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Basic Research
Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases
Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong
Diabetes Metab J. 2024;48(1):1-18.   Published online January 3, 2024
DOI: https://doi.org/10.4093/dmj.2023.0115
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  • 267 Download
AbstractAbstract PDFPubReader   ePub   
Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPRmt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPRmt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.
Basic Research
Heterogeneity of Islet Cells during Embryogenesis and Differentiation
Shugo Sasaki, Takeshi Miyatsuka
Diabetes Metab J. 2023;47(2):173-184.   Published online January 12, 2023
DOI: https://doi.org/10.4093/dmj.2022.0324
  • 3,936 View
  • 250 Download
  • 1 Web of Science
  • 1 Crossref
AbstractAbstract PDFPubReader   ePub   
Diabetes is caused by insufficient insulin secretion due to β-cell dysfunction and/or β-cell loss. Therefore, the restoration of functional β-cells by the induction of β-cell differentiation from embryonic stem (ES) and induced-pluripotent stem (iPS) cells, or from somatic non-β-cells, may be a promising curative therapy. To establish an efficient and feasible method for generating functional insulin-producing cells, comprehensive knowledge of pancreas development and β-cell differentiation, including the mechanisms driving cell fate decisions and endocrine cell maturation is crucial. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies have opened a new era in pancreas development and diabetes research, leading to clarification of the detailed transcriptomes of individual insulin-producing cells. Such extensive high-resolution data enables the inference of developmental trajectories during cell transitions and gene regulatory networks. Additionally, advancements in stem cell research have not only enabled their immediate clinical application, but also has made it possible to observe the genetic dynamics of human cell development and maturation in a dish. In this review, we provide an overview of the heterogeneity of islet cells during embryogenesis and differentiation as demonstrated by scRNA-seq studies on the developing and adult pancreata, with implications for the future application of regenerative medicine for diabetes.

Citations

Citations to this article as recorded by  
  • Newly discovered knowledge pertaining to glucagon and its clinical applications
    Dan Kawamori, Shugo Sasaki
    Journal of Diabetes Investigation.2023; 14(7): 829.     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
  • 4,697 View
  • 252 Download
  • 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;[Epub]     CrossRef
Others
Generation of Insulin-Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD
So-Hyun Lee, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes Metab J. 2017;41(5):405-416.   Published online September 5, 2017
DOI: https://doi.org/10.4093/dmj.2017.41.5.405
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  • 5 Web of Science
  • 5 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

To develop surrogate insulin-producing cells for diabetes therapy, adult stem cells have been identified in various tissues and studied for their conversion into β-cells. Pancreatic progenitor cells are derived from the endodermal epithelium and formed in a manner similar to gut progenitor cells. Here, we generated insulin-producing cells from the intestinal epithelial cells that induced many of the specific pancreatic transcription factors using adenoviral vectors carrying three genes: PMB (pancreatic and duodenal homeobox 1 [Pdx1], V-maf musculoaponeurotic fibrosarcoma oncogene homolog A [MafA], and BETA2/NeuroD).

Methods

By direct injection into the intestine through the cranial mesenteric artery, adenoviruses (Ad) were successfully delivered to the entire intestine. After virus injection, we could confirm that the small intestine of the mouse was appropriately infected with the Ad-Pdx1 and triple Ad-PMB.

Results

Four weeks after the injection, insulin mRNA was expressed in the small intestine, and the insulin gene expression was induced in Ad-Pdx1 and Ad-PMB compared to control Ad-green fluorescent protein. In addition, the conversion of intestinal cells into insulin-expressing cells was detected in parts of the crypts and villi located in the small intestine.

Conclusion

These data indicated that PMB facilitate the differentiation of mouse intestinal cells into insulin-expressing cells. In conclusion, the small intestine is an accessible and abundant source of surrogate insulin-producing cells.

Citations

Citations to this article as recorded by  
  • Harnessing gut cells for functional insulin production: Strategies and challenges
    Kelvin Baafi, John C. March
    Biotechnology Notes.2023; 4: 7.     CrossRef
  • Differential Morphological Diagnosis of Various Forms of Congenital Hyperinsulinism in Children
    Lubov Borisovna Mitrofanova, Anastasia Arkadyevna Perminova, Daria Viktorovna Ryzhkova, Anna Andreyevna Sukhotskaya, Vladimir Gireyevich Bairov, Irina Leorovna Nikitina
    Frontiers in Endocrinology.2021;[Epub]     CrossRef
  • Generation of iPSC-derived insulin-producing cells from patients with type 1 and type 2 diabetes compared with healthy control
    Min Jung Kim, Eun Young Lee, Young-Hye You, Hae Kyung Yang, Kun-Ho Yoon, Ji-Won Kim
    Stem Cell Research.2020; 48: 101958.     CrossRef
  • ERK Regulates NeuroD1-mediated Neurite Outgrowth via Proteasomal Degradation
    Tae-young Lee, In-Su Cho, Narayan Bashyal, Francisco J Naya, Ming-Jer Tsai, Jeong Seon Yoon, Jung-Mi Choi, Chang-Hwan Park, Sung-Soo Kim, Haeyoung Suh-Kim
    Experimental Neurobiology.2020; 29(3): 189.     CrossRef
  • Generation of a PDX1–EGFP reporter human induced pluripotent stem cell line, KSCBi005-A-3, using the CRISPR/Cas9 system
    Youngsun Lee, Hye Young Choi, Ara Kwon, Hyeyeon Park, Mi-Hyun Park, Ji-Won Kim, Min Jung Kim, Yong-Ou Kim, Sungwook Kwak, Soo Kyung Koo
    Stem Cell Research.2019; 41: 101632.     CrossRef
Others
Effect of Atorvastatin on Growth Differentiation Factor-15 in Patients with Type 2 Diabetes Mellitus and Dyslipidemia
Ji Min Kim, Min Kyung Back, Hyon-Seung Yi, Kyong Hye Joung, Hyun Jin Kim, Bon Jeong Ku
Diabetes Metab J. 2016;40(1):70-78.   Published online February 19, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.1.70
  • 4,270 View
  • 33 Download
  • 5 Web of Science
  • 5 Crossref
AbstractAbstract PDFPubReader   
Background

Elevated serum levels of growth differentiation factor-15 (GDF-15) are associated with type 2 diabetes. Therefore, the effects of atorvastatin on metabolic parameters and GDF-15 levels in patients with type 2 diabetes and dyslipidemia were evaluated.

Methods

In this prospective randomized trial from February 2013 to March 2014, 50 consecutive type 2 diabetic patients with a low density lipoprotein cholesterol (LDL-C) levels ≥100 mg/dL were enrolled. The patients were divided into two groups based on the amount of atorvastatin prescribed, 10 mg/day (n=23) or 40 mg/day (n=27). The effect of atorvastatin on metabolic parameters, including lipid profiles and GDF-15 levels, at baseline and after 8 weeks of treatment were compared.

Results

The baseline metabolic parameters and GDF-15 levels were not significantly different between the two groups. After 8 weeks of treatment, the total cholesterol (TC) and LDL-C levels were significantly decreased in both groups. The mean changes in TC and LDL-C levels were more significant in the 40 mg atorvastatin group. The GDF-15 level was decreased in the 10 mg atorvastatin group, from 1,460.6±874.8 to 1,451.0±770.8 pg/mL, and was increased in the 40 mg atorvastatin group, from 1,271.6±801.0 to 1,341.4±855.2 pg/mL. However, the change in the GDF-15 level was not statistically significant in the 10 or 40 mg atorvastatin group (P=0.665 and P=0.745, respectively).

Conclusion

The GDF-15 levels were not significantly changed after an 8-week treatment with atorvastatin in type 2 diabetic patients.

Citations

Citations to this article as recorded by  
  • The relationship of Growth differentiation factor-15 with renal damage and dyslipidemia in non-albuminuric and albuminuric Type-2 Diabetes Mellitus
    Hasan Esat Yücel, Bilal İlanbey
    Medical Science and Discovery.2022; 9(6): 334.     CrossRef
  • Comparative effectiveness of statins on non-high density lipoprotein cholesterol in people with diabetes and at risk of cardiovascular disease: systematic review and network meta-analysis
    Alexander Hodkinson, Dialechti Tsimpida, Evangelos Kontopantelis, Martin K Rutter, Mamas A Mamas, Maria Panagioti
    BMJ.2022; : e067731.     CrossRef
  • The Cytokine Growth Differentiation Factor-15 and Skeletal Muscle Health: Portrait of an Emerging Widely Applicable Disease Biomarker
    Boel De Paepe
    International Journal of Molecular Sciences.2022; 23(21): 13180.     CrossRef
  • Biomarkers of subclinical atherosclerosis in patients with psoriasis
    Hannah Kaiser, Xing Wang, Amanda Kvist-Hansen, Martin Krakauer, Peter Michael Gørtz, Benjamin D. McCauley, Lone Skov, Christine Becker, Peter Riis Hansen
    Scientific Reports.2021;[Epub]     CrossRef
  • Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages
    Kathrin Ackermann, Gabriel A. Bonaterra, Ralf Kinscherf, Anja Schwarz
    Atherosclerosis.2019; 281: 128.     CrossRef
GDF15 Is a Novel Biomarker for Impaired Fasting Glucose
Jun Hwa Hong, Hyo Kyun Chung, Hye Yoon Park, Kyong-Hye Joung, Ju Hee Lee, Jin Gyu Jung, Koon Soon Kim, Hyun Jin Kim, Bon Jeong Ku, Minho Shong
Diabetes Metab J. 2014;38(6):472-479.   Published online December 15, 2014
DOI: https://doi.org/10.4093/dmj.2014.38.6.472
  • 5,669 View
  • 78 Download
  • 69 Web of Science
  • 64 Crossref
AbstractAbstract PDFPubReader   
Background

Growth differentiation factor-15 (GDF15) is a protein that belongs to the transforming growth factor β superfamily. An elevated serum level of GDF15 was found to be associated with type 2 diabetes mellitus (T2DM). T2DM is an inflammatory disease that progresses from normal glucose tolerance (NGT) to impaired fasting glucose (IFG). Hence, we aimed to validate the relationship between GDF15 and IFG.

Methods

The participants were divided into the following three groups: NGT (n=137), IFG (n=29), and T2DM (n=75). The controls and T2DM outpatients visited the hospital for routine health check-ups. We used fasting blood glucose to detect IFG in nondiabetic patients. We checked the body mass index (BMI), C-reactive protein level, metabolic parameters, and fasting serum GDF15 level.

Results

Age, BMI, triglyceride, insulin, glucose, homeostatic model assessment-insulin resistance (HOMA-IR), and GDF15 levels were elevated in the IFG and T2DM groups compared to the NGT group. In the correlation analysis between metabolic parameters and GDF15, age and HOMA-IR had a significant positive correlation with GDF15 levels. GDF15 significantly discriminated between IFG and NGT, independent of age, BMI, and HOMA-IR. The serum levels of GDF15 were more elevated in men than in women. As a biomarker for IFG based on the receiver operating characteristic curve analysis, the cutoff value of GDF15 was 510 pg/mL in males and 400 pg/mL in females.

Conclusion

GDF15 had a positive correlation with IR independent of age and BMI, and the serum level of GDF15 was increased in the IFG and T2DM groups. GDF15 may be a novel biomarker for detecting IFG in nondiabetic patients.

Citations

Citations to this article as recorded by  
  • Effect of a 6-Week Carbohydrate-Reduced High-Protein Diet on Levels of FGF21 and GDF15 in People With Type 2 Diabetes
    Michael M Richter, Mads N Thomsen, Mads J Skytte, Sasha A S Kjeldsen, Amirsalar Samkani, Jan Frystyk, Faidon Magkos, Jens J Holst, Sten Madsbad, Thure Krarup, Steen B Haugaard, Nicolai J Wewer Albrechtsen
    Journal of the Endocrine Society.2024;[Epub]     CrossRef
  • Serum Growth Differentiation Factor 15 Levels Predict the Incidence of Frailty among Patients with Cardiometabolic Diseases
    Kazuhito Oba, Joji Ishikawa, Yoshiaki Tamura, Yasunori Fujita, Masafumi Ito, Ai Iizuka, Yoshinori Fujiwara, Remi Kodera, Kenji Toyoshima, Yuko Chiba, Masashi Tanaka, Atsushi Araki
    Gerontology.2024; 70(5): 517.     CrossRef
  • Growth differentiation factor 15 and malnutrition in older adults
    Nazanin Rostami, Blanca Fabre-Estremera, Antonio Buño-Soto, José R Banegas, Fernando Rodríguez-Artalejo, Rosario Ortolá
    The Journal of nutrition, health and aging.2024; 28(6): 100230.     CrossRef
  • Evaluation of the relation between subclinical systolic dysfunction defined by four-dimensional speckle-tracking echocardiography and growth differentiation factor-15 levels in patients with acromegaly
    Busra Firlatan, Ugur Nadir Karakulak, Vedat Hekimsoy, Burcin Gonul Iremli, Incilay Lay, Deniz Yuce, Selcuk Dagdelen, Giray Kabakci, Tomris Erbas
    Hormones.2024;[Epub]     CrossRef
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    Bernard J Crespi
    Evolution, Medicine, and Public Health.2024; 12(1): 75.     CrossRef
  • Exploration of meteorin-like peptide (metrnl) predictors in type 2 diabetic patients: the potential role of irisin, and other biochemical parameters
    Yaser Khajebishak, Amir Hossein Faghfouri, Ali Soleimani, Sadra Madani, Laleh Payahoo
    Hormone Molecular Biology and Clinical Investigation.2023; 44(2): 127.     CrossRef
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    Yaser Khajebishak, Sadra Madani, Amir Hossein Faghfouri, Ali Soleimani, Sara Ilaei, Said Peyrovi, Laleh Payahoo
    Nutrition & Food Science.2023; 53(5): 861.     CrossRef
  • Effects of acute exercise and exercise training on plasma GDF15 concentrations and associations with appetite and cardiometabolic health in individuals with overweight or obesity – A secondary analysis of a randomized controlled trial
    Jonas Salling Quist, Anders Bue Klein, Kristine Færch, Kristine Beaulieu, Mads Rosenkilde, Anne Sofie Gram, Anders Sjödin, Signe Torekov, Bente Stallknecht, Christoffer Clemmensen, Martin Bæk Blond
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  • Significant increase of serum extracellular vesicle-packaged growth differentiation factor 15 in type 2 diabetes mellitus: a cross-sectional study
    Wen Zhao, Xinwei Li, Xinxin Li, Lu Peng, Yu Li, Yunhui Du, Jianxun He, Yanwen Qin, Huina Zhang
    European Journal of Medical Research.2023;[Epub]     CrossRef
  • Association between growth differentiation factor 15 levels and gestational diabetes mellitus: A combined analysis
    Yi-Cheng Lu, Song-Liang Liu, Yu-Shan Zhang, Fei Liang, Xiao-Yan Zhu, Yue Xiao, Jing Wang, Cong Ding, Sudipta Banerjee, Jie-Yun Yin, Qiu-Ping Ma
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
  • Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight
    Song-Yang Zhang, Kyla Bruce, Zahra Danaei, Rosa J.W. Li, Daniel R. Barros, Rachel Kuah, Yu-Mi Lim, Laura H. Mariani, David Z. Cherney, Jennifer F.M. Chiu, Heather N. Reich, Tony K.T. Lam
    Cell Metabolism.2023; 35(5): 875.     CrossRef
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    Pedro Iglesias, Ramona A. Silvestre, Juan J. Díez
    Endocrine.2023; 81(3): 419.     CrossRef
  • Identification of biomarkers for glycaemic deterioration in type 2 diabetes
    Roderick C. Slieker, Louise A. Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N. Giordano, Mikael Åkerlund, Emma Ahlqvist, A
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  • Metabolic syndrome and Growth Differentiation Factor 15 in older adults
    Adrián Carballo-Casla, Esther García-Esquinas, Antonio Buño-Soto, Ellen A. Struijk, Esther López-García, Fernando Rodríguez-Artalejo, Rosario Ortolá
    GeroScience.2022; 44(2): 867.     CrossRef
  • Associations between GDF15 Levels and Pre-Diabetes in Non-Obese Subjects
    Hao-Chang Hung, Hung-Tsung Wu, Ching-Han Lin, Hsuan-Wen Chou, Horng-Yih Ou, Chih-Jen Chang
    Journal of Investigative Medicine.2022; 70(1): 79.     CrossRef
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    Dipayan Roy, Purvi Purohit, Anupama Modi, Manoj Khokhar, Ravindra Kumar Gayaprasad Shukla, Ramkaran Chaudhary, Shrimanjunath Sankanagoudar, Praveen Sharma
    Current Diabetes Reviews.2022;[Epub]     CrossRef
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    Peizheng Li, Hongbo Lv, Bohan Zhang, Ruonan Duan, Xiufang Zhang, Pengfei Lin, Chengyuan Song, Yiming Liu
    Frontiers in Aging Neuroscience.2022;[Epub]     CrossRef
  • GDF-15 as a Therapeutic Target of Diabetic Complications Increases the Risk of Gallstone Disease: Mendelian Randomization and Polygenic Risk Score Analysis
    Lili Yu, Yajing Zhou, Lijuan Wang, Xuan Zhou, Jing Sun, Jiarui Xiao, Xiaolin Xu, Susanna C. Larsson, Shuai Yuan, Xue Li
    Frontiers in Genetics.2022;[Epub]     CrossRef
  • Sex-specific modulation of circulating growth differentiation factor-15 in patients with type 2 diabetes and/or obesity
    Mohamed Asrih, Flore Sinturel, Richard Dubos, Idris Guessous, Zoltan Pataky, Charna Dibner, François R Jornayvaz, Karim Gariani
    Endocrine Connections.2022;[Epub]     CrossRef
  • Raised circulating soluble growth differentiation factor 15 is negatively associated with testosterone level in hypogonadic men with type 2 diabetes
    Yufeng Mei, Yongnan Lyu, Juan Le, Di Li, Hang Liu, Zhiming Zhao, Yan Li
    Diabetes/Metabolism Research and Reviews.2022;[Epub]     CrossRef
  • NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice
    Matthew J Jennings, Alexia Kagiava, Leen Vendredy, Emily L Spaulding, Marina Stavrou, Denisa Hathazi, Anika Grüneboom, Vicky De Winter, Burkhard Gess, Ulrike Schara, Oksana Pogoryelova, Hanns Lochmüller, Christoph H Borchers, Andreas Roos, Robert W Burges
    Brain.2022; 145(11): 3999.     CrossRef
  • Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure
    Hayder M. Al‐kuraishy, Ali I. Al‐Gareeb, Athanasios Alexiou, Marios Papadakis, Eman Hassan Nadwa, Sarah M. Albogami, Mohammed Alorabi, Hebatallah M. Saad, Gaber El‐Saber Batiha
    Journal of Diabetes.2022; 14(12): 806.     CrossRef
  • GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans
    Peter Plomgaard, Jakob S. Hansen, Logan K. Townsend, Anders Gudiksen, Niels H. Secher, Jens O. Clemmesen, Rene K. Støving, Jens P. Goetze, David C. Wright, Henriette Pilegaard
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    Sudipta Banerjee, Rana Bhattacharjee, Amitabh Sur, Pieu Adhikary, Subhankar Chowdhury
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    Yea Eun Kang, Jin Man Kim, Mi Ae Lim, Seong Eun Lee, Shinae Yi, Jung Tae Kim, Chan Oh, Lihua Liu, Yanli Jin, Seung-Nam Jung, Ho-Ryun Won, Jae Won Chang, Jeong Ho Lee, Hyun Jung Kim, Hyun Yong Koh, Sangmi Jun, Sun Wook Cho, Minho Shong, Bon Seok Koo
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  • The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe?
    Samuel N. Breit, David A. Brown, Vicky Wang-Wei Tsai
    Annual Review of Physiology.2021; 83(1): 127.     CrossRef
  • Associations of GDF-15 and GDF-15/adiponectin ratio with odds of type 2 diabetes in the Chinese population
    Xiaoying Wu, Wenting Xuan, Lili You, Hong Lian, Feng Li, Xiaoyun Zhang, Qingyu Chen, Kan Sun, Chaogang Chen, Mingtong Xu, Yan Li, Li Yan, Xiuwei Zhang, Meng Ren
    Endocrine.2021; 72(2): 423.     CrossRef
  • Decreased serum growth differentiation factor 15 levels after lifestyle intervention in patients with newly diagnosed type 2 diabetes mellitus
    Xingxing He, Jiaorong Su, Xiaojing Ma, Jingyi Lu, Yufei Wang, Jun Yin, Yuqian Bao, Gang Hu, Jian Zhou
    Obesity Medicine.2021; 24: 100345.     CrossRef
  • The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice
    Pattawika Lertpatipanpong, Jaehak Lee, Ilju Kim, Thomas Eling, Seung Yeon Oh, Je Kyung Seong, Seung Joon Baek
    Scientific Reports.2021;[Epub]     CrossRef
  • The Regulation of Circulating Hepatokines by Fructose Ingestion in Humans
    Michael M Richter, Peter Plomgaard
    Journal of the Endocrine Society.2021;[Epub]     CrossRef
  • GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease
    Dongdong Wang, Emily A. Day, Logan K. Townsend, Djordje Djordjevic, Sebastian Beck Jørgensen, Gregory R. Steinberg
    Nature Reviews Endocrinology.2021; 17(10): 592.     CrossRef
  • High Fat, High Sugar Diet and DJOS Bariatric Surgery Influence Plasma Levels of Fetuin-B, Growth Differentiation Factor-15, and Pentraxin 3 in Diet-Induced Obese Sprague–Dawley Rats
    Jakub Poloczek, Monika Tarnawska, Elżbieta Chełmecka, Piotr Łaszczyca, Janusz Gumprecht, Dominika Stygar
    Nutrients.2021; 13(10): 3632.     CrossRef
  • Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease
    Kazuhito Oba, Joji Ishikawa, Yoshiaki Tamura, Yasunori Fujita, Masafumi Ito, Ai Iizuka, Yoshinori Fujiwara, Remi Kodera, Ayumi Toba, Kenji Toyoshima, Yuko Chiba, Seijiro Mori, Masashi Tanaka, Hideki Ito, Kazumasa Harada, Atsushi Araki
    Geriatrics & Gerontology International.2020; 20(10): 980.     CrossRef
  • Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach
    Axel C. Carlsson, Christoph Nowak, Lars Lind, Carl Johan Östgren, Fredrik H. Nyström, Johan Sundström, Juan Jesus Carrero, Ulf Riserus, Erik Ingelsson, Tove Fall, Johan Ärnlöv
    Upsala Journal of Medical Sciences.2020; 125(1): 37.     CrossRef
  • Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults
    Richard D Semba, Marta Gonzalez-Freire, Toshiko Tanaka, Angelique Biancotto, Pingbo Zhang, Michelle Shardell, Ruin Moaddel, Luigi Ferrucci, Anne Newman
    The Journals of Gerontology: Series A.2020; 75(1): 175.     CrossRef
  • Circulating Cardiac Biomarkers in Diabetes Mellitus: A New Dawn for Risk Stratification—A Narrative Review
    Alexander E. Berezin, Alexander A. Berezin
    Diabetes Therapy.2020; 11(6): 1271.     CrossRef
  • Deterioration of Sleep Quality According to Glycemic Status
    Myung Haeng Hur, Mi-Kyoung Lee, Kayeon Seong, Jun Hwa Hong
    Diabetes & Metabolism Journal.2020; 44(5): 679.     CrossRef
  • Effects of plant and animal high protein diets on immune-inflammatory biomarkers: A 6-week intervention trial
    Mariya Markova, Liselot Koelman, Silke Hornemann, Olga Pivovarova, Stephanie Sucher, Juergen Machann, Natalia Rudovich, Ralph Thomann, Rosemarie Schneeweiss, Sascha Rohn, Andreas F.H. Pfeiffer, Krasimira Aleksandrova
    Clinical Nutrition.2020; 39(3): 862.     CrossRef
  • Effect of sleeve gastrectomy on plasma growth differentiation factor-15 (GDF15) in human
    Ponnie Robertlee Dolo, Libin Yao, Peng Peng Liu, Jason Widjaja, Song Meng, Chao Li, Xiaocheng Zhu
    The American Journal of Surgery.2020; 220(3): 725.     CrossRef
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    Alexander E. Berezin
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Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells
Young-Hye You, Dong-Sik Ham, Heon-Seok Park, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes Metab J. 2011;35(2):119-129.   Published online April 30, 2011
DOI: https://doi.org/10.4093/dmj.2011.35.2.119
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AbstractAbstract PDFPubReader   
Background

A limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells.

Methods

Adult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice.

Results

The adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells.

Conclusion

These data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.

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  • The pig pangenome provides insights into the roles of coding structural variations in genetic diversity and adaptation
    Zhengcao Li, Xiaohong Liu, Chen Wang, Zhenyang Li, Bo Jiang, Ruifeng Zhang, Lu Tong, Youping Qu, Sheng He, Haifan Chen, Yafei Mao, Qingnan Li, Torsten Pook, Yu Wu, Yanjun Zan, Hui Zhang, Lu Li, Keying Wen, Yaosheng Chen
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    Stem Cell Research & Therapy.2021;[Epub]     CrossRef
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  • Generation of Insulin-Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD
    So-Hyun Lee, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
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  • Generation of Functional Insulin-Producing Cells from Neonatal Porcine Liver-Derived Cells by PDX1/VP16, BETA2/NeuroD and MafA
    Dong-Sik Ham, Juyoung Shin, Ji-Won Kim, Heon-Seok Park, Jae-Hyoung Cho, Kun-Ho Yoon, Kathrin Maedler
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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 Articles
Transdifferentiation of Enteroendocrine K-cells into Insulin-expressing Cells.
Esder Lee, Jun Mo Yu, Min Kyung Lee, Gyeong Ryul Ryu, Seung Hyun Ko, Yu Bae Ahn, Sung Dae Moon, Ki Ho Song
Korean Diabetes J. 2009;33(6):475-484.   Published online December 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.6.475
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AbstractAbstract PDF
BACKGROUND
Despite a recent breakthough in human islet transplantation for treating type 1 diabetes mellitus, the limited availability of donor pancreases remains a major obstacle. Endocrine cells within the gut epithelium (enteroendocrine cells) and pancreatic beta cells share similar pathways of differentiation during embryonic development. In particular, K-cells that secrete glucose-dependent insulinotropic polypeptide (GIP) have been shown to express many of the key proteins found in beta cells. Therefore, we hypothesize that K-cells can be transdifferentiated into beta cells because both cells have remarkable similarities in their embryonic development and cellular phenotypes. METHODS: K-cells were purified from heterogeneous STC-1 cells originating from an endocrine tumor of a mouse intestine. In addition, a K-cell subclone expressing stable Nkx6.1, called "Kn4-cells," was successfully obtained. In vitro differentiation of K-cells or Kn4-cells into beta cells was completed after exendin-4 treatment and serum deprivation. The expressions of insulin mRNA and protein were examined by RT-PCR and immunocytochemistry. The interacellular insulin content was also measured. RESULTS: K-cells were found to express glucokinase and GIP as assessed by RT-PCR and Western blot analysis. RT-PCR showed that K-cells also expressed Pdx-1, NeuroD1/Beta2, and MafA, but not Nkx6.1. After exendin-4 treatment and serum deprivation, insulin mRNA and insulin or C-peptide were clearly detected in Kn4-cells. The intracellular insulin content was also increased significantly in these cells. CONCLUSION: K-cells are an attractive potential source of insulin-producing cells for treatment of type 1 diabetes mellitus. However, more experiments are necessary to optimize a strategy for converting K-cells into beta cells.

Citations

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  • Reprogramming of enteroendocrine K cells to pancreatic β-cells through the combined expression of Nkx6.1 and Neurogenin3, and reaggregation in suspension culture
    Esder Lee, Gyeong Ryul Ryu, Sung-Dae Moon, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
    Biochemical and Biophysical Research Communications.2014; 443(3): 1021.     CrossRef
Effect of Adipose Differentiation-Related Protein (ADRP) on Glucose Uptake of Skeletal Muscle.
Yun Hyi Ku, Min Kim, Sena Kim, Ho Seon Park, Han Jong Kim, In Kyu Lee, Dong Hoon Shin, Sung Soo Chung, Sang Gyu Park, Young Min Cho, Hong Kyu Lee, Kyong Soo Park
Korean Diabetes J. 2009;33(3):206-214.   Published online June 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.3.206
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AbstractAbstract PDF
BACKGROUND
Skeletal muscle is the most important tissue contributing to insulin resistance. Several studies have shown that accumulation of intramyocellular lipid is associated with the development of insulin resistance. Thus, proteins involved in lipid transport, storage and metabolism might also be involved in insulin action in skeletal muscle. Adipose differentiation-related protein (ADRP), which is localized at the surface of lipid droplets, is known to be regulated by peroxisome proliferator activated receptor gamma (PPARgamma). However, it is not known whether ADRP plays a role in regulating glucose uptake and insulin action in skeletal muscle. METHODS: ADRP expression in skeletal muscle was measured by RT-PCR and western blot in db/db mice with and without PPARgamma agonist. The effect of PPARgamma agonist or high lipid concentration (0.4% intralipos) on ADRP expression was also obtained in cultured human skeletal muscle cells. Glucose uptake was measured when ADRP was down-regulated with siRNA or when ADRP was overexpressed with adenovirus. RESULTS: ADRP expression increased in the skeletal muscle of db/db mice in comparison with normal controls and tended to increase with the treatment of PPARgamma agonist. In cultured human skeletal muscle cells, the treatment of PPARgamma agonist or high lipid concentration increased ADRP expression. siADRP treatment decreased both basal and insulin-stimulated glucose uptake whereas ADRP overexpression increased glucose uptake in cultured human skeletal muscle cells. CONCLUSION: ADRP expression in skeletal muscle is increased by PPARgamma agonist or exposure to high lipid concentration. In these conditions, increased ADRP contributed to increase glucose uptake. These results suggest that insulin-sensitizing effects of PPARgamma are at least partially achieved by the increase of ADRP expression, and ADRP has a protective effect against intramyocellular lipid-induced insulin resistance.
Differentiation of Pancreatic beta Cells from Human Pancreatic Duct Cells Derived from a Partial Pancreas Tissue.
Ki Ho Song, Myung Mee Kim, Min Kyung Lee, Gyeong Ryul Ryu, Seung Hyun Ko, Sung Dae Moon, Yu Bae Ahn, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Hyung Min Chin
Korean Diabetes J. 2007;31(3):236-242.   Published online May 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.3.236
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AbstractAbstract PDF
BACKGROUND
Despite a recent breakthrough in human islet transplantation for treating diabetes mellitus, the limited availability of insulin-producing tissue is still a major obstacle. This has led to a search for alternative sources of transplantable insulin-producing cells including pancreatic duct cells. We aimed to establish in vitro culture of pancreatic duct cells from a partial pancreas tissue in human, which could be harnessed to differentiate into pancreatic beta cells. METHODS: We isolated pancreatic duct cells from small pieces of pancreas tissue (1~3 g) derived from non-diabetic humans (n = 8) undergoing pancreatic surgery due to cancer. Pancreas tissue was finely minced after injection of collagenase P into the parenchyma. The mince was incubated in a shaking water bath at 37degrees C for 25 min and passed through a 150 micrometer mesh. The released cells were recovered, washed, and plated in a dish containing CMRL culture medium with serum. RESULTS: Isolated pancreatic cells grew in monolayer and became confluent in 1~2 wks showing typical epithelial cobblestone morphology. Immunochemistry demonstrated that ~90% of the cultured cells were cytokeratin7-positive duct cells. To induce beta cell differentiation, the cells were incubated in DMEM/F12 culture medium without serum. In addition, treatment with Matrigel overlay, exendin-4, cholera toxin or forskolin was done. Though beta cell differentiation was found by immunostaining and RT-PCR, the differentiation efficiency was very low. Over-expression of neurogenin-3 by recombinant adenovirus did not increase beta cell differentiation of the cultured duct cells significantly. CONCLUSION: We established in vitro culture of pancreatic duct cells from a partial pancreas tissue in human, which differentiate into pancreatic cells. However, a strategy to optimize beta cell differentiation in this model is needed.

Citations

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  • Transdifferentiation of Enteroendocrine K-cells into Insulin-expressing Cells
    Esder Lee, Jun Mo Yu, Min Kyung Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Sung-Dae Moon, Ki-Ho Song
    Korean Diabetes Journal.2009; 33(6): 475.     CrossRef
PDX-1/VP16 Overexpression Induce the Transdifferentiation of Canine Adult Pancreatic Cells into Beta-cells.
Young Hye You, Sun Cheol Park, Seung Hwan Lee, Heon Seok Park, Dong Sik Ham, Marie Rhee, Ji Won Kim, Ki Ho Song, Kun Ho Yoon
Korean Diabetes J. 2007;31(1):51-62.   Published online January 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.1.51
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AbstractAbstract PDF
BACKGROUND
A major obstacle of islet transplantation is an inadequate supply of insulin-producing tissue. Ad-PDX-1/VP16 overexpression and Exendin-4 treatment have been proved the effects on differentiation and proliferation of pancreatic stem cells. But, the study is insufficient using adult animal pancreatic stem cells. METHODS: Pancreatic cells were prepared from the non-endocrine fraction of canine pancreases. This cells were cultivated free floating state and monolayer culture after dispersion. The floating pancreatic cells were transplanted under the kidney capsule of normoglycaemic nude mice. The dispersed pancreatic cells were infected with Ad-PDX-1/VP16 or Ad-GFP. After infection, those cells were transplanted of nude mice. After transplantation, mice were treated with either 1 nmol/kg exendin-4 or saline solution by intraperitoneal injection for 10 days. RESULTS: The relative volume of the beta-cells in the grafts of the free floating cultured pancreatic cells were 23.4 +/- 13.1% at two weeks and 5.2 +/- 2.0% at eight weeks. At two weeks after transplantation, the relative volume of insulin-positive cells in the grafts of dispersed pancreatic cells were 28 +/- 5.7%, 20.5 +/- 0.7% and 31 +/- 1.4% in control, GFP and PDX-1/VP16 treated groups respectively. At eight weeks after transplantation, the relative volume of insulin-positive cells in the grafts were 11.8 +/- 5.9%, 8 +/- 7.3% and 16.6 +/- 7.4% in control, GFP and PDX-1/VP16 treated groups respectively. Exendin-4 treatment didn't show any additive effects on transdifferentiation of pancreas stem cell into beta-cells. CONCLUSION: The expansion and transdifferentiation were not observed after the transplantation of the free floating cultured pancreatic cells. PDX-1/VP16 overexpression induces the transdifferentiation of adult pancreatic cells into beta-cells. However Exendin-4 treatment hasn't any effects on the expansion and transdifferentiation of the cells in the grafts.

Citations

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  • Generation of Functional Insulin-Producing Cells from Neonatal Porcine Liver-Derived Cells by PDX1/VP16, BETA2/NeuroD and MafA
    Dong-Sik Ham, Juyoung Shin, Ji-Won Kim, Heon-Seok Park, Jae-Hyoung Cho, Kun-Ho Yoon, Kathrin Maedler
    PLoS ONE.2013; 8(11): e79076.     CrossRef
  • Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells
    Young-Hye You, Dong-Sik Ham, Heon-Seok Park, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
    Diabetes & Metabolism Journal.2011; 35(2): 119.     CrossRef
  • Transdifferentiation of Enteroendocrine K-cells into Insulin-expressing Cells
    Esder Lee, Jun Mo Yu, Min Kyung Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Sung-Dae Moon, Ki-Ho Song
    Korean Diabetes Journal.2009; 33(6): 475.     CrossRef
Review
The Roles of Clusterin on Morphogenesis of Beta Cells During Pancreas Regeneration.
Seok Woo Hong, KC Ranjan, Song Lee, Yong Jae Shin, Bon Hong Min, In Sun Park
Korean Diabetes J. 2007;31(1):1-8.   Published online January 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.1.1
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AbstractAbstract PDF
Clusterin is a highly glycosylated heterodimeric glycoprotein that plays diverse biological roles in various organs. The secreted clusterin has been established as a major form of the protein that exerts diverse tissue effects. For instance, clusterin is known to act in cell protection through the actions of extra-cellular molecular chaperones. In the extracellular milieu, clusterin participates in specific interactions with a diverse array of native biological molecules including LRP-2 (Lipoprotein receptor-related protein 2, also known as gp330 or megalin), which is involved in ligand endocytosis at the surfaces of certain epithelia. Clusterin is expressed transiently in developing and differentiating endocrine pancreatic cells and might be involved in pancreas development. This transient expression of clusterin at specific time points of pancreas development and cell differentiation during pancreas regeneration implies that the protein is a regulatory factor for cytodifferentiation as well as for replication. A specific action of the clusterin in the reconstruction and remodeling of the endocrine pancreas has been demonstrated. It also strongly stimulates duct cell differentiation into insulin-secreting cells under in vitro culture conditions. Clusterin appears thus as a potent regulator of insulin cell morphogenesis.

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  • Effect of African Mango (Irvingia gabonesis, IGOB 131TM) Extract on Glucose Regulation in STZ-Induced Diabetes
    Yejin Ha, Minhee Lee, Han Ol Kwon, Yoo-Hyun Lee
    Journal of the Korean Society of Food Science and Nutrition.2015; 44(11): 1607.     CrossRef
Original Articles
Characterization of Preadipocyte factor-1 (Pref-1) Expressing Pancreatic Cells.
Marie Rhee, Sun Hee Suh, Youn Joo Yang, Ji Won Kim, Sung Yoon Jeon, Oak Kee Hong, Seung Hyun Ko, Yoon Hee Choi, Bong Yun Cha, Ho Yong Son, Kun Ho Yoon
Korean Diabetes J. 2005;29(6):507-516.   Published online November 1, 2005
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AbstractAbstract PDF
BACKGROUND
Preadipocyte factor-1/Delta-like 1(Pref-1/Dlk1) is a type I membrane protein that has six epidermal growth factor (EGF)-like repeats in its extracellular and a short cytoplasmic domain. It is widely expressed in embryonic tissues, whereas its expressions were limited in adult and postnatal stage. To characterize the Pref-1 expressing cells during pancreas development and regeneration after birth, we analyzed Pref-1 expression in embryonic and adult partial pancreatectomized rat pancreas, and primary cultured neonatal pig pancreatic cells. METHODS: Whole fetuses or pieces of rat pancreas were obtained at E20. 90% partial pancreatectomy (Px) and sham operation were done using 5 week-old Sprague-Dawley rats. Experimental animals were divided into 11 groups by time of killing after surgery; 0, 1, 3, 6 and 12 hours, 1, 2, 3, 5, 7, and 14 days. All tissues were immunostained with Pref-1 and analysed by reverse transcriptase (RT)-PCR. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. Cells were harvested on day 0, 3, 4, 5, 6, and 7 after dispersion. All cells were immunostained with Pref-1 and other specific cell markers such as Pan-cytokeratin (Pan-CK), vimentin (VT) and islet hormones, and confirmed by Western blot, RT-PCR and fluorescence activated cell sorting (FACS) analysis. RESULTS: In the rat embryonic pancreas at E20, Pref-1 expression was restricted only in the small branching ductules. In adult rat pancreas, Pref-1 was not expressed at all. Whereas, Pref-1 transiently expressed in the small regenerating duct cells located in foci of regeneration in Px model, then completely disappeared at day 7. The Pref-1 mRNA measured by RT-PCR was peaked at day 3 after Px and then gradually disappeared. Pref-1 expression pattern was also reproduced in monolayer cultured NPCCs. In NPCCs, protein levels of Pref-1 were peaked at day 0 to day 4 then gradually disappeared until day 7 by western blot. Most of Pref-1 expressing cells were co-stained with cytokeratin. The proportion of Pref-1 expressing cells in dispersed NPCCs were counted and isolated by FACS at 3 days after culture were 25% and then decreased over time during 7 days culture period. CONCLUSIONS: Pref-1 expression was regained in adult pancreatic cells during regeneration in vivo and in vitro and Pref-1 might be a useful marker for the pancreatic protodifferentiated cells.
The Effects of Dexamethasone on the Expansion and Transdifferentiation of Transplanted Porcine Neonatal Pancreas Cell Clusters into beta-cells in Normal Nude Mice.
Ji Hun Yang, Sun Hee Suh, Sung Yoon Jeon, Oak Kee Hong, Kun Ho Yoon
Korean Diabetes J. 2004;28(5):356-366.   Published online October 1, 2004
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BACKGROUND
Several studies have suggested that glucocorticoid has an influence on the development and function of the -cells. Thus, we undertook this study to determine whether exposure to dexamethasone (Dx) has an influence on the expansion or transdifferentiation of transplanted porcine NPCCs. METHODS: After transplantation (Tx) of 4,000 islet equivalents (IEQs) of porcine NPCCs into normal nude mice, Dx (1mg/kg) or the control vehicle were injected daily for 10 weeks. To clarify the effects of timing and duration of the Dx, one group was treated by Dx at the first 2 weeks (n=10) and the other group was treated later 8 weeks (n=10) during the 10 weeks treatment period. Thr total graft and beta-cell masses were determined by morphometric analysis. We preformed semi-quantitative RT-PCR for evaluating the pancreas transcription factors. RESULTS: The relative volume and absolute mass of the beta-cells and the total graft were significantly decreased by 10 weeks Dx treatment. Moreover, Dx treatment at thr first 2 weeks (n=10) also significantly decreased the total graft mass and absolute mass of the beta-cells. The relative volume of the beta-cells was negatively correlated and the area of the duct cysts was positively correlated with the duration of the Dx treatment. Pancreas transcription factors including PDX1, Ngn 3, ISL1 and NKx6.1 were decreased in the graft by 2 days treatment of Dx. CONCLUSION: These results suggest that Dx treatment suppresses the expansion and transdifferentiation of transplanted pancreas precursor cells into beta-cell.

Diabetes Metab J : Diabetes & Metabolism Journal