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13 pages, 2436 KiB

Open AccessArticle

Hyperglycemic Stress Induces Expression, Degradation, and Nuclear Association of Rho GDP Dissociation Inhibitor 2 (RhoGDIβ) in Pancreatic β-Cells

by Noah Gleason and Anjaneyulu Kowluru

Cells 2024, 13(3), 272; https://doi.org/10.3390/cells13030272 - 1 Feb 2024

Viewed by 1231

Abstract

Small G proteins (e.g., Rac1) play critical regulatory roles in islet β-cell function in health (physiological insulin secretion) and in metabolic stress (cell dysfunction and demise). Multiple regulatory factors for these G proteins, such as GDP dissociation inhibitors (GDIs), have been implicated in [...] Read more.

Small G proteins (e.g., Rac1) play critical regulatory roles in islet β-cell function in health (physiological insulin secretion) and in metabolic stress (cell dysfunction and demise). Multiple regulatory factors for these G proteins, such as GDP dissociation inhibitors (GDIs), have been implicated in the functional regulation of these G proteins. The current set of investigations is aimed at understanding impact of chronic hyperglycemic stress on the expression and subcellular distribution of three known isoforms of RhoGDIs (RhoGDIα, RhoGDIβ, and RhoGDIγ) in insulin-secreting β-cells. The data accrued in these studies revealed that the expression of RhoGDIβ, but not RhoGDIα or RhoGDIγ, is increased in INS-1 832/13 cells, rat islets, and human islets. Hyperglycemic stress also promoted the cleavage of RhoGDIβ, leading to its translocation to the nuclear compartment. We also report that RhoGDIα, but not RhoGDIγ, is associated with the nuclear compartment. However, unlike RhoGDIβ, hyperglycemic conditions exerted no effects on RhoGDIα’s association with nuclear fraction. Based on these observations, and our earlier findings of the translocation of Rac1 to the nuclear compartment under the duress of metabolic stress, we conclude that the RhoGDIβ-Rac1 signaling module promotes signals from the cytosolic to the nucleus, culminating in accelerated β-cell dysfunction under metabolic stress. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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14 pages, 1681 KiB

Open AccessFeature PaperArticle

Butyrate and Class I Histone Deacetylase Inhibitors Promote Differentiation of Neonatal Porcine Islet Cells into Beta Cells

by Yichen Zhang, Yutian Lei, Mohsen Honarpisheh, Elisabeth Kemter, Eckhard Wolf and Jochen Seissler

Cells 2021, 10(11), 3249; https://doi.org/10.3390/cells10113249 - 19 Nov 2021

Cited by 12 | Viewed by 2976

Abstract

Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and endocrine cells, which undergo a maturation process lasting several weeks until the normal beta cell function has developed. [...] Read more.

Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and endocrine cells, which undergo a maturation process lasting several weeks until the normal beta cell function has developed. Here, we investigated the effects of short-chain fatty acids on the maturation of islet cells isolated from two to three day-old piglets. NPICCs were cultivated with acetate, butyrate and propionate (0–2000 µM) for one to eight days. Incubation with butyrate resulted in a significant upregulation of insulin gene expression and an increased beta cell number, whereas acetate or propionate had only marginal effects. Treatment with specific inhibitors of G-protein-coupled receptor GPR41 (β-hydroxybutyrate) and/or GPR43 (GPLG0974) did not abolish butyrate induced insulin expression. However, incubation of NPICCs with class I histone deacetylase inhibitors (HDACi) mocetinostat and MS275, but not selective class II HDACi (TMP269, MC1568) mimicked the butyrate effect on beta cell differentiation. Our study revealed that butyrate treatment has the capacity to increase the number of beta cells, which may be predominantly mediated through its HDAC inhibitory activity. Butyrate and specific class I HDAC inhibitors may represent beneficial supplements to promote differentiation of neonatal porcine islet cells towards beta cells for cell replacement therapies. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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19 pages, 4379 KiB

Open AccessArticle

The MicroRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts

by Geert A. Martens, Geert Stangé, Lorenzo Piemonti, Jasper Anckaert, Zhidong Ling, Daniel G. Pipeleers, Frans K. Gorus, Pieter Mestdagh, Dieter De Smet, Jo Vandesompele, Bart Keymeulen and Sarah Roels

Cells 2021, 10(7), 1693; https://doi.org/10.3390/cells10071693 - 4 Jul 2021

Cited by 5 | Viewed by 2952

Abstract

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to [...] Read more.

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. microRNA-375 (miR-375) ranks among the top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 h before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to the identification of eight microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome, and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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14 pages, 2460 KiB

Open AccessArticle

Dual Mode of Action of Acetylcholine on Cytosolic Calcium Oscillations in Pancreatic Beta and Acinar Cells In Situ

by Nastja Sluga, Sandra Postić, Srdjan Sarikas, Ya-Chi Huang, Andraž Stožer and Marjan Slak Rupnik

Cells 2021, 10(7), 1580; https://doi.org/10.3390/cells10071580 - 23 Jun 2021

Cited by 8 | Viewed by 5377

Abstract

Cholinergic innervation in the pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in [...] Read more.

Cholinergic innervation in the pancreas controls both the release of digestive enzymes to support the intestinal digestion and absorption, as well as insulin release to promote nutrient use in the cells of the body. The effects of muscarinic receptor stimulation are described in detail for endocrine beta cells and exocrine acinar cells separately. Here we describe morphological and functional criteria to separate these two cell types in situ in tissue slices and simultaneously measure their response to ACh stimulation on cytosolic Ca²⁺ oscillations [Ca²⁺]_c in stimulatory glucose conditions. Our results show that both cell types respond to glucose directly in the concentration range compatible with the glucose transporters they express. The physiological ACh concentration increases the frequency of glucose stimulated [Ca²⁺]_c oscillations in both cell types and synchronizes [Ca²⁺]_c oscillations in acinar cells. The supraphysiological ACh concentration further increases the oscillation frequency on the level of individual beta cells, inhibits the synchronization between these cells, and abolishes oscillatory activity in acinar cells. We discuss possible mechanisms leading to the observed phenomena. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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14 pages, 2740 KiB

Open AccessArticle

Direct Stimulatory Effects of the CB₂ Ligand JTE 907 in Human and Mouse Islets

by Inmaculada Ruz-Maldonado, Patricio Atanes, Guo Cai Huang, Bo Liu and Shanta J Persaud

Cells 2021, 10(3), 700; https://doi.org/10.3390/cells10030700 - 22 Mar 2021

Cited by 2 | Viewed by 2913

Abstract

Aims: The endocannabinoid system is a complex cell-signaling network through which endogenous cannabinoid ligands regulate cell function by interaction with CB₁ and CB₂ cannabinoid receptors, and with the novel cannabinoid receptor GPR55. CB₁, CB₂, and GPR55 are [...] Read more.

Aims: The endocannabinoid system is a complex cell-signaling network through which endogenous cannabinoid ligands regulate cell function by interaction with CB₁ and CB₂ cannabinoid receptors, and with the novel cannabinoid receptor GPR55. CB₁, CB₂, and GPR55 are expressed by islet β-cells where they modulate insulin secretion. We have previously shown that administration of the putative CB₂ antagonist/inverse agonist JTE 907 to human islets did not affect the insulinotropic actions of CB₂ agonists and it unexpectedly stimulated insulin secretion on its own. In this study, we evaluated whether the lack of antagonism could be related to the ability of JTE 907 to act as a GPR55 agonist. Materials and Methods: We used islets isolated from human donors and from Gpr55^+/+ and Gpr55^−/− mice and quantified the effects of incubation with 10 μM JTE 907 on dynamic insulin secretion, apoptosis, and β-cell proliferation by radioimmunoassay, luminescence caspase 3/7 activity, and immunofluorescence, respectively. We also measured islet IP₁ and cAMP accumulation using fluorescence assays, and monitored [Ca²⁺]_i elevations by Fura-2 single cell microfluorometry. Results: JTE 907 significantly stimulated insulin secretion from islets isolated from human donors and islets from Gpr55^+/+ and Gpr55^−/− mice. These stimulatory effects were accompanied by significant elevations of IP₁ and [Ca²⁺]_i, but there were no changes in cAMP generation. JTE 907 also significantly reduced cytokine-induced apoptosis in human and mouse islets and promoted human β-cell proliferation. Conclusion: Our observations show for the first time that JTE 907 acts as a G_q-coupled agonist in islets to stimulate insulin secretion and maintain β-cell mass in a GPR55-independent fashion. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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Review

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12 pages, 931 KiB

Open AccessReview

GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

by David W. Scoville and Anton M. Jetten

Cells 2021, 10(12), 3471; https://doi.org/10.3390/cells10123471 - 9 Dec 2021

Cited by 9 | Viewed by 4221

Abstract

Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the [...] Read more.

Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3. Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes. As a significant progress has been made in understanding some of GLIS3’s roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors. While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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24 pages, 1413 KiB

Open AccessReview

Role of High Voltage-Gated Ca²⁺ Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function

by Petronel Tuluc, Tamara Theiner, Noelia Jacobo-Piqueras and Stefanie M. Geisler

Cells 2021, 10(8), 2004; https://doi.org/10.3390/cells10082004 - 6 Aug 2021

Cited by 18 | Viewed by 6816

Abstract

The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The β-cells, the major cellular component of the pancreatic islets, secrete insulin, the only hormone capable of lowering the plasma glucose concentration. The counter-regulatory hormone glucagon is secreted by the α-cells [...] Read more.

The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The β-cells, the major cellular component of the pancreatic islets, secrete insulin, the only hormone capable of lowering the plasma glucose concentration. The counter-regulatory hormone glucagon is secreted by the α-cells while δ-cells secrete somatostatin that via paracrine mechanisms regulates the α- and β-cell activity. These three peptide hormones are packed into secretory granules that are released through exocytosis following a local increase in intracellular Ca²⁺ concentration. The high voltage-gated Ca²⁺ channels (HVCCs) occupy a central role in pancreatic hormone release both as a source of Ca²⁺ required for excitation-secretion coupling as well as a scaffold for the release machinery. HVCCs are multi-protein complexes composed of the main pore-forming transmembrane α₁ and the auxiliary intracellular β, extracellular α₂δ, and transmembrane γ subunits. Here, we review the current understanding regarding the role of all HVCC subunits expressed in pancreatic β-cell on electrical activity, excitation-secretion coupling, and β-cell mass. The evidence we review was obtained from many seminal studies employing pharmacological approaches as well as genetically modified mouse models. The significance for diabetes in humans is discussed in the context of genetic variations in the genes encoding for the HVCC subunits. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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26 pages, 20412 KiB

Open AccessReview

The Role of cAMP in Beta Cell Stimulus–Secretion and Intercellular Coupling

by Andraž Stožer, Eva Paradiž Leitgeb, Viljem Pohorec, Jurij Dolenšek, Lidija Križančić Bombek, Marko Gosak and Maša Skelin Klemen

Cells 2021, 10(7), 1658; https://doi.org/10.3390/cells10071658 - 1 Jul 2021

Cited by 26 | Viewed by 8447

Abstract

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and [...] Read more.

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus–secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca²⁺ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans. Full article

(This article belongs to the Special Issue Signal Transduction in the Islets of Langerhans)

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