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Nagao M. Real-Time Detection of Somatostatin Release From Single Pancreatic Islets Reveals δ-Cell Dysfunction in Type 2 Diabetes. Acta Physiol (Oxf) 2025; 241:e70045. [PMID: 40183501 DOI: 10.1111/apha.70045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Affiliation(s)
- Mototsugu Nagao
- Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
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2
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Peng X, Wang K, Chen L. Biphasic glucose-stimulated insulin secretion over decades: a journey from measurements and modeling to mechanistic insights. LIFE METABOLISM 2025; 4:loae038. [PMID: 39872989 PMCID: PMC11770817 DOI: 10.1093/lifemeta/loae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 01/30/2025]
Abstract
Glucose-stimulated insulin release from pancreatic β-cells is critical for maintaining blood glucose homeostasis. An abrupt increase in blood glucose concentration evokes a rapid and transient rise in insulin secretion followed by a prolonged, slower phase. A diminished first phase is one of the earliest indicators of β-cell dysfunction in individuals predisposed to develop type 2 diabetes. Consequently, researchers have explored the underlying mechanisms for decades, starting with plasma insulin measurements under physiological conditions and advancing to single-vesicle exocytosis measurements in individual β-cells combined with molecular manipulations. Based on a chain of evidence gathered from genetic manipulation to in vivo mouse phenotyping, a widely accepted theory posits that distinct functional insulin vesicle pools in β-cells regulate biphasic glucose-stimulated insulin secretion (GSIS) via activation of different metabolic signal pathways. Recently, we developed a high-resolution imaging technique to visualize single vesicle exocytosis from β-cells within an intact islet. Our findings reveal that β-cells within the islet exhibit heterogeneity in their secretory capabilities, which also differs from the heterogeneous Ca2+ signals observed in islet β-cells in response to glucose stimulation. Most importantly, we demonstrate that biphasic GSIS emerges from the interactions among α-, β-, and δ-cells within the islet and is driven by a small subset of hypersecretory β-cells. Finally, we propose that a shift from reductionism to holism may be required to fully understand the etiology of complex diseases such as diabetes.
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Affiliation(s)
- Xiaohong Peng
- New Cornerstone Science Laboratory, State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, National Biomedical Imaging Center, The Beijing Laboratory of Biomedical Imaging, Peking-Tsinghua Center for Life Sciences, School of Future Technology, Peking University, Beijing 100871, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Liangyi Chen
- New Cornerstone Science Laboratory, State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, National Biomedical Imaging Center, The Beijing Laboratory of Biomedical Imaging, Peking-Tsinghua Center for Life Sciences, School of Future Technology, Peking University, Beijing 100871, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
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3
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Yang M, Mandal K, Södergren M, Dumral Ö, Winroth L, Tengholm A. Real-time detection of somatostatin release from single islets reveals hypersecretion in type 2 diabetes. Acta Physiol (Oxf) 2025; 241:e14268. [PMID: 39803760 PMCID: PMC11726413 DOI: 10.1111/apha.14268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/01/2024] [Accepted: 01/01/2025] [Indexed: 01/16/2025]
Abstract
AIM Somatostatin from pancreatic δ-cells is a paracrine regulator of insulin and glucagon secretion, but the release kinetics and whether secretion is altered in diabetes is unclear. This study aimed to improve understanding of somatostatin secretion by developing a tool for real-time detection of somatostatin release from individual pancreatic islets. METHODS Reporter cells responding to somatostatin with cytoplasmic Ca2+ concentration ([Ca2+]i) changes were generated by co-expressing somatostatin receptor SSTR2, the G-protein Gα15 and a fluorescent Ca2+ sensor in HeLa cells. RESULTS Somatostatin induced dose-dependent [Ca2+]i increases in reporter cells with half-maximal and maximal effects at 1.6 ± 0.4 and ~30 nM, respectively. Mouse and human islets induced reporter cell [Ca2+]i elevations that were inhibited by the SSTR2 antagonist CYN154806. Depolarization of islets by high K+, KATP channel blockade or increasing the glucose concentration from 3 to 11 mM evoked concomitant elevations of [Ca2+]i in islets and reporter cells. Exposure of islets to glucagon, GLP-1 and ghrelin also triggered reporter cell [Ca2+]i responses, whereas little effect was obtained by islet exposure to insulin, glutamate, GABA and urocortin-3. Islets from type 2 diabetic human donors induced higher reporter cell [Ca2+]i responses at 11 mM and after K+ depolarization compared with non-diabetic islets, although fewer δ-cells were identified by immunostaining. CONCLUSION Type 2 diabetes is associated with hypersecretion of somatostatin, which has implications for paracrine regulation of insulin and glucagon secretion. The new reporter cell assay for real-time detection of single-islet somatostatin release holds promise for further studies of somatostatin secretion in islet physiology and pathophysiology.
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Affiliation(s)
- Mingyu Yang
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Kousik Mandal
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Moa Södergren
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Özge Dumral
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Lena Winroth
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Anders Tengholm
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
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Shukla S, Comerci CJ, Süel GM, Jahed Z. Bioelectronic tools for understanding the universal language of electrical signaling across species and kingdoms. Biosens Bioelectron 2025; 267:116843. [PMID: 39426280 DOI: 10.1016/j.bios.2024.116843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/10/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024]
Abstract
Modern bioelectronic tools are rapidly advancing to detect electric potentials within networks of electrogenic cells, such as cardiomyocytes, neurons, and pancreatic beta cells. However, it is becoming evident that electrical signaling is not limited to the animal kingdom but may be a universal form of cell-cell communication. In this review, we discuss the existing evidence of, and tools used to collect, subcellular, single-cell and network-level electrical signals across kingdoms, including bacteria, plants, fungi, and even viruses. We discuss how cellular networks employ altered electrical "circuitry" and intercellular mechanisms across kingdoms, and we assess the functionality and scalability of cutting-edge nanobioelectronics to collect electrical signatures regardless of cell size, shape, or function. Researchers today aim to design micro- and nano-topographic structures which harness mechanosensitive membrane and cytoskeletal pathways that enable tight electrical coupling to subcellular compartments within high-throughput recording systems. Finally, we identify gaps in current knowledge of inter-species and inter-kingdom electrical signaling and propose critical milestones needed to create a central theory of electrical signaling across kingdoms. Our discussion demonstrates the need for high resolution, high throughput tools which can probe multiple, diverse cell types at once in their native or experimentally-modeled environments. These advancements will not only reveal the underlying biophysical laws governing the universal language of electrical communication, but can enable bidirectional electrical communication and manipulation of biological systems.
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Affiliation(s)
- Shivani Shukla
- Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, United States; Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California San Diego, La Jolla, CA, United States
| | - Colin J Comerci
- Department of Molecular Biology, University of California San Diego, La Jolla, CA, United States
| | - Gürol M Süel
- Department of Molecular Biology, University of California San Diego, La Jolla, CA, United States
| | - Zeinab Jahed
- Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA, United States; Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California San Diego, La Jolla, CA, United States.
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5
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Hill TG, Gao R, Benrick A, Kothegala L, Rorsman N, Santos C, Acreman S, Briant LJ, Dou H, Gandasi NR, Guida C, Haythorne E, Wallace M, Knudsen JG, Miranda C, Tolö J, Clark A, Davison L, Størling J, Tarasov A, Ashcroft FM, Rorsman P, Zhang Q. Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes. Nat Metab 2024; 6:2070-2081. [PMID: 39313541 PMCID: PMC11599053 DOI: 10.1038/s42255-024-01139-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/30/2024] [Indexed: 09/25/2024]
Abstract
Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion1. In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D)2, which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D3. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists4-7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, KATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This 'electric brake' is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk8.
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Affiliation(s)
- Thomas G Hill
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Rui Gao
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Anna Benrick
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Lakshmi Kothegala
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
- Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru, India
| | - Nils Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Cristiano Santos
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Samuel Acreman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Linford J Briant
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Haiqiang Dou
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Nikhil R Gandasi
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
- Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru, India
| | - Claudia Guida
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Elizabeth Haythorne
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Marsha Wallace
- Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford, UK
- The Royal Veterinary College, Hatfield, Hertfordshire, UK
| | - Jakob G Knudsen
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Caroline Miranda
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Johan Tolö
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Anne Clark
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Lucy Davison
- Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford, UK
- The Royal Veterinary College, Hatfield, Hertfordshire, UK
| | - Joachim Størling
- Steno Diabetes Center Copenhagen, Translational Type 1 Diabetes Research, Herlev, Denmark
| | - Andrei Tarasov
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Frances M Ashcroft
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
- Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden.
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
- Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, UK.
| | - Quan Zhang
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
- Center for Neuroscience and Cell Biology (CNC), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
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Gangemi CG, Janovjak H. Optogenetics in Pancreatic Islets: Actuators and Effects. Diabetes 2024; 73:1566-1582. [PMID: 38976779 PMCID: PMC11417442 DOI: 10.2337/db23-1022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 06/19/2024] [Indexed: 07/10/2024]
Abstract
The islets of Langerhans reside within the endocrine pancreas as highly vascularized microorgans that are responsible for the secretion of key hormones, such as insulin and glucagon. Islet function relies on a range of dynamic molecular processes that include Ca2+ waves, hormone pulses, and complex interactions between islet cell types. Dysfunction of these processes results in poor maintenance of blood glucose homeostasis and is a hallmark of diabetes. Recently, the development of optogenetic methods that rely on light-sensitive molecular actuators has allowed perturbation of islet function with near physiological spatiotemporal acuity. These actuators harness natural photoreceptor proteins and their engineered variants to manipulate mouse and human cells that are not normally light-responsive. Until recently, optogenetics in islet biology has primarily focused on controlling hormone production and secretion; however, studies on further aspects of islet function, including paracrine regulation between islet cell types and dynamics within intracellular signaling pathways, are emerging. Here, we discuss the applicability of optogenetics to islets cells and comprehensively review seminal as well as recent work on optogenetic actuators and their effects in islet function and diabetes mellitus. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Christina G. Gangemi
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
- Australian Regenerative Medicine Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- European Molecular Biology Laboratory Australia, Monash University, Clayton, Victoria, Australia
| | - Harald Janovjak
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
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7
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Perez-Frances M, Bru-Tari E, Cohrs C, Abate MV, van Gurp L, Furuyama K, Speier S, Thorel F, Herrera PL. Regulated and adaptive in vivo insulin secretion from islets only containing β-cells. Nat Metab 2024; 6:1791-1806. [PMID: 39169271 PMCID: PMC11422169 DOI: 10.1038/s42255-024-01114-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/22/2024] [Indexed: 08/23/2024]
Abstract
Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-β-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ.
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Affiliation(s)
- Marta Perez-Frances
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Eva Bru-Tari
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Cohrs
- Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Maria Valentina Abate
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Léon van Gurp
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Kenichiro Furuyama
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Stephan Speier
- Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Fabrizio Thorel
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Pedro L Herrera
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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8
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Wang KY, Gao MX, Qi HB, An WT, Lin JY, Ning SL, Yang F, Xiao P, Cheng J, Pan W, Cheng QX, Wang J, Fang L, Sun JP, Yu X. Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells. Br J Pharmacol 2024; 181:2600-2621. [PMID: 38613153 DOI: 10.1111/bph.16351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 12/29/2023] [Accepted: 02/05/2024] [Indexed: 04/14/2024] Open
Abstract
BACKGROUND AND PURPOSE Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic β cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and β-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with β-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic β-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.
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Affiliation(s)
- Kai-Yu Wang
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Ming-Xin Gao
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Hai-Bo Qi
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wen-Tao An
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing-Yu Lin
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Shang-Lei Ning
- Department of Hepatobiliary Surgery, General surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Fan Yang
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Peng Xiao
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jie Cheng
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Pan
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Qiu-Xia Cheng
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jin Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Le Fang
- Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jin-Peng Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiao Yu
- Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China
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9
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Chen L, Wang N, Zhang T, Zhang F, Zhang W, Meng H, Chen J, Liao Z, Xu X, Ma Z, Xu T, Liu H. Directed differentiation of pancreatic δ cells from human pluripotent stem cells. Nat Commun 2024; 15:6344. [PMID: 39068220 PMCID: PMC11283558 DOI: 10.1038/s41467-024-50611-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 07/11/2024] [Indexed: 07/30/2024] Open
Abstract
Dysfunction of pancreatic δ cells contributes to the etiology of diabetes. Despite their important role, human δ cells are scarce, limiting physiological studies and drug discovery targeting δ cells. To date, no directed δ-cell differentiation method has been established. Here, we demonstrate that fibroblast growth factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic δ-cell lineage via FGF receptor 1. We develop a differentiation method to generate δ cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These δ cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress insulin secretion from in vitro co-cultured β cells and mouse β cells upon transplantation. The generation of human pancreatic δ cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes.
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Affiliation(s)
- Lihua Chen
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Nannan Wang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tongran Zhang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Feng Zhang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Wei Zhang
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Hao Meng
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Jingyi Chen
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China
| | - Zhiying Liao
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Xiaopeng Xu
- Guangzhou National Laboratory, Guangzhou, Guangdong, China
| | - Zhuo Ma
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Tao Xu
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China.
- Guangzhou National Laboratory, Guangzhou, Guangdong, China.
| | - Huisheng Liu
- School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China.
- Guangzhou National Laboratory, Guangzhou, Guangdong, China.
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China.
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10
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Noguchi GM, Castillo VC, Donaldson CJ, Flisher MR, Momen AT, Saghatelian A, Huising MO. Urocortin 3 contributes to paracrine inhibition of islet alpha cells in mice. J Endocrinol 2024; 261:e240018. [PMID: 38593829 PMCID: PMC11095665 DOI: 10.1530/joe-24-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 04/08/2024] [Indexed: 04/11/2024]
Abstract
Pancreatic alpha cell activity and glucagon secretion lower as glucose levels increase. While part of the decrease is regulated by glucose itself, paracrine signaling by their neighboring beta and delta cells also plays an important role. Somatostatin from delta cells is an important local inhibitor of alpha cells at high glucose. Additionally, urocortin 3 (UCN3) is a hormone that is co-released from beta cells with insulin and acts locally to potentiate somatostatin secretion from delta cells. UCN3 thus inhibits insulin secretion via a negative feedback loop with delta cells, but its role with respect to alpha cells and glucagon secretion is not understood. We hypothesize that the somatostatin-driven glucagon inhibition at high glucose is regulated in part by UCN3 from beta cells. Here, we use a combination of live functional Ca2+ and cAMP imaging as well as direct glucagon secretion measurement, all from alpha cells in intact mouse islets, to determine the contributions of UCN3 to alpha cell behavior. Exogenous UCN3 treatment decreased alpha cell Ca2+ and cAMP levels and inhibited glucagon release. Blocking endogenous UCN3 signaling increased alpha cell Ca2+ by 26.8 ± 7.6%, but this did not result in increased glucagon release at high glucose. Furthermore, constitutive deletion of Ucn3 did not increase Ca2+ activity or glucagon secretion relative to controls. UCN3 is thus capable of inhibiting mouse alpha cells, but, given the subtle effects of endogenous UCN3 signaling on alpha cells, we propose that UCN3-driven somatostatin may serve to regulate local paracrine glucagon levels in the islet instead of inhibiting gross systemic glucagon release.
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Affiliation(s)
- Glyn M. Noguchi
- Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, CA, USA
| | - Vincent C. Castillo
- Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, CA, USA
| | | | - Marcus R. Flisher
- Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, CA, USA
| | - Ariana T. Momen
- Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, CA, USA
| | | | - Mark O. Huising
- Department of Neurobiology, Physiology & Behavior, University of California Davis, Davis, CA, USA
- Department of Physiology & Membrane Biology, University of California Davis, Davis, CA, USA
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11
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Hill TG, Hill DJ. The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes. Int J Mol Sci 2024; 25:4070. [PMID: 38612880 PMCID: PMC11012451 DOI: 10.3390/ijms25074070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.
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Affiliation(s)
- Thomas G. Hill
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - David J. Hill
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada;
- Departments of Medicine, Physiology and Pharmacology, Western University, London, ON N6A 3K7, Canada
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12
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Bostancıklıoğlu M. Exploring new frontiers: Effects of psychedelics on neurotransmitter-regulated glucagon release in pancreatic islets. Diabetes Obes Metab 2024; 26:1147-1149. [PMID: 38093674 DOI: 10.1111/dom.15411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/23/2023] [Accepted: 11/28/2023] [Indexed: 03/05/2024]
Affiliation(s)
- Mehmet Bostancıklıoğlu
- Institute of Experimental and Clinical Research, Pole of Endocrinology, Diabetes and Nutrition, Université Catholique de Louvain, Brussels, Belgium
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13
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Villaca CBP, Mastracci TL. Pancreatic Crosstalk in the Disease Setting: Understanding the Impact of Exocrine Disease on Endocrine Function. Compr Physiol 2024; 14:5371-5387. [PMID: 39109973 PMCID: PMC11425433 DOI: 10.1002/cphy.c230008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.
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Affiliation(s)
| | - Teresa L Mastracci
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
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14
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Hoffman EG, D’Souza NC, Liggins RT, Riddell MC. Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes. Front Pharmacol 2024; 14:1295639. [PMID: 38298268 PMCID: PMC10829877 DOI: 10.3389/fphar.2023.1295639] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/13/2023] [Indexed: 02/02/2024] Open
Abstract
Glucose homeostasis is primarily maintained by pancreatic hormones, insulin and glucagon, with an emerging role for a third islet hormone, somatostatin, in regulating insulin and glucagon responses. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells inhibits both insulin and glucagon release through somatostatin receptor- induced cAMP-mediated downregulation and paracrine inhibition of β- and α-cells, respectively. Since glucagon is the body's most important anti-hypoglycemic hormone, and because glucagon counterregulation to hypoglycemia is lost in diabetes, the study of somatostatin biology has led to new investigational medications now in development that may help to restore glucagon counterregulation in type 1 diabetes. This review highlights the normal regulatory role of pancreatic somatostatin signaling in healthy islet function and how the inhibition of somatostatin receptor signaling in pancreatic α-cells may restore normal glucagon counterregulation in diabetes mellitus.
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Affiliation(s)
- Emily G. Hoffman
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Ninoschka C. D’Souza
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | | | - Michael C. Riddell
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
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15
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Félix-Martínez GJ, Godínez-Fernández JR. A primer on modelling pancreatic islets: from models of coupled β-cells to multicellular islet models. Islets 2023; 15:2231609. [PMID: 37415423 PMCID: PMC10332213 DOI: 10.1080/19382014.2023.2231609] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/27/2023] [Indexed: 07/08/2023] Open
Abstract
Pancreatic islets are mini-organs composed of hundreds or thousands of ɑ, β and δ-cells, which, respectively, secrete glucagon, insulin and somatostatin, key hormones for the regulation of blood glucose. In pancreatic islets, hormone secretion is tightly regulated by both internal and external mechanisms, including electrical communication and paracrine signaling between islet cells. Given its complexity, the experimental study of pancreatic islets has been complemented with computational modeling as a tool to gain a better understanding about how all the mechanisms involved at different levels of organization interact. In this review, we describe how multicellular models of pancreatic cells have evolved from the early models of electrically coupled β-cells to models in which experimentally derived architectures and both electrical and paracrine signals have been considered.
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Affiliation(s)
- Gerardo J. Félix-Martínez
- Investigador por México CONAHCYT-Department of Electrical Engineering, Universidad Autónoma Metropolitana, Mexico, Mexico
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Mexico, Mexico
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16
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Briggs JK, Gresch A, Marinelli I, Dwulet JM, Albers DJ, Kravets V, Benninger RKP. β-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network. eLife 2023; 12:e83147. [PMID: 38018905 PMCID: PMC10803032 DOI: 10.7554/elife.83147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/27/2023] [Indexed: 11/30/2023] Open
Abstract
Diabetes is caused by the inability of electrically coupled, functionally heterogeneous β-cells within the pancreatic islet to provide adequate insulin secretion. Functional networks have been used to represent synchronized oscillatory [Ca2+] dynamics and to study β-cell subpopulations, which play an important role in driving islet function. The mechanism by which highly synchronized β-cell subpopulations drive islet function is unclear. We used experimental and computational techniques to investigate the relationship between functional networks, structural (gap junction) networks, and intrinsic β-cell dynamics in slow and fast oscillating islets. Highly synchronized subpopulations in the functional network were differentiated by intrinsic dynamics, including metabolic activity and KATP channel conductance, more than structural coupling. Consistent with this, intrinsic dynamics were more predictive of high synchronization in the islet functional network as compared to high levels of structural coupling. Finally, dysfunction of gap junctions, which can occur in diabetes, caused decreases in the efficiency and clustering of the functional network. These results indicate that intrinsic dynamics rather than structure drive connections in the functional network and highly synchronized subpopulations, but gap junctions are still essential for overall network efficiency. These findings deepen our interpretation of functional networks and the formation of functional subpopulations in dynamic tissues such as the islet.
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Affiliation(s)
- Jennifer K Briggs
- Department of Bioengineering, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Anne Gresch
- Department of Bioengineering, University of Colorado Anschutz Medical CampusAuroraUnited States
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Isabella Marinelli
- Centre for Systems Modelling and Quantitative Biomedicine, University of BirminghamBirminghamUnited Kingdom
| | - JaeAnn M Dwulet
- Department of Bioengineering, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - David J Albers
- Department of Bioengineering, University of Colorado Anschutz Medical CampusAuroraUnited States
- Department of Biomedical Informatics, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Vira Kravets
- Department of Bioengineering, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Richard KP Benninger
- Department of Bioengineering, University of Colorado Anschutz Medical CampusAuroraUnited States
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical CampusAuroraUnited States
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17
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Zhang J, Katada K, Mosleh E, Yuhas A, Peng G, Golson ML. The leptin receptor has no role in delta-cell control of beta-cell function in the mouse. Front Endocrinol (Lausanne) 2023; 14:1257671. [PMID: 37850099 PMCID: PMC10577419 DOI: 10.3389/fendo.2023.1257671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 09/05/2023] [Indexed: 10/19/2023] Open
Abstract
Introduction Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Several mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) throughout the pancreatic epithelium results in altered glucose homeostasis and ex vivo insulin secretion and Ca2+ dynamics. However, Lepr removal from neither alpha nor beta cells mimics this result. Moreover, scRNAseq data has revealed an enrichment of LEPR in human islet delta cells. Methods We confirmed LEPR upregulation in human delta cells by performing RNAseq on fixed, sorted beta and delta cells. We then used a mouse model to test whether delta cells mediate the diminished glucose-stimulated insulin secretion in response to leptin. Results Ablation of Lepr within mouse delta cells did not change glucose homeostasis or insulin secretion, whether mice were fed a chow or high-fat diet. We further show, using a publicly available scRNAseq dataset, that islet cells expressing Lepr lie within endothelial cell clusters. Conclusions In mice, leptin does not influence beta-cell function through delta cells.
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Affiliation(s)
- Jia Zhang
- Department of Genetics, University of Pennsylvania, Philadephia, PA, United States
| | - Kay Katada
- School of Medicine, University of Pennsylvania, Philadephia, PA, United States
| | - Elham Mosleh
- Department of Genetics, University of Pennsylvania, Philadephia, PA, United States
- School of Medicine, University of Pennsylvania, Philadephia, PA, United States
| | - Andrew Yuhas
- Department of Genetics, University of Pennsylvania, Philadephia, PA, United States
- School of Medicine, University of Pennsylvania, Philadephia, PA, United States
| | - Guihong Peng
- Department of Medicine, Divison of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University, Baltimore, MD, United States
| | - Maria L. Golson
- Department of Genetics, University of Pennsylvania, Philadephia, PA, United States
- School of Medicine, University of Pennsylvania, Philadephia, PA, United States
- Department of Medicine, Divison of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University, Baltimore, MD, United States
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18
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Luchetti N, Filippi S, Loppini A. Multilevel synchronization of human β-cells networks. FRONTIERS IN NETWORK PHYSIOLOGY 2023; 3:1264395. [PMID: 37808419 PMCID: PMC10557430 DOI: 10.3389/fnetp.2023.1264395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/08/2023] [Indexed: 10/10/2023]
Abstract
β-cells within the endocrine pancreas are fundamental for glucose, lipid and protein homeostasis. Gap junctions between cells constitute the primary coupling mechanism through which cells synchronize their electrical and metabolic activities. This evidence is still only partially investigated through models and numerical simulations. In this contribution, we explore the effect of combined electrical and metabolic coupling in β-cell clusters using a detailed biophysical model. We add heterogeneity and stochasticity to realistically reproduce β-cell dynamics and study networks mimicking arrangements of β-cells within human pancreatic islets. Model simulations are performed over different couplings and heterogeneities, analyzing emerging synchronization at the membrane potential, calcium, and metabolites levels. To describe network synchronization, we use the formalism of multiplex networks and investigate functional network properties and multiplex synchronization motifs over the structural, electrical, and metabolic layers. Our results show that metabolic coupling can support slow wave propagation in human islets, that combined electrical and metabolic synchronization is realized in small aggregates, and that metabolic long-range correlation is more pronounced with respect to the electrical one.
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Affiliation(s)
- Nicole Luchetti
- Center for Life Nano and Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy
- Engineering Department, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Simonetta Filippi
- Engineering Department, Università Campus Bio-Medico di Roma, Rome, Italy
- National Institute of Optics, National Research Council, Florence, Italy
- International Center for Relativistic Astrophysics Network, Pescara, Italy
| | - Alessandro Loppini
- Center for Life Nano and Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy
- Engineering Department, Università Campus Bio-Medico di Roma, Rome, Italy
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19
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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20
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Brown A, Tzanakakis ES. Mathematical modeling clarifies the paracrine roles of insulin and glucagon on the glucose-stimulated hormonal secretion of pancreatic alpha- and beta-cells. Front Endocrinol (Lausanne) 2023; 14:1212749. [PMID: 37645413 PMCID: PMC10461634 DOI: 10.3389/fendo.2023.1212749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/21/2023] [Indexed: 08/31/2023] Open
Abstract
Introduction Blood sugar homeostasis relies largely on the action of pancreatic islet hormones, particularly insulin and glucagon. In a prototypical fashion, glucagon is released upon hypoglycemia to elevate glucose by acting on the liver while elevated glucose induces the secretion of insulin which leads to sugar uptake by peripheral tissues. This simplified view of glucagon and insulin does not consider the paracrine roles of the two hormones modulating the response to glucose of α- and β-cells. In particular, glucose-stimulated glucagon secretion by isolated α-cells exhibits a Hill-function pattern, while experiments with intact pancreatic islets suggest a 'U'-shaped response. Methods To this end, a framework was developed based on first principles and coupled to experimental studies capturing the glucose-induced response of pancreatic α- and β-cells influenced by the two hormones. The model predicts both the transient and steady-state profiles of secreted insulin and glucagon, including the typical biphasic response of normal β-cells to hyperglycemia. Results and discussion The results underscore insulin activity as a differentiating factor of the glucagon secretion from whole islets vs. isolated α-cells, and highlight the importance of experimental conditions in interpreting the behavior of islet cells in vitro. The model also reproduces the hyperglucagonemia, which is experienced by diabetes patients, and it is linked to a failure of insulin to inhibit α-cell activity. The framework described here is amenable to the inclusion of additional islet cell types and extrapancreatic tissue cells simulating multi-organ systems. The study expands our understanding of the interplay of insulin and glucagon for pancreas function in normal and pathological conditions.
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Affiliation(s)
- Aedan Brown
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States
| | - Emmanuel S. Tzanakakis
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States
- Genetics, Molecular and Cellular Biology, Tufts University, Boston, MA, United States
- Pharmacology and Drug Development, Tufts University, Boston, MA, United States
- Clinical and Translational Science Institute, Tufts University, Boston, MA, United States
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21
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Deepa Maheshvare M, Raha S, König M, Pal D. A pathway model of glucose-stimulated insulin secretion in the pancreatic β-cell. Front Endocrinol (Lausanne) 2023; 14:1185656. [PMID: 37600713 PMCID: PMC10433753 DOI: 10.3389/fendo.2023.1185656] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/08/2023] [Indexed: 08/22/2023] Open
Abstract
The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic β-cell is the main mechanism for reducing elevated plasma glucose. Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). Steps include retrieval of information from databases, curation of experimental and clinical data for model calibration and validation, integration of heterogeneous data including absolute and relative measurements, unit normalization, data normalization, and model annotation. An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools. The workflow was applied to construct a novel data-driven kinetic model of GSIS in the pancreatic β-cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and β-cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and phenomenological equations for insulin secretion coupled to cellular energy state, ATP dynamics and (ATP/ADP ratio). Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the β-cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion. The observed glucose-dependent increase in glycolytic intermediates and the resulting change in ATP/ADP ratios and insulin secretion is a robust phenomenon observed across data sets, experimental systems and species. Model predictions of the glucose-dependent response of glycolytic intermediates and biphasic insulin secretion are in good agreement with experimental measurements. Our model predicts that factors affecting ATP consumption, ATP formation, hexokinase, phosphofructokinase, and ATP/ADP-dependent insulin secretion have a major effect on GSIS. In conclusion, we have developed and applied a systematic modeling workflow for pathway models that allowed us to gain insight into key mechanisms in GSIS in the pancreatic β-cell.
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Affiliation(s)
- M. Deepa Maheshvare
- Department of Computational and Data Sciences, Indian Institute of Science, Bangalore, India
| | - Soumyendu Raha
- Department of Computational and Data Sciences, Indian Institute of Science, Bangalore, India
| | - Matthias König
- Institute for Biology, Institute for Theoretical Biology, Humboldt-University Berlin, Berlin, Germany
| | - Debnath Pal
- Department of Computational and Data Sciences, Indian Institute of Science, Bangalore, India
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22
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Hamilton A, Eliasson L, Knudsen JG. Amino acids and the changing face of the α-cell. Peptides 2023:171039. [PMID: 37295651 DOI: 10.1016/j.peptides.2023.171039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/31/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
Glucagon has long been defined by its glucogenic action and as a result α-cells have been characterised based largely on their interaction with glucose. Recent findings have challenged this preconception, bringing to the fore the significant role glucagon plays in amino acid breakdown and underlining the importance of amino acids in glucagon secretion. The challenge that remains is defining the mechanism that underlie these effects - understanding which amino acids are most important, how they act on the α-cell and how their actions integrate with other fuels such as glucose and fatty acids. This review will describe the current relationship between amino acids and glucagon and how we can use this knowledge to redefine the α-cell.
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Affiliation(s)
- Alexander Hamilton
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Denmark; Department of Clinical Sciences in Malmö, Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Malmö, Sweden.
| | - Lena Eliasson
- Department of Clinical Sciences in Malmö, Islet Cell Exocytosis, Lund University Diabetes Centre, Lund University, Malmö, Sweden.
| | - Jakob G Knudsen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Denmark.
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23
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Fu Q, Jiang H, Qian Y, Lv H, Dai H, Zhou Y, Chen Y, He Y, Gao R, Zheng S, Liang Y, Li S, Xu X, Xu K, Yang T. Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice. Diabetologia 2023; 66:724-740. [PMID: 36538064 PMCID: PMC9765371 DOI: 10.1007/s00125-022-05849-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 10/13/2022] [Indexed: 12/24/2022]
Abstract
AIMS/HYPOTHESIS Islets have complex heterogeneity and subpopulations. Cell surface markers representing alpha, beta and delta cell subpopulations are urgently needed for investigations to explore the compositional changes of each subpopulation in obesity progress and diabetes onset, and the adaptation mechanism of islet metabolism induced by a high-fat diet (HFD). METHODS Single-cell RNA sequencing (scRNA-seq) was applied to identify alpha, beta and delta cell subpopulation markers in an HFD-induced mouse model of glucose intolerance. Flow cytometry and immunostaining were used to sort and assess the proportion of each subpopulation. Single-cell proteomics was performed on sorted cells, and the functional status of each alpha, beta and delta cell subpopulation in glucose intolerance was deeply elucidated based on protein expression. RESULTS A total of 33,999 cells were analysed by scRNA-seq and clustered into eight populations, including alpha, beta and delta cells. For alpha cells, scRNA-seq revealed that the Ace2low subpopulation had downregulated expression of genes related to alpha cell function and upregulated expression of genes associated with beta cell characteristics in comparison with the Ace2high subpopulation. The impaired function and increased fragility of ACE2low alpha cells exposure to HFD was further suggested by single-cell proteomics. As for beta cells, the CD81high subpopulation may indicate an immature signature of beta cells compared with the CD81low subpopulation, which had robust function. We also found differential expression of Slc2a2 in delta cells and a potentially stronger cellular function and metabolism in GLUT2low delta cells than GLUT2high delta cells. Moreover, an increased proportion of ACE2low alpha cells and CD81low beta cells, with a constant proportion of GLUT2low delta cells, were observed in HFD-induced glucose intolerance. CONCLUSIONS/INTERPRETATION We identified ACE2, CD81 and GLUT2 as surface markers to distinguish, respectively, alpha, beta and delta cell subpopulations with heterogeneous maturation and function. The changes in the proportion and functional status of islet endocrine subpopulations reflect the metabolic adaptation of islets to high-fat stress, which weakened the function of alpha cells and enhanced the function of beta and delta cells to bring about glycaemic homeostasis. Our findings provide a fundamental resource for exploring the mechanisms maintaining each islet endocrine subpopulation's fate and function in health and disease. DATA AVAILABILITY The scRNA-seq analysis datasets from the current study are available in the Gene Expression Omnibus (GEO) repository under the accession number GSE203376.
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Affiliation(s)
- Qi Fu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hemin Jiang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yu Qian
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Lv
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hao Dai
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuncai Zhou
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yunqiang He
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Gao
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuai Zheng
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yucheng Liang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Siqi Li
- BGI-Shenzhen, Shenzhen, China
- BGI-Wuhan Clinical Laboratories, BGI-Shenzhen, Wuhan, China
| | - Xinyu Xu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kuanfeng Xu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Tao Yang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Kalwat MA, Rodrigues-dos-Santos K, Binns DD, Wei S, Zhou A, Evans MR, Posner BA, Roth MG, Cobb MH. Small molecule glucagon release inhibitors with activity in human islets. Front Endocrinol (Lausanne) 2023; 14:1114799. [PMID: 37152965 PMCID: PMC10157210 DOI: 10.3389/fendo.2023.1114799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 04/07/2023] [Indexed: 05/09/2023] Open
Abstract
Purpose Type 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting pancreatic islet β-cells are destroyed by the immune system, but glucagon-secreting islet α-cells survive. These remaining α-cells no longer respond properly to fluctuating blood glucose concentrations. Dysregulated α-cell function contributes to hyper- and hypoglycemia which can lead to macrovascular and microvascular complications. To this end, we sought to discover small molecules that suppress α-cell function for their potential as preclinical candidate compounds. Prior high-throughput screening identified a set of glucagon-suppressing compounds using a rodent α-cell line model, but these compounds were not validated in human systems. Results Here, we dissociated and replated primary human islet cells and exposed them to 24 h treatment with this set of candidate glucagon-suppressing compounds. Glucagon accumulation in the medium was measured and we determined that compounds SW049164 and SW088799 exhibited significant activity. Candidate compounds were also counter-screened in our InsGLuc-MIN6 β-cell insulin secretion reporter assay. SW049164 and SW088799 had minimal impact on insulin release after a 24 h exposure. To further validate these hits, we treated intact human islets with a selection of the top candidates for 24 h. SW049164 and SW088799 significantly inhibited glucagon release into the medium without significantly altering whole islet glucagon or insulin content. In concentration-response curves SW088799 exhibited significant inhibition of glucagon release with an IC50 of 1.26 µM. Conclusion Given the set of tested candidates were all top hits from the primary screen in rodent α-cells, this suggests some conservation of mechanism of action between human and rodents, at least for SW088799. Future structure-activity relationship studies of SW088799 may aid in elucidating its protein target(s) or enable its use as a tool compound to suppress α-cell activity in vitro.
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Affiliation(s)
- Michael A. Kalwat
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN, United States
- Indiana University School of Medicine, Center for Diabetes and Metabolic Diseases, Indianapolis, IN, United States
- *Correspondence: Michael A. Kalwat, ;
| | - Karina Rodrigues-dos-Santos
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN, United States
| | - Derk D. Binns
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Shuguang Wei
- Department Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Anwu Zhou
- Department Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Matthew R. Evans
- Department Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Bruce A. Posner
- Department Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Michael G. Roth
- Department Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Melanie H. Cobb
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, United States
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25
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Abstract
The islets of Langerhans are highly organized structures that have species-specific, three-dimensional tissue architecture. Islet architecture is critical for proper hormone secretion in response to nutritional stimuli. Islet architecture is disrupted in all types of diabetes mellitus and in cadaveric islets for transplantation during isolation, culture, and perfusion, limiting patient outcomes. Moreover, recapitulating native islet architecture remains a key challenge for in vitro generation of islets from stem cells. In this review, we discuss work that has led to the current understanding of determinants of pancreatic islet architecture, and how this architecture is maintained or disrupted during tissue remodeling in response to normal and pathological metabolic changes. We further discuss both empirical and modeling data that highlight the importance of islet architecture for islet function.
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Affiliation(s)
- Melissa T. Adams
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Barak Blum
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA
- CONTACT Barak Blum Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI53705, USA
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26
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Abstract
Glucagon hypersecretion from the pancreatic α-cell is a characteristic sign of diabetes, which exacerbates fasting hyperglycemia. Thus, targeting glucagon secretion from α-cells may be a promising approach for combating hyperglucagonemia. We have recently identified stathmin-2 as an α-cell protein that regulates glucagon secretion by directing glucagon toward the endolysosomal system in αTC1-6 cells. We hypothesized that disruption of Stmn2-mediated trafficking of glucagon to the endolysosomes in diabetes contributes to hyperglucagonemia. In isolated islets from male mice treated with streptozotocin (STZ), glucagon secretion and cellular content were augmented, but cellular Stmn2 levels were reduced (p < .01), as measured by both ELISA and immunofluorescence intensity. Using confocal immunofluorescence microscopy, the colocalization of glucagon and Stmn2 in Lamp2A+ lysosomes was dramatically reduced (p < .001) in islets from diabetic mice, and the colocalization of Stmn2, but not glucagon, with the late endosome marker, Rab7, significantly (p < .01) increased. Further studies were conducted in αTC1-6 cells cultured in media containing high glucose (16.7 mM) for 2 weeks to mimic glucagon hypersecretion of diabetes. Surprisingly, treatment of αTC1-6 cells with the lysosomal inhibitor bafilomycin A1 reduced K+-induced glucagon secretion, suggesting that high glucose may induce glucagon secretion from another lysosomal compartment. Both glucagon and Stmn2 co-localized with Lamp1, which marks secretory lysosomes, in cells cultured in high glucose. We propose that, in addition to enhanced trafficking and secretion through the regulated secretory pathway, the hyperglucagonemia of diabetes may also be due to re-routing of glucagon from the degradative Lamp2A+ lysosome toward the secretory Lamp1+ lysosome.
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Affiliation(s)
- Farzad Asadi
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Savita Dhanvantari
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
- Department of Medical Biophysics, Western University, London, ON, Canada
- Metabolism & Diabetes and Imaging Programs, Lawson Health Research Institute, London, ON, Canada
- CONTACT Savita Dhanvantari Lawson Health Research Institute, PO Box 5777, Stn B, London, ONN6A 4V2, Canada
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27
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Brüning D, Morsi M, Früh E, Scherneck S, Rustenbeck I. Metabolic Regulation of Hormone Secretion in Beta-Cells and Alpha-Cells of Female Mice: Fundamental Differences. Endocrinology 2022; 163:6656576. [PMID: 35931024 DOI: 10.1210/endocr/bqac125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Indexed: 11/19/2022]
Abstract
It is unclear whether the secretion of glucagon is regulated by an alpha-cell-intrinsic mechanism and whether signal recognition by the mitochondrial metabolism plays a role in it. To measure changes of the cytosolic ATP/ADP ratio, single alpha-cells and beta-cells from NMRI mice were adenovirally transduced with the fluorescent indicator PercevalHR. The cytosolic Ca2+ concentration ([Ca2+]i) was measured by use of Fura2 and the mitochondrial membrane potential by use of TMRE. Perifused islets were used to measure the secretion of glucagon and insulin. At 5 mM glucose, the PercevalHR ratio in beta-cells was significantly lower than in alpha-cells. Lowering glucose to 1 mM decreased the ratio to 69% within 10 minutes in beta-cells, but only to 94% in alpha-cells. In this situation, 30 mM glucose, 10 mM alpha-ketoisocaproic acid, and 10 mM glutamine plus 10 mM BCH (a nonmetabolizable leucine analogue) markedly increased the PercevalHR ratio in beta-cells. In alpha-cells, only glucose was slightly effective. However, none of the nutrients increased the mitochondrial membrane potential in alpha-cells, whereas all did so in beta-cells. The kinetics of the PercevalHR increase were reflected by the kinetics of [Ca2+]i. increase in the beta-cells and insulin secretion. Glucagon secretion was markedly increased by washing out the nutrients with 1 mM glucose, but not by reducing glucose from 5 mM to 1 mM. This pattern was still recognizable when the insulin secretion was strongly inhibited by clonidine. It is concluded that mitochondrial energy metabolism is a signal generator in pancreatic beta-cells, but not in alpha-cells.
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Affiliation(s)
- Dennis Brüning
- Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, D 38106 Braunschweig, Germany
| | - Mai Morsi
- Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, D 38106 Braunschweig, Germany
- Department of Pharmacology, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
| | - Eike Früh
- Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, D 38106 Braunschweig, Germany
| | - Stephan Scherneck
- Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, D 38106 Braunschweig, Germany
| | - Ingo Rustenbeck
- Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, D 38106 Braunschweig, Germany
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28
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Sridhar A, Khan D, Abdelaal M, Elliott JA, Naughton V, Flatt PR, Le Roux CW, Docherty NG, Moffett CR. Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats. PLoS One 2022; 17:e0274788. [PMID: 36137097 PMCID: PMC9499270 DOI: 10.1371/journal.pone.0274788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/05/2022] [Indexed: 11/19/2022] Open
Abstract
Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission.
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Affiliation(s)
- Ananyaa Sridhar
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Dawood Khan
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
- * E-mail:
| | - Mahmoud Abdelaal
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Jessie A. Elliott
- Department of Surgery, Trinity Centre for Health Sciences and St. James’s Hospital, Dublin, Ireland
| | - Violetta Naughton
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Peter R. Flatt
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Carel W. Le Roux
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Neil G. Docherty
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Charlotte R. Moffett
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
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29
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Subramanian V, Bagger JI, Holst JJ, Knop FK, Vilsbøll T. A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment. Front Physiol 2022; 13:911616. [PMID: 36148302 PMCID: PMC9485803 DOI: 10.3389/fphys.2022.911616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6-36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)-1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)-1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (-0.79, 0.002), (-0.73,.007), (-0.86,.0003)) respectively).
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Affiliation(s)
- Vijaya Subramanian
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Jonatan I. Bagger
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Jens J. Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K. Knop
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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30
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Zaborska KE, Jordan KL, Thorson AS, Dadi PK, Schaub CM, Nakhe AY, Dickerson MT, Lynch JC, Weiss AJ, Dobson JR, Jacobson DA. Liraglutide increases islet Ca 2+ oscillation frequency and insulin secretion by activating hyperpolarization-activated cyclic nucleotide-gated channels. Diabetes Obes Metab 2022; 24:1741-1752. [PMID: 35546791 PMCID: PMC9843726 DOI: 10.1111/dom.14747] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 01/19/2023]
Abstract
AIM To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca2+ handling and insulin secretion. METHODS The impact of liraglutide (GLP-1 analogue) on islet Ca2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated β-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or β cells. RESULTS Liraglutide increased β-cell Ca2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased β-cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to β cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in β-cell Ca2+ oscillation frequency, β-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca2+ oscillations. CONCLUSION The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with β-cell Ca2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a β-cell-dependent manner.
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Affiliation(s)
- Karolina E Zaborska
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Kelli L Jordan
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Ariel S Thorson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Prasanna K Dadi
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Charles M Schaub
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Arya Y Nakhe
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Matthew T Dickerson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Joshua C Lynch
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Adam J Weiss
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Jordyn R Dobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - David A Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
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31
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Ren H, Li Y, Han C, Yu Y, Shi B, Peng X, Zhang T, Wu S, Yang X, Kim S, Chen L, Tang C. Pancreatic α and β cells are globally phase-locked. Nat Commun 2022; 13:3721. [PMID: 35764654 PMCID: PMC9240067 DOI: 10.1038/s41467-022-31373-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 06/15/2022] [Indexed: 11/25/2022] Open
Abstract
The Ca2+ modulated pulsatile glucagon and insulin secretions by pancreatic α and β cells play a crucial role in glucose homeostasis. However, how α and β cells coordinate to produce various Ca2+ oscillation patterns is still elusive. Using a microfluidic device and transgenic mice, we recorded Ca2+ signals from islet α and β cells, and observed heterogeneous Ca2+ oscillation patterns intrinsic to each islet. After a brief period of glucose stimulation, α and β cells’ oscillations were globally phase-locked. While the activation of α cells displayed a fixed time delay of ~20 s to that of β cells, β cells activated with a tunable period. Moreover, islet α cell number correlated with oscillation frequency. We built a mathematical model of islet Ca2+ oscillation incorporating paracrine interactions, which quantitatively agreed with the experimental data. Our study highlights the importance of cell-cell interaction in generating stable but tunable islet oscillation patterns. The Ca2+ modulated pulsatile glucagon and insulin secretions by pancreatic α and β cells are critical in glucose homeostasis. Here the authors show that the Ca2+ oscillations of α and β cells are phase-locked, and that the oscillation pattern is tuned by paracrine interactions between α and β cells.
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Affiliation(s)
- Huixia Ren
- Center for Quantitative Biology, Peking University, Beijing, 100871, China.,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Yanjun Li
- Center for Quantitative Biology, Peking University, Beijing, 100871, China.,Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, 100871, China
| | - Chengsheng Han
- Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, 100871, China
| | - Yi Yu
- Center for Quantitative Biology, Peking University, Beijing, 100871, China
| | - Bowen Shi
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Xiaohong Peng
- Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, 100871, China
| | - Tianming Zhang
- Yuanpei College, Peking University, Beijing, 100871, China
| | - Shufang Wu
- Center for Quantitative Biology, Peking University, Beijing, 100871, China
| | - Xiaojing Yang
- Center for Quantitative Biology, Peking University, Beijing, 100871, China.,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China
| | - Sneppen Kim
- Niels Bohr Institute, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Liangyi Chen
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. .,Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, 100871, China.
| | - Chao Tang
- Center for Quantitative Biology, Peking University, Beijing, 100871, China. .,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
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Tudurí E, Soriano S, Almagro L, Montanya E, Alonso-Magdalena P, Nadal Á, Quesada I. The pancreatic β-cell in ageing: Implications in age-related diabetes. Ageing Res Rev 2022; 80:101674. [PMID: 35724861 DOI: 10.1016/j.arr.2022.101674] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/07/2022] [Accepted: 06/14/2022] [Indexed: 11/15/2022]
Abstract
The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt β-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity. However, a precise understanding of the pancreatic β-cell response in ageing is still lacking. In this review, we summarize the age-related alterations, adaptations and/or failures of β-cells at the molecular, morphological and functional levels in mouse and human. Age-associated alterations include processes such as β-cell proliferation, apoptosis and cell identity that can influence β-cell mass. Age-related changes also affect β-cell function at distinct steps including electrical activity, Ca2+ signaling and insulin secretion, among others. We will consider the potential impact of these alterations and those mediated by senescence pathways on β-cells and their implications in age-related T2D. Finally, given the great diversity of results in the field of β-cell ageing, we will discuss the sources of this heterogeneity. A better understanding of β-cell biology during ageing, particularly at older ages, will improve our insight into the contribution of β-cells to age-associated T2D and may boost new therapeutic strategies.
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Affiliation(s)
- Eva Tudurí
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain; Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
| | - Sergi Soriano
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Lucía Almagro
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain
| | - Eduard Montanya
- Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain; Department of Clinical Sciences, University of Barcelona, Barcelona, Spain; Bellvitge Hospital-IDIBELL, Barcelona, Spain, University of Barcelona, Barcelona, Spain
| | - Paloma Alonso-Magdalena
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Ángel Nadal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Ivan Quesada
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
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Stožer A, Šterk M, Paradiž Leitgeb E, Markovič R, Skelin Klemen M, Ellis CE, Križančić Bombek L, Dolenšek J, MacDonald PE, Gosak M. From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science. Front Endocrinol (Lausanne) 2022; 13:922640. [PMID: 35784543 PMCID: PMC9240343 DOI: 10.3389/fendo.2022.922640] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
Islets of Langerhans are multicellular microorgans located in the pancreas that play a central role in whole-body energy homeostasis. Through secretion of insulin and other hormones they regulate postprandial storage and interprandial usage of energy-rich nutrients. In these clusters of hormone-secreting endocrine cells, intricate cell-cell communication is essential for proper function. Electrical coupling between the insulin-secreting beta cells through gap junctions composed of connexin36 is particularly important, as it provides the required, most important, basis for coordinated responses of the beta cell population. The increasing evidence that gap-junctional communication and its modulation are vital to well-regulated secretion of insulin has stimulated immense interest in how subpopulations of heterogeneous beta cells are functionally arranged throughout the islets and how they mediate intercellular signals. In the last decade, several novel techniques have been proposed to assess cooperation between cells in islets, including the prosperous combination of multicellular imaging and network science. In the present contribution, we review recent advances related to the application of complex network approaches to uncover the functional connectivity patterns among cells within the islets. We first provide an accessible introduction to the basic principles of network theory, enumerating the measures characterizing the intercellular interactions and quantifying the functional integration and segregation of a multicellular system. Then we describe methodological approaches to construct functional beta cell networks, point out possible pitfalls, and specify the functional implications of beta cell network examinations. We continue by highlighting the recent findings obtained through advanced multicellular imaging techniques supported by network-based analyses, giving special emphasis to the current developments in both mouse and human islets, as well as outlining challenges offered by the multilayer network formalism in exploring the collective activity of islet cell populations. Finally, we emphasize that the combination of these imaging techniques and network-based analyses does not only represent an innovative concept that can be used to describe and interpret the physiology of islets, but also provides fertile ground for delineating normal from pathological function and for quantifying the changes in islet communication networks associated with the development of diabetes mellitus.
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Affiliation(s)
- Andraž Stožer
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Marko Šterk
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Eva Paradiž Leitgeb
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Rene Markovič
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
- Institute of Mathematics and Physics, Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia
| | - Maša Skelin Klemen
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Cara E. Ellis
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | | | - Jurij Dolenšek
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Patrick E. MacDonald
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Marko Gosak
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Department of Physics, Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
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Farhat R, Aiken J, D'Souza NC, Appadurai D, Hull G, Simonson E, Liggins RT, Riddell MC, Chan O. ZT-01: A novel somatostatin receptor 2 antagonist for restoring the glucagon response to hypoglycaemia in type 1 diabetes. Diabetes Obes Metab 2022; 24:908-917. [PMID: 35060297 DOI: 10.1111/dom.14652] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/02/2022] [Accepted: 01/16/2022] [Indexed: 01/17/2023]
Abstract
AIM To evaluate the pharmacokinetics and efficacy of a novel somatostatin receptor 2 antagonist, ZT-01, to stimulate glucagon release in rats with type 1 diabetes (T1D). METHODS The pharmacokinetics of ZT-01 and PRL-2903 were assessed following intraperitoneal or subcutaneous dosing at 10 mg/kg. We compared the efficacy of ZT-01 with PRL-2903 to prevent hypoglycaemia during an insulin bolus challenge and under hypoglycaemic clamp conditions. RESULTS Within 1 hour after intraperitoneal administration, ZT-01 achieved more than 10-fold higher plasma Cmax compared with PRL-2903. Twenty-four hour exposure was 4.7× and 11.3× higher with ZT-01 by the intraperitoneal and subcutaneous routes, respectively. The median time to reach hypoglycaemia of more than 3.0 mmol/L was 60, 70, and 125 minutes following vehicle, PRL-2903, or ZT-01 administration, respectively. Furthermore, rats receiving ZT-01 had significantly higher glucose nadirs following insulin administration compared with PRL-2903- and vehicle-treated rats. During the hypoglycaemic clamp, ZT-01 increased peak glucagon responses by ~4-fold over PRL-2903. CONCLUSIONS We conclude that ZT-01 may be effective in restoring glucagon responses and preventing the onset of hypoglycaemia in patients with T1D.
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Affiliation(s)
- Rawad Farhat
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA
| | - Julian Aiken
- School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
| | - Ninoschka C D'Souza
- School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
| | - Daniel Appadurai
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA
| | - Grayson Hull
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA
| | - Eric Simonson
- Zucara Therapeutics, Vancouver, British Columbia, Canada
| | | | - Michael C Riddell
- School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
- Zucara Therapeutics, Vancouver, British Columbia, Canada
| | - Owen Chan
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA
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Honzawa N, Fujimoto K, Kobayashi M, Kohno D, Kikuchi O, Yokota-Hashimoto H, Wada E, Ikeuchi Y, Tabei Y, Dorn GW, Utsunomiya K, Nishimura R, Kitamura T. Protein Kinase C (Pkc)-δ Mediates Arginine-Induced Glucagon Secretion in Pancreatic α-Cells. Int J Mol Sci 2022; 23:4003. [PMID: 35409362 PMCID: PMC8999522 DOI: 10.3390/ijms23074003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 03/28/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.
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Affiliation(s)
- Norikiyo Honzawa
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan; (N.H.); (K.U.); (R.N.)
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Kei Fujimoto
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University Daisan Hospital, 4-11-1, Izumihoncho, Komae-shi, Tokyo 201-8601, Japan
| | - Masaki Kobayashi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Daisuke Kohno
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Osamu Kikuchi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Hiromi Yokota-Hashimoto
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Eri Wada
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Yuichi Ikeuchi
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Yoko Tabei
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
| | - Gerald W. Dorn
- Center for Pharmacogenomics, Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Kazunori Utsunomiya
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan; (N.H.); (K.U.); (R.N.)
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan; (N.H.); (K.U.); (R.N.)
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan; (M.K.); (D.K.); (O.K.); (H.Y.-H.); (E.W.); (Y.I.); (Y.T.)
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Yang YHC, Briant LJB, Raab CA, Mullapudi ST, Maischein HM, Kawakami K, Stainier DYR. Innervation modulates the functional connectivity between pancreatic endocrine cells. eLife 2022; 11:64526. [PMID: 35373736 PMCID: PMC9007585 DOI: 10.7554/elife.64526] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 04/03/2022] [Indexed: 11/20/2022] Open
Abstract
The importance of pancreatic endocrine cell activity modulation by autonomic innervation has been debated. To investigate this question, we established an in vivo imaging model that also allows chronic and acute neuromodulation with genetic and optogenetic tools. Using the GCaMP6s biosensor together with endocrine cell fluorescent reporters, we imaged calcium dynamics simultaneously in multiple pancreatic islet cell types in live animals in control states and upon changes in innervation. We find that by 4 days post fertilization in zebrafish, a stage when islet architecture is reminiscent of that in adult rodents, prominent activity coupling between beta cells is present in basal glucose conditions. Furthermore, we show that both chronic and acute loss of nerve activity result in diminished beta–beta and alpha–beta activity coupling. Pancreatic nerves are in contact with all islet cell types, but predominantly with beta and delta cells. Surprisingly, a subset of delta cells with detectable peri-islet neural activity coupling had significantly higher homotypic coupling with other delta cells suggesting that some delta cells receive innervation that coordinates their output. Overall, these data show that innervation plays a vital role in the maintenance of homotypic and heterotypic cellular connectivity in pancreatic islets, a process critical for islet function.
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Affiliation(s)
- Yu Hsuan Carol Yang
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | | | - Christopher A Raab
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Sri Teja Mullapudi
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Hans-Martin Maischein
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Koichi Kawakami
- Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan
| | - Didier Y R Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Singh B, Khattab F, Gilon P. Glucose inhibits glucagon secretion by decreasing [Ca2+]c and by reducing the efficacy of Ca2+ on exocytosis via somatostatin-dependent and independent mechanisms. Mol Metab 2022; 61:101495. [PMID: 35421610 PMCID: PMC9065434 DOI: 10.1016/j.molmet.2022.101495] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 03/15/2022] [Accepted: 04/04/2022] [Indexed: 11/15/2022] Open
Abstract
Objective Methods Results Conclusions
Glucose modulates [Ca2+]c in α-cells within islets but not in dispersed α-cells. In α-cells within islets, it decreases [Ca2+]c independently of their KATP channels. It decreases α-cell [Ca2+]c partly via somatostatin. All glucose-induced [Ca2+]c changes trigger parallel changes in glucagon release. Glucose also decreases the efficacy of Ca2+ on exocytosis (attenuating pathway).
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Affiliation(s)
- Bilal Singh
- Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d'Endocrinologie, Diabète et Nutrition, Brussels, Belgium
| | - Firas Khattab
- Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d'Endocrinologie, Diabète et Nutrition, Brussels, Belgium
| | - Patrick Gilon
- Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d'Endocrinologie, Diabète et Nutrition, Brussels, Belgium.
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38
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Guérineau NC, Campos P, Le Tissier PR, Hodson DJ, Mollard P. Cell Networks in Endocrine/Neuroendocrine Gland Function. Compr Physiol 2022; 12:3371-3415. [PMID: 35578964 DOI: 10.1002/cphy.c210031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Reproduction, growth, stress, and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a "textbook" view of endocrine gland organization which has emanated from 20th century histological studies on thin 2D tissue sections. However, 21st -century technological advances, including in-depth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multicellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This article focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves. © 2022 American Physiological Society. Compr Physiol 12:3371-3415, 2022.
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Affiliation(s)
| | - Pauline Campos
- College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, UK
| | - Paul R Le Tissier
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, UK.,Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.,COMPARE University of Birmingham and University of Nottingham Midlands, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Patrice Mollard
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
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39
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Miranda JG, Schleicher WE, Wells KL, Ramirez DG, Landgrave SP, Benninger RKP. Dynamic changes in β-cell [Ca 2+] regulate NFAT activation, gene transcription, and islet gap junction communication. Mol Metab 2022; 57:101430. [PMID: 34979329 PMCID: PMC8804269 DOI: 10.1016/j.molmet.2021.101430] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Diabetes occurs because of insufficient insulin secretion due to β-cell dysfunction within the islet of Langerhans. Elevated glucose levels trigger β-cell membrane depolarization, action potential generation, and slow sustained free-Ca2+ ([Ca2+]) oscillations, which trigger insulin release. Nuclear factor of activated T-cell (NFAT) is a transcription factor, which is regulated by the increases in [Ca2+] and calceineurin (CaN) activation. NFAT regulation links cell activity with gene transcription in many systems and regulates proliferation and insulin granule biogenesis within the β-cell. However, the link between the regulation of β-cell electrical activity and oscillatory [Ca2+] dynamics with NFAT activation and downstream transcription is poorly understood. Here, we tested whether dynamic changes to β-cell electrical activity and [Ca2+] regulate NFAT activation and downstream transcription. METHODS In cell lines, mouse islets, and human islets, including those from donors with type 2 diabetes, we applied both agonists/antagonists of ion channels together with optogenetics to modulate β-cell electrical activity. We measured the dynamics of [Ca2+] and NFAT activation as well as performed whole transcriptome and functional analyses. RESULTS Both glucose-induced membrane depolarization and optogenetic stimulation triggered NFAT activation as well as increased the transcription of NFAT targets and intermediate early genes (IEGs). Importantly, slow, sustained [Ca2+] oscillation conditions led to NFAT activation and downstream transcription. In contrast, in human islets from donors with type2 diabetes, NFAT activation by glucose was diminished, but rescued upon pharmacological stimulation of electrical activity. NFAT activation regulated GJD2 expression and increased Cx36 gap junction permeability upon elevated oscillatory [Ca2+] dynamics. However, it is unclear if NFAT directly binds the GJD2 gene to regulate expression. CONCLUSIONS This study provides an insight into the specific patterns of electrical activity that regulate NFAT activation, gene transcription, and islet function. In addition, it provides information on how these factors are disrupted in diabetes.
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Affiliation(s)
- Jose G Miranda
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA
| | - Wolfgang E Schleicher
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA
| | - Kristen L Wells
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - David G Ramirez
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA
| | - Samantha P Landgrave
- Program in Cell Biology, Stem Cell and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Richard K P Benninger
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora CO, 80045, USA; Program in Cell Biology, Stem Cell and Development, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA; Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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40
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Yanowski E, Yacovzada NS, David E, Giladi A, Jaitin D, Farack L, Egozi A, Ben-Zvi D, Itzkovitz S, Amit I, Hornstein E. Physically interacting beta-delta pairs in the regenerating pancreas revealed by single-cell sequencing. Mol Metab 2022; 60:101467. [PMID: 35240340 PMCID: PMC8983436 DOI: 10.1016/j.molmet.2022.101467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 02/05/2022] [Accepted: 02/25/2022] [Indexed: 11/12/2022] Open
Abstract
Objectives Until recently, communication between neighboring cells in islets of Langerhans was overlooked by genomic technologies, which require rigorous tissue dissociation into single cells. Methods We utilize sorting of physically interacting cells (PICs) with single-cell RNA-sequencing to systematically map cellular interactions in the endocrine pancreas after pancreatectomy. Results The pancreas cellular landscape features pancreatectomy associated heterogeneity of beta-cells, including an interaction-specific program between paired beta and delta-cells. Conclusions Our analysis suggests that the particular cluster of beta-cells that pairs with delta-cells benefits from stress protection, implying that the interaction between beta- and delta-cells might safeguard against pancreatectomy associated challenges. The work encourages testing the potential relevance of physically-interacting beta-delta-cells also in diabetes mellitus.
Single-cell RNA-sequencing systematically maps physically interacting endocrine cells in the pancreas. The landscape of pancreatectomy associated beta-cell heterogeneity is mapped in a single cell resolution. Interaction-specific beta - delta cellular program safeguards beta cells against pancreatectomy-associated stress. Physically interacting beta delta pairs were discovered in an injury model and may also be relevant in diabetes.
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Affiliation(s)
- Eran Yanowski
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular neuroscience, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Nancy-Sarah Yacovzada
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular neuroscience, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Eyal David
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Amir Giladi
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Diego Jaitin
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Lydia Farack
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Adi Egozi
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Danny Ben-Zvi
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, 9112102, Israel
| | - Shalev Itzkovitz
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Ido Amit
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Eran Hornstein
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular neuroscience, Weizmann Institute of Science, Rehovot 7610001, Israel.
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41
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Andersen DB, Holst JJ. Peptides in the regulation of glucagon secretion. Peptides 2022; 148:170683. [PMID: 34748791 DOI: 10.1016/j.peptides.2021.170683] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/21/2021] [Accepted: 11/02/2021] [Indexed: 02/06/2023]
Abstract
Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.
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Affiliation(s)
- Daniel B Andersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200, Copenhagen N, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200, Copenhagen N, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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42
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Ghila L, Legøy TA, Chera S. A Method for Encapsulation and Transplantation into Diabetic Mice of Human Induced Pluripotent Stem Cells (hiPSC)-Derived Pancreatic Progenitors. Methods Mol Biol 2022; 2454:327-349. [PMID: 33786775 DOI: 10.1007/7651_2021_356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Pancreatic islet endocrine cells generated from patient-derived induced pluripotent stem cells represent a great strategy for both disease modeling and regenerative medicine. Nevertheless, these cells inherently miss the effects of the intricate network of systemic signals characterizing the living organisms. Xenotransplantation of in vitro differentiating cells into murine hosts substantially compensates for this drawback.Here we describe our transplantation strategy of encapsulated differentiating pancreatic progenitors into diabetic immunosuppressed (NSG) overtly diabetic mice generated by the total ablation of insulin-producing cells following diphtheria toxin administration. We will detail the differentiation protocol employed, the alginate encapsulation procedure, and the xenotransplantation steps required for a successful and reproducible experiment.
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Affiliation(s)
- Luiza Ghila
- Department of Clinical Science, Faculty of Medicine, Center for Diabetes Research, University of Bergen, Bergen, Norway
| | - Thomas Aga Legøy
- Department of Clinical Science, Faculty of Medicine, Center for Diabetes Research, University of Bergen, Bergen, Norway
| | - Simona Chera
- Department of Clinical Science, Faculty of Medicine, Center for Diabetes Research, University of Bergen, Bergen, Norway.
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43
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Langlois A, Dumond A, Vion J, Pinget M, Bouzakri K. Crosstalk Communications Between Islets Cells and Insulin Target Tissue: The Hidden Face of Iceberg. Front Endocrinol (Lausanne) 2022; 13:836344. [PMID: 35185804 PMCID: PMC8851682 DOI: 10.3389/fendo.2022.836344] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022] Open
Abstract
The regulation of insulin secretion is under control of a complex inter-organ/cells crosstalk involving various metabolites and/or physical connections. In this review, we try to illustrate with current knowledge how β-cells communicate with other cell types and organs in physiological and pathological contexts. Moreover, this review will provide a better understanding of the microenvironment and of the context in which β-cells exist and how this can influence their survival and function. Recent studies showed that β-cell insulin secretion is regulated also by a direct and indirect inter-organ/inter-cellular communication involving various factors, illustrating the idea of "the hidden face of the iceberg". Moreover, any disruption on the physiological communication between β-cells and other cells or organs can participate on diabetes onset. Therefore, for new anti-diabetic treatments' development, it is necessary to consider the entire network of cells and organs involved in the regulation of β-cellular function and no longer just β-cell or pancreatic islet alone. In this context, we discuss here the intra-islet communication, the β-cell/skeletal muscle, β-cell/adipose tissue and β-cell/liver cross talk.
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44
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Miranda C, Begum M, Vergari E, Briant LJB. Gap junction coupling and islet delta-cell function in health and disease. Peptides 2022; 147:170704. [PMID: 34826505 DOI: 10.1016/j.peptides.2021.170704] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/12/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022]
Abstract
The pancreatic islets contain beta-cells and alpha-cells, which are responsible for secreting two principal gluco-regulatory hormones; insulin and glucagon, respectively. However, they also contain delta-cells, a relatively sparse cell type that secretes somatostatin (SST). These cells have a complex morphology allowing them to establish an extensive communication network throughout the islet, despite their scarcity. Delta-cells are electrically excitable cells, and SST secretion is released in a glucose- and KATP-dependent manner. SST hyperpolarises the alpha-cell membrane and suppresses exocytosis. In this way, islet SST potently inhibits glucagon release. Recent studies investigating the activity of delta-cells have revealed they are electrically coupled to beta-cells via gap junctions, suggesting the delta-cell is more than just a paracrine inhibitor. In this Review, we summarize delta-cell morphology, function, and the role of SST signalling for regulating islet hormonal output. A distinguishing feature of this Review is that we attempt to use the discovery of this gap junction pathway, together with what is already known about delta-cells, to reframe the role of these cells in both health and disease. In particular, we argue that the discovery of gap junction communication between delta-cells and beta-cells provides new insights into the contribution of delta-cells to the islet hormonal defects observed in both type 1 and type 2 diabetes. This reappraisal of the delta-cell is important as it may offer novel insights into how the physiology of this cell can be utilised to restore islet function in diabetes.
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Affiliation(s)
- Caroline Miranda
- Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Göteborg, 405 30, Göteborg, Sweden
| | - Manisha Begum
- Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Göteborg, 405 30, Göteborg, Sweden; University of Skӧvde, Department of Infection Biology, Högskolevägen 1, 541 28, Skövde, Sweden
| | - Elisa Vergari
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, OX4 7LE, Oxford, UK
| | - Linford J B Briant
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, OX4 7LE, Oxford, UK; Department of Computer Science, University of Oxford, OX1 3QD, Oxford, UK.
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Abstract
The continuous interaction between experimental and theoretical work has proven to be extremely useful for the study of pancreatic cells and, recently, of pancreatic islets. This prolific interaction relies on the capability of implementing computational models and methods to derive quantitative data for the analysis and interpretation of experimental observations. In this addendum I introduce Isletlab, a multiplatform application developed to provide the research community with a user-friendly interface for the implementation of computational algorithms for the characterization and simulation of pancreatic islets.
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Affiliation(s)
- Gerardo J. Félix-Martínez
- Cátedras CONACYT, Consejo Nacional de Ciencia y Tecnología, México City, México
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, México City, México
- CONTACT Gerardo J. Félix-Martínez ; ; Laboratorio de Biofísica E Ingeniería de Tejidos, Universidad Autónoma Metropolitana, Unidad Iztapalapa. San Rafael Atlixco 186, Col. Vicentina, México City09340, México
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46
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Benninger RKP, Kravets V. The physiological role of β-cell heterogeneity in pancreatic islet function. Nat Rev Endocrinol 2022; 18:9-22. [PMID: 34667280 PMCID: PMC8915749 DOI: 10.1038/s41574-021-00568-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 01/03/2023]
Abstract
Endocrine cells within the pancreatic islets of Langerhans are heterogeneous in terms of transcriptional profile, protein expression and the regulation of hormone release. Even though this heterogeneity has long been appreciated, only within the past 5 years have detailed molecular analyses led to an improved understanding of its basis. Although we are beginning to recognize why some subpopulations of endocrine cells are phenotypically different to others, arguably the most important consideration is how this heterogeneity affects the regulation of hormone release to control the homeostasis of glucose and other energy-rich nutrients. The focus of this Review is the description of how endocrine cell heterogeneity (and principally that of insulin-secreting β-cells) affects the regulation of hormone secretion within the islets of Langerhans. This discussion includes an overview of the functional characteristics of the different islet cell subpopulations and describes how they can communicate to influence islet function under basal and glucose-stimulated conditions. We further discuss how changes to the specific islet cell subpopulations or their numbers might underlie islet dysfunction in type 2 diabetes mellitus. We conclude with a discussion of several key open questions regarding the physiological role of islet cell heterogeneity.
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Affiliation(s)
- Richard K P Benninger
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Vira Kravets
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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47
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Abstract
Intra-islet communication via electrical, paracrine and autocrine signals, is highly dependent on the organization of cells within the islets and is key for an adequate response to changes in blood glucose and other stimuli. In spite of the fact that relevant structural differences between mouse and human islet architectures have been described, the functional implications of these differences remain only partially understood. In this work, aiming to contribute to a better understanding of the relationship between structural and functional properties of pancreatic islets, we reconstructed human and mice islets in order to perform a structural comparison based on both morphologic and network-derived metrics. According to our results, human islets constitute a more efficient network from a connectivity viewpoint, mainly due to the higher proportion of heterotypic contacts between islet cells in comparison to mice islets.
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Affiliation(s)
- Gerardo J. Félix-Martínez
- Cátedras CONACYT, Consejo Nacional de Ciencia y Tecnología, México City, México
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, México City, México
- CONTACT Gerardo J. Félix-Martínez Universidad Autónoma Metropolitana Unidad Iztapalapa. San Rafael Atlixco 186, Col. Vicentina 09340, México City, México
| | - J. R. Godínez-Fernández
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, México City, México
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48
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Kim A, Knudsen JG, Madara JC, Benrick A, Hill TG, Abdul Kadir L, Kellard JA, Mellander L, Miranda C, Lin H, James T, Suba K, Spigelman AF, Wu Y, MacDonald PE, Wernstedt Asterholm I, Magnussen T, Christensen M, Vilsbøll T, Salem V, Knop FK, Rorsman P, Lowell BB, Briant LJB. Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes. eLife 2021; 10:e72919. [PMID: 34787082 PMCID: PMC8654374 DOI: 10.7554/elife.72919] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/16/2021] [Indexed: 01/27/2023] Open
Abstract
Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
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Affiliation(s)
- Angela Kim
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Program in Neuroscience, Harvard Medical SchoolBostonUnited States
| | - Jakob G Knudsen
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
- Section for Cell Biology and Physiology, Department of Biology, University of CopenhagenCopenhagenDenmark
| | - Joseph C Madara
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
| | - Anna Benrick
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Thomas G Hill
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Lina Abdul Kadir
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Joely A Kellard
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Lisa Mellander
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Caroline Miranda
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Haopeng Lin
- Alberta Diabetes Institute, Li Ka Shing Centre for Health Research InnovationEdmontonCanada
| | - Timothy James
- Department of Clinical Biochemistry, John Radcliffe, Oxford NHS TrustOxfordUnited Kingdom
| | - Kinga Suba
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College LondonLondonUnited Kingdom
| | - Aliya F Spigelman
- Alberta Diabetes Institute, Li Ka Shing Centre for Health Research InnovationEdmontonCanada
| | - Yanling Wu
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Patrick E MacDonald
- Alberta Diabetes Institute, Li Ka Shing Centre for Health Research InnovationEdmontonCanada
| | - Ingrid Wernstedt Asterholm
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Tore Magnussen
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
| | - Mikkel Christensen
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of CopenhagenCopenhagenDenmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of CopenhagenCopenhagenDenmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of CopenhagenCopenhagenDenmark
- Steno Diabetes Center CopenhagenCopenhagenDenmark
| | - Victoria Salem
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College LondonLondonUnited Kingdom
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of CopenhagenCopenhagenDenmark
- Steno Diabetes Center CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenCopenhagenDenmark
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Bradford B Lowell
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Program in Neuroscience, Harvard Medical SchoolBostonUnited States
| | - Linford JB Briant
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
- Department of Computer Science, University of OxfordOxfordUnited Kingdom
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Asadi F, Dhanvantari S. Pathways of Glucagon Secretion and Trafficking in the Pancreatic Alpha Cell: Novel Pathways, Proteins, and Targets for Hyperglucagonemia. Front Endocrinol (Lausanne) 2021; 12:726368. [PMID: 34659118 PMCID: PMC8511682 DOI: 10.3389/fendo.2021.726368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/13/2021] [Indexed: 12/15/2022] Open
Abstract
Patients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the underlying cause of the hyperglycemia of diabetes. Defective alpha cell secretory responses to glucose and paracrine effectors in both Type 1 and Type 2 diabetes may drive the development of hyperglucagonemia. Therefore, uncovering the mechanisms that regulate glucagon secretion from the pancreatic alpha cell is critical for developing improved treatments for diabetes. In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha cell dysfunction in diabetes: proglucagon processing, intrinsic and paracrine control of glucagon secretion, secretory granule dynamics, and alterations in intracellular trafficking. We explore possible clues gleaned from these studies in how inhibition of glucagon secretion can be targeted as a treatment for diabetes mellitus.
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Affiliation(s)
- Farzad Asadi
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
- Program in Metabolism and Diabetes, Lawson Health Research Institute, London, ON, Canada
| | - Savita Dhanvantari
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
- Program in Metabolism and Diabetes, Lawson Health Research Institute, London, ON, Canada
- Imaging Research Program, Lawson Health Research Institute, London, ON, Canada
- Department of Medical Biophysics, Western University, London, ON, Canada
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50
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Fischer KL, Jaffredo M, Lang J, Raoux M. [Pancreatic α and β cells: Best enemies or partners for life?]. Med Sci (Paris) 2021; 37:752-758. [PMID: 34491183 DOI: 10.1051/medsci/2021111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Diabetes are major metabolic diseases constantly increasing in the population, caused by reduced secretion and action of insulin, the only hormone lowering efficiently the glycaemia. Insulin is secreted by β cells within the pancreatic islets of Langerhans. The islet micro-organs also contain 15 to 35% of α cells, well-known for their opposite effects on glycaemia. Considered until now as potentially harmful in diabetes, α cells are emerging as potent enhancers of β cell activity when studied in physiological nutritional setting and should therefore be reconsidered in a therapeutic point of view. This review summarizes the latest concepts regarding β cell function in physiological states and the involvement of dynamic functional interactions between α and β cells for the regulation of nutrient homeostasis.
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Affiliation(s)
- Karen Leal Fischer
- Institut de chimie et de biologie des membranes et des nano-objets, CBMN, Université de Bordeaux, CNRS UMR 5248, B14 allée Geoffroy Saint Hilaire, F-33600, Pessac, France
| | - Manon Jaffredo
- Institut de chimie et de biologie des membranes et des nano-objets, CBMN, Université de Bordeaux, CNRS UMR 5248, B14 allée Geoffroy Saint Hilaire, F-33600, Pessac, France
| | - Jochen Lang
- Institut de chimie et de biologie des membranes et des nano-objets, CBMN, Université de Bordeaux, CNRS UMR 5248, B14 allée Geoffroy Saint Hilaire, F-33600, Pessac, France
| | - Matthieu Raoux
- Institut de chimie et de biologie des membranes et des nano-objets, CBMN, Université de Bordeaux, CNRS UMR 5248, B14 allée Geoffroy Saint Hilaire, F-33600, Pessac, France
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