Prediabetic State ◽  
Zinc Depletion ◽  
Packaging Efficiency ◽  
Glucose Stimulated Insulin Secretion

Zinc ions are essential for the formation of insulin crystals in pancreatic β cells, thereby contributing to packaging efficiency of stored insulin. Zinc fluxes are regulated through the SLC30A (zinc transporter, ZNT) family. Here, we investigated the effect of metabolic stress associated with the prediabetic state (zinc depletion, glucotoxicity, and lipotoxicity) on ZNT expression and human pancreatic islet function. Both zinc depletion and lipotoxicity (but not glucotoxicity) downregulatedZNT8(SLC30A8) expression and altered the glucose-stimulated insulin secretion index (GSIS).ZNT8overexpression in human islets protected them from the decrease in GSIS induced by tetrakis-(2-pyridylmethyl) ethylenediamine and palmitate but not from cell death. In addition, zinc supplementation decreased palmitate-induced human islet cell death without restoring GSIS. Altogether, we showed thatZNT8expression responds to variation in zinc and lipid levels in human β cells, with repercussions on insulin secretion. Prospects for increasingZNT8expression and/or activity may prove beneficial in type 2 diabetes in humans.

Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection

2019 ◽  
Vol 25 (23) ◽  
pp. 2555-2568 ◽  
Author(s):  
Rajeev Taliyan ◽  
Sarathlal K. Chandran ◽  
Violina Kakoty
Keyword(s):  
Diabetes Mellitus ◽  
Protein Trafficking ◽  
Metabolic Stress ◽  
Insulin Receptors ◽  
Metabolic Dysfunction ◽  
Beneficial Effects ◽  
Glucose And Lipid Metabolism ◽  
Endocrine Hormone ◽  
Metabolic Conditions ◽  
The Brain

Neurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

2017 ◽  
Vol 1861 (8) ◽  
pp. 2039-2047 ◽  
Author(s):  
Yun Xie ◽  
Canqi Cui ◽  
Aifang Nie ◽  
Yan Wang ◽  
Qicheng Ni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Metabolic Stress ◽  
Β Cells ◽  
Pancreatic Β Cells

Evaluation effects of Quercetin on streptozotocin-treated RINm5F pancreatic β-cells in vitro

2021 ◽  
Vol 16 ◽  
Author(s):  
Maryam Mazraesefidi ◽  
Maryam Mohammad Sadeghipour ◽  
Hossein Khorramdelazad ◽  
Mahdi Mahmoodi ◽  
Alireza Khoshdel ◽  
...  
Keyword(s):  
Cell Viability ◽  
Insulin Content ◽  
Β Cells ◽  
Simultaneous Treatment ◽  
Beneficial Effects ◽  
Naturally Occurring ◽  
Low Toxicity ◽  
Pre Treatment ◽  
Glucose Stimulated Insulin Secretion

Background and objectives: Quercetin is a naturally occurring phenolic compound abundantly present in plants as a secondary metabolite. The purpose of this study was to investigate the effect of quercetin on improving RINm5F β-insulinemia cell viability, glucose-stimulated insulin secretion (GSIS), and cell insulin content in the presence or absence of streptozotocin (STZ). Methods: This experimental study was conducted on RINm5F β-insulinemia cell line. The cell viability was evaluated by MTT assay. The necrosis was confirmed by flowcytometry and insulin ELISA kit was used to measure the GSIS level and cell insulin content. It should be noted that for testing of cells by 50μM of quercetin, simultaneous treatment and pre-treatment of quercetin were performed in the presence of STZ (20mM). Results: The quercetin was able to improve the viability of RINm5F cells in the presence of STZ and to increase the GSIS level and cell insulin content under STZ and glucotoxic conditions Conclusion: The quercetin seems to have beneficial effects on β-cells, especially the synthesis and secretion of insulin. In addition to the therapeutic effect, given the low toxicity of this flavonoid and the results of this study, the quercetin as a preventive agent may play an important role in maintaining the health of β-cells in people at risk of diabetes.

scholarly journals Furin controls β cell function via mTORC1 signaling

2020 ◽  
Author(s):  
Bas Brouwers ◽  
Ilaria Coppola ◽  
Katlijn Vints ◽  
Bastian Dislich ◽  
Nathalie Jouvet ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Cell Function ◽  
Mammalian Target Of Rapamycin ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Differential Proteomics ◽  
Atpase Subunit ◽  
Proteolytic Activation ◽  
Mtorc1 Signaling

AbstractFurin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific furin knockout (βfurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on βfurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βfurKO cells show impaired cleavage of the essential V-ATPase subunit Ac45, and by blocking this pump in β cells the mTORC1 pathway is activated. Furthermore, βfurKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction.

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