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Masschelin PM, Ochsner SA, Hartig SM, McKenna NJ, Cox AR. Islet single-cell transcriptomic profiling during obesity-induced beta cell expansion in female mice. iScience 2025; 28:112031. [PMID: 40104055 PMCID: PMC11914824 DOI: 10.1016/j.isci.2025.112031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 09/06/2024] [Accepted: 02/11/2025] [Indexed: 03/20/2025] Open
Abstract
Targeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-body Lepr gene deletion in adult mice induces obesity and massive beta cell expansion. Here, using single-cell transcriptomics with female Lepr KO islets, we identified distinct populations of beta cells undergoing unfolded protein response (UPR), stress resolution, and cell cycle progression. Lepr KO beta cells undergoing UPR markedly increased chaperone protein, ribosomal biogenesis, and cell cycle transcriptional programs that were enriched for Xbp1 and Myc target genes. Our findings suggest a coordinated transcriptional mechanism involving Xbp1 and Myc to alleviate UPR and stimulate beta cell proliferation in obese female mice.
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Affiliation(s)
- Peter M Masschelin
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77019, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Scott A Ochsner
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Sean M Hartig
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77019, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Neil J McKenna
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Aaron R Cox
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77019, USA
- Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, Univeristy of Texas Health Science Center at Houston, Houston TX 77019, USA
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2
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Wong A, Alejandro EU. Post translational modification regulation of transcription factors governing pancreatic β-cell identity and functional mass. Front Endocrinol (Lausanne) 2025; 16:1562646. [PMID: 40134803 PMCID: PMC11932907 DOI: 10.3389/fendo.2025.1562646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Dysfunction of the insulin-secreting β-cells is a key hallmark of Type 2 diabetes (T2D). In the natural history of the progression of T2D, factors such as genetics, early life exposures, lifestyle, and obesity dictate an individual's susceptibility risk to disease. Obesity is associated with insulin resistance and increased demand for insulin to maintain glucose homeostasis. Studies in both mouse and human islets have implicated the β-cell's ability to compensate through proliferation and survival (increasing functional β-cell mass) as a tipping point toward the development of disease. A growing body of evidence suggests the reduction of β-cell mass in T2D is driven majorly by loss of β-cell identity, rather than by apoptosis alone. The development and maintenance of pancreatic β-cell identity, function, and adaptation to stress is governed, in part, by the spatiotemporal expression of transcription factors (TFs), whose activity is regulated by signal-dependent post-translational modifications (PTM). In this review, we examine the role of these TFs in the developing pancreas and in the mature β-cell. We discuss functional implications of post-translational modifications on these transcription factors' activities and how an understanding of the pathways they regulate can inform therapies to promoteβ-cell regeneration, proliferation, and survival in diabetes.
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Affiliation(s)
- Alicia Wong
- Department of Genetics, Cell Biology, and Development, University of Minnesota Twin Cities, Minneapolis, MN, United States
| | - Emilyn U. Alejandro
- Department of Integrative Biology and Physiology, University of Minnesota Twin Cities, Minneapolis, MN, United States
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3
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Hill JH, Bell R, Barrios L, Baird H, Ost K, Greenewood M, Monts JK, Tracy E, Meili CH, Chiaro TR, Weis AM, Guillemin K, Beaudin AE, Murtaugh LC, Stephens WZ, Round JL. Neonatal fungi promote lifelong metabolic health through macrophage-dependent β cell development. Science 2025; 387:eadn0953. [PMID: 40048508 PMCID: PMC12036834 DOI: 10.1126/science.adn0953] [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] [Received: 11/21/2023] [Accepted: 11/19/2024] [Indexed: 03/14/2025]
Abstract
Loss of early-life microbial diversity is correlated with diabetes, yet mechanisms by which microbes influence disease remain elusive. We report a critical neonatal window in mice when microbiota disruption results in lifelong metabolic consequences stemming from reduced β cell development. We show evidence for the existence of a similar program in humans and identify specific fungi and bacteria that are sufficient for β cell growth. The microbiota also plays an important role in seeding islet-resident macrophages, and macrophage depletion during development reduces β cells. Candida dubliniensis increases β cells in a macrophage-dependent manner through distinctive cell wall composition and reduces murine diabetes incidence. Provision of C. dubliniensis after β cell ablation or antibiotic treatment improves β cell function. These data identify fungi as critical early-life commensals that promote long-term metabolic health.
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Affiliation(s)
- Jennifer Hampton Hill
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Rickesha Bell
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Logan Barrios
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Halli Baird
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Kyla Ost
- Department of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Morgan Greenewood
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Josh K. Monts
- HSC Flow Cytometry Core, University of Utah, Salt Lake City, UT, USA
| | - Erin Tracy
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Casey H. Meili
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
| | - Tyson R. Chiaro
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Allison M. Weis
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - Karen Guillemin
- Institute of Molecular Biology, University of Oregon, Eugene, OR, USA
- Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, Ontario, Canada
| | - Anna E. Beaudin
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
- Department of Internal Medicine, Division of Hematology and Hematologic Malignancies, and Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA
| | | | - W. Zac Stephens
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
| | - June L. Round
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, USA
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Ma H, Peng G, Hu Y, Lu B, Zheng Y, Wu Y, Feng W, Shi Y, Pan X, Song L, Stützer I, Liu Y, Fei J. Revealing the biological features of the axolotl pancreas as a new research model. Front Cell Dev Biol 2025; 13:1531903. [PMID: 39958891 PMCID: PMC11825805 DOI: 10.3389/fcell.2025.1531903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/07/2025] [Indexed: 02/18/2025] Open
Abstract
Introduction The pancreas plays a crucial role in digestion and blood glucose regulation. Current animal models, primarily mice and zebrafish, have limited the exploration of pancreatic biology from an evolutionary-developmental perspective. Tetrapod vertebrate axolotl (Ambystoma mexicanum) serves as a valuable model in developmental, regenerative, and evolutionary biology. However, the fundamental biology of the axolotl pancreas remains underexplored. This study aims to characterize the unique developmental, functional, and evolutionary features of the axolotl pancreas to expand the understanding of pancreatic biology. Methods We conducted morphological, histological, and transcriptomic analyses to investigate the axolotl pancreas. Pancreatic development was observed using in situ hybridization and immunostaining for key pancreatic markers. RNA sequencing was performed to profile global gene expression during larva and adult stages. And differential gene expression analysis was used to characterize the conserved and unique gene patterns in the axolotl pancreas. Functional assays, including glucose tolerance tests and insulin tolerance tests, were optimized for individual axolotls. To assess pancreatic gene function, Pdx1 mutants were generated using CRISPR/Cas9-mediated gene editing, and their effects on pancreatic morphology, endocrine cell populations, and glucose homeostasis were analyzed. Results The axolotl pancreas contains all known pancreatic cell types and develops from dorsal and ventral buds. Both of buds contribute to exocrine and endocrine glands. The dorsal bud produces the major endocrine cell types, while the ventral bud generates α and δ cells, but not β cells. Differential gene expression analysis indicated a transition in global gene expression from pancreatic cell fate commitment and the cell cycle to glucose response, hormone synthesis, and secretion, following the development progression. Notably, the adult axolotl pancreas exhibits slower metabolic activity compared to mammals, as evidenced by the results of GTT and ITT. The mutation of Pdx1 resulted in hyperglycemia and a significant reduction in pancreatic cell mass, including a complete loss of endocrine cells, although it did not lead to a lethal phenotype. Discussion This study examines the axolotl pancreas, highlighting the conservation of pancreatic development. Our study highlights the unique features of the axolotl pancreas and broadens the scope of animal models available for pancreatic evolution and disease research.
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Affiliation(s)
- Hui Ma
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- BGI Research, Qingdao, China
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Guangcong Peng
- Key Laboratory of Brain, Cognition and Education Sciences, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China
| | - Yan Hu
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Binbin Lu
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yiying Zheng
- Key Laboratory of Brain, Cognition and Education Sciences, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China
| | - Yingxian Wu
- Key Laboratory of Brain, Cognition and Education Sciences, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China
| | - Weimin Feng
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Yu Shi
- Key Laboratory of Brain, Cognition and Education Sciences, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China
| | - Xiangyu Pan
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Li Song
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Ina Stützer
- Deutsche Forschungsgemeinschaft (DFG)-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Yanmei Liu
- Key Laboratory of Brain, Cognition and Education Sciences, Guangdong Key Laboratory of Mental Health and Cognitive Science, Ministry of Education, Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China
| | - Jifeng Fei
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China
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Morozumi R, Okamoto K, Enomoto E, Tsukamoto Y, Kyakuno M, Suzuki N, Tazawa I, Furuno N, Ogino H, Kamei Y, Matsunami M, Shigenobu S, Suzuki K, Uemasu H, Namba N, Hayashi T. Urodele amphibian newt bridges the missing link in evo-devo of the pancreas. Dev Dyn 2025. [PMID: 39777819 DOI: 10.1002/dvdy.763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/14/2024] [Accepted: 10/25/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND The pancreas exhibits diverse structures and roles across vertebrates. The pancreas has evolved to include both endocrine and exocrine cells, a change that occurred during the transition from fish to amphibian. This event emphasizes the evolutionary significance of amphibians. However, research has focused predominantly on anuran amphibians, with urodeles, such as newts, remaining underexplored. In this study, we investigated the development of the pancreas using Pleurodeles waltl as a model species of urodele. RESULTS The newt pancreas consists of a single organ with exocrine tissue characterized by acinar structures and endocrine tissue forming islets. Notably, the newt possesses unique pancreas-like tissues on their intestines. We found that disruption of the newt Pancreatic and Duodenal Homeobox (Pdx) 1 gene resulted in an underdeveloped pancreas. Conversely, disruption of the Pdx2 paralog in newt had no significant impact on pancreatic development. CONCLUSION The newt pancreas shows a morphology similar to that of the mammalian pancreas, which includes both exocrine and endocrine tissues. These results highlight the intermediate evolutionary position of the newt in the context of the evolution of pancreatic development. Our findings indicate that characterization of the newt pancreas will be crucial for understanding the evolutionary progression of pancreatic function in vertebrates.
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Affiliation(s)
- Ryosuke Morozumi
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Kazuko Okamoto
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Eriko Enomoto
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Yuta Tsukamoto
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Mitsuki Kyakuno
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
- Faculty of Life and Environmental Sciences, Shimane University, Matsue, Shimane, Japan
| | - Nanoka Suzuki
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Ichiro Tazawa
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Nobuaki Furuno
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Hajime Ogino
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
| | - Yasuhiro Kamei
- Trans-Scale Biology Center, National Institute for Basic Biology, Okazaki, Aichi, Japan
| | | | - Shuji Shigenobu
- Trans-Scale Biology Center, National Institute for Basic Biology, Okazaki, Aichi, Japan
| | - Kenichi Suzuki
- Trans-Scale Biology Center, National Institute for Basic Biology, Okazaki, Aichi, Japan
| | - Hitoshi Uemasu
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Noriyuki Namba
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Toshinori Hayashi
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
- Amphibian Research Center, Hiroshima University, Hiroshima, Japan
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Abdalla MMI. Advancing diabetes management: Exploring pancreatic beta-cell restoration's potential and challenges. World J Gastroenterol 2024; 30:4339-4353. [PMID: 39494103 PMCID: PMC11525866 DOI: 10.3748/wjg.v30.i40.4339] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/05/2024] [Accepted: 09/24/2024] [Indexed: 10/16/2024] Open
Abstract
Diabetes mellitus, characterized by chronic hyperglycemia due to insulin deficiency or resistance, poses a significant global health burden. Central to its pathogenesis is the dysfunction or loss of pancreatic beta cells, which are res-ponsible for insulin production. Recent advances in beta-cell regeneration research offer promising strategies for diabetes treatment, aiming to restore endogenous insulin production and achieve glycemic control. This review explores the physiological basis of beta-cell function, recent scientific advan-cements, and the challenges in translating these findings into clinical applications. It highlights key developments in stem cell therapy, gene editing technologies, and the identification of novel regenerative molecules. Despite the potential, the field faces hurdles such as ensuring the safety and long-term efficacy of regen-erative therapies, ethical concerns around stem cell use, and the complexity of beta-cell differentiation and integration. The review highlights the importance of interdisciplinary collaboration, increased funding, the need for patient-centered approaches and the integration of new treatments into comprehensive care strategies to overcome these challenges. Through continued research and collaboration, beta-cell regeneration holds the potential to revolutionize diabetes care, turning a chronic condition into a manageable or even curable disease.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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7
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Rashwan AM, Abumandour MMA, Kandyel R, Choudhary OP, Soliman RM, El Sharaby A, Nomir AG. Implications of endoplasmic reticulum stress and beta-cell loss in immunodeficient diabetic NRG-Akita mice for understanding monogenic diabetes. Int J Surg 2024; 110:6231-6242. [PMID: 38329104 PMCID: PMC11486971 DOI: 10.1097/js9.0000000000001148] [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: 10/09/2023] [Accepted: 01/26/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND Immunodeficient mice models have become increasingly important as in vivo models engrafted with human cells or tissues for research. The NOD-Rag1 null Ins2 Akita Il2r null (NRG-Akita) mice is a model combined with immunodeficient NRG and monogenic diabetes Akita mice that develop spontaneous hyperglycemia with progressive loss of pancreatic insulin-producing beta-cells with age. This model is one of the monogenic diabetic models, which has been providing a powerful platform for transplantation experiments of stem cells-generated human β-cells. This research aimed to provide insights into the mechanisms underlying this monogenic diabetes, which remains incompletely understood. METHODS Histological and immunofluorescence analyses were conducted on endocrine pancreatic islets to compare NRG wild-type (Wt) controls with NRG-Akita mice. Our investigation focused on assessing the expression of endocrine hormones, transcription factors, proliferation, ER stress, and apoptosis. RESULTS Histological analyses on NRG-Akita mice revealed smaller islets at 6-weeks-old, due to fewer β-cells in the islets, compared to NRG-Wt controls, which further progressed with age. The proliferation rate decreased, and apoptosis was abundant in β-cells in NRG-Akita mice. Interestingly, our mechanistic analyses revealed that β-cells in NRG-Akita mice progressively accumulated the endoplasmic reticulum (ER) stresses, leading to a decreased expression of pivotal β-cell transcriptional factor PDX1. CONCLUSIONS Altogether, our mechanistic insight into β-cell loss in this model could shed light on essential links between ER stress, proliferation, and cell identity, which might open the door to new therapeutic strategies for various diseases since ER stress is one of the most common features not only in diabetes but also in other degenerative diseases.
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Affiliation(s)
- Ahmed M. Rashwan
- Department of Anatomy and Embryology
- Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Japan
| | | | - Ramadan Kandyel
- Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt
- Department of Biology, Faculty of Arts and Sciences, Najran University, Najran, Saudi Arabia
| | - Om P. Choudhary
- Department of Veterinary Anatomy, College of Veterinary Science, Guru Angad Dev Veterinary and Animal Sciences University, Rampura Phul, Bathinda, Punjab, India
| | - Rofaida M. Soliman
- Department of Animal Medicine, Faculty of Veterinary Medicine, Damanhour University, Damanhour
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8
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Elkoshi Z. Autoimmune diseases refractory to corticosteroids and immunosuppressants. Front Immunol 2024; 15:1447337. [PMID: 39351223 PMCID: PMC11439723 DOI: 10.3389/fimmu.2024.1447337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/21/2024] [Indexed: 10/04/2024] Open
Abstract
Corticosteroids and immunosuppressive drugs can alleviate the symptoms of most autoimmune diseases and induce remission by restraining the autoimmune attack and limiting the damage to the target tissues. However, four autoimmune non-degenerative diseases-adult advanced type 1 diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, and advanced primary biliary cholangitis-are refractory to these drugs. This article suggests that the refractoriness of certain autoimmune diseases is due to near-total loss of secreting cells coupled with the extremely low regenerative capacity of the affected tissues. The near-complete destruction of cells responsible for secreting insulin, thyroid hormones, or biliary HCO3 - diminishes the protective effects of immunosuppressants against further damage. The slow regeneration rate of these cells hinders tissue recovery, even after drug-induced immune suppression, thus preventing remission. Although the liver can fully regenerate after injury, severe primary biliary cholangitis may impair this ability, preventing liver recovery. Consequently, these four autoimmune diseases are resistant to immunosuppressive drugs and corticosteroids. In contrast, early stages of type 1 diabetes and early primary biliary cholangitis, where damage to secreting cells is partial, may benefit from immunosuppressant treatment. In contrast to these four diseases, chronic degenerative autoimmune conditions like multiple sclerosis may respond positively to corticosteroid use despite the limited regenerative potential of the affected tissue (the central nervous system). The opposite is true for acute autoimmune conditions like Guillain-Barré syndrome.
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Affiliation(s)
- Zeev Elkoshi
- Research and Development Department, Taro Pharmaceutical Industries Ltd, Haifa, Israel
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9
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Staels W, Berthault C, Bourgeois S, Laville V, Lourenço C, De Leu N, Scharfmann R. Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation. Mol Metab 2024; 87:101990. [PMID: 39009220 PMCID: PMC11327396 DOI: 10.1016/j.molmet.2024.101990] [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: 05/08/2024] [Revised: 07/09/2024] [Accepted: 07/09/2024] [Indexed: 07/17/2024] Open
Abstract
OBJECTIVES This study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to validate age-related alterations within these cell populations. METHODS We leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, and intersection analysis. RESULTS Alpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in neuron-like features processes during the transition from newborn to adult mice. Progressing from adult to old mice, we identified an inflammatory gene signature related to aging (inflammaging) encompassing an increase in β-2 microglobulin and major histocompatibility complex (MHC) Class I expression. CONCLUSIONS Our study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified an inflammaging gene signature with increased β-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation and age-related diabetes.
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Affiliation(s)
- W Staels
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France; Genetics, Reproduction and Development (GRAD), Vrije Universiteit Brussel (VUB), Brussels, Belgium; Division of Pediatric Endocrinology, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.
| | - C Berthault
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - S Bourgeois
- Genetics, Reproduction and Development (GRAD), Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - V Laville
- Stem Cells and Development Unit, Institut Pasteur, Paris, France; UMR CNRS 3738, Institut Pasteur, Paris, France; Université Paris Cité, Bioinformatics and Biostatistics Hub, Paris, France
| | - C Lourenço
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France
| | - N De Leu
- Genetics, Reproduction and Development (GRAD), Vrije Universiteit Brussel (VUB), Brussels, Belgium; Endocrinology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium; Endocrinology, ASZ Aalst, 9300 Aalst, Belgium
| | - R Scharfmann
- Université de Paris, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France
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10
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Toledo MP, Xie G, Wang YJ. Comprehensive Characterization of Islet Remodeling in Development and in Diabetes Using Mass Cytometry. Endocrinology 2024; 165:bqae094. [PMID: 39058908 DOI: 10.1210/endocr/bqae094] [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: 04/30/2024] [Revised: 07/11/2024] [Accepted: 07/25/2024] [Indexed: 07/28/2024]
Abstract
The pancreatic islet is the functional and structural unit of the pancreatic endocrine portion. Islet remodeling occurs in both normal development and pathogenesis of type 1 (T1D) and type 2 diabetes (T2D). However, accurately quantifying changes in islet cellular makeup and hormone expressions poses significant challenges due to large intra- and inter-donor heterogeneity and the limited scalability of traditional methods such as immunostaining. The cytometry by time-of-flight (CyTOF) technology enables simultaneous quantification of more than 30 protein markers at single-cell resolution in a high-throughput fashion. Moreover, with distinct DNA and viability markers, single live cells can be explicitly selected in CyTOF. Here, leveraging the CyTOF data generated by the Human Pancreas Analysis Program, we characterized more than 12 million islet cells from 71 donors. Our data revealed continued age-related changes in islet endocrine cell compositions, but the maturity of endocrine cells is reached by 3 years of age. We also observed significant changes in beta cell numbers and key protein expressions, along with a significant increase in bihormonal cells in T1D donors. In contrast, T2D donors exhibited minimal islet remodeling events. Our data shine a light on the islet dynamics during development and diabetes pathogenesis and suggest divergent pathogenesis processes of T1D and T2D. Our comprehensive approach not only elucidates islet plasticity but also establishes a foundation for integrated CyTOF analysis in islet biology and beyond.
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Affiliation(s)
- Maria Pilar Toledo
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Gengqiang Xie
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
| | - Yue J Wang
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA
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11
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Chernysheva МB, Ruchko ЕS, Karimova МV, Vorotelyak ЕA, Vasiliev АV. Development, regeneration, and physiological expansion of functional β-cells: Cellular sources and regulators. Front Cell Dev Biol 2024; 12:1424278. [PMID: 39045459 PMCID: PMC11263198 DOI: 10.3389/fcell.2024.1424278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 06/18/2024] [Indexed: 07/25/2024] Open
Abstract
Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review is to provide a comprehensive understanding of the emergence of a functionally active population of insulin-secreting β-cells in the adult pancreas. The renewal of β-cells is governed by a multifaceted interaction between cellular sources of genetic and epigenetic factors. Understanding the development and heterogeneity of β-cell populations is crucial for functional β-cell regeneration. The functional mass of pancreatic β-cells increases in situations such as pregnancy and obesity. However, the specific markers of mature β-cell populations and postnatal pancreatic progenitors capable of increasing self-reproduction in these conditions remain to be elucidated. The capacity to regenerate the β-cell population through various pathways, including the proliferation of pre-existing β-cells, β-cell neogenesis, differentiation of β-cells from a population of progenitor cells, and transdifferentiation of non-β-cells into β-cells, reveals crucial molecular mechanisms for identifying cellular sources and inducers of functional cell renewal. This provides an opportunity to identify specific cellular sources and mechanisms of regeneration, which could have clinical applications in treating various pathologies, including in vitro cell-based technologies, and deepen our understanding of regeneration in different physiological conditions.
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Affiliation(s)
- М. B. Chernysheva
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Moscow, Russia
| | - Е. S. Ruchko
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Moscow, Russia
| | - М. V. Karimova
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Moscow, Russia
- Department of Biology and Biotechnologies Charles Darwin, The Sapienza University of Rome, Rome, Italy
| | - Е. A. Vorotelyak
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Moscow, Russia
| | - А. V. Vasiliev
- Cell Biology Laboratory, Koltzov Institute of Developmental Biology, Moscow, Russia
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12
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Wortham M, Ramms B, Zeng C, Benthuysen JR, Sai S, Pollow DP, Liu F, Schlichting M, Harrington AR, Liu B, Prakash TP, Pirie EC, Zhu H, Baghdasarian S, Auwerx J, Shirihai OS, Sander M. Metabolic control of adaptive β-cell proliferation by the protein deacetylase SIRT2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.24.581864. [PMID: 38464227 PMCID: PMC10925077 DOI: 10.1101/2024.02.24.581864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Selective and controlled expansion of endogenous β-cells has been pursued as a potential therapy for diabetes. Ideally, such therapies would preserve feedback control of β-cell proliferation to avoid excessive β-cell expansion and an increased risk of hypoglycemia. Here, we identified a regulator of β-cell proliferation whose inactivation results in controlled β-cell expansion: the protein deacetylase Sirtuin 2 (SIRT2). Sirt2 deletion in β-cells of mice increased β-cell proliferation during hyperglycemia with little effect in homeostatic conditions, indicating preservation of feedback control of β-cell mass. SIRT2 restrains proliferation of human islet β-cells cultured in glucose concentrations above the glycemic set point, demonstrating conserved SIRT2 function. Analysis of acetylated proteins in islets treated with a SIRT2 inhibitor revealed that SIRT2 deacetylates enzymes involved in oxidative phosphorylation, dampening the adaptive increase in oxygen consumption during hyperglycemia. At the transcriptomic level, Sirt2 inactivation has context-dependent effects on β-cells, with Sirt2 controlling how β-cells interpret hyperglycemia as a stress. Finally, we provide proof-of-principle that systemic administration of a GLP1-coupled Sirt2-targeting antisense oligonucleotide achieves β-cell selective Sirt2 inactivation and stimulates β-cell proliferation under hyperglycemic conditions. Overall, these studies identify a therapeutic strategy for increasing β-cell mass in diabetes without circumventing feedback control of β-cell proliferation.
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Affiliation(s)
- Matthew Wortham
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Bastian Ramms
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Chun Zeng
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Jacqueline R Benthuysen
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Somesh Sai
- Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Dennis P Pollow
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Fenfen Liu
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Michael Schlichting
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Austin R Harrington
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Bradley Liu
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Thazha P Prakash
- Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, CA, USA
| | - Elaine C Pirie
- Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, CA, USA
| | - Han Zhu
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
| | - Siyouneh Baghdasarian
- Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Johan Auwerx
- Laboratory of Integrated Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Orian S Shirihai
- Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Maike Sander
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California San Diego, La Jolla, CA, USA
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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13
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Hela F, Aguayo-Mazzucato C. Interaction between Autophagy and Senescence in Pancreatic Beta Cells. BIOLOGY 2023; 12:1205. [PMID: 37759604 PMCID: PMC10525299 DOI: 10.3390/biology12091205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/01/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023]
Abstract
Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of developing different cardiometabolic diseases like diabetes. Cellular senescence and autophagy, both hallmarks of aging and stress-coping mechanisms, have gained increased attention for their role in the pathophysiology of diabetes. Studies show that impairing senescence dampens and even prevents diabetes while the role of autophagy is more contradictory, implying a context- and disease-stage-dependent effect. Reports show conflicting data about the effect of autophagy on senescence while the knowledge about this interaction in beta cells remains scarce. Elucidating this interaction between autophagy and senescence in pancreatic beta cells will lead to an identification of their respective roles and the extent of the effect each mechanism has on beta cells and open new horizons for developing novel therapeutic agents. To help illuminate this relationship we will review the latest findings of cellular senescence and autophagy with a special emphasis on pancreatic beta cells and diabetes.
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Affiliation(s)
| | - Cristina Aguayo-Mazzucato
- Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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14
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Sugawara H, Imai J, Yamamoto J, Izumi T, Kawana Y, Endo A, Kohata M, Seike J, Kubo H, Komamura H, Munakata Y, Asai Y, Hosaka S, Sawada S, Kodama S, Takahashi K, Kaneko K, Katagiri H. A highly sensitive strategy for monitoring real-time proliferation of targeted cell types in vivo. Nat Commun 2023; 14:3253. [PMID: 37316473 DOI: 10.1038/s41467-023-38897-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 05/22/2023] [Indexed: 06/16/2023] Open
Abstract
Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic β-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of β-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research.
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Affiliation(s)
- Hiroto Sugawara
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Junpei Yamamoto
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yohei Kawana
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Endo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masato Kohata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junro Seike
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Haremaru Kubo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroshi Komamura
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuichiro Munakata
- Division of Metabolism and Diabetes, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinichiro Hosaka
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shojiro Sawada
- Division of Metabolism and Diabetes, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
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15
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Li M, Zhang R, Ge Q, Yue L, Ma D, Khattab F, Xie W, Cui Y, Gilon P, Zhao X, Li X, Cheng R. Chemerin as an Inducer of β Cell Proliferation Mediates Mitochondrial Homeostasis and Promotes β Cell Mass Expansion. Int J Mol Sci 2023; 24:ijms24119136. [PMID: 37298086 DOI: 10.3390/ijms24119136] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Loss of the β cell population is a crucial feature of type 2 diabetes. Restoring the β cell mass by stimulating β cell proliferation and preventing its apoptosis was proposed as a therapeutic approach to treating diabetes. Therefore, researchers have been increasingly interested in identifying exogenous factors that can stimulate β cell proliferation in situ and in vitro. Adipokine chemerin, which is secreted from adipose tissue and the liver, has been identified as a chemokine that plays a critical role in the regulation of metabolism. In this study, we demonstrate that chemerin as a circulating adipokine promotes β cell proliferation in vivo and in vitro. Chemerin serum levels and the expression of the main receptors within islets are highly regulated under a variety of challenging conditions, including obesity and type 2 diabetes. As compared to their littermates, mice overexpressing chemerin had a larger islet area and increased β cell mass with both a normal and high-fat diet. Moreover, in chemerin-overexpressed mice, we observed improved mitochondrial homeostasis and increased insulin synthesis. In summary, our findings confirm the potential role of chemerin as an inducer of β cell proliferation, and they provide novel insights into the helpful strategy to expand β cell population.
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Affiliation(s)
- Min Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ruifan Zhang
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Qian Ge
- The First Clinical College, Chongqing Medical University, Chongqing 400016, China
| | - Lingzhi Yue
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Dan Ma
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Firas Khattab
- Pôle d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Wenhua Xie
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yewei Cui
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Patrick Gilon
- Pôle d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, 1200 Brussels, Belgium
| | - Xueya Zhao
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Xi Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Rui Cheng
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China
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16
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Varghese SS, Dhawan S. Senescence: a double-edged sword in beta-cell health and failure? Front Endocrinol (Lausanne) 2023; 14:1196460. [PMID: 37229454 PMCID: PMC10203573 DOI: 10.3389/fendo.2023.1196460] [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: 03/29/2023] [Accepted: 04/19/2023] [Indexed: 05/27/2023] Open
Abstract
Cellular senescence is a complex process marked by permanent cell-cycle arrest in response to a variety of stressors, and acts as a safeguard against the proliferation of damaged cells. Senescence is not only a key process underlying aging and development of many diseases, but has also been shown to play a vital role in embryogenesis as well as tissue regeneration and repair. In context of the pancreatic beta-cells, that are essential for maintaining glucose homeostasis, replicative senescence is responsible for the age-related decline in regenerative capacity. Stress induced premature senescence is also a key early event underlying beta-cell failure in both type 1 and type 2 diabetes. Targeting senescence has therefore emerged as a promising therapeutic avenue for diabetes. However, the molecular mechanisms that mediate the induction of beta-cell senescence in response to various stressors remain unclear. Nor do we know if senescence plays any role during beta-cell growth and development. In this perspective, we discuss the significance of senescence in beta-cell homeostasis and pathology and highlight emerging directions in this area that warrant our attention.
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Affiliation(s)
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, United States
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17
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Bauer BM, Irimia JM, Bloom-Saldana E, Jeong JW, Fueger PT. Pancreatic loss of Mig6 alters murine endocrine cell fate and protects functional beta cell mass in an STZ-induced model of diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.07.536046. [PMID: 37066257 PMCID: PMC10104126 DOI: 10.1101/2023.04.07.536046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Background Maintaining functional beta cell mass (BCM) to meet glycemic demands is essential to preventing or reversing the progression of diabetes. Yet the mechanisms that establish and regulate endocrine cell fate are incompletely understood. We sought to determine the impact of deletion of mitogen-inducible gene 6 (Mig6), a negative feedback inhibitor of epidermal growth factor receptor (EGFR) signaling, on mouse endocrine cell fate. The extent to which loss of Mig6 might protect against loss of functional BCM in a multiple very low dose (MVLD) STZ-induced model of diabetes was also determined. Methods Ten-week-old male mice with whole pancreas (Pdx1:Cre, PKO) and beta cell-specific (Ins1:Cre, BKO) knockout of Mig6 were used alongside control (CON) littermates. Mice were given MVLD STZ (35 mg/kg for five days) to damage beta cells and induce hyperglycemia. In vivo fasting blood glucose and glucose tolerance were used to assess beta cell function. Histological analyses of isolated pancreata were utilized to assess islet morphology and beta cell mass. We also identified histological markers of beta cell replication, dedifferentiation, and death. Isolated islets were used to reveal mRNA and protein markers of beta cell fate and function. Results PKO mice had significantly increased alpha cell mass with no detectable changes to beta or delta cells. The increase in alpha cells alone did not impact glucose tolerance, BCM, or beta cell function. Following STZ treatment, PKO mice had 18±8% higher BCM than CON littermates and improved glucose tolerance. Interestingly, beta cell-specific loss of Mig6 was insufficient for protection, and BKO mice had no discernable differences compared to CON mice. The increase in BCM in PKO mice was the result of decreased beta cell loss and increased beta cell replication. Finally, STZ-treated PKO mice had more Ins+/Gcg+ bi-hormonal cells compared to controls suggesting alpha to beta cell transdifferentiation. Conclusions Mig6 exerted differential effects on alpha and beta cell fate. Pancreatic loss of Mig6 reduced beta cell loss and promoted beta cell growth following STZ. Thus, suppression of Mig6 may provide relief of diabetes.
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Affiliation(s)
- Brandon M. Bauer
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Jose M. Irimia
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
- Comprehensive Metabolic Phenotyping Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Elizabeth Bloom-Saldana
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
- Comprehensive Metabolic Phenotyping Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Jae-Wook Jeong
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, MO 65211
| | - Patrick T. Fueger
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
- Comprehensive Metabolic Phenotyping Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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18
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Sehrawat A, Mishra J, Mastana SS, Navik U, Bhatti GK, Reddy PH, Bhatti JS. Dysregulated autophagy: A key player in the pathophysiology of type 2 diabetes and its complications. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166666. [DOI: https:/doi.org/10.1016/j.bbadis.2023.166666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
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19
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Sehrawat A, Mishra J, Mastana SS, Navik U, Bhatti GK, Reddy PH, Bhatti JS. Dysregulated autophagy: A key player in the pathophysiology of type 2 diabetes and its complications. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166666. [PMID: 36791919 DOI: 10.1016/j.bbadis.2023.166666] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/27/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023]
Abstract
Autophagy is essential in regulating the turnover of macromolecules via removing damaged organelles, misfolded proteins in various tissues, including liver, skeletal muscles, and adipose tissue to maintain the cellular homeostasis. In these tissues, a specific type of autophagy maintains the accumulation of lipid droplets which is directly related to obesity and the development of insulin resistance. It appears to play a protective role in a normal physiological environment by eliminating the invading pathogens, protein aggregates, and damaged organelles and generating energy and new building blocks by recycling the cellular components. Ageing is also a crucial modulator of autophagy process. During stress conditions involving nutrient deficiency, lipids excess, hypoxia etc., autophagy serves as a pro-survival mechanism by recycling the free amino acids to maintain the synthesis of proteins. The dysregulated autophagy has been found in several ageing associated diseases including type 2 diabetes (T2DM), cancer, and neurodegenerative disorders. So, targeting autophagy can be a promising therapeutic strategy against the progression to diabetes related complications. Our article provides a comprehensive outline of understanding of the autophagy process, including its types, mechanisms, regulation, and role in the pathophysiology of T2DM and related complications. We also explored the significance of autophagy in the homeostasis of β-cells, insulin resistance (IR), clearance of protein aggregates such as islet amyloid polypeptide, and various insulin-sensitive tissues. This will further pave the way for developing novel therapeutic strategies for diabetes-related complications.
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Affiliation(s)
- Abhishek Sehrawat
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Jayapriya Mishra
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Sarabjit Singh Mastana
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.
| | - Umashanker Navik
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India.
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20
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Yang H, Fang B, Wang Z, Chen Y, Dong Y. The Timing Sequence and Mechanism of Aging in Endocrine Organs. Cells 2023; 12:cells12070982. [PMID: 37048056 PMCID: PMC10093290 DOI: 10.3390/cells12070982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/15/2023] [Accepted: 03/22/2023] [Indexed: 04/14/2023] Open
Abstract
The world is increasingly aging, and there is an urgent need to find a safe and effective way to delay the aging of the body. It is well known that the endocrine glands are one of the most important organs in the context of aging. Failure of the endocrine glands lead to an abnormal hormonal environment, which in turn leads to many age-related diseases. The aging of endocrine glands is closely linked to oxidative stress, cellular autophagy, genetic damage, and hormone secretion. The first endocrine organ to undergo aging is the pineal gland, at around 6 years old. This is followed in order by the hypothalamus, pituitary gland, adrenal glands, gonads, pancreatic islets, and thyroid gland. This paper summarises the endocrine gland aging-related genes and pathways by bioinformatics analysis. In addition, it systematically summarises the changes in the structure and function of aging endocrine glands as well as the mechanisms of aging. This study will advance research in the field of aging and help in the intervention of age-related diseases.
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Affiliation(s)
- He Yang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100193, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Bing Fang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100193, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
| | - Zixu Wang
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yaoxing Chen
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yulan Dong
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100193, China
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
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21
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Burgos-Gamez X, Morales-Castillo P, Fernandez-Mejia C. Maternal adaptations of the pancreas and glucose homeostasis in lactation and after lactation. Mol Cell Endocrinol 2023; 559:111778. [PMID: 36162635 DOI: 10.1016/j.mce.2022.111778] [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: 05/01/2022] [Revised: 09/04/2022] [Accepted: 09/13/2022] [Indexed: 02/03/2023]
Abstract
During lactation, the maternal physiology adapts to bear the nutritional requirements of the offspring. The exocrine and endocrine pancreas are central to nutrient handling, promoting digestion and metabolism. In concert with prolactin, insulin is a determinant factor for milk synthesis. The investigation of the pancreas during lactation has been scattered over several periods. The investigations that laid the foundation of lactating pancreatic physiology and glucose homeostasis were conducted in the decades of 1970-1980. With the development of molecular biology, newer studies have revealed the molecular mechanisms involved in the endocrine pancreas during breastfeeding. There has been a surge of information recently about unexpected changes in the pancreas at the end of the lactation period and after weaning. In this review, we aim to gather information on the changes in the pancreas and glucose homeostasis during and after lactation and discuss the outcomes derived from the current discoveries.
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Affiliation(s)
- Xadeni Burgos-Gamez
- Unidad de Genética de la Nutrición. Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México/ Instituto Nacional de Pediatría. Avenida del Iman#1, 4th floor, Mexico City, 04500, Mexico
| | - Paulina Morales-Castillo
- Unidad de Genética de la Nutrición. Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México/ Instituto Nacional de Pediatría. Avenida del Iman#1, 4th floor, Mexico City, 04500, Mexico
| | - Cristina Fernandez-Mejia
- Unidad de Genética de la Nutrición. Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México/ Instituto Nacional de Pediatría. Avenida del Iman#1, 4th floor, Mexico City, 04500, Mexico.
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22
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Liu YY, Huo D, Zeng LT, Fan GQ, Shen T, Zhang TM, Cai JP, Cui J. Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential. Ageing Res Rev 2022; 82:101763. [PMID: 36272696 DOI: 10.1016/j.arr.2022.101763] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/18/2022] [Accepted: 10/15/2022] [Indexed: 01/31/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel evolutionarily conserved protein present in both vertebrate and invertebrate species. MANF shows distinct structural and functional properties than the traditional neurotrophic factors (NTF). MANF is composed of an N-terminal saposin-like lipid-binding domain and a C-terminal SAF-A/B, Acinus and PIAS (SAP) domain connected by a short linker. The two well-described activities of MANF include (1) role as a neurotrophic factor that plays direct neuroprotective effects in the nervous system and (2) cell protective effects in the animal models of non-neuronal diseases, including retinal damage, diabetes mellitus, liver injury, myocardial infarction, nephrotic syndrome, etc. The main objective of the current review is to provide up-to-date insights regarding the structure of MANF, mechanisms regulating its expression and secretion, physiological functions in various tissues and organs, protective effects during aging, and potential clinical applications. Together, this review highlights the importance of MANF in reversing age-related dysfunction and geroprotection.
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Affiliation(s)
- Yuan-Yuan Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Da Huo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Lv-Tao Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Guo-Qing Fan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Tao Shen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Tie-Mei Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China.
| | - Ju Cui
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China.
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23
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Chu CMJ, Modi H, Ellis C, Krentz NAJ, Skovsø S, Zhao YB, Cen H, Noursadeghi N, Panzhinskiy E, Hu X, Dionne DA, Xia YH, Xuan S, Huising MO, Kieffer TJ, Lynn FC, Johnson JD. Dynamic Ins2 Gene Activity Defines β-Cell Maturity States. Diabetes 2022; 71:2612-2631. [PMID: 36170671 DOI: 10.2337/db21-1065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 09/20/2022] [Indexed: 01/11/2023]
Abstract
Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments using FACS and single-cell RNA sequencing, in β-cells from Ins2GFP knockin mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ∼25% of β-cells exhibited significantly higher activity at the evolutionarily conserved insulin gene, Ins2. Live cell imaging over days captured Ins2 gene activity dynamics in single β-cells. Autocorrelation analysis revealed a subset of oscillating cells, with mean oscillation periods of 17 h. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single-cell RNA sequencing showed that Ins2(GFP)HIGH β-cells were enriched for markers of β-cell maturity. Ins2(GFP)HIGH β-cells were also significantly less viable at all glucose concentrations and in the context of endoplasmic reticulum stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β-cells, can be accounted for by dynamic states of insulin gene activity.
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Affiliation(s)
- Chieh Min Jamie Chu
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Honey Modi
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Cara Ellis
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Nicole A J Krentz
- BC Children's Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Søs Skovsø
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Yiwei Bernie Zhao
- Biomedical Research Centre, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Haoning Cen
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Nilou Noursadeghi
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Evgeniy Panzhinskiy
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Xiaoke Hu
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Derek A Dionne
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Yi Han Xia
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Shouhong Xuan
- Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center, New York, NY
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA
- Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA
| | - Timothy J Kieffer
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
| | - Francis C Lynn
- BC Children's Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, Canada
| | - James D Johnson
- Diabetes Focus Team, Life Sciences Institute, Departments of Cellular and Physiological Sciences and Surgery, University of British Columbia, Vancouver, Canada
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24
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Goode RA, Hum JM, Kalwat MA. Therapeutic Strategies Targeting Pancreatic Islet β-Cell Proliferation, Regeneration, and Replacement. Endocrinology 2022; 164:6836713. [PMID: 36412119 PMCID: PMC9923807 DOI: 10.1210/endocr/bqac193] [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: 09/09/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022]
Abstract
Diabetes results from insufficient insulin production by pancreatic islet β-cells or a loss of β-cells themselves. Restoration of regulated insulin production is a predominant goal of translational diabetes research. Here, we provide a brief overview of recent advances in the fields of β-cell proliferation, regeneration, and replacement. The discovery of therapeutic targets and associated small molecules has been enabled by improved understanding of β-cell development and cell cycle regulation, as well as advanced high-throughput screening methodologies. Important findings in β-cell transdifferentiation, neogenesis, and stem cell differentiation have nucleated multiple promising therapeutic strategies. In particular, clinical trials are underway using in vitro-generated β-like cells from human pluripotent stem cells. Significant challenges remain for each of these strategies, but continued support for efforts in these research areas will be critical for the generation of distinct diabetes therapies.
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Affiliation(s)
- Roy A Goode
- Division of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, USA
| | - Julia M Hum
- Division of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, USA
| | - Michael A Kalwat
- Correspondence: Michael A. Kalwat, PhD, Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, 1210 Waterway Blvd, Suite 2000, Indianapolis, IN 46202, USA. or
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25
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Prolonged insulin-induced hypoglycaemia reduces ß-cell activity rather than number in pancreatic islets in non-diabetic rats. Sci Rep 2022; 12:14113. [PMID: 35982111 PMCID: PMC9388517 DOI: 10.1038/s41598-022-18398-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/10/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic β-cells have an extraordinary ability to adapt to acute fluctuations in glucose levels by rapid changing insulin production to meet metabolic needs. Although acute changes have been characterised, effects of prolonged metabolic stress on β-cell dynamics are still unclear. Here, the aim was to investigate pancreatic β-cell dynamics and function during and after prolonged hypoglycaemia. Hypoglycaemia was induced in male and female rats by infusion of human insulin for 8 weeks, followed by a 4-week infusion-free recovery period. Animals were euthanized after 4 or 8 weeks of infusion, and either 2 days and 4 weeks after infusion-stop. Total volumes of pancreatic islets and β-cell nuclei, islet insulin and glucagon content, and plasma c-peptide levels were quantified. Prolonged hypoglycaemia reduced c-peptide levels, islet volume and almost depleted islet insulin. Relative β-cell nuclei: total pancreas volume decreased, while being unchanged relative to islet volume. Glucagon: total pancreas volume decreased during hypoglycaemia, whereas glucagon: islet volume increased. Within two days after infusion-stop, plasma glucose and c-peptide levels normalised and all remaining parameters were fully reversed after 4 weeks. In conclusion, our findings indicate that prolonged hypoglycaemia inactivates β-cells, which can rapidly be reactivated when needed, demonstrating the high plasticity of β-cells even following prolonged suppression.
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26
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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor. Signal Transduct Target Ther 2022; 7:248. [PMID: 35864094 PMCID: PMC9304326 DOI: 10.1038/s41392-022-01034-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 01/02/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of β-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute β-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.
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27
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Wu Y, Wong CW, Chiles EN, Mellinger AL, Bae H, Jung S, Peterson T, Wang J, Negrete M, Huang Q, Wang L, Jang C, Muddiman DC, Su X, Williamson I, Shen X. Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance. Cell Metab 2022; 34:1042-1053.e6. [PMID: 35688154 PMCID: PMC9897509 DOI: 10.1016/j.cmet.2022.05.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 12/21/2021] [Accepted: 05/18/2022] [Indexed: 02/06/2023]
Abstract
Dietary fructose, especially in the context of a high-fat western diet, has been linked to type 2 diabetes. Although the effect of fructose on liver metabolism has been extensively studied, a significant portion of the fructose is first metabolized in the small intestine. Here, we report that dietary fat enhances intestinal fructose metabolism, which releases glycerate into the blood. Chronic high systemic glycerate levels induce glucose intolerance by slowly damaging pancreatic islet cells and reducing islet sizes. Our findings provide a link between dietary fructose and diabetes that is modulated by dietary fat.
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Affiliation(s)
- Yanru Wu
- Department of Prosthodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
| | - Chi Wut Wong
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA; Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Eric N Chiles
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Allyson L Mellinger
- FTMS Laboratory for Human Health Research, Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA
| | - Hosung Bae
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Sunhee Jung
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Ted Peterson
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
| | - Jamie Wang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
| | - Marcos Negrete
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
| | - Qiang Huang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA; Department of Pediatric Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710004, China
| | - Lihua Wang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - David C Muddiman
- FTMS Laboratory for Human Health Research, Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA; Molecular Education, Technology and Research Innovation Center, North Carolina State University, Raleigh, NC 27695, USA
| | - Xiaoyang Su
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA; Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
| | - Ian Williamson
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA; Gastroenterology Division, Department of Medicine, Duke University, Durham, NC 27710, USA.
| | - Xiling Shen
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA; Terasaki Institute for Biomedical Innovation, Los Angeles, CA 90024, USA.
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28
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Kohata M, Imai J, Izumi T, Yamamoto J, Kawana Y, Endo A, Sugawara H, Seiko J, Kubo H, Kawamura H, Sato T, Osaka S, Munakata Y, Asai Y, Kodama S, Takahashi K, Kaneko K, Katagiri H. Roles of FoxM1-driven basal β-cell proliferation in maintenance of β-cell mass and glucose tolerance during adulthood. J Diabetes Investig 2022; 13:1666-1676. [PMID: 35633298 PMCID: PMC9533047 DOI: 10.1111/jdi.13846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/12/2022] [Accepted: 05/26/2022] [Indexed: 12/03/2022] Open
Abstract
Aims/Introduction Whether basal β‐cell proliferation during adulthood is involved in maintaining sufficient β‐cell mass, and if so, the molecular mechanism(s) underlying basal β‐cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in ‘adaptive’ β‐cell proliferation, which facilitates rapid increases in β‐cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β‐cell FoxM1 in ‘basal’ β‐cell proliferation under normal conditions and in the maintenance of sufficient β‐cell mass as well as glucose homeostasis during adulthood. Materials and Methods FoxM1 deficiency was induced specifically in β‐cells of 8‐week‐old mice, followed by analyzing its short‐ (2 weeks) and long‐ (10 months) term effects on β‐cell proliferation, β‐cell mass, and glucose tolerance. Results FoxM1 deficiency suppressed β‐cell proliferation at both ages, indicating critical roles of FoxM1 in basal β‐cell proliferation throughout adulthood. While short‐term FoxM1 deficiency affected neither β‐cell mass nor glucose tolerance, long‐term FoxM1 deficiency suppressed β‐cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long‐term β‐cell FoxM1 deficiency. Therefore, β‐cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long‐term β‐cell FoxM1 deficiency. Conclusions Basal low‐level proliferation of β‐cells during adulthood is important for maintaining sufficient β‐cell mass and good glucose tolerance and β‐cell FoxM1 underlies this mechanism. Preserving β‐cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age.
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Affiliation(s)
- Masato Kohata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - June Yamamoto
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Yohei Kawana
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Akira Endo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Hiroto Sugawara
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Juno Seiko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Hiroharu Kubo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Hiroshi Kawamura
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Toshihiro Sato
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Shinichiro Osaka
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Yuichiro Munakata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 980-8575, Japan
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Abstract
The pancreatic β-cells are essential for regulating glucose homeostasis through the coordinated release of the insulin hormone. Dysfunction of the highly specialized β-cells results in diabetes mellitus, a growing global health epidemic. In this review, we describe the development and function of β-cells the emerging concept of heterogeneity within insulin-producing cells, and the potential of other cell types to assume β-cell functionality via transdifferentiation. We also discuss emerging routes to design cells with minimal β-cell properties and human stem cell differentiation efforts that carry the promise to restore normoglycemia in patients suffering from diabetes.
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Affiliation(s)
- Natanya Kerper
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA
| | - Sudipta Ashe
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA
| | - Matthias Hebrok
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA
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30
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Varghese SS, Dhawan S. Polycomb Repressive Complexes: Shaping Pancreatic Beta-Cell Destiny in Development and Metabolic Disease. Front Cell Dev Biol 2022; 10:868592. [PMID: 35602600 PMCID: PMC9116887 DOI: 10.3389/fcell.2022.868592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/15/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic beta-cells secrete the hormone insulin, which is essential for the regulation of systemic glucose homeostasis. Insufficiency of insulin due to loss of functional beta-cells results in diabetes. Epigenetic mechanisms orchestrate the stage-specific transcriptional programs that guide the differentiation, functional maturation, growth, and adaptation of beta-cells in response to growth and metabolic signals throughout life. Primary among these mechanisms is regulation by the Polycomb Repressive Complexes (PRC) that direct gene-expression via histone modifications. PRC dependent histone modifications are pliable and provide a degree of epigenetic plasticity to cellular processes. Their modulation dictates the spatio-temporal control of gene-expression patterns underlying beta-cell homeostasis. Emerging evidence shows that dysregulation of PRC-dependent epigenetic control is also a hallmark of beta-cell failure in diabetes. This minireview focuses on the multifaceted contributions of PRC modules in the specification and maintenance of terminally differentiated beta-cell phenotype, as well as beta-cell growth and adaptation. We discuss the interaction of PRC regulation with different signaling pathways and mechanisms that control functional beta-cell mass. We also highlight recent advances in our understanding of the epigenetic regulation of beta-cell homeostasis through the lens of beta-cell pathologies, namely diabetes and insulinomas, and the translational relevance of these findings. Using high-resolution epigenetic profiling and epigenetic engineering, future work is likely to elucidate the PRC regulome in beta-cell adaptation versus failure in response to metabolic challenges and identify opportunities for therapeutic interventions.
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31
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Lee JH, Lee J. Endoplasmic Reticulum (ER) Stress and Its Role in Pancreatic β-Cell Dysfunction and Senescence in Type 2 Diabetes. Int J Mol Sci 2022; 23:ijms23094843. [PMID: 35563231 PMCID: PMC9104816 DOI: 10.3390/ijms23094843] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 04/22/2022] [Accepted: 04/26/2022] [Indexed: 02/07/2023] Open
Abstract
An increased life span and accompanying nutritional affluency have led to a rapid increase in diseases associated with aging, such as obesity and type 2 diabetes, imposing a tremendous economic and health burden on society. Pancreatic β-cells are crucial for controlling glucose homeostasis by properly producing and secreting the glucose-lowering hormone insulin, and the dysfunction of β-cells determines the outcomes for both type 1 and type 2 diabetes. As the native structure of insulin is formed within the endoplasmic reticulum (ER), ER homeostasis should be appropriately maintained to allow for the proper metabolic homeostasis and functioning of β-cells. Recent studies have found that cellular senescence is critically linked with cellular stresses, including ER stress, oxidative stress, and mitochondrial stress. These studies implied that β-cell senescence is caused by ER stress and other cellular stresses and contributes to β-cells’ dysfunction and the impairment of glucose homeostasis. This review documents and discusses the current understanding of cellular senescence, β-cell function, ER stress, its associated signaling mechanism (unfolded protein response), and the effect of ER stress on β-cell senescence and dysfunction.
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Affiliation(s)
- Ji-Hye Lee
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea;
- New Biology Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
| | - Jaemin Lee
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea;
- New Biology Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
- Well Aging Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea
- Correspondence:
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32
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Mesenchymal Stem Cells Ameliorate Hyperglycemia in Type I Diabetic Developing Male Rats. Stem Cells Int 2022; 2022:7556278. [PMID: 35463813 PMCID: PMC9020910 DOI: 10.1155/2022/7556278] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/10/2022] [Accepted: 03/23/2022] [Indexed: 11/18/2022] Open
Abstract
One of the most promising treatments for diabetes mellitus (DM) is stem cell therapy. This study is aimed at elucidating the antidiabetic effect of mesenchymal stem cells (MSCs) on streptozotocin- (STZ-) induced DM in developing male rats. Twenty-four male albino rats (4 weeks old) were divided into control, diabetic, diabetic+MSCs1 (received MSCs one week after STZ treatment), and diabetic+MSCs2 (received MSCs 4 weeks after STZ treatment). Diabetic rats showed marked impairment (
) in serum levels of glucose, insulin, C-peptide, glycosylated hemoglobin (HbA1c), malondialdehyde (MDA), total antioxidant status (TAS), and total oxidant status (TOS) in addition to disruption of the calculated values of homeostatic model assessment of insulin resistance (HOMA-IR), pancreatic β cell function (HOMA-β), and oxidative stress index (OSI). These biochemical alterations were confirmed by the histopathological and ultrastructural assessments which showed marked destructive effect on pancreatic islet cells. MSC therapy in an early stage reversed most of the biochemical, histological, and ultrastructural alterations in the STZ-induced diabetic model and restored the normal cellular population of most acinar cells and islet of Langerhans. These results indicate that MSC therapy of STZ-induced diabetic developing rats during an early stage has the capacity of β cell restoration and the control of blood glycemic homeostasis.
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Murakami T, Inagaki N, Kondoh H. Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic β Cells. Front Endocrinol (Lausanne) 2022; 13:869414. [PMID: 35432205 PMCID: PMC9009089 DOI: 10.3389/fendo.2022.869414] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/02/2022] [Indexed: 12/15/2022] Open
Abstract
Increased insulin resistance and impaired insulin secretion are significant characteristics manifested by patients with type 2 diabetes mellitus (T2DM). The degree and extent of these two features in T2DM vary among races and individuals. Insulin resistance is accelerated by obesity and is accompanied by accumulation of dysfunctional adipose tissues. In addition, dysfunction of pancreatic β-cells impairs insulin secretion. T2DM is significantly affected by aging, as the β-cell mass diminishes with age. Moreover, both obesity and hyperglycemia-related metabolic changes in developing diabetes are associated with accumulation of senescent cells in multiple organs, that is, organismal aging. Cellular senescence is defined as a state of irreversible cell cycle arrest with concomitant functional decline. It is caused by telomere shortening or senescence-inducing stress. Senescent cells secrete proinflammatory cytokines and chemokines, which is designated as the senescence-associated secretory phenotype (SASP), and this has a negative impact on adipose tissues and pancreatic β-cells. Recent advances in aging research have suggested that senolysis, the removal of senescent cells, can be a promising therapeutic approach to prevent or improve aging-related diseases, including diabetes. The attenuation of a SASP may be beneficial, although the pathophysiological involvement of cellular senescence in diabetes is not fully understood. In the clinical application of senotherapy, tissue-context-dependent senescent cells are increasingly being recognized as an issue to be solved. Recent studies have observed highly heterogenic and complex senescent cell populations that serve distinct roles among tissues, various stages of disease, and different ages. For example, in high-fat-diet induced diabetes with obesity, mouse adipose tissues display accumulation of p21Cip1-highly-expressing (p21high) cells in the early stage, followed by increases in both p21high and p16INK4a-highly-expressing (p16high) cells in the late stage. Interestingly, elimination of p21high cells in visceral adipose tissue can prevent or improve insulin resistance in mice with obesity, while p16high cell clearance is less effective in alleviating insulin resistance. Importantly, in immune-deficient mice transplanted with fat from obese patients, dasatinib plus quercetin, a senolytic cocktail that reduces the number of both p21high and p16high cells, improves both glucose tolerance and insulin resistance. On the other hand, in pancreatic β cells, p16high cells become increasingly predominant with age and development of diabetes. Consistently, elimination of p16high cells in mice improves both glucose tolerance and glucose-induced insulin secretion. Moreover, a senolytic compound, the anti-Bcl-2 inhibitor ABT263 reduces p16INK4a expression in islets and restores glucose tolerance in mice when combined with insulin receptor antagonist S961 treatment. In addition, efficacy of senotherapy in targeting mouse pancreatic β cells has been validated not only in T2DM, but also in type 1 diabetes mellitus. Indeed, in non-obese diabetic mice, treatment with anti-Bcl-2 inhibitors, such as ABT199, eliminates senescent pancreatic β cells, resulting in prevention of diabetes mellitus. These findings clearly indicate that features of diabetes are partly determined by which or where senescent cells reside in vivo, as adipose tissues and pancreatic β cells are responsible for insulin resistance and insulin secretion, respectively. In this review, we summarize recent advances in understanding cellular senescence in adipose tissues and pancreatic β cells in diabetes. We review the different potential molecular targets and distinctive senotherapeutic strategies in adipose tissues and pancreatic β cells. We propose the novel concept of a dual-target tailored approach in senotherapy against diabetes.
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Affiliation(s)
- Takaaki Murakami
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroshi Kondoh
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Geriatric Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Hirano M, So Y, Tsunekawa S, Kabata M, Ohta S, Sagara H, Sankoda N, Taguchi J, Yamada Y, Ukai T, Kato M, Nakamura J, Ozawa M, Yamamoto T, Yamada Y. MYCL-mediated reprogramming expands pancreatic insulin-producing cells. Nat Metab 2022; 4:254-268. [PMID: 35145326 DOI: 10.1038/s42255-022-00530-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 01/11/2022] [Indexed: 11/09/2022]
Abstract
β cells have a limited capacity for regeneration, which predisposes towards diabetes. Here, we show that, of the MYC family members, Mycl plays a key role in proliferation of pancreatic endocrine cells. Genetic ablation of Mycl causes a reduction in the proliferation of pancreatic endocrine cells in neonatal mice. By contrast, the expression of Mycl in adult mice stimulates the proliferation of β and α cells, and the cells persist after withdrawal of Mycl expression. A subset of the expanded α cells give rise to insulin-producing cells after this withdrawal. Transient Mycl expression in vivo is sufficient to normalize the hyperglycaemia of diabetic mice. In vitro expression of Mycl similarly provokes active replication in islet cells, even in those from aged mice. Finally, we show that MYCL stimulates the division of human adult cadaveric islet cells. Our results demonstrate that the induction of Mycl alone expands the functional β-cell population, which may provide a regenerative strategy for β cells.
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Affiliation(s)
- Michitada Hirano
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yusei So
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Shin Tsunekawa
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan
| | - Mio Kabata
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Sho Ohta
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroshi Sagara
- Medical Proteomics Laboratory, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Nao Sankoda
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Jumpei Taguchi
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yosuke Yamada
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Tomoyo Ukai
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Makoto Kato
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan
| | - Jiro Nakamura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, Japan
| | - Manabu Ozawa
- Laboratory of Reproductive Systems Biology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Takuya Yamamoto
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
- AMED-CREST, AMED, Tokyo, Japan
- Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
- Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan
| | - Yasuhiro Yamada
- Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
- AMED-CREST, AMED, Tokyo, Japan.
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Title AC, Karsai M, Mir-Coll J, Grining ÖY, Rufer C, Sonntag S, Forschler F, Jawurek S, Klein T, Yesildag B. Evaluation of the Effects of Harmine on β-cell Function and Proliferation in Standardized Human Islets Using 3D High-Content Confocal Imaging and Automated Analysis. Front Endocrinol (Lausanne) 2022; 13:854094. [PMID: 35860702 PMCID: PMC9289187 DOI: 10.3389/fendo.2022.854094] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/10/2022] [Indexed: 01/09/2023] Open
Abstract
Restoration of β-cell mass through the induction of proliferation represents an attractive therapeutic approach for the treatment of diabetes. However, intact and dispersed primary islets suffer from rapidly deteriorating viability and function ex vivo, posing a significant challenge for their experimental use in proliferation studies. Here, we describe a novel method for the assessment of compound effects on β-cell proliferation and count using reaggregated primary human islets, or islet microtissues (MTs), which display homogeneous size and tissue architecture as well as robust and stable functionality and viability for 4 weeks in culture. We utilized this platform to evaluate the dose-dependent short- and long-term effects of harmine on β-cell proliferation and function. Following compound treatment and EdU incorporation, islet MTs were stained and confocal-imaged for DAPI (nuclear marker), NKX6.1 (β-cell marker), and EdU (proliferation marker), allowing automated 3D-analysis of number of total cells, β-cells, and proliferating β- and non-β-cells per islet MT. In parallel, insulin secretion, intracellular insulin and ATP contents, and Caspase 3/7 activity were analyzed to obtain a comprehensive overview of islet MT function and viability. We observed that 4-day harmine treatment increased β- and non-β-cell proliferation, NKX6.1 expression, and basal and stimulated insulin secretion in a dose-dependent manner, while fold-stimulation of secretion peaked at intermediate harmine doses. Interestingly, 15-day harmine treatment led to a general reduction in harmine's proliferative effects as well as altered dose-dependent trends. The described methodology provides a unique tool for in vitro high-throughput evaluation of short- and long-term changes in human β-cell proliferation, count and fraction along with a variety of functional parameters, in a representative 3D human islet model.
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Affiliation(s)
| | - Maria Karsai
- Diabetes Research, InSphero AG, Schlieren, Switzerland
| | - Joan Mir-Coll
- Diabetes Research, InSphero AG, Schlieren, Switzerland
| | | | - Chantal Rufer
- Diabetes Research, InSphero AG, Schlieren, Switzerland
| | | | | | - Sayro Jawurek
- Diabetes Research, InSphero AG, Schlieren, Switzerland
| | - Thomas Klein
- Department of Cardio-Metabolic Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Burcak Yesildag
- Diabetes Research, InSphero AG, Schlieren, Switzerland
- *Correspondence: Burcak Yesildag,
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Cai Z, Liu F, Yang Y, Li D, Hu S, Song L, Yu S, Li T, Liu B, Luo H, Zhang W, Zhou Z, Zhang J. GRB10 regulates β cell mass by inhibiting β cell proliferation and stimulating β cell dedifferentiation. J Genet Genomics 2021; 49:208-216. [PMID: 34861413 DOI: 10.1016/j.jgg.2021.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/07/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the expression levels of the growth factor receptor-bound protein 10 (GRB10), a negative regulator of insulin and mTORC1 signaling, are markedly induced in islets of diabetic mice and high glucose-treated insulinoma cell line INS-1cells. β-cell-specific knockout of Grb10 in mice increased β-cell mass and improved β-cell function. Grb10-deficient β-cells exhibit enhanced mTORC1 signaling and reduced β-cell dedifferentiation, which could be blocked by rapamycin. On the contrary, Grb10 overexpression induced β-cell dedifferentiation in MIN6 cells. Our study identifies GRB10 as a critical regulator of β-cell dedifferentiation and β-cell mass, which exerts its effect by inhibiting mTORC1 signaling.
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Affiliation(s)
- Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Fen Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yan Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Dandan Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Shanbiao Hu
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Lei Song
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Shaojie Yu
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ting Li
- Department of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Bilian Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Hairong Luo
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Weiping Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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Böni-Schnetzler M, Méreau H, Rachid L, Wiedemann SJ, Schulze F, Trimigliozzi K, Meier DT, Donath MY. IL-1beta promotes the age-associated decline of beta cell function. iScience 2021; 24:103250. [PMID: 34746709 PMCID: PMC8554531 DOI: 10.1016/j.isci.2021.103250] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/03/2021] [Accepted: 10/07/2021] [Indexed: 11/08/2022] Open
Abstract
Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.
Islets from aged mice have increased IL-1beta and decreased IL-1Ra expression Islet immune cells are the source of increased IL-1beta expression during aging Myeloid-cell-specific IL-1beta knockout preserves insulin secretion in aged mice IL-1beta targets genes regulating insulin secretion and proliferation during aging
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Affiliation(s)
- Marianne Böni-Schnetzler
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Hélène Méreau
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Leila Rachid
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Sophia J Wiedemann
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Friederike Schulze
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Kelly Trimigliozzi
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Daniel T Meier
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
| | - Marc Y Donath
- Endocrinology, Diabetes, and Metabolism, University Hospital of Basel, 4031 Basel, Switzerland.,Department of Biomedicine, Diabetes Research, University of Basel, 4031 Basel, Switzerland
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Narasimhan A, Flores RR, Robbins PD, Niedernhofer LJ. Role of Cellular Senescence in Type II Diabetes. Endocrinology 2021; 162:6345039. [PMID: 34363464 PMCID: PMC8386762 DOI: 10.1210/endocr/bqab136] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Indexed: 01/10/2023]
Abstract
Cellular senescence is a cell fate that occurs in response to numerous types of stress and can promote tissue repair or drive inflammation and disruption of tissue homeostasis depending on the context. Aging and obesity lead to an increase in the senescent cell burden in multiple organs. Senescent cells release a myriad of senescence-associated secretory phenotype factors that directly mediate pancreatic β-cell dysfunction, adipose tissue dysfunction, and insulin resistance in peripheral tissues, which promote the onset of type II diabetes mellitus. In addition, hyperglycemia and metabolic changes seen in diabetes promote cellular senescence. Diabetes-induced cellular senescence contributes to various diabetic complications. Thus, type II diabetes is both a cause and consequence of cellular senescence. This review summarizes recent studies on the link between aging, obesity, and diabetes, focusing on the role of cellular senescence in disease processes.
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Affiliation(s)
- Akilavalli Narasimhan
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
| | - Rafael R Flores
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
| | - Paul D Robbins
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
| | - Laura J Niedernhofer
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, 55455, USA
- Correspondence: Laura J. Niedernhofer, MD, PhD, Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN 55455, USA.
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Yong J, Parekh VS, Reilly SM, Nayak J, Chen Z, Lebeaupin C, Jang I, Zhang J, Prakash TP, Sun H, Murray S, Guo S, Ayala JE, Satin LS, Saltiel AR, Kaufman RJ. Chop/ Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice. Sci Transl Med 2021; 13:13/604/eaba9796. [PMID: 34321322 DOI: 10.1126/scitranslmed.aba9796] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/07/2021] [Accepted: 06/23/2021] [Indexed: 12/21/2022]
Abstract
Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high-fat diet (HFD)-fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells conferred therapeutic benefits. First, we showed that Chop deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca2+ buffering capacity and modulates glucose-induced islet Ca2+ oscillations, leading to transcriptional changes of ER chaperone profile ("ER remodeling"). Last, we demonstrated that a GLP1-conjugated Chop antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that Chop depletion in β cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.
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Affiliation(s)
- Jing Yong
- Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA. .,Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
| | - Vishal S Parekh
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.,Department of Pharmacology, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA
| | - Shannon M Reilly
- Department of Pharmacology, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA.,Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jonamani Nayak
- Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.,Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
| | - Zhouji Chen
- Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.,Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
| | - Cynthia Lebeaupin
- Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.,Department of Pharmacology, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA.,Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.,Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Insook Jang
- Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.,Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
| | - Jiangwei Zhang
- Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.,Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Thazha P Prakash
- Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.,Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Hong Sun
- Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.,Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Sue Murray
- Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.,Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Shuling Guo
- Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.,Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
| | - Julio E Ayala
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.,Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Leslie S Satin
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.,Department of Pharmacology, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA
| | - Alan R Saltiel
- Department of Pharmacology, University of Michigan Medical School, 1000 Wall St., Ann Arbor, MI 48105, USA.,Division of Metabolism and Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.,Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
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Sato T, Ishiwatari C, Kaneko YK, Ishikawa Y, Kimura Y, Watanabe N, Aoshima I, Matsuda Y, Nakayama T, Chiba R, Fujinuki T, Iwata K, Lu Q, Usuki T, Sakane F, Ishikawa T. Diacylglycerol kinase δ functions as a proliferation suppressor in pancreatic β-cells. FASEB J 2021; 35:e21420. [PMID: 33774855 DOI: 10.1096/fj.202001279rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 11/11/2022]
Abstract
Although an aberrant reduction in pancreatic β-cell mass contributes to the pathogenesis of diabetes, the mechanism underlying the regulation of β-cell mass is poorly understood. Here, we show that diacylglycerol kinase δ (DGKδ) is a key enzyme in the regulation of β-cell mass. DGKδ expression was detected in the nucleus of β-cells. We developed β-cell-specific DGKδ knockout (βDGKδ KO) mice, which showed lower blood glucose, higher plasma insulin levels, and better glucose tolerance compared to control mice. Moreover, an increased number of small islets and Ki-67-positive islet cells, as well as elevated cyclin B1 expression in the islets, were detected in the pancreas of βDGKδ KO mice. DGKδ knockdown in the β-cell line MIN6 induced significant increases in bromodeoxyuridine (BrdU) incorporation and cyclin B1 expression. Finally, we confirmed that streptozotocin-induced hyperglycemia and β-cell loss were alleviated in βDGKδ KO mice. Thus, suppressing the expression or enzymatic activity of DGKδ that functions as a suppressor of β-cell proliferation could be a novel therapeutic approach to increase β-cell mass for the treatment of diabetes.
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Affiliation(s)
- Taiji Sato
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Chihiro Ishiwatari
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yukiko K Kaneko
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yoko Ishikawa
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yuki Kimura
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naoya Watanabe
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Ikumi Aoshima
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yukari Matsuda
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takahiro Nakayama
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Rina Chiba
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Takahiro Fujinuki
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kai Iwata
- Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan
| | - Qiang Lu
- Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan
| | - Takako Usuki
- Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan
| | - Fumio Sakane
- Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan
| | - Tomohisa Ishikawa
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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41
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Wang P, Karakose E, Choleva L, Kumar K, DeVita RJ, Garcia-Ocaña A, Stewart AF. Human Beta Cell Regenerative Drug Therapy for Diabetes: Past Achievements and Future Challenges. Front Endocrinol (Lausanne) 2021; 12:671946. [PMID: 34335466 PMCID: PMC8322843 DOI: 10.3389/fendo.2021.671946] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/10/2021] [Indexed: 01/02/2023] Open
Abstract
A quantitative deficiency of normally functioning insulin-producing pancreatic beta cells is a major contributor to all common forms of diabetes. This is the underlying premise for attempts to replace beta cells in people with diabetes by pancreas transplantation, pancreatic islet transplantation, and transplantation of beta cells or pancreatic islets derived from human stem cells. While progress is rapid and impressive in the beta cell replacement field, these approaches are expensive, and for transplant approaches, limited by donor organ availability. For these reasons, beta cell replacement will not likely become available to the hundreds of millions of people around the world with diabetes. Since the large majority of people with diabetes have some residual beta cells in their pancreata, an alternate approach to reversing diabetes would be developing pharmacologic approaches to induce these residual beta cells to regenerate and expand in a way that also permits normal function. Unfortunately, despite the broad availability of multiple classes of diabetes drugs in the current diabetes armamentarium, none has the ability to induce regeneration or expansion of human beta cells. Development of such drugs would be transformative for diabetes care around the world. This picture has begun to change. Over the past half-decade, a novel class of beta cell regenerative small molecules has emerged: the DYRK1A inhibitors. Their emergence has tremendous potential, but many areas of uncertainty and challenge remain. In this review, we summarize the accomplishments in the world of beta cell regenerative drug development and summarize areas in which most experts would agree. We also outline and summarize areas of disagreement or lack of unanimity, of controversy in the field, of obstacles to beta cell regeneration, and of challenges that will need to be overcome in order to establish human beta cell regenerative drug therapeutics as a clinically viable class of diabetes drugs.
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Affiliation(s)
- Peng Wang
- The Diabetes Obesity Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Esra Karakose
- The Diabetes Obesity Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Lauryn Choleva
- The Division of Pediatric Endocrinology, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kunal Kumar
- The Drug Discovery Institute, The Department of Pharmacological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Robert J. DeVita
- The Drug Discovery Institute, The Department of Pharmacological Sciences, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Adolfo Garcia-Ocaña
- The Diabetes Obesity Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Andrew F. Stewart
- The Diabetes Obesity Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States
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42
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Rodriguez UA, Socorro M, Criscimanna A, Martins CP, Mohamed N, Hu J, Prasadan K, Gittes GK, Esni F. Conversion of α-Cells to β-Cells in the Postpartum Mouse Pancreas Involves Lgr5 Progeny. Diabetes 2021; 70:1508-1518. [PMID: 33906911 PMCID: PMC8336010 DOI: 10.2337/db20-1059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/23/2021] [Indexed: 12/14/2022]
Abstract
In contrast to the skin and the gut, where somatic stem cells and their niche are well characterized, a definitive pancreatic multipotent cell population in the adult pancreas has yet to be revealed. Of particular interest is whether such cells may be endogenous in patients with diabetes, and if so, can they be used for therapeutic purposes? In the current study, we used two separate reporter lines to target Cre-recombinase expression to the Lgr5- or glucagon-expressing cells in the pancreas. We provide evidence for the existence of a population of cells within and in the proximity of the ducts that transiently express the stem-cell marker Lgr5 during late gestational stages. Careful timing of tamoxifen treatment in Lgr5EGFP-IRES-CreERT2 ;R26 Tomato mice allowed us to show that these Lgr5-expressing progenitor cells can differentiate into α-cells during pregnancy. Furthermore, we report on a spontaneous lineage conversion of α- to β-cells specifically after parturition. The contribution of Lgr5 progeny to the β-cell compartment through an α-cell intermediate phase early after pregnancy appears to be part of a novel mechanism that would counterbalance against excessive β-cell mass reduction during β-cell involution.
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Affiliation(s)
- Uylissa A Rodriguez
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Mairobys Socorro
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
- Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA
| | - Angela Criscimanna
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Christina P Martins
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Nada Mohamed
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Jing Hu
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Krishna Prasadan
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - George K Gittes
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Farzad Esni
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA
- UPMC Hillman Cancer Center, Pittsburgh, PA
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43
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Salinno C, Büttner M, Cota P, Tritschler S, Tarquis-Medina M, Bastidas-Ponce A, Scheibner K, Burtscher I, Böttcher A, Theis FJ, Bakhti M, Lickert H. CD81 marks immature and dedifferentiated pancreatic β-cells. Mol Metab 2021; 49:101188. [PMID: 33582383 PMCID: PMC7932895 DOI: 10.1016/j.molmet.2021.101188] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/31/2021] [Accepted: 02/06/2021] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE Islets of Langerhans contain heterogeneous populations of insulin-producing β-cells. Surface markers and respective antibodies for isolation, tracking, and analysis are urgently needed to study β-cell heterogeneity and explore the mechanisms to harness the regenerative potential of immature β-cells. METHODS We performed single-cell mRNA profiling of early postnatal mouse islets and re-analyzed several single-cell mRNA sequencing datasets from mouse and human pancreas and islets. We used mouse primary islets, iPSC-derived endocrine cells, Min6 insulinoma, and human EndoC-βH1 β-cell lines and performed FAC sorting, Western blotting, and imaging to support and complement the findings from the data analyses. RESULTS We found that all endocrine cell types expressed the cluster of differentiation 81 (CD81) during pancreas development, but the expression levels of this protein were gradually reduced in β-cells during postnatal maturation. Single-cell gene expression profiling and high-resolution imaging revealed an immature signature of β-cells expressing high levels of CD81 (CD81high) compared to a more mature population expressing no or low levels of this protein (CD81low/-). Analysis of β-cells from different diabetic mouse models and in vitro β-cell stress assays indicated an upregulation of CD81 expression levels in stressed and dedifferentiated β-cells. Similarly, CD81 was upregulated and marked stressed human β-cells in vitro. CONCLUSIONS We identified CD81 as a novel surface marker that labels immature, stressed, and dedifferentiated β-cells in the adult mouse and human islets. This novel surface marker will allow us to better study β-cell heterogeneity in healthy subjects and diabetes progression.
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Affiliation(s)
- Ciro Salinno
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany; Technische Universität München, School of Medicine, 81675, München, Germany
| | - Maren Büttner
- Institute of Computational Biology, Helmholtz Zentrum München, D-85764, Neuherberg, Germany
| | - Perla Cota
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany
| | - Sophie Tritschler
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; Institute of Computational Biology, Helmholtz Zentrum München, D-85764, Neuherberg, Germany
| | - Marta Tarquis-Medina
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany; Technische Universität München, School of Medicine, 81675, München, Germany
| | - Aimée Bastidas-Ponce
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany
| | - Katharina Scheibner
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany
| | - Ingo Burtscher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany
| | - Anika Böttcher
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany
| | - Fabian J Theis
- Institute of Computational Biology, Helmholtz Zentrum München, D-85764, Neuherberg, Germany; Technical University of Munich, Department of Mathematics, 85748, Munich, Germany
| | - Mostafa Bakhti
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany.
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), D-85764, Neuherberg, Germany; Technische Universität München, School of Medicine, 81675, München, Germany.
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44
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Lee S, Zhang J, Saravanakumar S, Flisher MF, Grimm DR, van der Meulen T, Huising MO. Virgin β-Cells at the Neogenic Niche Proliferate Normally and Mature Slowly. Diabetes 2021; 70:1070-1083. [PMID: 33563657 PMCID: PMC8173805 DOI: 10.2337/db20-0679] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 01/25/2021] [Indexed: 01/11/2023]
Abstract
Proliferation of pancreatic β-cells has long been known to reach its peak in the neonatal stages and decline during adulthood. However, β-cell proliferation has been studied under the assumption that all β-cells constitute a single, homogenous population. It is unknown whether a subpopulation of β-cells retains the capacity to proliferate at a higher rate and thus contributes disproportionately to the maintenance of mature β-cell mass in adults. We therefore assessed the proliferative capacity and turnover potential of virgin β-cells, a novel population of immature β-cells found at the islet periphery. We demonstrate that virgin β-cells can proliferate but do so at rates similar to those of mature β-cells from the same islet under normal and challenged conditions. Virgin β-cell proliferation rates also conform to the age-dependent decline previously reported for β-cells at large. We further show that virgin β-cells represent a long-lived, stable subpopulation of β-cells with low turnover into mature β-cells under healthy conditions. Our observations indicate that virgin β-cells at the islet periphery can divide but do not contribute disproportionately to the maintenance of adult β-cell mass.
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Affiliation(s)
- Sharon Lee
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
| | - Jing Zhang
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
| | - Supraja Saravanakumar
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
| | - Marcus F Flisher
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
| | - David R Grimm
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
| | - Talitha van der Meulen
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA
- Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, CA
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45
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Charbord J, Ren L, Sharma RB, Johansson A, Ågren R, Chu L, Tworus D, Schulz N, Charbord P, Stewart AF, Wang P, Alonso LC, Andersson O. In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR. Nat Metab 2021; 3:682-700. [PMID: 34031592 PMCID: PMC9756392 DOI: 10.1038/s42255-021-00391-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 04/14/2021] [Indexed: 02/03/2023]
Abstract
It is known that β cell proliferation expands the β cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for β cell regeneration in diabetes. Here, through a new high-throughput screen using a luminescence ubiquitination-based cell cycle indicator (LUCCI) in zebrafish, we identify HG-9-91-01 as a driver of proliferation and confirm this effect in mouse and human β cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIKs), and overexpression of Sik1 specifically in β cells blocks the effect of HG-9-91-01 on β cell proliferation. Single-cell transcriptomic analyses of mouse β cells demonstrate that HG-9-91-01 induces a wave of activating transcription factor (ATF)6-dependent unfolded protein response (UPR) before cell cycle entry. Importantly, the UPR wave is not associated with an increase in insulin expression. Additional mechanistic studies indicate that HG-9-91-01 induces multiple signalling effectors downstream of SIK inhibition, including CRTC1, CRTC2, ATF6, IRE1 and mTOR, which integrate to collectively drive β cell proliferation.
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Affiliation(s)
- Jérémie Charbord
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Lipeng Ren
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Rohit B Sharma
- Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, USA
| | - Anna Johansson
- Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Rasmus Ågren
- Department of Biology and Biological Engineering, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Chalmers University of Technology, Göteborg, Sweden
| | - Lianhe Chu
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Dominika Tworus
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Nadja Schulz
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Pierre Charbord
- Sorbonne Université, Institut de Biologie Paris-Seine, CNRS UMR 7622, Inserm, Paris, France
| | - Andrew F Stewart
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Peng Wang
- Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Laura C Alonso
- Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, USA
| | - Olov Andersson
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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46
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Gezginci-Oktayoglu S, Sancar S, Karatug-Kacar A, Bolkent S. miR-375 induces adipogenesis through targeting Erk1 in pancreatic duct cells under the influence of sodium palmitate. J Cell Physiol 2021; 236:3881-3895. [PMID: 33107061 DOI: 10.1002/jcp.30129] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 12/16/2022]
Abstract
The goal of this study was to research long-term saturated fatty acid overexposure that can induce differentiation of pancreatic duct cells into adipocytes and also into β-cells. The important findings can be summarized as follows: (i) adipogenesis and early stage β-cell differentiation were stimulated in duct cells under lipotoxicity and glucolipotoxicity conditions, (ii) miR-375 expression was upregulated while its target Erk1 was downregulated and miR-375 inhibitor upregulated Erk1 while expression of adipogenesis markers was downregulated in duct cells under both conditions, (iii) apoptosis was induced in β and duct cells under both conditions, (iv) lipotoxicity induced proliferation of co-cultured β-cells. These findings suggest that long-term saturated fatty acid overexposure may cause intrapancreatic fat accumulation by inducing differentiation of duct cells into adipocytes and it may contributes to β-cell compensation by stimulating the early stage of β-cell differentiation in duct cells. In addition, miR-375 may have the potential to be a new target in the treatment of Type 2 diabetes, and NAFPD due to its role in the adipogenesis of duct cells.
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Affiliation(s)
- Selda Gezginci-Oktayoglu
- Biology Department, Molecular Biology Section, Faculty of Science, Istanbul University, Vezneciler, Istanbul, Turkey
| | - Serap Sancar
- Biology Department, Molecular Biology Section, Faculty of Science, Istanbul University, Vezneciler, Istanbul, Turkey
| | - Ayse Karatug-Kacar
- Biology Department, Molecular Biology Section, Faculty of Science, Istanbul University, Vezneciler, Istanbul, Turkey
| | - Sehnaz Bolkent
- Biology Department, Molecular Biology Section, Faculty of Science, Istanbul University, Vezneciler, Istanbul, Turkey
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47
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Bevacqua RJ, Dai X, Lam JY, Gu X, Friedlander MSH, Tellez K, Miguel-Escalada I, Bonàs-Guarch S, Atla G, Zhao W, Kim SH, Dominguez AA, Qi LS, Ferrer J, MacDonald PE, Kim SK. CRISPR-based genome editing in primary human pancreatic islet cells. Nat Commun 2021; 12:2397. [PMID: 33893274 PMCID: PMC8065166 DOI: 10.1038/s41467-021-22651-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/22/2021] [Indexed: 02/02/2023] Open
Abstract
Gene targeting studies in primary human islets could advance our understanding of mechanisms driving diabetes pathogenesis. Here, we demonstrate successful genome editing in primary human islets using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). CRISPR-based targeting efficiently mutated protein-coding exons, resulting in acute loss of islet β-cell regulators, like the transcription factor PDX1 and the KATP channel subunit KIR6.2, accompanied by impaired β-cell regulation and function. CRISPR targeting of non-coding DNA harboring type 2 diabetes (T2D) risk variants revealed changes in ABCC8, SIX2 and SIX3 expression, and impaired β-cell function, thereby linking regulatory elements in these target genes to T2D genetic susceptibility. Advances here establish a paradigm for genetic studies in human islet cells, and reveal regulatory and genetic mechanisms linking non-coding variants to human diabetes risk.
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Affiliation(s)
- Romina J Bevacqua
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiaoqing Dai
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| | - Jonathan Y Lam
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Xueying Gu
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Mollie S H Friedlander
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Krissie Tellez
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Irene Miguel-Escalada
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Silvia Bonàs-Guarch
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Goutham Atla
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
| | - Weichen Zhao
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Seung Hyun Kim
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Antonia A Dominguez
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
| | - Lei S Qi
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA
- Chem-H, Stanford University, Stanford, CA, USA
| | - Jorge Ferrer
- Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- Section of Genetics and Genomics, Imperial College London, London, UK
| | - Patrick E MacDonald
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| | - Seung K Kim
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Medicine (Endocrinology), Stanford University School of Medicine, Stanford, CA, USA.
- Northern California JDRF Center of Excellence, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
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48
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Zhang MJ, Pisco AO, Darmanis S, Zou J. Mouse aging cell atlas analysis reveals global and cell type-specific aging signatures. eLife 2021; 10:62293. [PMID: 33847263 PMCID: PMC8046488 DOI: 10.7554/elife.62293] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 03/29/2021] [Indexed: 12/15/2022] Open
Abstract
Aging is associated with complex molecular and cellular processes that are poorly understood. Here we leveraged the Tabula Muris Senis single-cell RNA-seq data set to systematically characterize gene expression changes during aging across diverse cell types in the mouse. We identified aging-dependent genes in 76 tissue-cell types from 23 tissues and characterized both shared and tissue-cell-specific aging behaviors. We found that the aging-related genes shared by multiple tissue-cell types also change their expression congruently in the same direction during aging in most tissue-cell types, suggesting a coordinated global aging behavior at the organismal level. Scoring cells based on these shared aging genes allowed us to contrast the aging status of different tissues and cell types from a transcriptomic perspective. In addition, we identified genes that exhibit age-related expression changes specific to each functional category of tissue-cell types. Altogether, our analyses provide one of the most comprehensive and systematic characterizations of the molecular signatures of aging across diverse tissue-cell types in a mammalian system.
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Affiliation(s)
- Martin Jinye Zhang
- Department of Electrical Engineering, Stanford University, Palo Alto, United States.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, United States.,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
| | | | | | - James Zou
- Department of Electrical Engineering, Stanford University, Palo Alto, United States.,Chan-Zuckerberg Biohub, San Francisco, United States.,Department of Biomedical Data Science, Stanford University, Palo Alto, United States
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Miranda MA, Macias-Velasco JF, Lawson HA. Pancreatic β-cell heterogeneity in health and diabetes: classes, sources, and subtypes. Am J Physiol Endocrinol Metab 2021; 320:E716-E731. [PMID: 33586491 PMCID: PMC8238131 DOI: 10.1152/ajpendo.00649.2020] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pancreatic β-cells perform glucose-stimulated insulin secretion, a process at the center of type 2 diabetes etiology. Efforts to understand how β-cells behave in healthy and stressful conditions have revealed a wide degree of morphological, functional, and transcriptional heterogeneity. Sources of heterogeneity include β-cell topography, developmental origin, maturation state, and stress response. Advances in sequencing and imaging technologies have led to the identification of β-cell subtypes, which play distinct roles in the islet niche. This review examines β-cell heterogeneity from morphological, functional, and transcriptional perspectives, and considers the relevance of topography, maturation, development, and stress response. It also discusses how these factors have been used to identify β-cell subtypes, and how heterogeneity is impacted by diabetes. We examine open questions in the field and discuss recent technological innovations that could advance understanding of β-cell heterogeneity in health and disease.
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Affiliation(s)
- Mario A Miranda
- Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri
| | - Juan F Macias-Velasco
- Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri
| | - Heather A Lawson
- Department of Genetics, Washington University School of Medicine, Saint Louis, Missouri
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50
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Docherty FM, Sussel L. Islet Regeneration: Endogenous and Exogenous Approaches. Int J Mol Sci 2021; 22:ijms22073306. [PMID: 33804882 PMCID: PMC8037662 DOI: 10.3390/ijms22073306] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023] Open
Abstract
Both type 1 and type 2 diabetes are characterized by a progressive loss of beta cell mass that contributes to impaired glucose homeostasis. Although an optimal treatment option would be to simply replace the lost cells, it is now well established that unlike many other organs, the adult pancreas has limited regenerative potential. For this reason, significant research efforts are focusing on methods to induce beta cell proliferation (replication of existing beta cells), promote beta cell formation from alternative endogenous cell sources (neogenesis), and/or generate beta cells from pluripotent stem cells. In this article, we will review (i) endogenous mechanisms of beta cell regeneration during steady state, stress and disease; (ii) efforts to stimulate endogenous regeneration and transdifferentiation; and (iii) exogenous methods of beta cell generation and transplantation.
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