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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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Fu Q, Qian Y, Jiang H, He Y, Dai H, Chen Y, Xia Z, Liang Y, Zhou Y, Gao R, Zheng S, Lv H, Sun M, Xu K, Yang T. Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet β cells in various mouse models of diabetes with distinct age of initiation. SCIENCE CHINA. LIFE SCIENCES 2024; 67:504-517. [PMID: 37930473 DOI: 10.1007/s11427-022-2372-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 05/17/2023] [Indexed: 11/07/2023]
Abstract
During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of islet β cells. Cre-LoxP systems were used to generate islet cell type-specific (α, β, or δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing, thereinto β-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing (scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into a or δ cells in both youth- and adulthood-initiated mice while this phenomenon was barely observed in HFD models. β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice (both youth- and adulthood-initiated). In addition to the re-dedifferentiation of β cells, it is also highly likely that these "α or δ" cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of β cells. Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.
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Affiliation(s)
- Qi Fu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yu Qian
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hemin Jiang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yunqiang He
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hao Dai
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yang Chen
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhiqing Xia
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yucheng Liang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yuncai Zhou
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Rui Gao
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shuai Zheng
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hui Lv
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Min Sun
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Kuanfeng Xu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Tao Yang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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3
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Wan S, Xie J, Liang Y, Yu X. Pathological roles of bone marrow adipocyte-derived monocyte chemotactic protein-1 in type 2 diabetic mice. Cell Death Discov 2023; 9:412. [PMID: 37957155 PMCID: PMC10643445 DOI: 10.1038/s41420-023-01708-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/23/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has become a prevalent public health concern, with beta-cell dysfunction involved in its pathogenesis. Bone marrow adipose tissue (BMAT) increases in both the quantity and area in individuals with T2DM along with heightened monocyte chemotactic protein-1 (MCP-1) secretion. This study aims to investigate the influence and underlying mechanisms of MCP-1 originating from bone marrow adipocytes (BMAs) on systemic glucose homeostasis in T2DM. Initially, a substantial decrease in the proliferation and glucose-stimulated insulin secretion (GSIS) of islet cells was observed. Moreover, a comparative analysis between the control (Ctrl) group and db/db mice revealed significant alterations in the gene expression profiles of whole bone marrow cells, with a noteworthy upregulation of Mcp-1. And the primary enriched pathways included chemokine signaling pathway and AGE-RAGE signaling pathway in diabetic complications. In addition, the level of MCP-1 was distinctly elevated in BMA-derived conditional media (CM), leading to a substantial inhibition of proliferation, GSIS and the protein level of phosphorylated Akt (p-Akt) in Min6 cells. After blocking MCP-1 pathway, we observed a restoration of p-Akt and the proliferation of islet cells, resulting in a marked improvement in disordered glucose homeostasis. In summary, there is an accumulation of BMAs in T2DM, which secrete excessive MCP-1, exacerbating the abnormal accumulation of BMAs in the bone marrow cavity through paracrine signaling. The upregulated MCP-1, in turn, worsens glucose metabolism disorder by inhibiting the proliferation and insulin secretion of islet cells through an endocrine pathway. Inhibiting MCP-1 signaling can partially restore the proliferation and insulin secretion of islet cells, ultimately ameliorating glucose metabolism disorder. It's worth noting that to delve deeper into the impact of MCP-1 derived from BMAs on islet cells and its potential mechanisms, it is imperative to develop genetically engineered mice with conditional Mcp-1 knockout from BMAs.
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Affiliation(s)
- Shan Wan
- Laboratory of Endocrinology and Metabolism/Department of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jinwei Xie
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Liang
- Core Facilities of West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism/Department of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, China.
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4
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Kojima H, Katagi M, Okano J, Nakae Y, Ohashi N, Fujino K, Miyazawa I, Nakagawa T. Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice. Commun Biol 2023; 6:637. [PMID: 37311905 DOI: 10.1038/s42003-023-05010-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 06/02/2023] [Indexed: 06/15/2023] Open
Abstract
Despite the growing epidemic worldwide, diabetes is an incurable disease. We have been focusing on why diabetes manifests refractoriness to any therapy. We recently found that abnormal bone marrow-derived cells (BMDCs), namely, Vcam-1+ST-HSCs, was a key mechanism for diabetic complications. We then hypothesize that those aberrant BMDCs sustainedly impair pancreatic β cells. Here we show that eliminating abnormal BMDCs using bone marrow transplantation results in controlling serum glucose in diabetic mice, in which normoglycemia is sustained even after cessation of insulin therapy. Alternatively, abnormal BMDCs exhibiting epigenetic alterations are treated with an HDAC inhibitor, givinostat, in diabetic mice. As a result, those mice are normoglycemic along with restored insulin secretion even following the cessation of both insulin and givinostat. Diabetic cell fusion between abnormal BMDCs and resident cells is significantly blocked by the combination therapy in the pancreatic islets and thymus while surgical ablation of the thymus completely eliminates therapeutic protection in diabetic mice. In conclusion, diabetes is an epigenetic stem cell disorder with thymic disturbances. The combination may be applied to patients aiming at complete remission from diabetes in clinical medicine.
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Grants
- No. 18390100 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No. 023590378 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No. 16K19051 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No. 16K15756 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No.1515503ZZE Shiga University of Medical Science (SUMS)
- No. 1515503 W Shiga University of Medical Science (SUMS)
- No. 1515503ZE Shiga University of Medical Science (SUMS)
- No. 1515503ZB Shiga University of Medical Science (SUMS)
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Affiliation(s)
- Hideto Kojima
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan.
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan.
| | - Miwako Katagi
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan
| | - Junko Okano
- Department of Plastic and Reconstructive Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Yuki Nakae
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan
| | - Natsuko Ohashi
- Department of Medicine, Division of Diabetology, Endocrinology and Nephrology, Shiga University of Medical Science, Otsu, Japan
| | - Kazunori Fujino
- Department of Critical and Intensive Care Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Itsuko Miyazawa
- Department of Education Center for Medicine and Nursing, Shiga University of Medical Science, Otsu, Japan
| | - Takahiko Nakagawa
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan.
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan.
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5
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Smirnov VV, Beeraka NM, Butko DY, Nikolenko VN, Bondarev SA, Achkasov EE, Sinelnikov MY, Vikram PRH. Updates on Molecular Targets and Epigenetic-Based Therapies for PCOS. Reprod Sci 2023; 30:772-786. [PMID: 35764857 DOI: 10.1007/s43032-022-01013-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/14/2022] [Indexed: 12/23/2022]
Abstract
Polycystic ovarian syndrome (PCOS) can cause infertility in females due to hyperandrogenism and neuroendocrine abnormalities. The aim of this study is to decipher the impact of endocrine variables, hyperandogenism, insulin resistance, oxidative stress, and dietary conditions in PCOS conditions, subsequently to depict the role of epigenetic factors relative to phenotypic manifestations in PCOS conditions. We have reviewed several metabolic milieus pertinent to PCOS conditions. Comparative efficacies of various PCOS therapies, and recent clinical recommendations for the effective management of PCOS and role of metabolic/endocrine variables in PCOS conditions were described. Comparative therapeutic effects were vividly delineated according to the variable pathophysiology and internal variables during PCOS syndrome on the female body through the formation of cascade of endocrine pathology, which affects working capacity and fosters redox stress-induced cardiovascular, neural, and liver abnormalities. GLP-1 agonists, insulin sensitizers (metformin), and diet and exercise regimens efficacy were explained in enhancing the fertility outcomes among the overweight or obese females with PCOS. Comprehensive appraisal of DNA methylation as epigenetic changes and the manifestations of methylated genes in PCOS conditions were discussed particularly to screen novel molecular targets for developing efficient diagnostic indicators for predicting PCOS risk or its progression. Due to the reversible nature of epigenetic modifications, it is possible to screen the "druggable" regions to target or to correct abnormalities in the gene expression subsequently to develop chromatin-modifying therapies against PCOS.
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Affiliation(s)
- Viktor V Smirnov
- Department of Medical Rehabilitation and Sports Medicine, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation Saint Petersburg, Saint Petersburg, Russia
| | - Narasimha M Beeraka
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya str, Moscow, 119991, Russia. .,Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR; A DST-FIST Supported Center), Department of Biochemistry, JSS Medical College, Mysuru, India.
| | - Dmitry Yu Butko
- Department of Medical Rehabilitation and Sports Medicine, Saint Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation Saint Petersburg, Saint Petersburg, Russia
| | - Vladimir N Nikolenko
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya str, Moscow, 119991, Russia.,Department of Normal and Topographic Anatomy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Sergey A Bondarev
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya str, Moscow, 119991, Russia
| | - Evgeniy E Achkasov
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya str, Moscow, 119991, Russia
| | - Mikhail Y Sinelnikov
- Department of Human Anatomy, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya str, Moscow, 119991, Russia
| | - P R Hemanth Vikram
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
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6
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Mohandas S, Gayatri V, Kumaran K, Gopinath V, Paulmurugan R, Ramkumar KM. New Frontiers in Three-Dimensional Culture Platforms to Improve Diabetes Research. Pharmaceutics 2023; 15:pharmaceutics15030725. [PMID: 36986591 PMCID: PMC10056755 DOI: 10.3390/pharmaceutics15030725] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 02/25/2023] Open
Abstract
Diabetes mellitus is associated with defects in islet β-cell functioning and consequent hyperglycemia resulting in multi-organ damage. Physiologically relevant models that mimic human diabetic progression are urgently needed to identify new drug targets. Three-dimensional (3D) cell-culture systems are gaining a considerable interest in diabetic disease modelling and are being utilized as platforms for diabetic drug discovery and pancreatic tissue engineering. Three-dimensional models offer a marked advantage in obtaining physiologically relevant information and improve drug selectivity over conventional 2D (two-dimensional) cultures and rodent models. Indeed, recent evidence persuasively supports the adoption of appropriate 3D cell technology in β-cell cultivation. This review article provides a considerably updated view of the benefits of employing 3D models in the experimental workflow compared to conventional animal and 2D models. We compile the latest innovations in this field and discuss the various strategies used to generate 3D culture models in diabetic research. We also critically review the advantages and the limitations of each 3D technology, with particular attention to the maintenance of β-cell morphology, functionality, and intercellular crosstalk. Furthermore, we emphasize the scope of improvement needed in the 3D culture systems employed in diabetes research and the promises they hold as excellent research platforms in managing diabetes.
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Affiliation(s)
- Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Vijaya Gayatri
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Kriya Kumaran
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Vipin Gopinath
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Centre for Cancer Early Detection, Bio-X Program, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Molecular Oncology Division, Malabar Cancer Centre, Moozhikkara P.O, Thalassery 670103, Kerala, India
| | - Ramasamy Paulmurugan
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Centre for Cancer Early Detection, Bio-X Program, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Correspondence: (R.P.); (K.M.R.)
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
- Department of Radiology, Molecular Imaging Program at Stanford, Canary Centre for Cancer Early Detection, Bio-X Program, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Correspondence: (R.P.); (K.M.R.)
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7
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Dalco LJ, Dave KR. Diabetic Rodent Models for Chronic Stroke Studies. Methods Mol Biol 2023; 2616:429-439. [PMID: 36715951 DOI: 10.1007/978-1-0716-2926-0_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic diabetes may cause secondary complications like stroke and also increase post-stroke brain damage. In stroke research, the Stroke Therapy Academic Industry Roundtable (STAIR) identified criteria to increase translational value of preclinical studies, which highlighted the importance of using animal models of comorbidities. Numerous animal models have been used to study the aggravation of ischemic brain damage in diabetics. In this chapter, we discuss rat and mouse models of streptozotocin (STZ)-induced diabetes, with an efficient method provided. We also provide an overview of spontaneously diabetic rodent models. We present different pathophysiological features of diabetes in each rodent model along with the advantages and disadvantages of each model. Utilizing these models may aid the advancement of novel treatments and therapies to lower ischemic brain damage in patients of diabetes.
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Affiliation(s)
- Lea Julie Dalco
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, Department of Neurology and Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, Department of Neurology and Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA.
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8
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Zhang Y, Shen T, Wang S. Progression from prediabetes to type 2 diabetes mellitus induced by overnutrition. Hormones (Athens) 2022; 21:591-597. [PMID: 36197636 DOI: 10.1007/s42000-022-00399-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 09/19/2022] [Indexed: 12/31/2022]
Abstract
Prediabetes has developed into a global pandemic, its prevalence increasing year by year. Although lifestyle changes are advocated as the basis for prediabetes treatment, some patients fail to choose or adhere to appropriate interventions. The basis for selecting an appropriate intervention is determining the stage and cause of the disease. In this review, we aimed to examine the various types and disease processes of prediabetes caused by overnutrition, the present review supporting the hypothesis that overnutrition-induced hyperinsulinemia precedes insulin resistance (IR) and independently causes β-cell dysfunction. Tissue insulin resistance is the main feature of prediabetes with the crosstalk between tissues promoting the formation of systemic insulin resistance. Finally, both β-cell dysfunction induced by hyperinsulinemia or IR and reduced β-cell mass can lead to abnormal insulin secretion and contribute to development of type 2 diabetes mellitus (T2DM). Hence, overnutrition can cause multiple prediabetes phenotypes resulting in development of T2DM through different trajectories. Future diagnosis and treatment should therefore more carefully consider the disease phenotype and stage of development in patients with prediabetes to reduce the incidence of T2DM.
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Affiliation(s)
- Yuli Zhang
- School of Physical Education & Sports Science, South China Normal University, No.55, West of Zhongshan Ave., Tianhe District, Guangzhou City, 510006, Guangdong Province, China
| | - Tuming Shen
- School of Physical Education & Sports Science, South China Normal University, No.55, West of Zhongshan Ave., Tianhe District, Guangzhou City, 510006, Guangdong Province, China
| | - Songtao Wang
- School of Physical Education & Sports Science, South China Normal University, No.55, West of Zhongshan Ave., Tianhe District, Guangzhou City, 510006, Guangdong Province, China.
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9
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Basile G, Qadir MMF, Mauvais-Jarvis F, Vetere A, Shoba V, Modell AE, Pastori RL, Russ HA, Wagner BK, Dominguez-Bendala J. Emerging diabetes therapies: Bringing back the β-cells. Mol Metab 2022; 60:101477. [PMID: 35331962 PMCID: PMC8987999 DOI: 10.1016/j.molmet.2022.101477] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Stem cell therapies are finally coming of age as a viable alternative to pancreatic islet transplantation for the treatment of insulin-dependent diabetes. Several clinical trials using human embryonic stem cell (hESC)-derived β-like cells are currently underway, with encouraging preliminary results. Remaining challenges notwithstanding, these strategies are widely expected to reduce our reliance on human isolated islets for transplantation procedures, making cell therapies available to millions of diabetic patients. At the same time, advances in our understanding of pancreatic cell plasticity and the molecular mechanisms behind β-cell replication and regeneration have spawned a multitude of translational efforts aimed at inducing β-cell replenishment in situ through pharmacological means, thus circumventing the need for transplantation. SCOPE OF REVIEW We discuss here the current state of the art in hESC transplantation, as well as the parallel quest to discover agents capable of either preserving the residual mass of β-cells or inducing their proliferation, transdifferentiation or differentiation from progenitor cells. MAJOR CONCLUSIONS Stem cell-based replacement therapies in the mold of islet transplantation are already around the corner, but a permanent cure for type 1 diabetes will likely require the endogenous regeneration of β-cells aided by interventions to restore the immune balance. The promise of current research avenues and a strong pipeline of clinical trials designed to tackle these challenges bode well for the realization of this goal.
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Affiliation(s)
- G Basile
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - M M F Qadir
- Tulane University School of Medicine, New Orleans, LA, USA; Southeast Louisiana Veterans Affairs Medical Center, New Orleans, LA, USA
| | - F Mauvais-Jarvis
- Tulane University School of Medicine, New Orleans, LA, USA; Southeast Louisiana Veterans Affairs Medical Center, New Orleans, LA, USA
| | - A Vetere
- Broad Institute, Cambridge, MA, USA
| | - V Shoba
- Broad Institute, Cambridge, MA, USA
| | | | - R L Pastori
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - H A Russ
- Barbara Davis Center for Diabetes, Colorado University Anschutz Medical Campus, Aurora, CO, USA.
| | | | - J Dominguez-Bendala
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
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10
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Abstract
Leptin is a pluripotent peptide hormone produced mainly by adipocytes, as well as by other tissues such as the stomach. Leptin primarily acts on the central nervous system, particularly the hypothalamus, where this hormone regulates energy homeostasis and neuroendocrine function. Owing to this, disruption of leptin signaling has been linked with numerous pathological conditions. Recent studies have also highlighted the diverse roles of leptin in the digestive system including immune regulation, cell proliferation, tissue healing, and glucose metabolism. Of note, leptin acts differently under physiological and pathological conditions. Here, we review the current knowledge on the functions of leptin and its downstream signaling in the gastrointestinal tract and accessory digestive organs, with an emphasis on its physiological and pathological implications. We also discuss the current therapeutic uses of recombinant leptin, as well as its limitations.
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Affiliation(s)
- Min-Hyun Kim
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Hyeyoung Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
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11
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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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12
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Mimouni NEH, Paiva I, Barbotin AL, Timzoura FE, Plassard D, Le Gras S, Ternier G, Pigny P, Catteau-Jonard S, Simon V, Prevot V, Boutillier AL, Giacobini P. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. Cell Metab 2021; 33:513-530.e8. [PMID: 33539777 PMCID: PMC7928942 DOI: 10.1016/j.cmet.2021.01.004] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/20/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.
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Affiliation(s)
- Nour El Houda Mimouni
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France
| | - Isabel Paiva
- Université de Strasbourg, UMR 7364 CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), 12 Rue Goethe, Strasbourg 67000, France
| | - Anne-Laure Barbotin
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France
| | - Fatima Ezzahra Timzoura
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France
| | - Damien Plassard
- CNRS UMR 7104, INSERM U1258, GenomEast Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France
| | - Stephanie Le Gras
- CNRS UMR 7104, INSERM U1258, GenomEast Platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France
| | - Gaetan Ternier
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France
| | - Pascal Pigny
- CHU Lille, Service de Biochimie et Hormonologie, Centre de Biologie Pathologie, Lille, France
| | - Sophie Catteau-Jonard
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France; CHU Lille, Service de Gynécologie Médicale, Hôpital Jeanne de Flandre, Lille, France
| | - Virginie Simon
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France; CHU Lille, Service de Gynécologie Médicale, Hôpital Jeanne de Flandre, Lille, France
| | - Vincent Prevot
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France
| | - Anne-Laurence Boutillier
- Université de Strasbourg, UMR 7364 CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), 12 Rue Goethe, Strasbourg 67000, France.
| | - Paolo Giacobini
- Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Postnatal Brain, Lille Neuroscience & Cognition, UMR-S1172, FHU 1000 days for health, 59000 Lille, France.
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13
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A Practical Guide to Rodent Islet Isolation and Assessment Revisited. Biol Proced Online 2021; 23:7. [PMID: 33641671 PMCID: PMC7919091 DOI: 10.1186/s12575-021-00143-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/26/2021] [Indexed: 02/06/2023] Open
Abstract
Insufficient insulin secretion is a key component of both type 1 and type 2 diabetes. Since insulin is released by the islets of Langerhans, obtaining viable and functional islets is critical for research and transplantation. The effective and efficient isolation of these small islands of endocrine cells from the sea of exocrine tissue that is the rest of the pancreas is not necessarily simple or quick. Choosing and administering the digestive enzyme, separation of the islets from acinar tissue, and culture of islets are all things that must be considered. The purpose of this review is to provide a history of the development of islet isolation procedures and to serve as a practical guide to rodent islet research for newcomers to islet biology. We discuss key elements of mouse islet isolation including choosing collagenase, the digestion process, purification of islets using a density gradient, and islet culture conditions. In addition, this paper reviews techniques for assessing islet viability and function such as visual assessment, glucose-stimulated insulin secretion and intracellular calcium measurements. A detailed protocol is provided that describes a common method our laboratory uses to obtain viable and functional mouse islets for in vitro study. This review thus provides a strong foundation for successful procurement and purification of high-quality mouse islets for research purposes.
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14
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Casanova M, Branco S, Veiga IB, Barros A, Faísca P. Stereology in Grading and Prognosis of Canine Cutaneous Mast Cell Tumors. Vet Pathol 2021; 58:483-490. [PMID: 33576305 PMCID: PMC8064533 DOI: 10.1177/0300985820985138] [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] [Indexed: 11/25/2022]
Abstract
Canine cutaneous mast cell tumors (ccMCTs) are currently graded according to Patnaik and Kiupel grading schemes. The qualitative and semiquantitative parameters applied in these schemes may lead to inter- and intraobserver variability. This study investigates the prognostic value of volume-weighted mean nuclear volume (vv¯), a stereological estimation that provides information about nuclear size and its variability. vv¯ of 55 ccMCTs was estimated using the “point-sampled intercept” method and compared with histological grade and clinical outcome. The clinical history of dogs treated with surgical excision alone was available for 30 ccMCTs. Statistical differences in vv¯ were found between grade II (x¯ = 115 ± 29 µm3) and grade III ccMCTs (x ¯= 197 ± 63 µm3), as well as between low-grade (x ¯= 113 ± 28 µm3) and high-grade ccMCTs (x¯ = 184 ± 63 µm3). An optimal cutoff value of vv¯ ≥ 150 µm3 and vv¯ ≥ 140 µm3 was determined for grade III and high-grade ccMCTs, respectively. In terms of prognosis, vv¯ was not able to predict the clinical outcome in 42% of the cases; however, cases with vv¯ <125 µm3 had a favorable outcome. These results indicate that, despite having limited prognostic value when used as a solitary parameter, vv¯ is highly reproducible and is associated with histological grade as well as with benign behavior.
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Affiliation(s)
- Mafalda Casanova
- 70904Instituto Gulbenkian de Ciência, Oeiras, Portugal.,70989Universidade de Évora, Évora, Portugal
| | | | | | - André Barros
- 70904Instituto Gulbenkian de Ciência, Oeiras, Portugal
| | - Pedro Faísca
- 70904Instituto Gulbenkian de Ciência, Oeiras, Portugal.,FMV-ULHT, Lisbon, Portugal.,DNATech, Lisbon, Portugal
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15
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Field SL, Marrero MG, Dado-Senn B, Skibiel AL, Ramos PM, Scheffler TL, Laporta J. Peripheral serotonin regulates glucose and insulin metabolism in Holstein dairy calves. Domest Anim Endocrinol 2021; 74:106519. [PMID: 32739765 DOI: 10.1016/j.domaniend.2020.106519] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 06/24/2020] [Accepted: 07/02/2020] [Indexed: 12/28/2022]
Abstract
Peripheral serotonin regulates energy metabolism in several mammalian species, however, the potential contribution of serotonergic mechanisms as metabolic and endocrine regulators in growing dairy calves remain unexplored. Objectives were to characterize the role of serotonin in glucose and insulin metabolism in dairy calves with increased serotonin bioavailability. Milk replacer was supplemented with saline, 5-hydroxytryptophan (90 mg/d), or fluoxetine (40 mg/d) for 10-d (n = 8/treatment). Blood was collected daily during supplementation and on days 2, 7, and 14 during withdrawal. Calves were euthanized after 10-d supplementation or 14-d withdrawal periods to harvest liver and pancreas tissue. 5-hydroxytryptophan increased circulating insulin concentrations during the supplementation period, whereas both treatments increased circulating glucose concentration during the withdrawal period. The liver and pancreas of preweaned calves express serotonin factors (ie, TPH1, SERT, and cell surface receptors), indicating their ability to synthesize, uptake, and respond to serotonin. Supplementation of 5-hydroxytryptophan increased hepatic and pancreatic serotonin concentrations. After the withdrawal period, fluoxetine cleared from the pancreas but not liver tissue. Supplementation of 5-hydroxytryptophan upregulated hepatic mRNA expression of serotonin receptors (ie, 5-HTR1B, -1D, -2A, and -2B), and downregulated pancreatic 5-HTR1F mRNA and insulin-related proteins (ie, Akt and pAkt). Fluoxetine-supplemented calves had fewer pancreatic islets per microscopic field with reduced insulin intensity, whereas 5-hydroxytryptophan supplemented calves had increased islet number and area with greater insulin and serotonin and less glucagon intensities. After the 14-d withdrawal of 5-hydroxytryptophan, hepatic mRNA expression of glycolytic and gluconeogenic enzymes were simultaneously downregulated. Improving serotonin bioavailability could serve as a potent regulator of endocrine and metabolic processes in dairy calves.
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Affiliation(s)
- S L Field
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA
| | - M G Marrero
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA
| | - B Dado-Senn
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA
| | - A L Skibiel
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA
| | - P M Ramos
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA
| | - T L Scheffler
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA
| | - J Laporta
- Department of Animal Sciences, University of Florida, Gainesville, FL 32608, USA.
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16
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Roostalu U, Lercke Skytte J, Gravesen Salinas C, Klein T, Vrang N, Jelsing J, Hecksher-Sørensen J. 3D quantification of changes in pancreatic islets in mouse models of diabetes type I and II. Dis Model Mech 2020; 13:dmm045351. [PMID: 33158929 PMCID: PMC7758639 DOI: 10.1242/dmm.045351] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 10/16/2020] [Indexed: 01/16/2023] Open
Abstract
Diabetes is characterized by rising levels of blood glucose and is often associated with a progressive loss of insulin-producing beta cells. Recent studies have demonstrated that it is possible to regenerate new beta cells through proliferation of existing beta cells or trans-differentiation of other cell types into beta cells, raising hope that diabetes can be cured through restoration of functional beta cell mass. Efficient quantification of beta cell mass and islet characteristics is needed to enhance drug discovery for diabetes. Here, we report a 3D quantitative imaging platform for unbiased evaluation of changes in islets in mouse models of type I and II diabetes. To determine whether the method can detect pharmacologically induced changes in beta cell volume, mice were treated for 14 days with either vehicle or the insulin receptor antagonist S961 (2.4 nmol/day) using osmotic minipumps. Mice treated with S961 displayed increased blood glucose and insulin levels. Light-sheet imaging of insulin and Ki67 (also known as Mki67)-immunostained pancreata revealed a 43% increase in beta cell volume and 21% increase in islet number. S961 treatment resulted in an increase in islets positive for the cell proliferation marker Ki67, suggesting that proliferation of existing beta cells underlies the expansion of total beta cell volume. Using light-sheet imaging of a non-obese diabetic mouse model of type I diabetes, we also characterized the infiltration of CD45 (also known as PTPRC)-labeled leukocytes in islets. At 14 weeks, 40% of the small islets, but more than 80% of large islets, showed leukocyte infiltration. These results demonstrate how quantitative light-sheet imaging can capture changes in individual islets to help pharmacological research in diabetes.
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Affiliation(s)
| | | | | | - Thomas Klein
- Department of CardioMetabolic, Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, 88400 Biberach, Germany
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17
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Pandey S, Dvorakova MC. Future Perspective of Diabetic Animal Models. Endocr Metab Immune Disord Drug Targets 2020; 20:25-38. [PMID: 31241444 PMCID: PMC7360914 DOI: 10.2174/1871530319666190626143832] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/06/2019] [Accepted: 04/17/2019] [Indexed: 12/15/2022]
Abstract
Objective The need of today’s research is to develop successful and reliable diabetic animal models for understanding the disease susceptibility and pathogenesis. Enormous success of animal models had already been acclaimed for identifying key genetic and environmental factors like Idd loci and effects of microorganisms including the gut microbiota. Furthermore, animal models had also helped in identifying many therapeutic targets and strategies for immune-intervention. In spite of a quite success, we have acknowledged that many of the discovered immunotherapies are working on animals and did not have a significant impact on human. Number of animal models were developed in the past to accelerate drug discovery pipeline. However, due to poor initial screening and assessment on inequivalent animal models, the percentage of drug candidates who succeeded during clinical trials was very low. Therefore, it is essential to bridge this gap between pre-clinical research and clinical trial by validating the existing animal models for consistency. Results and Conclusion In this review, we have discussed and evaluated the significance of animal models on behalf of published data on PUBMED. Amongst the most popular diabetic animal models, we have selected six animal models (e.g. BioBreeding rat, “LEW IDDM rat”, “Nonobese Diabetic (NOD) mouse”, “STZ RAT”, “LEPR Mouse” and “Zucker Diabetic Fatty (ZDF) rat” and ranked them as per their published literature on PUBMED. Moreover, the vision and brief imagination for developing an advanced and robust diabetic model of 21st century was discussed with the theme of one mice-one human concept including organs-on-chips.
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Affiliation(s)
- Shashank Pandey
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Magdalena C Dvorakova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Physiology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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18
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Srebf2 Locus Overexpression Reduces Body Weight, Total Cholesterol and Glucose Levels in Mice Fed with Two Different Diets. Nutrients 2020; 12:nu12103130. [PMID: 33066385 PMCID: PMC7602228 DOI: 10.3390/nu12103130] [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: 09/22/2020] [Revised: 10/06/2020] [Accepted: 10/10/2020] [Indexed: 11/17/2022] Open
Abstract
Macronutrients represent risk factors for hyperlipidemia or diabetes. Lipid alterations and type 2 diabetes mellitus are global health problems. Overexpression of sterol regulatory element-binding factor (Srebf2) in transgenic animals is linked to elevated cholesterol levels and diabetes development. We investigated the impact of increased Srebf2 locus expression and the effects of control and high-fat, high-sucrose (HFHS) diets on body weight, glucose and lipid metabolisms in transgenic mice (S-mice). Wild type (WT) and S-mice were fed with both diets for 16 weeks. Plasma glucose, insulin and lipids were assessed (n = 25). Immunostainings were performed in liver, pancreas and fat (N = 10). Expression of Ldlr and Hmgcr in liver was performed by RT-PCR (N = 8). Control diet: S-mice showed reduced weight, insulin, total and HDL cholesterol and triglycerides (TG). HFHS diet widened differences in weight, total and HDL cholesterol, insulin and HOMA index but increased TG in S-mice. In S-mice, adipocyte size was lower while HFHS diet produced lower increase, pancreatic β-cell mass was lower with both diets and Srebf2, Ldlr and Hmgcr mRNA levels were higher while HFHS diet produced a rise in Srebf2 and Hmgcr levels. Srebf2 complete gene overexpression seems to have beneficial effects on metabolic parameters and to protect against HFHS diet effects.
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19
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Alvarsson A, Jimenez-Gonzalez M, Li R, Rosselot C, Tzavaras N, Wu Z, Stewart AF, Garcia-Ocaña A, Stanley SA. A 3D atlas of the dynamic and regional variation of pancreatic innervation in diabetes. SCIENCE ADVANCES 2020; 6:6/41/eaaz9124. [PMID: 33036983 PMCID: PMC7557000 DOI: 10.1126/sciadv.aaz9124] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 08/27/2020] [Indexed: 05/08/2023]
Abstract
Understanding the detailed anatomy of the endocrine pancreas, its innervation, and the remodeling that occurs in diabetes can provide new insights into metabolic disease. Using tissue clearing and whole-organ imaging, we identified the 3D associations between islets and innervation. This technique provided detailed quantification of α and β cell volumes and pancreatic nerve fibers, their distribution and heterogeneity in healthy tissue, canonical mouse models of diabetes, and samples from normal and diabetic human pancreata. Innervation was highly enriched in the mouse endocrine pancreas, with regional differences. Islet nerve density was increased in nonobese diabetic mice, in mice treated with streptozotocin, and in pancreata of human donors with type 2 diabetes. Nerve contacts with β cells were preserved in diabetic mice and humans. In summary, our whole-organ assessment allows comprehensive examination of islet characteristics and their innervation and reveals dynamic regulation of islet innervation in diabetes.
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Affiliation(s)
- Alexandra Alvarsson
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Maria Jimenez-Gonzalez
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rosemary Li
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Carolina Rosselot
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Nikolaos Tzavaras
- The Microscopy CoRE and Advanced Bioimaging Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Zhuhao Wu
- Department of Cell, Developmental & Regenerative Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Andrew F Stewart
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Adolfo Garcia-Ocaña
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sarah A Stanley
- Diabetes, Obesity, and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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20
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Miranda MA, Carson C, St. Pierre CL, Macias‐Velasco JF, Hughes JW, Kunzmann M, Schmidt H, Wayhart JP, Lawson HA. Spontaneous restoration of functional β-cell mass in obese SM/J mice. Physiol Rep 2020; 8:e14573. [PMID: 33113267 PMCID: PMC7592878 DOI: 10.14814/phy2.14573] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 12/23/2022] Open
Abstract
Maintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J's diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose-stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.
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Affiliation(s)
- Mario A. Miranda
- Department of GeneticsWashington University School of MedicineSaint LouisMOUSA
| | - Caryn Carson
- Department of GeneticsWashington University School of MedicineSaint LouisMOUSA
| | | | | | - Jing W. Hughes
- Department of MedicineWashington University School of MedicineSaint LouisMOUSA
| | - Marcus Kunzmann
- Department of GeneticsWashington University School of MedicineSaint LouisMOUSA
| | - Heather Schmidt
- Department of GeneticsWashington University School of MedicineSaint LouisMOUSA
| | - Jessica P. Wayhart
- Department of GeneticsWashington University School of MedicineSaint LouisMOUSA
| | - Heather A. Lawson
- Department of GeneticsWashington University School of MedicineSaint LouisMOUSA
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21
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Amouyal C, Castel J, Guay C, Lacombe A, Denom J, Migrenne-Li S, Rouault C, Marquet F, Georgiadou E, Stylianides T, Luquet S, Le Stunff H, Scharfmann R, Clément K, Rutter GA, Taboureau O, Magnan C, Regazzi R, Andreelli F. A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice. EBioMedicine 2020; 58:102895. [PMID: 32739864 PMCID: PMC7393530 DOI: 10.1016/j.ebiom.2020.102895] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/26/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. METHODS We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca2+-imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. FINDINGS EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. INTERPRETATION Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. FUNDING European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking (RHAPSODY), INSERM, Société Francophone du Diabète, Institut Benjamin Delessert, Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), Diabetes UK (BDA/11/0004210, BDA/15/0005275, BDA 16/0005485) project grants, National Science Foundation (310030-188447), Fondation de l'Avenir.
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Affiliation(s)
- Chloé Amouyal
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France; AP-HP, Pitié-Salpêtrière Hospital, Diabetology department, F-75013 Paris, France
| | - Julien Castel
- Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
| | - Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland
| | - Amélie Lacombe
- PreclinICAN, Institute of Cardiometabolism and Nutrition, Paris, France
| | - Jessica Denom
- Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
| | | | - Christine Rouault
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France
| | - Florian Marquet
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France
| | - Eleni Georgiadou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | | | - Serge Luquet
- Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
| | - Hervé Le Stunff
- Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France
| | - Raphael Scharfmann
- Université de Paris, Cochin Institute, Inserm U1016, Paris 75014, France
| | - Karine Clément
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France; APHP, Pitié-Salpêtrière Hospital, Nutrition department, F-75013 Paris, France
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Lee Kong Chian School of Medicine, Nan Yang Technological University, Singapore
| | - Olivier Taboureau
- Université de Paris, BFA, Team CMPLI, Inserm U1133, CNRS UMR 8251, Paris, France
| | | | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Rue du Bugnon 7, CH-1005 Lausanne, Switzerland
| | - Fabrizio Andreelli
- Sorbonne Université, INSERM, Nutrition and Obesities; Systemic approaches (NutriOmics), Paris, France; AP-HP, Pitié-Salpêtrière Hospital, Diabetology department, F-75013 Paris, France.
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22
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Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest 2020; 129:4001-4008. [PMID: 31424428 DOI: 10.1172/jci129188] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.
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Affiliation(s)
| | - Jane Eb Reusch
- Division of Endocrinology, University of Colorado Anschutz Medical Center, Aurora, Colorado, USA
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Lee D, Shin Y, Jang J, Park Y, Ahn J, Jeong S, Shin SS, Yoon M. The herbal extract ALS-L1023 from Melissa officinalis alleviates visceral obesity and insulin resistance in obese female C57BL/6J mice. JOURNAL OF ETHNOPHARMACOLOGY 2020; 253:112646. [PMID: 32027997 DOI: 10.1016/j.jep.2020.112646] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/13/2020] [Accepted: 02/01/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Melissa officinalis L. (Labiatae; lemon balm) has traditionally been used as a medicinal herb to treat stress, anxiety, and insomnia. Current reports suggest that not only chronic stress stimulates angiogenesis, but angiogenesis also regulates adipogenesis and obesity. Because the herbal extract ALS-L1023 from Melissa officinalis inhibits angiogenesis, we hypothesized that ALS-L1023 could suppress visceral obesity and insulin resistance in obese female C57BL/6J mice, a mouse model of obese premenopausal women. MATERIALS AND METHODS The mice were grouped and fed for 16 weeks as follows: 1) low-fat diet (LFD), 2) high-fat diet (HFD), or 3) HFD supplemented with 0.4 or 0.8% ALS-L1023. Variables and determinants of visceral obesity, insulin resistance, and pancreatic dysfunction were then assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS ALS-L1023 decreased weight gain, visceral adipocyte size, and serum lipid levels in HFD-fed obese mice. ALS-L1023 also normalized hyperglycemia and hyperinsulinemia and concomitantly reduced blood glucose levels during oral glucose tolerance tests. The pancreatic islet size and insulin-positive β-cell area were significantly reduced in ALS-L1023-treated mice compared with untreated obese controls, reaching a level similar to that of LFD-fed lean mice. ALS-L1023 suppressed pancreatic lipid accumulation, infiltration of inflammatory cells, and collagen levels. ALS-L1023 treatment altered the pancreatic expression of genes involved in steatosis, inflammation, and fibrosis. CONCLUSIONS Our findings indicate that the herbal extract ALS-L1023 from Melissa officinalis not only inhibits visceral obesity, but also attenuates the increased fasting blood glucose, impaired glucose tolerance, and pancreatic dysfunction seen in female obese mice. These results suggest that ALS-L1023 may be effective in the prevention of visceral obesity and insulin resistance in obese premenopausal women.
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Affiliation(s)
- Dongju Lee
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Yujin Shin
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Joonseong Jang
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Yonghyun Park
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Jiwon Ahn
- Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Sunhyo Jeong
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Soon Shik Shin
- Department of Formula Sciences, College of Oriental Medicine, Dongeui University, Busan, 47340, South Korea.
| | - Michung Yoon
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea.
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24
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Jensen VFH, Mølck AM, Bøgh IB, Nowak J, Viuff BM, Rasmussen CLM, Pedersen L, Fels JJ, Madsen SH, McGuigan FE, Tveden-Nyborg P, Lykkesfeldt J, Akesson KE. Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats. Sci Rep 2020; 10:5609. [PMID: 32221393 PMCID: PMC7101337 DOI: 10.1038/s41598-020-62554-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/16/2020] [Indexed: 11/12/2022] Open
Abstract
Maternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.
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Affiliation(s)
- Vivi F H Jensen
- Novo Nordisk A/S, Department of Toxicology, Safety Pharmacology and Pathology, Maaloev, Denmark. .,University of Copenhagen, Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Copenhagen, Denmark. .,Lund University, Department of Clinical Sciences Malmö and Skåne University Hospital, Department of Orthopedics, Malmö, Sweden.
| | - Anne-Marie Mølck
- Novo Nordisk A/S, Department of Toxicology, Safety Pharmacology and Pathology, Maaloev, Denmark
| | - Ingrid B Bøgh
- Novo Nordisk A/S, Department of Toxicology, Safety Pharmacology and Pathology, Maaloev, Denmark
| | - Jette Nowak
- Novo Nordisk A/S, Department of Toxicology, Safety Pharmacology and Pathology, Maaloev, Denmark
| | - Birgitte M Viuff
- Novo Nordisk A/S, Department of Toxicology, Safety Pharmacology and Pathology, Maaloev, Denmark
| | - Charlotte L M Rasmussen
- University of Copenhagen, Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Copenhagen, Denmark
| | - Louise Pedersen
- University of Copenhagen, Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Copenhagen, Denmark
| | - Johannes J Fels
- Novo Nordisk A/S, Department of Research Bioanalysis, Maaloev, Denmark
| | - Suzi H Madsen
- Novo Nordisk A/S, Department of Research Bioanalysis, Maaloev, Denmark
| | - Fiona E McGuigan
- Lund University, Department of Clinical Sciences Malmö and Skåne University Hospital, Department of Orthopedics, Malmö, Sweden
| | - Pernille Tveden-Nyborg
- University of Copenhagen, Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Copenhagen, Denmark
| | - Jens Lykkesfeldt
- University of Copenhagen, Department of Veterinary and Animal Sciences, Section for Experimental Animal Models, Copenhagen, Denmark
| | - Kristina E Akesson
- Lund University, Department of Clinical Sciences Malmö and Skåne University Hospital, Department of Orthopedics, Malmö, Sweden
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25
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Pittala S, Levy I, De S, Kumar Pandey S, Melnikov N, Hyman T, Shoshan-Barmatz V. The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus. Cells 2020; 9:E481. [PMID: 32093016 PMCID: PMC7072803 DOI: 10.3390/cells9020481] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 02/10/2020] [Accepted: 02/14/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus is a metabolic disorder approaching epidemic proportions. Non-alcoholic fatty liver disease (NAFLD) regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. Recently, we demonstrated that the voltage-dependent anion channel 1 (VDAC1) is involved in NAFLD. VDAC1 is an outer mitochondria membrane protein that serves as a mitochondrial gatekeeper, controlling metabolic and energy homeostasis, as well as crosstalk between the mitochondria and the rest of the cell. It is also involved in mitochondria-mediated apoptosis. Here, we demonstrate that the VDAC1-based peptide, R-Tf-D-LP4, affects several parameters of a NAFLD mouse model in which administration of streptozotocin (STZ) and high-fat diet 32 (STZ/HFD-32) led to both type 2 diabetes (T2D) and NAFLD phenotypes. We focused on diabetes, showing that R-Tf-D-LP4 peptide treatment of STZ/HFD-32 fed mice restored the elevated blood glucose back to close to normal levels, and increased the number and average size of islets and their insulin content as compared to untreated controls. Similar results were obtained when staining the islets for glucose transporter type 2. In addition, the R-Tf-D-LP4 peptide decreased the elevated glucose levels in a mouse displaying obese, diabetic, and metabolic symptoms due to a mutation in the obese (ob) gene. To explore the cause of the peptide-induced improvement in the endocrine pancreas phenotype, we analyzed the expression levels of the proliferation marker, Ki-67, and found it to be increased in the islets of STZ/HFD-32 fed mice treated with the R-Tf-D-LP4 peptide. Moreover, peptide treatment of STZ/HFD-32 fed mice caused an increase in the expression of β-cell maturation and differentiation PDX1 transcription factor that enhances the expression of the insulin-encoding gene, and is essential for islet development, function, proliferation, and maintenance of glucose homeostasis in the pancreas. This increase occurred mainly in the β-cells, suggesting that the source of their increased number after R-Tf-D-LP4 peptide treatment was most likely due to β-cell proliferation. These results suggest that the VDAC1-based R-Tf-D-LP4 peptide has potential as a treatment for diabetes.
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Affiliation(s)
| | | | | | | | | | | | - Varda Shoshan-Barmatz
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (S.P.); (I.L.); (S.D.); (S.K.P.); (N.M.); (T.H.)
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26
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Wan S, Zhang J, Chen X, Lang J, Li L, Chen F, Tian L, Meng Y, Yu X. MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment. Front Endocrinol (Lausanne) 2020; 11:9. [PMID: 32038500 PMCID: PMC6989481 DOI: 10.3389/fendo.2020.00009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/07/2020] [Indexed: 02/05/2023] Open
Abstract
Objective: To clarify the role and mechanism of miR-17-92 cluster in islet beta-cell repair after streptozotocin intervention. Methods: Genetically engineered mice (miR-17-92βKO) and control RIP-Cre mice were intraperitoneally injected with multiple low dose streptozotocin. Body weight, random blood glucose (RBG), fasting blood glucose, and intraperitoneal glucose tolerance test (IPGTT) were monitored regularly. Mice were sacrificed for histological analysis 8 weeks later. Morphological changes of pancreas islets, quantity, quality, apoptosis, and proliferation of beta-cells were measured. Islets from four groups were isolated. MiRNA and mRNA were extracted and quantified. Results:MiR-17-92βKO mice showed dramatically elevated fasting blood glucose and impaired glucose tolerance after streptozotocin treatment in contrast to control mice, the reason of which is reduced beta-cell number and total mass resulting from reduced proliferation, enhanced apoptosis of beta-cells. Genes related to cell proliferation and insulin transcription repression were significantly elevated in miR-17-92βKO mice treated with streptozotocin. Furthermore, genes involved in DNA biosynthesis and damage repair were dramatically increased in miR-17-92βKO mice with streptozotocin treatment. Conclusion: Collectively, our results demonstrate that homozygous deletion of miR-17-92 cluster in mouse pancreatic beta-cells promotes the development of experimental diabetes, indicating that miR-17-92 cluster may be positively related to beta-cells restoration and adaptation after streptozotocin-induced damage.
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Affiliation(s)
- Shan Wan
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Zhang
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jiangli Lang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Fei Chen
- Histology and Imaging Platform, Core Facility of West China Hospital, Sichuan University, Chengdu, China
| | - Li Tian
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Meng
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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27
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Dwijayanti DR, Shimada T, Ishii T, Okuyama T, Ikeya Y, Mukai E, Nishizawa M. Bitter melon fruit extract has a hypoglycemic effect and reduces hepatic lipid accumulation in ob/ob mice. Phytother Res 2019; 34:1338-1346. [PMID: 31845444 DOI: 10.1002/ptr.6600] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 11/12/2019] [Accepted: 12/01/2019] [Indexed: 01/14/2023]
Abstract
Bitter melon (Momordica charantia L.) is a vegetable and has been used as traditional medicine. Recently, we reported that bitter melon fruit extracts and its ethyl acetate (EtOAc)-soluble fraction markedly suppressed the expression of proinflammatory genes, including the inducible nitric oxide synthase gene. However, it is unclear whether bitter melon exhibits antidiabetic effects. In this study, we showed that cucurbitacin B, a cucurbitane-type triterpenoid, was present in an EtOAc-soluble fraction and suppressed nitric oxide production in hepatocytes. When the EtOAc-soluble fraction was administered for 7 days to ob/ob mice, a type 2 diabetes mellitus model, the mice fed with this fraction exhibited a significant decrease in body weight and blood glucose concentrations compared with the mice fed without the fraction. The administration of the fraction resulted in significant increases in serum insulin concentrations and the levels of both insulin receptor mRNA and protein in the ob/ob mouse liver. The EtOAc-soluble fraction decreased the interleukin-1β mRNA expression, as well as hepatic lipid accumulation in hepatocytes. Taken together, these results indicate that administration of an EtOAc-soluble fraction improved hyperglycemia and hepatic steatosis, suggesting that this fraction may be responsible for both the antidiabetic and anti-inflammatory effects of bitter melon fruit.
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Affiliation(s)
- Dinia R Dwijayanti
- Medical Chemistry Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Takumi Shimada
- Medical Physiology and Metabolism Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Toshinari Ishii
- Medical Chemistry Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Tetsuya Okuyama
- Medical Chemistry Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Yukinobu Ikeya
- Center for Supporting Pharmaceutical Education, Daiichi University of Pharmacy, Minami-ku, Fukuoka, Japan
| | - Eri Mukai
- Medical Physiology and Metabolism Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Mikio Nishizawa
- Medical Chemistry Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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28
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Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ. Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells. J Biol Chem 2019; 294:4656-4666. [PMID: 30700550 PMCID: PMC6433064 DOI: 10.1074/jbc.ra118.006085] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/25/2019] [Indexed: 12/18/2022] Open
Abstract
β-Cell mitochondria play a central role in coupling glucose metabolism with insulin secretion. Here, we identified a metabolic function of cyclin-dependent kinase 1 (CDK1)/cyclin B1-the activation of mitochondrial respiratory complex I-that is active in quiescent adult β-cells and hyperactive in β-cells from obese (ob/ob) mice. In WT islets, respirometry revealed that 65% of complex I flux and 49% of state 3 respiration is sensitive to CDK1 inhibition. Islets from ob/ob mice expressed more cyclin B1 and exhibited a higher sensitivity to CDK1 blockade, which reduced complex I flux by 76% and state 3 respiration by 79%. The ensuing reduction in mitochondrial NADH utilization, measured with two-photon NAD(P)H fluorescence lifetime imaging (FLIM), was matched in the cytosol by a lag in citrate cycling, as shown with a FRET reporter targeted to β-cells. Moreover, time-resolved measurements revealed that in ob/ob islets, where complex I flux dominates respiration, CDK1 inhibition is sufficient to restrict the duty cycle of ATP/ADP and calcium oscillations, the parameter that dynamically encodes β-cell glucose sensing. Direct complex I inhibition with rotenone mimicked the restrictive effects of CDK1 inhibition on mitochondrial respiration, NADH turnover, ATP/ADP, and calcium influx. These findings identify complex I as a critical mediator of obesity-associated metabolic remodeling in β-cells and implicate CDK1 as a regulator of complex I that enhances β-cell glucose sensing.
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Affiliation(s)
- Trillian Gregg
- From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and
| | - Sophia M Sdao
- From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and
| | - Rashpal S Dhillon
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Jarred W Rensvold
- Morgridge Institute for Research and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53715, and
| | - Sophie L Lewandowski
- From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and
| | - David J Pagliarini
- Morgridge Institute for Research and Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53715, and
| | - John M Denu
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705
| | - Matthew J Merrins
- From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705
- William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705
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29
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Zhong F, Jiang Y. Endogenous Pancreatic β Cell Regeneration: A Potential Strategy for the Recovery of β Cell Deficiency in Diabetes. Front Endocrinol (Lausanne) 2019; 10:101. [PMID: 30842756 PMCID: PMC6391341 DOI: 10.3389/fendo.2019.00101] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/04/2019] [Indexed: 12/11/2022] Open
Abstract
Endogenous pancreatic β cell regeneration is a potential strategy for β cell expansion or neogenesis to treat diabetes. Regeneration can occur through stimulation of existing β cell replication or conversion of other pancreatic cells into β cells. Recently, various strategies and approaches for stimulation of endogenous β cell regeneration have been evaluated, but they were not suitable for clinical application. In this paper, we comprehensively review these strategies, and further discuss various factors involved in regulation of β cell regeneration under physiological or pathological conditions, such as mediators, transcription factors, signaling pathways, and potential pharmaceutical drugs. Furthermore, we discuss possible reasons for the failure of regenerative medicines in clinical trials, and possible strategies for improving β cell regeneration. As β cell heterogeneity and plasticity determines their function and environmental adaptability, we focus on β cell subtype markers and discuss the importance of research evaluating the characteristics of new β cells. In addition, based on the autoimmunologic features of type 1 diabetes, NOD/Lt-SCID-IL2rg null (NSG) mice grafted with human immune cells and β cells are recommended for use in evaluation of antidiabetic regenerative medicines. This review will further understand current advances in endogenous β cell regeneration, and provide potential new strategies for the treatment of diabetes focused on cell therapy.
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Affiliation(s)
- Fan Zhong
- Department of Gastroenterology, Songjiang Hospital Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
- Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China
| | - Yan Jiang
- Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China
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30
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Ramos-Lobo AM, Teixeira PD, Furigo IC, Melo HM, de M Lyra E Silva N, De Felice FG, Donato J. Long-term consequences of the absence of leptin signaling in early life. eLife 2019; 8:40970. [PMID: 30694175 PMCID: PMC6384028 DOI: 10.7554/elife.40970] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 01/28/2019] [Indexed: 12/11/2022] Open
Abstract
Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the fourth or tenth week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems. Leptin is a hormone that keeps us healthy in many ways. It regulates our body weight by reining in our appetite and fine-tuning the energy we burn, and it helps us establish and maintain our fertility. It also participates in brain development. Leptin performs these roles by attaching to specific receptors in nerve cells and relaying relevant information to the brain. Early events can trigger life-long changes in the way our body works, a process called metabolic programming. Leptin is believed to participate in this reprogramming mechanism, but its role remains uncertain. In particular, it is still unclear which leptin-driven changes are permanent, and which ones are reversible. Being able to distinguish between the two types of alterations would help to better grasp the role leptin plays in early development. Here, Ramos-Lobo et al. examined genetically engineered mice born without a working leptin receptor. These animals were impervious to the effects of leptin. Then, once the rodents were adults, they were treated with a drug that restored their leptin receptors, making them sensitive to the hormone again. These experiments revealed that mice without leptin receptors during early life developed obesity, were less able to lose weight and burned less energy. Their reproductive success was also compromised. Finally, the lack of leptin during development caused permanent reduction of the animals’ brains, and changes in the activity of certain genes in the organ. The work by Ramos-Lobo et al. indicates that in mice, lacking leptin sensibility early in life conditions the body to permanently become ‘thrifty’, burning less energy and making it harder to lose weight. It is rare for humans to be born completely without leptin activity. Yet, having too much or too little food as a baby affects the level of the hormone, or our sensitivity to it: this may permanently change the way our bodies manage energy. Ultimately, learning more about these mechanisms could help us ward off or treat obesity.
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Affiliation(s)
- Angela M Ramos-Lobo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Pryscila Ds Teixeira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Isadora C Furigo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Helen M Melo
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Natalia de M Lyra E Silva
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Centre for Neuroscience Studies, Department of Psychiatry, Queen's University, Kingston, Canada
| | - Fernanda G De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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31
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Kumar SA, Delgado M, Mendez VE, Joddar B. Applications of stem cells and bioprinting for potential treatment of diabetes. World J Stem Cells 2019; 11:13-32. [PMID: 30705712 PMCID: PMC6354103 DOI: 10.4252/wjsc.v11.i1.13] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/26/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Currently, there does not exist a strategy that can reduce diabetes and scientists are working towards a cure and innovative approaches by employing stem cell-based therapies. On the other hand, bioprinting technology is a novel therapeutic approach that aims to replace the diseased or lost β-cells, insulin-secreting cells in the pancreas, which can potentially regenerate damaged organs such as the pancreas. Stem cells have the ability to differentiate into various cell lines including insulin-producing cells. However, there are still barriers that hamper the successful differentiation of stem cells into β-cells. In this review, we focus on the potential applications of stem cell research and bioprinting that may be targeted towards replacing the β-cells in the pancreas and may offer approaches towards treatment of diabetes. This review emphasizes on the applicability of employing both stem cells and other cells in 3D bioprinting to generate substitutes for diseased β-cells and recover lost pancreatic functions. The article then proceeds to discuss the overall research done in the field of stem cell-based bioprinting and provides future directions for improving the same for potential applications in diabetic research.
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Affiliation(s)
- Shweta Anil Kumar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Monica Delgado
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Victor E Mendez
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Binata Joddar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States.
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32
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Farack L, Golan M, Egozi A, Dezorella N, Bahar Halpern K, Ben-Moshe S, Garzilli I, Tóth B, Roitman L, Krizhanovsky V, Itzkovitz S. Transcriptional Heterogeneity of Beta Cells in the Intact Pancreas. Dev Cell 2018; 48:115-125.e4. [PMID: 30503750 DOI: 10.1016/j.devcel.2018.11.001] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 09/14/2018] [Accepted: 10/31/2018] [Indexed: 12/27/2022]
Abstract
Pancreatic beta cells have been shown to be heterogeneous at multiple levels. However, spatially interrogating transcriptional heterogeneity in the intact tissue has been challenging. Here, we developed an optimized protocol for single-molecule transcript imaging in the intact pancreas and used it to identify a sub-population of "extreme" beta cells with elevated mRNA levels of insulin and other secretory genes. Extreme beta cells contain higher ribosomal and proinsulin content but lower levels of insulin protein in fasted states, suggesting they may be tuned for basal insulin secretion. They exhibit a distinctive intra-cellular polarization pattern, with elevated mRNA concentrations in an apical ER-enriched compartment, distinct from the localization of nascent and mature proteins. The proportion of extreme cells increases in db/db diabetic mice, potentially facilitating the required increase in basal insulin. Our results thus highlight a sub-population of beta cells that may carry distinct functional roles along physiological and pathological timescales.
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Affiliation(s)
- Lydia Farack
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Matan Golan
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Adi Egozi
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Nili Dezorella
- Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Keren Bahar Halpern
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Shani Ben-Moshe
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Immacolata Garzilli
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Beáta Tóth
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Lior Roitman
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Valery Krizhanovsky
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Shalev Itzkovitz
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
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33
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Nakamura T, Ichii O, Irie T, Kouguchi H, Sotozaki K, Chihara M, Sunden Y, Nagasaki KI, Tatsumi O, Elewa YHA, Kon Y. Cotton rat (Sigmodon hispidus) develops metabolic disorders associated with visceral adipose inflammation and fatty pancreas without obesity. Cell Tissue Res 2018; 375:483-492. [PMID: 30155650 DOI: 10.1007/s00441-018-2908-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 08/07/2018] [Indexed: 12/27/2022]
Abstract
Obesity induces metabolic disorders such as type 2 diabetes, hypertension, and cardiovascular diseases and has become a global health concern. Recent studies imply that fat accumulation in nonadipose tissue correlates with metabolic disorders. However, there are no suitable animal models to evaluate this phenomenon. This study investigated the characteristics of metabolic disorders found in cotton rat (Sigmodon hispidus). Blood biochemical examinations revealed that cotton rats, predominantly males, developed hyperinsulinemia, hyperglycemia, and dyslipidemia when fed a normal diet. The islets increased in size through β-cell hyperplasia, which was associated with serum insulin level in both sexes, strongly indicating insulin resistance. In male cotton rats, oxidative stress was observed in β cells, and macrophage infiltration into the visceral white adipose tissue was reported, both of which were associated with serum insulin level without visceral obesity. In contrast, female cotton rats developed hyperinsulinemia without histopathological changes that were reported in males. Adipocytes were found to be accumulated in the pancreas but not in the liver of both sexes during aging. Pancreatic fat accumulation was associated with the serum insulin level only in females. Taken together, cotton rats developed metabolic disorders associated with visceral fat inflammation in the absence of obesity. In addition, pancreatic ectopic fat may also be related to the early stages of these conditions. Thus, the cotton rat may serve as a novel and useful model for metabolic disorders characterized by visceral adipose inflammation and ectopic fat accumulation in the pancreas without obesity.
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Affiliation(s)
- Teppei Nakamura
- Section of Biological Science, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Hokkaido, 066-0052, Japan.,Laboratory of Anatomy, Division of Veterinary Medicine, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Osamu Ichii
- Laboratory of Anatomy, Division of Veterinary Medicine, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Takao Irie
- Medical Zoology Group, Department of Infectious Diseases, Hokkaido Institute of Public Health, Sapporo, Hokkaido, 060-0819, Japan
| | - Hirokazu Kouguchi
- Medical Zoology Group, Department of Infectious Diseases, Hokkaido Institute of Public Health, Sapporo, Hokkaido, 060-0819, Japan
| | - Kozue Sotozaki
- Sankyo Labo Service Corporation, Inc., Sapporo, Hokkaido, 004-0802, Japan
| | - Masataka Chihara
- Laboratory of Anatomy, Division of Veterinary Medicine, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Yuji Sunden
- Laboratory of Veterinary Pathology, Faculty of Agriculture, Tottori University, Tottori, 680-0945, Japan
| | - Ken-Ichi Nagasaki
- Section of Biological Safety Research, Tama Laboratory, Japan Food Research Laboratories, Tama, Tokyo, 206-0025, Japan
| | - Osamu Tatsumi
- Section of Biological Science, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Hokkaido, 066-0052, Japan
| | - Yaser Hosny Ali Elewa
- Laboratory of Anatomy, Division of Veterinary Medicine, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.,Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Yasuhiro Kon
- Laboratory of Anatomy, Division of Veterinary Medicine, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
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Wang H, He X, Lei T, Liu Y, Huai G, Sun M, Deng S, Yang H, Tong R, Wang Y. Mangiferin induces islet regeneration in aged mice through regulating p16INK4a. Int J Mol Med 2018; 41:3231-3242. [PMID: 29512742 PMCID: PMC5881804 DOI: 10.3892/ijmm.2018.3524] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 02/28/2018] [Indexed: 12/13/2022] Open
Abstract
Previous studies by our group on mangiferin demonstrated that it exerts an anti‑hyperglycemic effect through the regulation of cell cycle proteins in 3‑month‑old, partially pancreatectomized (PPx) mice. However, β‑cell proliferation is known to become severely restricted with advanced age. Therefore, it is unknown whether mangiferin is able to reverse the diabetic condition and retain β‑cell regeneration capability in aged mice. In the present study, 12‑month‑old C57BL/6J mice that had undergone PPx were subjected to mangiferin treatment (90 mg/kg) for 28 days. Mangiferin‑treated aged mice exhibited decreased blood glucose levels and increased glucose tolerance, which was accompanied with higher serum insulin levels when compared with those in untreated PPx control mice. In addition, islet hyperplasia, elevated β‑cell proliferation and reduced β‑cell apoptosis were also identified in the mice that received mangiferin treatment. Further studies on the mRNA transcript and protein expression levels indicated comparatively increased levels of cyclins D1 and D2 and cyclin‑dependent kinase 4 in mangiferin‑treated mice, while the levels of p27Kip1 and p16INK4a were decreased relative to those in the untreated PPx controls. Of note, mangiferin treatment improved the proliferation rate of islet β‑cells in adult mice overexpressing p16INK4a, suggesting that mangiferin induced β‑cell proliferation via the regulation of p16INK4a. In addition, the mRNA transcription levels of critical genes associated with insulin secretion, including pancreatic and duodenal homeobox 1, glucose transporter 2 and glucokinase, were observed to be upregulated after mangiferin treatment. Taken together, it was indicated that mangiferin treatment significantly induced β‑cell proliferation and inhibited β‑cell apoptosis by regulating cell cycle checkpoint proteins. Furthermore, mangiferin was also demonstrated to regulate genes associated with insulin secretion. Collectively these, results suggest the therapeutic potential of mangiferin in the treatment of diabetes in aged individuals.
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Affiliation(s)
| | - Xia He
- Personalized Drug Therapy Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072
| | - Tiantian Lei
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054
| | - Yilong Liu
- Department of Pharmacy, The People's Hospital of Leshan, Leshan, Sichuan 614000
| | - Guoli Huai
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054
| | - Minghan Sun
- Department of Gynecology, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Shaoping Deng
- Institute of Organ Transplantation
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054
| | - Hongji Yang
- Institute of Organ Transplantation
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054
| | - Rongsheng Tong
- Personalized Drug Therapy Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054
| | - Yi Wang
- Personalized Drug Therapy Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054
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35
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Haupt-Jorgensen M, Larsen J, Josefsen K, Jørgensen TZ, Antvorskov JC, Hansen AK, Buschard K. Gluten-free diet during pregnancy alleviates signs of diabetes and celiac disease in NOD mouse offspring. Diabetes Metab Res Rev 2018; 34:e2987. [PMID: 29392873 DOI: 10.1002/dmrr.2987] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 01/08/2018] [Accepted: 01/22/2018] [Indexed: 01/23/2023]
Abstract
BACKGROUND Gluten-free (GF) diet during pregnancy ameliorates autoimmune diabetes in nonobese diabetic (NOD) mouse offspring. Due to comorbidity of celiac disease in type 1 diabetes, we hypothesized that GF diet in utero alleviates the humoral and histopathological signs of celiac disease in NOD mice. We aimed to establish the mechanisms behind the diabetes-protective effect of GF diet in utero. METHODS Breeding pairs of NOD mice were fed a GF or gluten-containing standard (STD) diet until parturition. The offspring were nursed by mothers on STD diet and continued on this diet until ages 4 and 13 weeks. Analyses of serum antitissue transglutaminase (anti-tTG) intestine and islet histology, islet transglutaminase (TG) activity, and cytokine expression in T cells from lymphoid organs were performed. RESULTS GF versus STD diet in utero led to reduced serum anti-tTG titre and increased villus-to-crypt ratio at both ages. Insulitis along with systemic and local inflammation were decreased, but islet TG activity was unchanged in 13-week-old GF mice. These mice had unchanged beta-cell volumes, but increased islet numbers throughout the prediabetic period. CONCLUSIONS Collectively, GF diet administered during pregnancy improves signs of celiac disease and autoimmune diabetes in the offspring. The diabetes-ameliorative effect of GF diet in utero is followed by dampening of inflammation, unchanged beta-cell volume, but increased islet numbers.
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Affiliation(s)
| | - Jesper Larsen
- The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark
| | - Knud Josefsen
- The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark
| | | | | | - Axel K Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
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36
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Stermann T, Menzel F, Weidlich C, Jeruschke K, Weiss J, Altenhofen D, Benninghoff T, Pujol A, Bosch F, Rustenbeck I, Ouwens DM, Thoresen GH, de Wendt C, Lebek S, Schallschmidt T, Kragl M, Lammert E, Chadt A, Al-Hasani H. Deletion of the RabGAP TBC1D1 Leads to Enhanced Insulin Secretion and Fatty Acid Oxidation in Islets From Male Mice. Endocrinology 2018; 159:1748-1761. [PMID: 29481597 DOI: 10.1210/en.2018-00087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 01/26/2018] [Indexed: 01/24/2023]
Abstract
The Rab guanosine triphosphatase-activating protein (RabGAP) TBC1D1 has been shown to be a key regulator of glucose and lipid metabolism in skeletal muscle. Its function in pancreatic islets, however, is not yet fully understood. Here, we aimed to clarify the specific impact of TBC1D1 on insulin secretion and substrate use in pancreatic islets. We analyzed the dynamics of glucose-stimulated insulin secretion (GSIS) and lipid metabolism in isolated islets from Tbc1d1-deficient (D1KO) mice. To further investigate the underlying cellular mechanisms, we conducted pharmacological studies in these islets. In addition, we determined morphology and number of both pancreatic islets and insulin vesicles in β-cells using light and transmission electron microscopy. Isolated pancreatic islets from D1KO mice exhibited substantially increased GSIS compared with wild-type (WT) controls. This was attributed to both enhanced first and second phase of insulin secretion, and this enhanced secretion persisted during repetitive glucose stimuli. Studies with sulfonylureas or KCl in isolated islets demonstrated that TBC1D1 exerts its function via a signaling pathway at the level of membrane depolarization. In line, ultrastructural analysis of isolated pancreatic islets revealed both higher insulin-granule density and number of docked granules in β-cells from D1KO mice compared with WT controls. Like in skeletal muscle, lipid use in isolated islets was enhanced upon D1KO, presumably as a result of a higher mitochondrial fission rate and/or higher mitochondrial activity. Our results clearly demonstrate a dual role of TBC1D1 in controlling substrate metabolism of the pancreatic islet.
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Affiliation(s)
- Torben Stermann
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Franziska Menzel
- German Institute for Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Carmen Weidlich
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
| | - Kay Jeruschke
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
| | - Jürgen Weiss
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
| | - Delsi Altenhofen
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Tim Benninghoff
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Anna Pujol
- Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Fatima Bosch
- Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ingo Rustenbeck
- Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technical University Braunschweig, Braunschweig, Germany
| | - D Margriet Ouwens
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
| | - G Hege Thoresen
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Christian de Wendt
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Sandra Lebek
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Tanja Schallschmidt
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Martin Kragl
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Eckhard Lammert
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Alexandra Chadt
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
| | - Hadi Al-Hasani
- German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany
- German Center for Diabetes Research, Duesseldorf, Germany
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Amiri A, Dehkordi RAF, Heidarnejad MS, Dehkordi MJ. Effect of the Zinc Oxide Nanoparticles and Thiamine for the Management of Diabetes in Alloxan-Induced Mice: a Stereological and Biochemical Study. Biol Trace Elem Res 2018; 181:258-264. [PMID: 28534098 DOI: 10.1007/s12011-017-1035-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 04/21/2017] [Indexed: 01/05/2023]
Abstract
This research was carried out to evaluate the antidiabetic effects of zinc oxide nanoparticles (ZnO NPs) and thiamine following experimental diabetes. Fifty-six 6-week-old female mice were used and divided into seven groups of eight animals. Diabetes was induced in fasted mice by using intraperitoneal (IP) injection of alloxan (180 mg/kg). Groups included (I) non-diabetic control, (II) thiamine (30 mg/l, IP), (III) alloxan-induced diabetic mice, (IV) diabetes + ZnO NPs (0.1 mg/kg IP), (V) diabetes + ZnO NPs (0.5 mg/kg IP), (VI) diabetes + ZnO NPs (0.1 mg/kg IP) + thiamine (30 mg/l, IP), and (VII) diabetes + ZnO NPs (0.5 mg/kg IP) + thiamine (30 mg/l, IP). Coincident with pancreas recovery, in diabetic treated mice (groups IV to VII), the mean islet volume, islets per square micrometer, and volume density of the pancreas had increased than in alloxan-induced diabetic mice. ZnO NPs and thiamine induced a decreasing blood glucose, lower serum triglyceride (TG), LDL, and total cholesterol (TC) levels in alloxan-induced diabetic mice treated with ZnO NPs and thiamine, simultaneously increasing HDL as well. In conclusion, ZnO NPs and thiamine are potent antidiabetic factors, and that, these compound supplementation possesses hypoglycemic properties and have effect on serum lipid parameters in diabetes mice.
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Affiliation(s)
| | | | | | - Mohsen Jafarian Dehkordi
- Department of Clinical pathology, Faculty of Veterinary Medicine, Azad University of Shahrekord, Shahrekord, Iran
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20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1. Nat Commun 2018; 9:177. [PMID: 29330456 PMCID: PMC5766607 DOI: 10.1038/s41467-017-02539-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 12/07/2017] [Indexed: 01/02/2023] Open
Abstract
The long-chain fatty acid receptor FFAR1 is highly expressed in pancreatic β-cells. Synthetic FFAR1 agonists can be used as antidiabetic drugs to promote glucose-stimulated insulin secretion (GSIS). However, the physiological role of FFAR1 in β-cells remains poorly understood. Here we show that 20-HETE activates FFAR1 and promotes GSIS via FFAR1 with higher potency and efficacy than dietary fatty acids such as palmitic, linoleic, and α-linolenic acid. Murine and human β-cells produce 20-HETE, and the ω-hydroxylase-mediated formation and release of 20-HETE is strongly stimulated by glucose. Pharmacological inhibition of 20-HETE formation and blockade of FFAR1 in islets inhibits GSIS. In islets from type-2 diabetic humans and mice, glucose-stimulated 20-HETE formation and 20-HETE-dependent stimulation of GSIS are strongly reduced. We show that 20-HETE is an FFAR1 agonist, which functions as an autocrine positive feed-forward regulator of GSIS, and that a reduced glucose-induced 20-HETE formation contributes to inefficient GSIS in type-2 diabetes. FFAR1 receptor is highly expressed in beta cells and its activation has been suggested as therapy against type-2 diabetes. Here, Tunaru et al. show that 20-hydroxyeicosatetraenoic acid, produced within the islets upon glucose stimulation, acts in an autocrine manner to stimulate insulin secretion via FFAR1 activation.
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39
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Agent-based modeling of the interaction between CD8+ T cells and Beta cells in type 1 diabetes. PLoS One 2018; 13:e0190349. [PMID: 29320541 PMCID: PMC5761894 DOI: 10.1371/journal.pone.0190349] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 12/13/2017] [Indexed: 12/16/2022] Open
Abstract
We propose an agent-based model for the simulation of the autoimmune response in T1D. The model incorporates cell behavior from various rules derived from the current literature and is implemented on a high-performance computing system, which enables the simulation of a significant portion of the islets in the mouse pancreas. Simulation results indicate that the model is able to capture the trends that emerge during the progression of the autoimmunity. The multi-scale nature of the model enables definition of rules or equations that govern cellular or sub-cellular level phenomena and observation of the outcomes at the tissue scale. It is expected that such a model would facilitate in vivo clinical studies through rapid testing of hypotheses and planning of future experiments by providing insight into disease progression at different scales, some of which may not be obtained easily in clinical studies. Furthermore, the modular structure of the model simplifies tasks such as the addition of new cell types, and the definition or modification of different behaviors of the environment and the cells with ease.
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40
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Kozuka C, Shimizu-Okabe C, Takayama C, Nakano K, Morinaga H, Kinjo A, Fukuda K, Kamei A, Yasuoka A, Kondo T, Abe K, Egashira K, Masuzaki H. Marked augmentation of PLGA nanoparticle-induced metabolically beneficial impact of γ-oryzanol on fuel dyshomeostasis in genetically obese-diabetic ob/ob mice. Drug Deliv 2017; 24:558-568. [PMID: 28181829 PMCID: PMC8241037 DOI: 10.1080/10717544.2017.1279237] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 01/01/2017] [Accepted: 01/03/2017] [Indexed: 12/19/2022] Open
Abstract
Our previous works demonstrated that brown rice-specific bioactive substance, γ-oryzanol acts as a chaperone, attenuates exaggerated endoplasmic reticulum (ER) stress in brain hypothalamus and pancreatic islets, thereby ameliorating metabolic derangement in high fat diet (HFD)-induced obese diabetic mice. However, extremely low absorption efficiency from intestine of γ-oryzanol is a tough obstacle for the clinical application. Therefore, in this study, to overcome extremely low bioavailability of γ-oryzanol with super-high lipophilicity, we encapsulated γ-oryzanol in polymer poly (DL-lactide-co-glycolide) (PLGA) nanoparticles (Nano-Orz), and evaluated its metabolically beneficial impact in genetically obese-diabetic ob/ob mice, the best-known severest diabetic model in mice. To our surprise, Nano-Orz markedly ameliorated fuel metabolism with an unexpected magnitude (∼1000-fold lower dose) compared with regular γ-oryzanol. Furthermore, such a conspicuous impact was achievable by its administration once every 2 weeks. Besides the excellent impact on dysfunction of hypothalamus and pancreatic islets, Nano-Orz markedly decreased ER stress and inflammation in liver and adipose tissue. Collectively, nanotechnology-based developments of functional foods oriented toward γ-oryzanol shed light on the novel approach for the treatment of a variety of metabolic diseases in humans.
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Affiliation(s)
- Chisayo Kozuka
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine and
| | - Chigusa Shimizu-Okabe
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Chitoshi Takayama
- Department of Molecular Anatomy, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Kaku Nakano
- Department of Cardiovascular Medicine and
- Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | | | | | | | - Asuka Kamei
- Kanagawa Academy of Science and Technology, Kanagawa, Japan, and
| | - Akihito Yasuoka
- Kanagawa Academy of Science and Technology, Kanagawa, Japan, and
| | - Takashi Kondo
- Kanagawa Academy of Science and Technology, Kanagawa, Japan, and
| | - Keiko Abe
- Kanagawa Academy of Science and Technology, Kanagawa, Japan, and
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kensuke Egashira
- Department of Cardiovascular Medicine and
- Department of Cardiovascular Research, Development, and Translational Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
- SENTAN Pharma Inc., Fukuoka, Japan
| | - Hiroaki Masuzaki
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine and
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41
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van Witteloostuijn SB, Dalbøge LS, Hansen G, Midtgaard SR, Jensen GV, Jensen KJ, Vrang N, Jelsing J, Pedersen SL. GUB06-046, a novel secretin/glucagon-like peptide 1 co-agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice. J Pept Sci 2017; 23:845-854. [DOI: 10.1002/psc.3048] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 09/18/2017] [Accepted: 09/19/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Søren B. van Witteloostuijn
- Gubra ApS; Hørsholm Kongevej 11B 2970 Hørsholm Denmark
- Department of Chemistry, Faculty of Science; University of Copenhagen; Thorvaldsensvej 40 1871 Frederiksberg C Denmark
| | | | - Gitte Hansen
- Gubra ApS; Hørsholm Kongevej 11B 2970 Hørsholm Denmark
| | - Søren Roi Midtgaard
- The Niels Bohr Institute, Faculty of Science; University of Copenhagen; Universitetsparken 5 2100 Copenhagen Denmark
| | - Grethe Vestergaard Jensen
- The Niels Bohr Institute, Faculty of Science; University of Copenhagen; Universitetsparken 5 2100 Copenhagen Denmark
| | - Knud J. Jensen
- Department of Chemistry, Faculty of Science; University of Copenhagen; Thorvaldsensvej 40 1871 Frederiksberg C Denmark
| | - Niels Vrang
- Gubra ApS; Hørsholm Kongevej 11B 2970 Hørsholm Denmark
| | - Jacob Jelsing
- Gubra ApS; Hørsholm Kongevej 11B 2970 Hørsholm Denmark
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Hernandez R, Graves SA, Gregg T, VanDeusen HR, Fenske RJ, Wienkes HN, England CG, Valdovinos HF, Jeffery JJ, Barnhart TE, Severin GW, Nickles RJ, Kimple ME, Merrins MJ, Cai W. Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes. Diabetes 2017; 66:2163-2174. [PMID: 28515126 PMCID: PMC5521871 DOI: 10.2337/db16-1285] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 05/12/2017] [Indexed: 01/09/2023]
Abstract
The noninvasive measurement of functional β-cell mass would be clinically valuable for monitoring the progression of type 1 and type 2 diabetes as well as the viability of transplanted insulin-producing cells. Although previous work using MRI has shown promise for functional β-cell mass determination through voltage-dependent Ca2+ channel (VDCC)-mediated internalization of Mn2+, the clinical utility of this technique is limited by the cytotoxic levels of the Mn2+ contrast agent. Here, we show that positron emission tomography (PET) is advantageous for determining functional β-cell mass using 52Mn2+ (t1/2: 5.6 days). We investigated the whole-body distribution of 52Mn2+ in healthy adult mice by dynamic and static PET imaging. Pancreatic VDCC uptake of 52Mn2+ was successfully manipulated pharmacologically in vitro and in vivo using glucose, nifedipine (VDCC blocker), the sulfonylureas tolbutamide and glibenclamide (KATP channel blockers), and diazoxide (KATP channel opener). In a mouse model of streptozotocin-induced type 1 diabetes, 52Mn2+ uptake in the pancreas was distinguished from healthy controls in parallel with classic histological quantification of β-cell mass from pancreatic sections. 52Mn2+-PET also reported the expected increase in functional β-cell mass in the ob/ob model of pretype 2 diabetes, a result corroborated by histological β-cell mass measurements and live-cell imaging of β-cell Ca2+ oscillations. These results indicate that 52Mn2+-PET is a sensitive new tool for the noninvasive assessment of functional β-cell mass.
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Affiliation(s)
- Reinier Hernandez
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI
| | - Stephen A Graves
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI
| | - Trillian Gregg
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI
- Program in Biophysics, University of Wisconsin-Madison, Madison, WI
| | - Halena R VanDeusen
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI
| | - Rachel J Fenske
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI
| | - Haley N Wienkes
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI
| | | | | | - Justin J Jeffery
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI
| | - Todd E Barnhart
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI
| | - Gregory W Severin
- Center for Nuclear Technologies, Technical University of Denmark, Roskilde, Denmark
- Department of Chemistry, Michigan State University, East Lansing, MI
| | - Robert J Nickles
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI
| | - Michelle E Kimple
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI
- William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Matthew J Merrins
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, Madison, WI
- William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI
| | - Weibo Cai
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI
- Department of Radiology, University of Wisconsin-Madison, Madison, WI
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43
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Rehni AK, Liu A, Perez-Pinzon MA, Dave KR. Diabetic aggravation of stroke and animal models. Exp Neurol 2017; 292:63-79. [PMID: 28274862 PMCID: PMC5400679 DOI: 10.1016/j.expneurol.2017.03.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 02/03/2017] [Accepted: 03/03/2017] [Indexed: 12/16/2022]
Abstract
Cerebral ischemia in diabetics results in severe brain damage. Different animal models of cerebral ischemia have been used to study the aggravation of ischemic brain damage in the diabetic condition. Since different disease conditions such as diabetes differently affect outcome following cerebral ischemia, the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines recommends use of diseased animals for evaluating neuroprotective therapies targeted to reduce cerebral ischemic damage. The goal of this review is to discuss the technicalities and pros/cons of various animal models of cerebral ischemia currently being employed to study diabetes-related ischemic brain damage. The rational use of such animal systems in studying the disease condition may better help evaluate novel therapeutic approaches for diabetes related exacerbation of ischemic brain damage.
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Affiliation(s)
- Ashish K Rehni
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Allen Liu
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Miguel A Perez-Pinzon
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Kunjan R Dave
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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44
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Shirakawa J, Fernandez M, Takatani T, El Ouaamari A, Jungtrakoon P, Okawa ER, Zhang W, Yi P, Doria A, Kulkarni RN. Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation. Cell Metab 2017; 25:868-882.e5. [PMID: 28286049 PMCID: PMC5382039 DOI: 10.1016/j.cmet.2017.02.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 01/09/2017] [Accepted: 02/08/2017] [Indexed: 12/01/2022]
Abstract
Investigation of cell-cycle kinetics in mammalian pancreatic β cells has mostly focused on transition from the quiescent (G0) to G1 phase. Here, we report that centromere protein A (CENP-A), which is required for chromosome segregation during the M-phase, is necessary for adaptive β cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1 to regulate expression of CENP-A and polo-like kinase-1 (PLK1) by modulating cyclin-dependent kinase-1/2. CENP-A deposition at the centromere is augmented by PLK1 to promote mitosis, while knocking down CENP-A limits β cell proliferation and survival. CENP-A deficiency in β cells leads to impaired adaptive proliferation in response to pregnancy, acute and chronic insulin resistance, and aging in mice. Insulin-stimulated CENP-A/PLK1 protein expression is blunted in islets from patients with type 2 diabetes. These data implicate the insulin-FoxM1/PLK1/CENP-A pathway-regulated mitotic cell-cycle progression as an essential component in the β cell adaptation to delay and/or prevent progression to diabetes.
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Affiliation(s)
- Jun Shirakawa
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Megan Fernandez
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Tomozumi Takatani
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Abdelfattah El Ouaamari
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Prapaporn Jungtrakoon
- Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
| | - Erin R Okawa
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Wei Zhang
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Peng Yi
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Alessandro Doria
- Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
| | - Rohit N Kulkarni
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
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45
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Chen Y, Tian L, Wan S, Xie Y, Chen X, Ji X, Zhao Q, Wang C, Zhang K, Hock JM, Tian H, Yu X. MicroRNA-17-92 cluster regulates pancreatic beta-cell proliferation and adaptation. Mol Cell Endocrinol 2016; 437:213-223. [PMID: 27568466 DOI: 10.1016/j.mce.2016.08.037] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 08/22/2016] [Accepted: 08/23/2016] [Indexed: 10/21/2022]
Abstract
MiR-17-92 cluster contributes to the regulation of mammalian development, aging and tumorigenesis. The functional roles of miR-17-92 in pancreatic beta-cells are largely unknown. In this study, we found that conditional deletion of miR-17-92 in mouse pancreatic beta-cells (miR-17-92βKO) significantly reduces glucose tolerance and the first phase of insulin secretion, despite normal ad libitum fed and fasting glucose levels. Proliferation is down-regulated in pancreatic beta-cells after deleting miR-17-92. MiR-17-92βKO mice show higher phosphatase and tensin homologue (PTEN) and lower phosphorylated AKT in islets. Under high fat diet challenge for 16 weeks, miR-17-92βKO mice lose compensation and exhibit higher glucose levels, and lower insulin secretion. Collectively, these data suggest that miR-17-92 is a critical contributor to molecular mechanisms regulating glucose-stimulated insulin secretion and pancreatic beta-cell adaptation under metabolic stress.
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Affiliation(s)
- Yaxi Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Li Tian
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Shan Wan
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Ying Xie
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Xiang Chen
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Xiao Ji
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Qian Zhao
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Chunyu Wang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Kun Zhang
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Janet M Hock
- The Polis Center, Indiana University-Purdue University Indianapolis, 1200 Waterway Blvd # 100, Indianapolis, IN 46202, USA
| | - Haoming Tian
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, 610041, PR China.
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46
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Jung HS, Kang YM, Park HS, Ahn BY, Lee H, Kim MJ, Jang JY, Kim SW. Senp2 expression was induced by chronic glucose stimulation in INS1 cells, and it was required for the associated induction of Ccnd1 and Mafa. Islets 2016; 8:207-216. [PMID: 27644314 PMCID: PMC5161141 DOI: 10.1080/19382014.2016.1235677] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Post-translational modification by bonding of small ubiquitin-like modifier (SUMO) peptides influences various cellular functions, and is regulated by SUMO-specific proteases (SENPs). Several proteins have been suggested to have diverse impact on insulin synthesis and secretion through SUMO modification in β cells. However, the role of SUMO modification in β cell mass has not been established. Here, we examined the changes in expression of Senp in INS1 cells and pancreatic islets under diabetes-relevant stress conditions and associated changes in β cell mass. Treatment with 25 mM glucose for 72 h induced Senp2 mRNA expression but not that of Senp1 in INS1 cells. Immunohistochemical staining with anti-SENP2 antibody on human pancreas sections revealed that SENP2 was localized in the nucleus. Moreover, in a patient with type 2 diabetes, SENP2 levels were enhanced, especially in the cytoplasm. Senp2 cytoplasmic levels were also increased in islet cells in obese diabetic mice. Cell number peaked earlier in INS1 cells cultured in high-glucose conditions compared to those cultured in control media. This finding was associated with increased Ccnd1 mRNA expression in high-glucose conditions, and siRNA-mediated Senp2 suppression abrogated it. Mafa expression, unlike Pdx1, was also dependent on Senp2 expression during high-glucose conditions. In conclusion, Senp2 may play a role in β cell mass in response to chronic high-glucose through Cyclin D1 and Mafa.
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Affiliation(s)
- Hye Seung Jung
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Innovative Research Institute for Cell Therapy, Seoul, Republic of Korea
- CONTACT Hye Seung Jung Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
| | - Yu Mi Kang
- Innovative Research Institute for Cell Therapy, Seoul, Republic of Korea
| | - Ho Seon Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Byung Yong Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hakmo Lee
- Innovative Research Institute for Cell Therapy, Seoul, Republic of Korea
| | - Min Joo Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sun-Whe Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
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47
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Parween S, Kostromina E, Nord C, Eriksson M, Lindström P, Ahlgren U. Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas. Sci Rep 2016; 6:34885. [PMID: 27713548 PMCID: PMC5054357 DOI: 10.1038/srep34885] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/19/2016] [Indexed: 01/22/2023] Open
Abstract
The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.
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Affiliation(s)
- Saba Parween
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Elena Kostromina
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Christoffer Nord
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Maria Eriksson
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Per Lindström
- Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - Ulf Ahlgren
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
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48
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Haupt-Jorgensen M, Buschard K, Hansen AK, Josefsen K, Antvorskov JC. Gluten-free diet increases beta-cell volume and improves glucose tolerance in an animal model of type 2 diabetes. Diabetes Metab Res Rev 2016; 32:675-684. [PMID: 26991675 DOI: 10.1002/dmrr.2802] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 02/10/2016] [Accepted: 02/22/2016] [Indexed: 11/05/2022]
Abstract
BACKGROUND Gluten-free (GF) diet alleviates type 1 diabetes in animal models and possibly in humans. We recently showed that fatty acid-induced insulin secretion is enhanced by enzymatically digested gluten (gliadin) stimulation in INS-1E insulinoma cells. We therefore hypothesized that GF diet would induce beta-cell rest and ameliorate type 2 diabetes. METHODS C57BL/6JBomTac (B6) mice were fed a high-fat (HF), gluten-free high-fat (GF-HF), standard (STD) or gluten-free (GF) diet for 42 weeks. RESULTS Short-term (6-24 weeks) GF-HF versus HF feeding impaired glucose tolerance and increased fasting glucose. Long-term (36-42 weeks) GF-HF versus HF feeding improved glucose tolerance and decreased fasting leptin. Mice fed a GF-HF versus HF diet for 42 weeks showed higher volumes of beta cells, islets and pancreas. The beta-cell volume correlated with the islet- and pancreas volume as well as body weight. GF-HF versus HF diet did not influence toll-like receptor 4 (Tlr4), interleukin 1 (IL-1), interleukin 6 (IL-6) or tumour necrosis factor-alpha (TNF-alpha) mRNA expression in intestine. STD versus GF feeding did not affect any parameter studied. CONCLUSIONS Long-term feeding with GF-HF versus HF increases beta-cell volume and improves glucose tolerance in B6 mice. The mechanism may include beta-cell rest, but is unlikely to include TLR4 and proinflammatory cytokines in the intestine. Beta-cell volume correlates with pancreas volume and body weight, indicating that insulin secretion capacity controls pancreas volume. Thus, long-term GF diets may be beneficial for obese type 2 diabetes patients and trials should be performed. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
| | | | - Axel K Hansen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Knud Josefsen
- The Bartholin Institute, Rigshospitalet, Copenhagen, Denmark
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49
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Abstract
Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of Langerhans. While typically representing only 1% to 2% of the total pancreatic mass, the islets have a remarkable ability to adapt to disparate situations demanding a change in hormone release, such as peripheral insulin resistance. There are many different routes to the onset of insulin resistance, including obesity, lipodystrophy, glucocorticoid excess, and the chronic usage of atypical antipsychotic drugs. All of these situations are coupled to an increase in pancreatic islet size, often with a corresponding increase in insulin production. These adaptive responses within the islets are ultimately intended to maintain glycemic control and to promote macronutrient homeostasis during times of stress. Herein, we review the consequences of specific metabolic trauma that lead to insulin resistance and the corresponding adaptive alterations within the pancreatic islets.
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Affiliation(s)
- Susan J. Burke
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808
| | - Michael D. Karlstad
- Department of Surgery, Graduate School of Medicine, University of Tennessee Health Science Center, Knoxville, TN 37920
| | - J. Jason Collier
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808
- Department of Surgery, Graduate School of Medicine, University of Tennessee Health Science Center, Knoxville, TN 37920
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50
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Morris JL, Bridson TL, Alim MA, Rush CM, Rudd DM, Govan BL, Ketheesan N. Development of a diet-induced murine model of diabetes featuring cardinal metabolic and pathophysiological abnormalities of type 2 diabetes. Biol Open 2016; 5:1149-62. [PMID: 27402965 PMCID: PMC5004603 DOI: 10.1242/bio.016790] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The persistent rise in global incidence of type 2 diabetes (T2D) continues to have significant public health and economic implications. The availability of relevant animal models of T2D is critical to elucidating the complexity of the pathogenic mechanisms underlying this disease and the implications this has on susceptibility to T2D complications. Whilst many high-fat diet-induced rodent models of obesity and diabetes exist, growing appreciation of the contribution of high glycaemic index diets on the development of hyperglycaemia and insulin resistance highlight the requirement for animal models that more closely represent global dietary patterns reflective of modern society. To that end, we sought to develop and validate a murine model of T2D based on consumption of an energy-dense diet containing moderate levels of fat and a high glycaemic index to better reflect the aetiopathogenesis of T2D. Male C57BL/6 mice were fed an energy-dense (ED) diet and the development of pathological features used in the clinical diagnosis of T2D was assessed over a 30-week period. Compared with control mice, 87% of mice fed an ED diet developed pathognomonic signs of T2D including glucose intolerance, hyperglycaemia, glycosylated haemoglobin (HbA1c) and glycosuria within 30 weeks. Furthermore, dyslipidaemia, chronic inflammation, alterations in circulating leucocytes and renal impairment were also evident in ED diet-fed mice compared with mice receiving standard rodent chow. Longitudinal profiling of metabolic and biochemical parameters provide support of an aetiologically and clinically relevant model of T2D that will serve as a valuable tool for mechanistic and therapeutic studies investigating the pathogenic complications of T2D.
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Affiliation(s)
- Jodie L Morris
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Tahnee L Bridson
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Md Abdul Alim
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Catherine M Rush
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Donna M Rudd
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Brenda L Govan
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Natkunam Ketheesan
- Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
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