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Targeting Pancreatic Islets from a Therapeutic Perspective

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 26412

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Special Issue Editors

Dr. Björn Tyrberg

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Guest Editor

1. Cardiovascular and Metabolic Diseases, Institute de recherche Servier, Suresnes, France
2. Department of Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
Interests: Pancreatic islets; insulin secretion; diabetes;stem cell differentiation;iPS cells; alpha-cells; beta-cells; beta-cell proliferation; beta-cell loss; drug discovery; incretins; GPCRs

Dr. Maria Sörhede Winzell

E-Mail Website
Guest Editor

1. AstraZeneca PLC, South San Francisco, CA, USA
2. Department of Medicine, Lund University, Lund, Sweden
Interests: pancreatic islets; insulin secretion; diabetes; alpha cells; beta cells; islet cell plasticity; drug discovery; incretins; GPCRs; transplantation and transplantation devices

Special Issue Information

This Special Issue of the Biomediciens focuses on the pancreatic islet as a target for future treatments of diabetes. New drug classes, such as GLP-1 analogues and SGLT2 inhibitors, indeed show great promise for diabetics in the coming decades. Not only do they efficiently lower blood glucose, but they also reduce weight and are associated with positive long-term effects on the heart, kidney, and liver. Nevertheless, drugs that tackle islet-cell failure and loss are still lacking. We believe such drugs are necessary to fully stop the diabetes epidemic. In this Special Issue, we want to highlight the pancreatic islet, its role in diabetes pathophysiology, and what could be done to intervene and stop the progression of disease by attacking function and regulation of the various cell types in the islet. We welcome original articles and reviews that, for example, discuss the discovery of novel potential drug targets or pathways, novel molecules that may rescue function and loss of islet cells, and repurposing ideas of approved drugs that show promise in achieving this goal. We invite contributions with human translational backing but will not be accepting manuscripts with a sole focus on rodents, to make this Special Issue truly focused on potential novel therapeutic avenues.

Dr. Björn Tyrberg
Dr. Maria Sörhede Winzell
Guest Editors

Manuscript Submission Information

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Keywords

Islets of Langerhans
type 2 diabetes
type 1 diabetes
therapeutics
pancreas
translational medicine
beta cell
alpha cell
delta cell

Published Papers (10 papers)

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Research

Jump to: Review

19 pages, 4425 KiB

Open AccessArticle

Defective Proinsulin Handling Modulates the MHC I Bound Peptidome and Activates the Inflammasome in β-Cells

by Muhammad Saad Khilji, Pouya Faridi, Erika Pinheiro-Machado, Carolin Hoefner, Tina Dahlby, Ritchlynn Aranha, Søren Buus, Morten Nielsen, Justyna Klusek, Thomas Mandrup-Poulsen, Kirti Pandey, Anthony W. Purcell and Michal T. Marzec

Biomedicines 2022, 10(4), 814; https://doi.org/10.3390/biomedicines10040814 - 30 Mar 2022

Cited by 3 | Viewed by 2835

Abstract

How immune tolerance is lost to pancreatic β-cell peptides triggering autoimmune type 1 diabetes is enigmatic. We have shown that loss of the proinsulin chaperone glucose-regulated protein (GRP) 94 from the endoplasmic reticulum (ER) leads to mishandling of proinsulin, ER stress, and activation of the immunoproteasome. We hypothesize that inadequate ER proinsulin folding capacity relative to biosynthetic need may lead to an altered β-cell major histocompatibility complex (MHC) class-I bound peptidome and inflammasome activation, sensitizing β-cells to immune attack. We used INS-1E cells with or without GRP94 knockout (KO), or in the presence or absence of GRP94 inhibitor PU-WS13 (GRP94i, 20 µM), or exposed to proinflammatory cytokines interleukin (IL)-1β or interferon gamma (IFNγ) (15 pg/mL and 10 ng/mL, respectively) for 24 h. RT1.A (rat MHC I) expression was evaluated using flow cytometry. The total RT1.A-bound peptidome analysis was performed on cell lysates fractionated by reverse-phase high-performance liquid chromatography (RP-HPLC), followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein (NLRP1), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and (pro) IL-1β expression and secretion were investigated by Western blotting. GRP94 KO increased RT1.A expression in β-cells, as did cytokine exposure compared to relevant controls. Immunopeptidome analysis showed increased RT1.A-bound peptide repertoire in GRP94 KO/i cells as well as in the cells exposed to cytokines. The GRP94 KO/cytokine exposure groups showed partial overlap in their peptide repertoire. Notably, proinsulin-derived peptide diversity increased among the total RT1.A peptidome in GRP94 KO/i along with cytokines exposure. NLRP1 expression was upregulated in GRP94 deficient cells along with decreased IκBα content while proIL-1β cellular levels declined, coupled with increased secretion of mature IL-1β. Our results suggest that limiting β-cell proinsulin chaperoning enhances RT1.A expression alters the MHC-I peptidome including proinsulin peptides and activates inflammatory pathways, suggesting that stress associated with impeding proinsulin handling may sensitize β-cells to immune-attack. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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11 pages, 4836 KiB

Open AccessArticle

Irisin—A Pancreatic Islet Hormone

by Daniel Norman, Carl Johan Drott, Per-Ola Carlsson and Daniel Espes

Biomedicines 2022, 10(2), 258; https://doi.org/10.3390/biomedicines10020258 - 25 Jan 2022

Cited by 4 | Viewed by 2846

Abstract

Irisin is a myokine involved in glucose homeostasis. It is primarily expressed in skeletal muscle, but also in the pancreas. This study aimed to elucidate its presence and role in the islets of Langerhans—i.e., its effect on insulin and glucagon secretion as well as on blood flow in the pancreas. The precursor of irisin, fibronectin type III domain-containing protein 5 (FNDC5), was identified in rat and human islets by both qPCR and immunohistochemistry. Both α- and β-cells stained positive for FNDC5. In human islets, we found that irisin was secreted in a glucose-dependent manner. Neither irisin nor an irisin-neutralizing antibody affected insulin or glucagon secretion from human or rat islets in vitro. The insulin and glucagon content in islets was not altered by irisin. The intravenous infusion of irisin in Sprague Dawley rats resulted in nearly 50% reduction in islet blood flow compared to the control. We conclude that irisin is an islet hormone that has a novel role in pancreatic islet physiology, exerting local vascular effects by diminishing islet blood flow without affecting insulin secretion per se. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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16 pages, 1991 KiB

Open AccessArticle

Inhibition of SGLT2 Preserves Function and Promotes Proliferation of Human Islets Cells In Vivo in Diabetic Mice

by Daniel Karlsson, Andrea Ahnmark, Alan Sabirsh, Anne-Christine Andréasson, Peter Gennemark, Ann-Sofie Sandinge, Lihua Chen, Björn Tyrberg, Daniel Lindén and Maria Sörhede Winzell

Biomedicines 2022, 10(2), 203; https://doi.org/10.3390/biomedicines10020203 - 18 Jan 2022

Cited by 3 | Viewed by 2350

Abstract

Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67⁺glucagon⁺ and Ki67⁺insulin⁺) while apoptosis was reduced (caspase3⁺glucagon⁺ and caspase3⁺insulin⁺). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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13 pages, 2063 KiB

Open AccessArticle

Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis

by Joan Serrano, Nishita N. Meshram, Mangala M. Soundarapandian, Kathleen R. Smith, Carter Mason, Ian S. Brown, Björn Tyrberg and George A. Kyriazis

Biomedicines 2022, 10(1), 120; https://doi.org/10.3390/biomedicines10010120 - 06 Jan 2022

Cited by 6 | Viewed by 2253

Abstract

Background: Saccharin is a common artificial sweetener and a bona fide ligand for sweet taste receptors (STR). STR can regulate insulin secretion in beta cells, so we investigated whether saccharin can stimulate insulin secretion dependent on STR and the activation of phospholipase C (PLC) signaling. Methods: We performed in vivo and in vitro approaches in mice and cells with loss-of-function of STR signaling and specifically assessed the involvement of a PLC signaling cascade using real-time biosensors and calcium imaging. Results: We found that the ingestion of a physiological amount of saccharin can potentiate insulin secretion dependent on STR. Similar to natural sweeteners, saccharin triggers the activation of the PLC signaling cascade, leading to calcium influx and the vesicular exocytosis of insulin. The effects of saccharin also partially require transient receptor potential cation channel M5 (TRPM5) activity. Conclusions: Saccharin ingestion may transiently potentiate insulin secretion through the activation of the canonical STR signaling pathway. These physiological effects provide a framework for understanding the potential health impact of saccharin use and the contribution of STR in peripheral tissues. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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13 pages, 3233 KiB

Open AccessArticle

Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion

by Iwona Szczerbinska, Annamaria Tessitore, Lena Kristina Hansson, Asmita Agrawal, Alejandro Ragel Lopez, Marianne Helenius, Andrzej R. Malinowski, Barak Gilboa, Maxwell A. Ruby, Ramneek Gupta and Carina Ämmälä

Biomedicines 2022, 10(1), 103; https://doi.org/10.3390/biomedicines10010103 - 04 Jan 2022

Cited by 11 | Viewed by 3608

Abstract

Type 2 diabetes (T2D) is a chronic metabolic disorder affecting almost half a billion people worldwide. Impaired function of pancreatic β-cells is both a hallmark of T2D and an underlying factor in the pathophysiology of the disease. Understanding the cellular mechanisms regulating appropriate insulin secretion has been of long-standing interest in the scientific and clinical communities. To identify novel genes regulating insulin secretion we developed a robust arrayed siRNA screen measuring basal, glucose-stimulated, and augmented insulin secretion by EndoC-βH1 cells, a human β-cell line, in a 384-well plate format. We screened 521 candidate genes selected by text mining for relevance to T2D biology and identified 23 positive and 68 negative regulators of insulin secretion. Among these, we validated ghrelin receptor (GHSR), and two genes implicated in endoplasmic reticulum stress, ATF4 and HSPA5. Thus, we have demonstrated the feasibility of using EndoC-βH1 cells for large-scale siRNA screening to identify candidate genes regulating β-cell insulin secretion as potential novel drug targets. Furthermore, this screening format can be adapted to other disease-relevant functional endpoints to enable large-scale screening for targets regulating cellular mechanisms contributing to the progressive loss of functional β-cell mass occurring in T2D. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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8 pages, 372 KiB

Open AccessArticle

Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes

by Henrik Hill, Andris Elksnis, Per Lundkvist, Kumari Ubhayasekera, Jonas Bergquist, Bryndis Birnir, Per-Ola Carlsson and Daniel Espes

Biomedicines 2022, 10(1), 91; https://doi.org/10.3390/biomedicines10010091 - 31 Dec 2021

Cited by 4 | Viewed by 1919

Abstract

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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11 pages, 2660 KiB

Open AccessArticle

Pharmacological Inhibition of NOX4 Improves Mitochondrial Function and Survival in Human Beta-Cells

by Andris Elksnis, Jing Cen, Per Wikström, Per-Ola Carlsson and Nils Welsh

Biomedicines 2021, 9(12), 1865; https://doi.org/10.3390/biomedicines9121865 - 08 Dec 2021

Cited by 8 | Viewed by 2569

Abstract

Previous studies have reported beneficial effects of NADPH oxidase 4 (NOX4) inhibition on beta-cell survival in vitro and in vivo. The mechanisms by which NOX4 inhibition protects insulin producing cells are, however, not known. The aim of the present study was to investigate the effects of a pharmacological NOX4 inhibitor (GLX7013114) on human islet and EndoC-βH1 cell mitochondrial function, and to correlate such effects with survival in islets of different size, activity, and glucose-stimulated insulin release responsiveness. We found that maximal oxygen consumption rates, but not the rates of acidification and proton leak, were increased in islets after acute NOX4 inhibition. In EndoC-βH1 cells, NOX4 inhibition increased the mitochondrial membrane potential, as estimated by JC-1 fluorescence; mitochondrial reactive oxygen species (ROS) production, as estimated by MitoSOX fluorescence; and the ATP/ADP ratio, as assessed by a bioluminescent assay. Moreover, the insulin release from EndoC-βH1 cells at a high glucose concentration increased with NOX4 inhibition. These findings were paralleled by NOX4 inhibition-induced protection against human islet cell death when challenged with high glucose and sodium palmitate. The NOX4 inhibitor protected equally well islets of different size, activity, and glucose responsiveness. We conclude that pharmacological alleviation of NOX4-induced inhibition of beta-cell mitochondria leads to increased, and not decreased, mitochondrial ROS, and this was associated with protection against cell death occurring in different types of heterogeneous islets. Thus, NOX4 inhibition or modulation may be a therapeutic strategy in type 2 diabetes that targets all types of islets. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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Review

Jump to: Research

17 pages, 1362 KiB

Open AccessReview

Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function: Review on Mathematical Modelling Approaches

by Giovanni Pacini, Bo Ahrén, Christian Göbl and Andrea Tura

Biomedicines 2022, 10(5), 1060; https://doi.org/10.3390/biomedicines10051060 - 03 May 2022

Cited by 4 | Viewed by 1725

Abstract

Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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Graphical abstract

8 pages, 418 KiB

Open AccessReview

Approaches to Inducing β-Cell Regeneration

by Fred Levine

Biomedicines 2022, 10(3), 571; https://doi.org/10.3390/biomedicines10030571 - 28 Feb 2022

Cited by 4 | Viewed by 2253

Abstract

β-cell number and/or function is reduced in diabetes. Thus, inducing the formation of new β-cells has been a major goal of diabetes research. However, the pathway(s) by which new β-cells form when preexisting β-cells are decreased in number or cease to function has remained obscure. Many pathways have been proposed, but definitive evidence, particularly in humans, has been lacking. Replication of preexisting β-cells, neogenesis from ducts, redifferentiation from β-cells that dedifferentiated under metabolic stress, and transdifferentiation from other cell types, particularly within the islet, are the major mechanisms that have been proposed for generating increased numbers of functional β-cells. Here, I will discuss those approaches critically, with particular attention to transdifferentiation of preexisting α-cells to β-cells. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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14 pages, 3446 KiB

Open AccessReview

The Current State of Beta-Cell-Mass PET Imaging for Diabetes Research and Therapies

by Pierre Cheung and Olof Eriksson

Biomedicines 2021, 9(12), 1824; https://doi.org/10.3390/biomedicines9121824 - 03 Dec 2021

Cited by 5 | Viewed by 2621

Abstract

Diabetes is a chronic metabolic disease affecting over 400 million people worldwide and one of the leading causes of death, especially in developing nations. The disease is characterized by chronic hyperglycemia, caused by defects in the insulin secretion or action pathway. Current diagnostic methods measure metabolic byproducts of the disease such as glucose level, glycated hemoglobin (HbA1c), insulin or C-peptide levels, which are indicators of the beta-cell function. However, they inaccurately reflect the disease progression and provide poor longitudinal information. Beta-cell mass has been suggested as an alternative approach to study disease progression in correlation to beta-cell function, as it behaves differently in the diabetes physiopathology. Study of the beta-cell mass, however, requires highly invasive and potentially harmful procedures such as pancreatic biopsies, making diagnosis and monitoring of the disease tedious. Nuclear medical imaging techniques using radiation emitting tracers have been suggested as strong non-invasive tools for beta-cell mass. A highly sensitive and high-resolution technique, such as positron emission tomography, provides an ideal solution for the visualization of beta-cell mass, which is particularly essential for better characterization of a disease such as diabetes, and for estimating treatment effects towards regeneration of the beta-cell mass. Development of novel, validated biomarkers that are aimed at beta-cell mass imaging are thus highly necessary and would contribute to invaluable breakthroughs in the field of diabetes research and therapies. This review aims to describe the various biomarkers and radioactive probes currently available for positron emission tomography imaging of beta-cell mass, as well as highlight the need for precise quantification and visualization of the beta-cell mass for designing new therapy strategies and monitoring changes in the beta-cell mass during the progression of diabetes. Full article

(This article belongs to the Special Issue Targeting Pancreatic Islets from a Therapeutic Perspective)

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