Diabetes & Metabolism Journal

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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; 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

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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

The Effect of Glucose Fluctuation on Apoptosis and Function of INS-1 Pancreatic Beta Cells: Mi Kyung Kim, Hye Sook Jung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Min Jeong Kwon, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2010;34(1):47-54. Published online February 28, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.1.47

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Background

Blood glucose level continuously fluctuates within a certain range in the human body. In diabetes patients, the extent of such fluctuation is large, despite the strict control of blood glucose. Blood glucose fluctuation has been shown to mediate more adverse effects on vascular endothelial cells and diabetes complications than chronic hyperglycemia, which has been explained as due to oxidative stress. As few previous studies have reported the effects of chronic and intermittent hyperglycemia on the apoptosis and function of pancreatic beta cells, this study reported herein was performed to investigate such effects on these cells.

Methods

For chronic hyperglycemia, INS-1 cells were cultured for 5 days with changes of RPMI 1640 medium containing 33 mM glucose every 12 hours. For intermittent hyperglycemia, the medium containing 11 mM glucose was exchanged with the medium containing 33 mM glucose every 12 hours. Apoptosis was assessed by TUNEL assay Hoechst staining and cleaved caspase 3. Insulin secretory capacity was assessed, and the expression of Mn-SOD and Bcl-2 was measured by Western blotting.

Results

In comparison to the control group, INS-1 cells exposed to chronic hyperglycemia and intermittent hyperglycemia showed an increase in apoptosis. The apoptosis of INS-1 cells exposed to intermittent hyperglycemia increased significantly more than the apoptosis of INS-1 cells exposed to chronic hyperglycemia. In comparison to the control group, the insulin secretory capacity in the two hyperglycemic states was decreased, and more with intermittent hyperglycemia than with chronic hyperglycemia. The expression of Mn-SOD and Bcl-2 increased more with chronic hyperglycemia than with intermittent hyperglycemia.

Conclusion

Intermittent hyperglycemia induced a higher degree of apoptosis and decreased the insulin secretory capacity more in pancreatic beta cells than chronic hyperglycemia. This activity may be mediated by the anti-oxidative enzyme Mn-SOD and the anti-apoptotic signal Bcl-2.

Citations

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Association between hemoglobin glycation index and diabetic kidney disease in type 2 diabetes mellitus in China: A cross- sectional inpatient study
Sixu Xin, Xin Zhao, Jiaxiang Ding, Xiaomei Zhang
Frontiers in Endocrinology.2023;[Epub] CrossRef
Plant polyphenols mechanisms of action on insulin resistance and against the loss of pancreatic beta cells
Camelia Papuc, Gheorghe V. Goran, Corina N. Predescu, Liliana Tudoreanu, Georgeta Ștefan
Critical Reviews in Food Science and Nutrition.2022; 62(2): 325. CrossRef
Correlation between HbA1c and Triglyceride Level with Coronary Stenosis Degree in Type 2 Diabetes Mellitus with Coronary Heart Disease
Laily Adninta, Indranila Samsuria, Edward Kurnia Setiawan Limijadi
Open Access Macedonian Journal of Medical Sciences.2022; 10(B): 944. CrossRef
Age‐specific associations of glycated haemoglobin variability with cardiovascular disease and mortality in patients with type 2 diabetes mellitus: A 10‐ year cohort study
Eric Yuk Fai Wan, Esther Yee Tak Yu, Weng Yee Chin, Florence Ting Yan Ng, Shu Ming Cheryl Chia, Ian Chi Kei Wong, Esther Wai Yin Chan, Cindy Lo Kuen Lam
Diabetes, Obesity and Metabolism.2020; 22(8): 1316. CrossRef
Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications
Zhen-Ye Zhang, Ling-Feng Miao, Ling-Ling Qian, Ning Wang, Miao-Miao Qi, Yu-Min Zhang, Shi-Peng Dang, Ying Wu, Ru-Xing Wang
Frontiers in Endocrinology.2019;[Epub] CrossRef
Resolution on the results of the first working meeting of the scientific advisory board «Actual problems of glycemic variability as a new criterion of glycemic control and safety of diabetes therapy»
Mikhail B. Antsiferov, Gagik R. Galstyan, Alexey V. Zilov, Alexander Y. Mayorov, Tatyana N. Markova, Nikolay A. Demidov, Olga M. Koteshkova, Dmitry N. Laptev, Alisa V. Vitebskaya
Diabetes mellitus.2019; 22(3): 281. CrossRef
Intermittent High Glucose Enhances the Proliferation of Rat Aortic Vascular Smooth Muscle Cells More Than Constant High Glucose via the Mitogen-Activated Protein Kinase Pathway
Sung Hoon Yu, Hyung Joon Yoo, Dong Hyun Kang, Shin Je Moon, Jae Myung Yu
Annals of Geriatric Medicine and Research.2017; 21(3): 131. CrossRef
Association of variability in hemoglobin A1c with cardiovascular diseases and mortality in Chinese patients with type 2 diabetes mellitus — A retrospective population-based cohort study
Eric Yuk Fai Wan, Colman Siu Cheung Fung, Daniel Yee Tak Fong, Cindy Lo Kuen Lam
Journal of Diabetes and its Complications.2016; 30(7): 1240. CrossRef
Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress
You Jeong Kim, Su Min Park, Hye Sook Jung, Eun Ju Lee, Tae Kyoon Kim, Tae-Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Byoung Doo Rhee, Mi-kyung Kim, Jeong Hyun Park
Islets.2016; 8(3): 57. CrossRef
Different antihyperglycaemic drug effects on glycaemic variability in Type 2 diabetic patients
Alina Babenko, Elena Ivanovna Krasilnikova, Nikolay Pavlovich Likhonosov, Anna Pavlovna Likhonosova, Elena Nikolaevna Grineva
Diabetes mellitus.2014; 17(4): 72. CrossRef
Exercising for Metabolic Control: Is Timing Important
Jonida Haxhi, Alessandro Scotto di Palumbo, Massimo Sacchetti
Annals of Nutrition and Metabolism.2013; 62(1): 14. CrossRef
Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats
Yunli Yu, Xinting Wang, Can Liu, Dan Yao, Mengyue Hu, Jia Li, Nan Hu, Li Liu, Xiaodong Liu
Toxicology and Applied Pharmacology.2013; 266(3): 375. CrossRef
Blood glucose fluctuation affects skin collagen metabolism in the diabetic mouse by inhibiting the mitogen-activated protein kinase and Smad pathways
X. Ye, X. Cheng, L. Liu, D. Zhao, Y. Dang
Clinical and Experimental Dermatology.2013; 38(5): 530. CrossRef
Glucose exposure pattern determines glucagon-like peptide 1 receptor expression and signaling through endoplasmic reticulum stress in rat insulinoma cells
Ye-Hwang Cheong, Mi-Kyung Kim, Moon-Ho Son, Bong-Kiun Kaang
Biochemical and Biophysical Research Communications.2011; 414(1): 220. CrossRef
Overexpression of Insig-1 protects β cell against glucolipotoxicity via SREBP-1c
Ke Chen, ping jin, Hong-hui He, Yan-hong Xie, Xiao-yun Xie, Zhao-hui Mo
Journal of Biomedical Science.2011;[Epub] CrossRef
Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes
Gong Su, Shuhua Mi, Hong Tao, Zhao Li, Hongxia Yang, Hong Zheng, Yun Zhou, Changsheng Ma
Cardiovascular Diabetology.2011;[Epub] CrossRef
Lithospermic acid B protects beta-cells from cytokine-induced apoptosis by alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2–HO-1 and Sirt1
Byung-Wan Lee, Sung Wan Chun, Soo Hyun Kim, Yongho Lee, Eun Seok Kang, Bong-Soo Cha, Hyun Chul Lee
Toxicology and Applied Pharmacology.2011; 252(1): 47. CrossRef
WITHDRAWN: Effect of blood glucose fluctuation on the function of rat pancreatic islets in vivo
Wang Yanjun, Xiao Yue, Li Shixing
Regulatory Peptides.2011;[Epub] CrossRef

Protective Effects of Glucagon Like Peptide-1 on HIT-T15 beta Cell Apoptosis via ER Stress Induced by 2-deoxy-D-glucose.: Ju Young Kim, Seong Kyu Lee, Haing Woon Baik, Ki Ho Lee, Hyun Jin Kim, Kang Seo Park, Byung Joon Kim; Korean Diabetes J. 2008;32(6):477-487. Published online December 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.6.477

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Abstract PDF

BACKGROUND
The characteristic feature of pancreatic beta cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important function, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various stress conditions can interfere with ER function. Pancreatic beta cells may be particularly vulnerable to ER stress that causes to impair insulin biosynthesis and beta cell survival through apoptosis. Glucagon like peptide-1 (GLP-1) is a new drug for treatment of type 2 diabetes and has effects on stimulation of insulin secretion and beta cell preservation. Also, it may have an antiapoptotic effect on beta cells, but detailed mechanisms are not proven. Therefore, we investigated the protective mechanism of GLP-1 in beta cells through ER stress response induced by 2-deoxy-D-glucose (2DG). METHODS: For induction of the ER stress, HIT-T15 cells (hamster beta cell line) were treated with 2DG (10 mM). Apoptosis was evaluated with MTT assay, hoechst 33342 staining and Annexin/PI flow cytometry. Expression of ER stress-related molecules was determined by real-time PCR or western blot. For blocking ER stress, we pretreated HIT-T15 cells with exendin-4 (Ex-4; GLP-1 receptor agonist) for 1 hour before stress induction. RESULTS: After induction with ER stress (2DG), beta cells were lost by apoptosis. We found that Ex-4 had a protective effect through ER stress related molecules (GRP78, GRP94, XBP-1, eIF2alpha, CHOP) modulation. Also, Ex-4 recovered the expression of insulin2 mRNA in beta cells. CONCLUSION: These results suggest that GLP-1 may protect beta cells apoptosis through ER stress modulation.

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Exendin-4 Protects Against Sulfonylurea-Induced β-Cell Apoptosis
Ju-Young Kim, Dong-Mee Lim, Hyung-Seo Park, Chan-Il Moon, Kyung-Jin Choi, Seong-Kyu Lee, Haing-Woon Baik, Keun-Young Park, Byung-Joon Kim
Journal of Pharmacological Sciences.2012; 118(1): 65. CrossRef
GLP-1 Can Protect Proinflammatory Cytokines Induced Beta Cell Apoptosis through the Ubiquitination
Dong Mee Lim, Ju Young Kim, Kang Woo Lee, Keun Young Park, Byung Joon Kim
Endocrinology and Metabolism.2011; 26(2): 142. CrossRef
Exendin-4 Protects Oxidative Stress-Induced β-Cell Apoptosis through Reduced JNK and GSK3β Activity
Ju-Young Kim, Dong-Mee Lim, Chan Il Moon, Kyung-Jin Jo, Seong-Kyu Lee, Haing-Woon Baik, Ki-Ho Lee, Kang-Woo Lee, Keun-Young Park, Byung-Joon Kim
Journal of Korean Medical Science.2010; 25(11): 1626. 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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Abstract 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 131^TM) 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

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