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10 "Islets of Langerhans"
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Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea
Byung-Joon Kim, Jun-Seop Shin, Byoung-Hoon Min, Jong-Min Kim, Chung-Gyu Park, Hee-Jung Kang, Eung Soo Hwang, Won-Woo Lee, Jung-Sik Kim, Hyun Je Kim, Iov Kwon, Jae Sung Kim, Geun Soo Kim, Joonho Moon, Du Yeon Shin, Bumrae Cho, Heung-Mo Yang, Sung Joo Kim, Kwang-Won Kim
Received August 7, 2023  Accepted January 17, 2024  Published online May 21, 2024  
DOI: https://doi.org/10.4093/dmj.2023.0260    [Epub ahead of print]
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans.
Methods
A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness.
Conclusion
A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.
Basic Research
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Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner
Seoil Moon, Ji Yoon Lim, Mirang Lee, Youngmin Han, Hongbeom Kim, Wooil Kwon, Jin-Young Jang, Mi Na Kim, Kyong Soo Park, Hye Seung Jung
Diabetes Metab J. 2024;48(2):231-241.   Published online September 6, 2023
DOI: https://doi.org/10.4093/dmj.2022.0366
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Administration of pancreatic endoplasmic reticulum kinase inhibitor (PERKi) improved insulin secretion and hyperglycemia in obese diabetic mice. In this study, autophagic balance was studied whether to mediate it.
Methods
Human islets were isolated from living patients without diabetes. PERKi GSK2606414 effects were evaluated in the islets under glucolipotoxicity by palmitate. Islet insulin contents and secretion were measured. Autophagic flux was assessed by microtubule associated protein 1 light chain 3 (LC3) conversion, a red fluorescent protein (RFP)-green fluorescent protein (GFP)- LC3 tandem assay, and P62 levels. For mechanical analyses, autophagy was suppressed using 3-methyladenine in mouse islets. Small interfering RNA for an autophagy-related gene autophagy related 7 (Atg7) was transfected to interfere autophagy.
Results
PERKi administration to mice decreased diabetes-induced P62 levels in the islets. Glucolipotoxicity significantly increased PERK phosphorylation by 70% and decreased insulin contents by 50% in human islets, and addition of PERKi (40 to 80 nM) recovered both. PERKi also enhanced glucose-stimulated insulin secretion (6-fold). PERKi up-regulated LC3 conversion suppressed by glucolipotoxicity, and down-regulated P62 contents without changes in P62 transcription, indicating enhanced autophagic flux. Increased autophagosome-lysosome fusion by PERKi was visualized in mouse islets, where PERKi enhanced ATG7 bound to LC3. Suppression of Atg7 eliminated PERKi-induced insulin contents and secretion.
Conclusion
This study provided functional changes of human islets with regard to autophagy under glucolipotoxicity, and suggested modulation of autophagy as an anti-diabetic mechanism of PERKi.
Review
Basic Research
Article image
Rediscovering Primary Cilia in Pancreatic Islets
Eun Young Lee, Jing W. Hughes
Diabetes Metab J. 2023;47(4):454-469.   Published online April 28, 2023
DOI: https://doi.org/10.4093/dmj.2022.0442
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AbstractAbstract PDFPubReader   ePub   
Primary cilia are microtubule-based sensory and signaling organelles on the surfaces of most eukaryotic cells. Despite their early description by microscopy studies, islet cilia had not been examined in the functional context until recent decades. In pancreatic islets as in other tissues, primary cilia facilitate crucial developmental and signaling pathways in response to extracellular stimuli. Many human developmental and genetic disorders are associated with ciliary dysfunction, some manifesting as obesity and diabetes. Understanding the basis for metabolic diseases in human ciliopathies has been aided by close examination of cilia action in pancreatic islets at cellular and molecular levels. In this article, we review the evidence for ciliary expression on islet cells, known roles of cilia in pancreas development and islet hormone secretion, and summarize metabolic manifestations of human ciliopathy syndromes. We discuss emerging data on primary cilia regulation of islet cell signaling and the structural basis of cilia-mediated cell crosstalk, and offer our interpretation on the role of cilia in glucose homeostasis and human diseases.

Citations

Citations to this article as recorded by  
  • Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus
    Asma A Elashi, Salman M Toor, Umm-Kulthum Ismail Umlai, Yasser A Al-Sarraj, Shahrad Taheri, Karsten Suhre, Abdul Badi Abou-Samra, Omar M E Albagha
    BMC Medical Genomics.2024;[Epub]     CrossRef
  • Beta cell primary cilia mediate somatostatin responsiveness via SSTR3
    Samantha E. Adamson, Zipeng A. Li, Jing W. Hughes
    Islets.2023;[Epub]     CrossRef
Original Articles
Basic Research
Differentiation of Microencapsulated Neonatal Porcine Pancreatic Cell Clusters in Vitro Improves Transplant Efficacy in Type 1 Diabetes Mellitus Mice
Gyeong-Jin Cheon, Heon-Seok Park, Eun-Young Lee, Min Jung Kim, Young-Hye You, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes Metab J. 2022;46(5):677-688.   Published online February 7, 2022
DOI: https://doi.org/10.4093/dmj.2021.0202
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  • 2 Web of Science
  • 2 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Neonatal porcine pancreatic cell clusters (NPCCs) have been proposed as an alternative source of β cells for islet transplantation because of their low cost and growth potential after transplantation. However, the delayed glucose lowering effect due to the immaturity of NPCCs and immunologic rejection remain as a barrier to NPCC’s clinical application. Here, we demonstrate accelerated differentiation and immune-tolerant NPCCs by in vitro chemical treatment and microencapsulation.
Methods
NPCCs isolated from 3-day-old piglets were cultured in F-10 media and then microencapsulated with alginate on day 5. Differentiation of NPCCs is facilitated by media supplemented with activin receptor-like kinase 5 inhibitor II, triiodothyronine and exendin-4 for 2 weeks. Marginal number of microencapsulated NPCCs to cure diabetes with and without differentiation were transplanted into diabetic mice and observed for 8 weeks.
Results
The proportion of insulin-positive cells and insulin mRNA levels of NPCCs were significantly increased in vitro in the differentiated group compared with the undifferentiated group. Blood glucose levels decreased eventually after transplantation of microencapsulated NPCCs in diabetic mice and normalized after 7 weeks in the differentiated group. In addition, the differentiated group showed nearly normal glucose tolerance at 8 weeks after transplantation. In contrast, neither blood glucose levels nor glucose tolerance were improved in the undifferentiated group. Retrieved graft in the differentiated group showed greater insulin response to high glucose compared with the undifferentiated group.
Conclusion
in vitro differentiation of microencapsulated immature NPCCs increased the proportion of insulin-positive cells and improved transplant efficacy in diabetic mice without immune rejection.

Citations

Citations to this article as recorded by  
  • Dual-targeted nano-encapsulation of neonatal porcine islet-like cell clusters with triiodothyronine-loaded bifunctional polymersomes
    Sang Hoon Lee, Minse Kim, Eun-Jin Lee, Sun Mi Ahn, Yu-Rim Ahn, Jaewon Choi, Jung-Taek Kang, Hyun-Ouk Kim
    Discover Nano.2024;[Epub]     CrossRef
  • Long‐term efficacy of encapsulated xenogeneic islet transplantation: Impact of encapsulation techniques and donor genetic traits
    Heon‐Seok Park, Eun Young Lee, Young‐Hye You, Marie Rhee, Jong‐Min Kim, Seong‐Soo Hwang, Poong‐Yeon Lee
    Journal of Diabetes Investigation.2024; 15(6): 693.     CrossRef
Basic Research
Article image
Hypoxia Increases β-Cell Death by Activating Pancreatic Stellate Cells within the Islet
Jong Jin Kim, Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
Diabetes Metab J. 2020;44(6):919-927.   Published online May 11, 2020
DOI: https://doi.org/10.4093/dmj.2019.0181
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  • 15 Web of Science
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AbstractAbstract PDFPubReader   ePub   
Background

Hypoxia can occur in pancreatic islets in type 2 diabetes mellitus. Pancreatic stellate cells (PSCs) are activated during hypoxia. Here we aimed to investigate whether PSCs within the islet are also activated in hypoxia, causing β-cell injury.

Methods

Islet and primary PSCs were isolated from Sprague Dawley rats, and cultured in normoxia (21% O2) or hypoxia (1% O2). The expression of α-smooth muscle actin (α-SMA), as measured by immunostaining and Western blotting, was used as a marker of PSC activation. Conditioned media (hypoxia-CM) were obtained from PSCs cultured in hypoxia.

Results

Islets and PSCs cultured in hypoxia exhibited higher expressions of α-SMA than did those cultured in normoxia. Hypoxia increased the production of reactive oxygen species. The addition of N-acetyl-L-cysteine, an antioxidant, attenuated the hypoxia-induced PSC activation in islets and PSCs. Islets cultured in hypoxia-CM showed a decrease in cell viability and an increase in apoptosis.

Conclusion

PSCs within the islet are activated in hypoxia through oxidative stress and promote islet cell death, suggesting that hypoxia-induced PSC activation may contribute to β-cell loss in type 2 diabetes mellitus.

Citations

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    Purnima Sharma, Jian-Xing Ma, Dimitrios Karamichos
    Experimental Eye Research.2024; 240: 109790.     CrossRef
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    Kai Duan, Mengyang Zhou, Yong Wang, Jose Oberholzer, Joe F. Lo
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    Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
    Molecular and Cellular Endocrinology.2023; 572: 111947.     CrossRef
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    Zhengfeng Wang, Ru He, Shi Dong, Wence Zhou
    Frontiers in Oncology.2023;[Epub]     CrossRef
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    Anushikha Ghosh, Arka Sanyal, Abhik Mallick
    Exploration of Medicine.2023; : 886.     CrossRef
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    Sarah S. Malik, Diksha Padmanabhan, Rebecca L. Hull-Meichle
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
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    Xue-Jiao Sun, Nai-Feng Liu
    Cellular Signalling.2022; 91: 110219.     CrossRef
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    Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune
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    Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune
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    Xiangyun Zhu, Dechen Liu, Guoqing Li, Mengmeng Zhi, Ji Sun, Liang Qi, Jingbo Li, Stephen J. Pandol, Ling Li
    Molecular and Cellular Endocrinology.2022; 551: 111653.     CrossRef
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    Yue Yuan, Zhiren Li, Miaomiao Li, Tong Jin, Xiaoyun Zhang, Xinjuan Liu, Jianyu Hao
    Toxicology in Vitro.2022; 84: 105436.     CrossRef
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    Miaomiao Li, Yue Yuan, Xue Han, Xinjuan Liu, Weizhen Zhang, Jianyu Hao
    Journal of Inflammation Research.2022; Volume 15: 4409.     CrossRef
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    Le Li, Xing-jia Yu, Lei Gao, Long Cheng, Bei Sun, Gang Wang
    Antioxidants & Redox Signaling.2022; 37(16-18): 1206.     CrossRef
  • Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia
    Matias Estaras, Manuel R. Gonzalez-Portillo, Miguel Fernandez-Bermejo, Jose M. Mateos, Daniel Vara, Gerardo Blanco-Fernandez, Diego Lopez-Guerra, Vicente Roncero, Gines M. Salido, Antonio González
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    Microcirculation.2021;[Epub]     CrossRef
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Brief Report
Basic Research
A Novel Pancreatic Imaging Window for Stabilized Longitudinal In Vivo Observation of Pancreatic Islets in Murine Model
Inwon Park, Sujung Hong, Yoonha Hwang, Pilhan Kim
Diabetes Metab J. 2020;44(1):193-198.   Published online May 29, 2019
DOI: https://doi.org/10.4093/dmj.2018.0268
  • 4,918 View
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AbstractAbstract PDFSupplementary MaterialPubReader   

Longitudinal imaging of murine pancreas is technically challenging due to the mechanical softness of the tissue influenced by peristalsis. Here, we report a novel pancreatic imaging window for long-term stabilized cellular-level observation of the islets in the pancreas in vivo. By spatially separating the pancreas from the bowel movement and physiologic respiration with a metal plate integrated in the imaging window, we successfully tracked the pancreatic islets up to three weeks and visualized the dumbbell-shape transformation from the single islet. This window can be a useful tool for long-term cellular-level visualization of the microstructure in the pancreas.

Citations

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    Cindy V. Bui, Curtis W. Boswell, Brian Ciruna, Jonathan V. Rocheleau
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    Erwin Ilegems, Per-Olof Berggren
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Original Article
Pathophysiology
Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3
Kanghoon Lee, Hyunki Kim, Joonyub Lee, Chang-Myung Oh, Heein Song, Hyeongseok Kim, Seung-Hoi Koo, Junguee Lee, Ajin Lim, Hail Kim
Diabetes Metab J. 2019;43(5):649-658.   Published online April 8, 2019
DOI: https://doi.org/10.4093/dmj.2018.0232
  • 5,553 View
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AbstractAbstract PDFPubReader   
Background

Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.

Methods

Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.

Results

Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.

Conclusion

PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

Citations

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  • Role of protein arginine methyltransferase 1 in obesity‐related metabolic disorders: Research progress and implications
    Xiaolei Xuan, Yongjiao Zhang, Yufan Song, Bingyang Zhang, Junjun Liu, Dong Liu, Sumei Lu
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  • Arginine 65 methylation of Neurogenin 3 by PRMT1 is required for pancreatic endocrine development of hESCs
    Gahyang Cho, Kwangbeom Hyun, Jieun Choi, Eunji Shin, Bumsoo Kim, Hail Kim, Jaehoon Kim, Yong-Mahn Han
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    Gahyang Cho, Kwangbeom Hyun, Jieun Choi, Eun Ji Shin, Bumsoo Kim, Hail Kim, Jaehoon Kim, Yong-Mahn Han
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Short Communication
Islet Studies and Transplantation
Alginate-Catechol Cross-Linking Interferes with Insulin Secretion Capacity in Isolated Murine Islet Cells
Yu-Sik Kim, Seung-Woo Cho, Bomin Ko, Jisoo Shin, Chul Woo Ahn
Diabetes Metab J. 2018;42(2):164-168.   Published online March 28, 2018
DOI: https://doi.org/10.4093/dmj.2018.42.2.164
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AbstractAbstract PDFPubReader   

Over the past three decades, human pancreatic islet isolation and transplantation techniques have developed as a routine clinical procedure for selected patients with type 1 diabetes mellitus. However, due to the donor shortage and required chronic systemic immunosuppression, the widespread application of islet transplantation is limited. To overcome these limitations, providing a physical barrier to transplanted islet cells with encapsulating biomaterial has emerged as a promising approach to enhance engraftment and promote islet survival post-transplantation. Alginate has been considered to be a reliable biomaterial, as it enhances islet survival and does not hamper hormone secretion. Alginate-catechol (Al-CA) hydrogel was reported to provide high mechanical strength and chemical stability without deformation over a wide range of pH values. In this study, we, demonstrated, for the first time in the literature, that encapsulation of murine pancreatic islet cells with Al-CA hydrogel does not induce cytotoxicity ex vivo for an extended period; however, it does markedly abate glucose-stimulated insulin secretion. Catechol should not be considered as a constituent for alginate gelation for encapsulating islet cells in the application of islet transplantation.

Citations

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    Chandan Maity, Nikita Das
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Review
Cell Replacement and Regeneration Therapy for Diabetes
Hee-Sook Jun
Korean Diabetes J. 2010;34(2):77-83.   Published online April 30, 2010
DOI: https://doi.org/10.4093/kdj.2010.34.2.77
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AbstractAbstract PDFPubReader   

Reduction of beta cell function and a beta cell mass is observed in both type 1 and type 2 diabetes. Therefore, restoration of this deficiency might be a therapeutic option for treatment of diabetes. Islet transplantation has benefits, such as reduced incidence of hypoglycemia and achievement of insulin independence. However, the major drawback is an insufficient supply of islet donors. Transplantation of cells differentiated in vitro or in vivo regeneration of insulin-producing cells are possible approaches for beta cell/islet regenerative therapy. Embryonic and adult stem cells, pancreatic ductal progenitor cells, acinar cells, and other endocrine cells have been shown to differentiate into pancreatic beta cells. Formation of fully functional beta cells and the safety of these cells are critical issues for successful clinical application.

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Original Article
Effects of Anti-Vascular Endothelial Growth Factor (VEGF) on Pancreatic Islets in Mouse Model of Type 2 Diabetes Mellitus.
Ji Won Kim, Dong Sik Ham, Heon Seok Park, Yu Bai Ahn, Ki Ho Song, Kun Ho Yoon, Ki Dong Yoo, Myung Jun Kim, In Kyung Jeong, Seung Hyun Ko
Korean Diabetes J. 2009;33(3):185-197.   Published online June 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.3.185
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AbstractAbstract PDF
BACKGROUND
Vascular endothelial growth factor (VEGF) is associated with the development of diabetic complications. However, it is unknown whether systemic VEGF treatment has any effects on the pancreatic islets in an animal model of type 2 diabetes mellitus. METHODS: Anti-VEGF peptide (synthetic ATWLPPR, VEGF receptor type 2 antagonist) was injected into db/db mice for 12 weeks. We analyzed pancreatic islet morphology and quantified beta-cell mass. Endothelial cell proliferation and the severity of islet fibrosis were also measured. VEGF expression in isolated islets was determined using Western blot analysis. RESULTS: When anti-VEGF was administered, db/db mice exhibited more severe hyperglycemia and associated delayed weight gain than non-treated db/db mice. Pancreas weight and pancreatic beta-cell mass were also significantly decreased in the anti-VEGF-treated group. VEGF and VEGF receptor proteins (types 1 and 2) were expressed in the pancreatic islets, and their expression was significantly increased in the db/db group compared with the db/dm group. However, the elevated VEGF expression was significantly reduced by anti-VEGF treatment compared with the db/db group. The anti-VEGF-treated group had more prominent islet fibrosis and islet destruction than db/db mice. Intra-islet endothelial cell proliferation was also remarkably reduced by the anti-VEGF peptide. CONCLUSION: Inhibition of VEGF action by the VEGF receptor 2 antagonist not only suppressed the proliferation of intra-islet endothelial cells but also accelerated pancreatic islet destruction and aggravated hyperglycemia in a type 2 diabetes mouse model. Therefore, the potential effects of anti-VEGF treatment on pancreatic beta cell damage should be considered.

Diabetes Metab J : Diabetes & Metabolism Journal
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