Diabetes & Metabolism Journal

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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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

Epidemiology
Serum Betatrophin Concentrations and the Risk of Incident Diabetes: A Nested Case-Control Study from Chungju Metabolic Disease Cohort: Seung-Hwan Lee, Marie Rhee, Hyuk-Sang Kwon, Yong-Moon Park, Kun-Ho Yoon; Diabetes Metab J. 2018;42(1):53-62. Published online November 3, 2017; DOI: https://doi.org/10.4093/dmj.2018.42.1.53

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Background

Betatrophin is a newly identified hormone derived from the liver and adipose tissue, which has been suggested to regulate glucose and lipid metabolism. Circulating levels of betatrophin are altered in various metabolic diseases, although the results are inconsistent. We aimed to examine whether betatrophin is a useful biomarker in predicting the development of diabetes.

Methods

A nested case-control study was performed using a prospective Chungju Metabolic disease Cohort Study. During a 4-year follow-up period, we analyzed 167 individuals who converted to diabetes and 167 non-converters, who were matched by age, sex, and body mass index. Serum betatrophin levels were measured by an ELISA (enzyme-linked immunosorbent assay).

Results

Baseline serum betatrophin levels were significantly higher in the converter group compared to the non-converter group (1,315±598 pg/mL vs. 1,072±446 pg/mL, P<0.001). After adjusting for age, sex, body mass index, fasting plasma glucose, systolic blood pressure, total cholesterol, and family history of diabetes, the risk of developing diabetes showed a stepwise increase across the betatrophin quartile groups. Subjects in the highest baseline quartile of betatrophin levels had more than a threefold higher risk of incident diabetes than the subjects in the lowest quartile (relative risk, 3.275; 95% confidence interval, 1.574 to 6.814; P=0.010). However, no significant relationships were observed between serum betatrophin levels and indices of insulin resistance or β-cell function.

Conclusion

Circulating levels of betatrophin could be a potential biomarker for predicting new-onset diabetes. Further studies are needed to understand the underlying mechanism of this association.

Citations

Citations to this article as recorded by

Maternal and cord blood betatrophin (angiopoietin‐like protein 8) in pregnant women with gestational diabetes and normoglycemic controls: A systematic review, meta‐analysis, and meta‐regression
Faustino R. Pérez‐López, Junhua Yuan, Manuel Sánchez‐Prieto, María T. López‐Baena, Gonzalo R. Pérez‐Roncero, Seshadri Reddy Varikasuvu
Diabetes/Metabolism Research and Reviews.2023;[Epub] CrossRef
Evaluation of Adiponectin and ANGPTL8 in Women With Metabolic Syndrome in the Madinah Region of Saudi Arabia
Walaa Mohammedsaeed, Ahmed Ahmed, Nada Alharbi, Amjaad Aljohani, Razan Alruwaithi, Reem Alharbi, Shatha Alahmadi
Cureus.2023;[Epub] CrossRef
Associations Between Betatrophin with Irisin and Metabolic Factors: Effects of Two Exercise Trainings in Diabetic Rats
Hassan Tavassoli, Ali Heidarianpour
The American Journal of the Medical Sciences.2021; 362(5): 496. CrossRef
Evidences for Expression and Location of ANGPTL8 in Human Adipose Tissue
Leonardo Catalano-Iniesta, Virginia Sánchez Robledo, María Carmen Iglesias-Osma, Amparo Galán Albiñana, Sixto Carrero, Enrique J. Blanco, Marta Carretero-Hernández, José Carretero, María José García-Barrado
Journal of Clinical Medicine.2020; 9(2): 512. CrossRef
Higher circulating levels of ANGPTL8 are associated with body mass index, triglycerides, and endothelial dysfunction in patients with coronary artery disease
Reza Fadaei, Hossein Shateri, Johanna K. DiStefano, Nariman Moradi, Mohammad Mohammadi, Farzad Emami, Hassan Aghajani, Nasrin Ziamajidi
Molecular and Cellular Biochemistry.2020; 469(1-2): 29. CrossRef
Effects of a diet with or without physical activity on angiopoietin-like protein 8 concentrations in overweight/obese patients with newly diagnosed type 2 diabetes: a randomized controlled trial
Hao Hu, Guoyue Yuan, Xinchen Wang, Jin Sun, Zhaohua Gao, Tingting Zhou, Wenwen Yin, Ruonan Cai, Xing Ye, Zhaoling Wang
Endocrine Journal.2019; 66(1): 89. CrossRef
The potential role of angiopoietin-like protein-8 in type 2 diabetes mellitus: a possibility for predictive diagnosis and targeted preventive measures?
Yasmine Amr Issa, Samar Samy Abd ElHafeez, Noha Gaber Amin
EPMA Journal.2019; 10(3): 239. CrossRef
A Short Review on ANGPTL-8 as an Important Regulator in Diabetes
Maryam Esfahani, Mohammad Taghi Goodarzi
Avicenna Journal of Medical Biochemistry.2019; 7(2): 61. 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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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

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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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.

Citations

Citations to this article as recorded by

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
Genome Research.2023; 33(10): 1833. CrossRef
Improvement of the therapeutic capacity of insulin-producing cells trans-differentiated from human liver cells using engineered cell sheet
Yu Na Lee, Hye-Jin Yi, Eun Hye Seo, Jooyun Oh, Song Lee, Sarah Ferber, Teruo Okano, In Kyong Shim, Song Cheol Kim
Stem Cell Research & Therapy.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
Effect of FIGF overexpression on liver cells transforming to insulin-producing cells
Yaqin He, Xiaoliang Xie, Xiaoyan Li, Shikuo Rong, Yukui Li, Zhenhui Lu
Journal of Biosciences.2019;[Epub] CrossRef
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 & Metabolism Journal.2017; 41(5): 405. CrossRef
Quantitative Raman spectral changes of the differentiation of mesenchymal stem cells into islet-like cells by biochemical component analysis and multiple peak fitting
Xin Su, Shaoyin Fang, Daosen Zhang, Qinnan Zhang, Yingtian He, Xiaoxu Lu, Shengde Liu, Liyun Zhong
Journal of Biomedical Optics.2015; 20(12): 125002. CrossRef
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
PPARγ Activation Attenuates Glycated-Serum Induced Pancreatic Beta-Cell Dysfunction through Enhancing Pdx1 and Mafa Protein Stability
Yunxia Zhu, Ai Ma, Hongxiu Zhang, Chaojun Li, Rebecca Berdeaux
PLoS ONE.2013; 8(2): e56386. CrossRef
β‐Cell differentiation and regeneration in type 1 diabetes
L. Ding, C. Gysemans, C. Mathieu
Diabetes, Obesity and Metabolism.2013; 15(s3): 98. 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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Abstract 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

Citations to this article as recorded by

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

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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Abstract 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.

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