Diabetes & Metabolism Journal

Reviews

Basic Research
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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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

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Beta cell primary cilia mediate somatostatin responsiveness via SSTR3
Samantha E. Adamson, Zipeng A. Li, Jing W. Hughes
Islets.2023;[Epub] CrossRef

Basic Research
Regulation of Cellular Senescence in Type 2 Diabetes Mellitus: From Mechanisms to Clinical Applications: Kanako Iwasaki, Cristian Abarca, Cristina Aguayo-Mazzucato; Diabetes Metab J. 2023;47(4):441-453. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0416

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Cellular senescence is accelerated by hyperglycemia through multiple pathways. Therefore, senescence is an important cellular mechanism to consider in the pathophysiology of type 2 diabetes mellitus (T2DM) and an additional therapeutic target. The use of drugs that remove senescent cells has led to improvements in blood glucose levels and diabetic complications in animal studies. Although the removal of senescent cells is a promising approach for the treatment of T2DM, two main challenges limit its clinical application: the molecular basis of cellular senescence in each organ is yet to be understood, and the specific effect of removing senescent cells in each organ has to be determined. This review aims to discuss future applications of targeting senescence as a therapeutic option in T2DM and elucidate the characteristics of cellular senescence and senescence-associated secretory phenotype in the tissues important for regulating glucose levels: pancreas, liver, adipocytes, and skeletal muscle.

Citations

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Amide Alkaloids as Privileged Sources of Senomodulators for Therapeutic Purposes in Age-Related Diseases
Mazzarine Dotou, Aurore L’honoré, Roba Moumné, Chahrazade El Amri
Journal of Natural Products.2024; 87(3): 617. CrossRef
Study on the Pathogenesis of Cell Senescence in Non-Alcoholic Fatty Liver
丽媛黄
Medical Diagnosis.2024; 14(01): 76. CrossRef
Senescent adipocytes and type 2 diabetes – current knowledge and perspective concepts
Weronika Kruczkowska, Julia Gałęziewska, Mateusz Kciuk, Adrianna Gielecińska, Elżbieta Płuciennik, Zbigniew Pasieka, Lin-Yong Zhao, Yi-Jin Yu, Damian Kołat, Żaneta Kałuzińska-Kołat
Biomolecular Concepts.2024;[Epub] CrossRef
The Effect of Long-Term Passage on Porcine SMCs’ Function and the Improvement of TGF-β1 on Porcine SMCs’ Secretory Function in Late Passage
Yan-Yan Zheng, Ze-Nan Hu, Zheng Liu, Yi-Chen Jiang, Ren-Peng Guo, Shi-Jie Ding, Guang-Hong Zhou
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Exploring the Relationship between Cellular Senescence Markers and Aging-Related Diseases
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Advances in Clinical Medicine.2023; 13(08): 12298. CrossRef

Pathophysiology
Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells: Seoil Moon, Hye Seung Jung; Diabetes Metab J. 2022;46(4):533-542. Published online July 27, 2022; DOI: https://doi.org/10.4093/dmj.2022.0070

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Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

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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 & Metabolism Journal.2024; 48(2): 231. CrossRef
Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders
Giorgio Vivacqua, Romina Mancinelli, Stefano Leone, Rosa Vaccaro, Ludovica Garro, Simone Carotti, Ludovica Ceci, Paolo Onori, Luigi Pannarale, Antonio Franchitto, Eugenio Gaudio, Arianna Casini
Neurogastroenterology & Motility.2024;[Epub] CrossRef
Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells
Seok-Woo Hong, Jinmi Lee, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee
Endocrinology and Metabolism.2024; 39(2): 353. CrossRef
Pancreatic islet remodeling in cotadutide-treated obese mice
Renata Spezani, Thatiany Souza Marinho, Luiz E. Macedo Cardoso, Marcia Barbosa Aguila, Carlos Alberto Mandarim-de-Lacerda
Life Sciences.2023; 327: 121858. CrossRef
Modulation of Unfolded Protein Response Restores Survival and Function of β-Cells Exposed to the Endocrine Disruptor Bisphenol A
Laura Maria Daian, Gabriela Tanko, Andrei Mircea Vacaru, Luiza Ghila, Simona Chera, Ana-Maria Vacaru
International Journal of Molecular Sciences.2023; 24(3): 2023. CrossRef
Interplay of skeletal muscle and adipose tissue: sarcopenic obesity
Min Jeong Park, Kyung Mook Choi
Metabolism.2023; 144: 155577. CrossRef
Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes
Kun Cui, Zhizheng Li
Frontiers in Endocrinology.2023;[Epub] CrossRef
Sestrin2 in diabetes and diabetic complications
Xiaodan Zhang, Zirui Luo, Jiahong Li, Yaxuan Lin, Yu Li, Wangen Li
Frontiers in Endocrinology.2023;[Epub] CrossRef
Crosstalk between autophagy and insulin resistance: evidence from different tissues
Asie Sadeghi, Maryam Niknam, Mohammad Amin Momeni-Moghaddam, Maryam Shabani, Hamid Aria, Alireza Bastin, Maryam Teimouri, Reza Meshkani, Hamed Akbari
European Journal of Medical Research.2023;[Epub] CrossRef
Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding
Patricia Thomas, Meurig T. Gallagher, Gabriela Da Silva Xavier
Frontiers in Endocrinology.2023;[Epub] CrossRef

Islet Studies and Transplantation
Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction: Shun-ichiro Asahara, Hiroyuki Inoue, Yoshiaki Kido; Diabetes Metab J. 2022;46(1):38-48. Published online January 27, 2022; DOI: https://doi.org/10.4093/dmj.2021.0045

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The main pathogenic mechanism of diabetes consists of an increase in insulin resistance and a decrease in insulin secretion from pancreatic β-cells. The number of diabetic patients has been increasing dramatically worldwide, especially in Asian people whose capacity for insulin secretion is inherently lower than that of other ethnic populations. Causally, changes of environmental factors in addition to intrinsic genetic factors have been considered to have an influence on the increased prevalence of diabetes. Particular focus has been placed on “gene-environment interactions” in the development of a reduced pancreatic β-cell mass, as well as type 1 and type 2 diabetes mellitus. Changes in the intrauterine environment, such as intrauterine growth restriction, contribute to alterations of gene expression in pancreatic β-cells, ultimately resulting in the development of pancreatic β-cell failure and diabetes. As a molecular mechanism underlying the effect of the intrauterine environment, epigenetic modifications have been widely investigated. The association of diabetes susceptibility genes or dietary habits with gene-environment interactions has been reported. In this review, we provide an overview of the role of gene-environment interactions in pancreatic β-cell failure as revealed by previous reports and data from experiments.

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Increased risk of incident diabetes after therapy with immune checkpoint inhibitor compared with conventional chemotherapy: A longitudinal trajectory analysis using a tertiary care hospital database
Minyoung Lee, Kyeongseob Jeong, Yu Rang Park, Yumie Rhee
Metabolism.2023; 138: 155311. CrossRef
The ameliorating effects of mesenchymal stem cells compared to α‐tocopherol on apoptosis and autophagy in streptozotocin‐induced diabetic rats: Implication of PI3K/Akt signaling pathway and entero‐insular axis
Heba A. Mubarak, Manal M. Kamal, Yossra Mahmoud, Fatma S. Abd‐Elsamea, Eman Abdelbary, Marwa G. Gamea, Reham I. El‐Mahdy
Journal of Cellular Biochemistry.2023; 124(11): 1705. CrossRef
Leptin Rs7799039 polymorphism is associated with type 2 diabetes mellitus Egyptian patients
Amal Ahmed Mohamed, Dina M. Abo-Elmatty, Alaa S. Wahba, Omnia Ezzat Esmail, Hadeer Saied Mahmoud Salim, Wafaa Salah Mohammed Hegab, Mona Mostafa Farid Ghanem, Nadia Youssef Riad, Doaa Ghaith, Lamiaa I Daker, Shorouk Issa, Noha Hassan Radwan, Eman Sultan,
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Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians
Haeng Jeon Hur, Hye Jeong Yang, Min Jung Kim, Kyun-Hee Lee, Myung-Sunny Kim, Sunmin Park
Nutrients.2022; 14(15): 3222. CrossRef
Chemical Compounds and Ambient Factors Affecting Pancreatic Alpha-Cells Mass and Function: What Evidence?
Gaia Chiara Mannino, Elettra Mancuso, Stefano Sbrignadello, Micaela Morettini, Francesco Andreozzi, Andrea Tura
International Journal of Environmental Research and Public Health.2022; 19(24): 16489. CrossRef

Original Articles

Pathophysiology
Relationships between Islet-Specific Autoantibody Titers and the Clinical Characteristics of Patients with Diabetes Mellitus: Yiqian Zhang, Tong Yin, Xinlei Wang, Rongping Zhang, Jie Yuan, Yi Sun, Jing Zong, Shiwei Cui, Yunjuan Gu; Diabetes Metab J. 2021;45(3):404-416. Published online July 21, 2020; DOI: https://doi.org/10.4093/dmj.2019.0239

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Background

Dysimmunity plays a key role in diabetes, especially type 1 diabetes mellitus. Islet-specific autoantibodies (ISAs) have been used as diagnostic markers for different phenotypic classifications of diabetes. This study was aimed to explore the relationships between ISA titers and the clinical characteristics of diabetic patients.

Methods

A total of 509 diabetic patients admitted to Department of Endocrinology and Metabolism at the Affiliated Hospital of Nantong University were recruited. Anthropometric parameters, serum biochemical index, glycosylated hemoglobin, urinary microalbumin/creatinine ratio, ISAs, fat mass, and islet β-cell function were measured. Multiple linear regression analysis was performed to identify relationships between ISA titers and clinical characteristics.

Results

Compared with autoantibody negative group, blood pressure, weight, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), visceral fat mass, fasting C-peptide (FCP), 120 minutes C-peptide (120minCP) and area under C-peptide curve (AUC_CP) of patients in either autoantibody positive or glutamate decarboxylase antibody (GADA) positive group were lower. Body mass index (BMI), waist circumference, triglycerides (TGs), body fat mass of patients in either autoantibody positive group were lower than autoantibody negative group. GADA titer negatively correlated with TC, LDL-C, FCP, 120minCP, and AUC_CP. The islet cell antibody and insulin autoantibody titers both negatively correlated with body weight, BMI, TC, TG, and LDL-C. After adjusting confounders, multiple linear regression analysis showed that LDL-C and FCP negatively correlated with GADA titer.

Conclusion

Diabetic patients with a high ISA titer, especially GADA titer, have worse islet β-cell function, but less abdominal obesity and fewer features of the metabolic syndrome.

Citations

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Relationship between β-Cell Autoantibodies and Their Combination with Anthropometric and Metabolic Components and Microvascular Complications in Latent Autoimmune Diabetes in Adults
Tomislav Bulum, Marijana Vučić Lovrenčić, Jadranka Knežević Ćuća, Martina Tomić, Sandra Vučković-Rebrina, Lea Duvnjak
Biomedicines.2023; 11(9): 2561. CrossRef
RETRACTED ARTICLE: MiRNA-27a mediates insulin resistance in 3T3-L1 cells through the PPARγ
Yangming Zhuang, Ming Li
Molecular and Cellular Biochemistry.2022; 477(4): 1107. CrossRef
Correlation between Insulin Resistance and Microalbuminuria Creatinine Ratio in Postmenopausal Women
Han Na, Rong Wang, Hai-Long Zheng, Xiao-Pan Chen, Lin-Yang Zheng, Faustino R. Perez-Lopez
International Journal of Endocrinology.2022; 2022: 1. CrossRef
The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants
C L Williams, R Fareed, G L M Mortimer, R J Aitken, I V Wilson, G George, K M Gillespie, A J K Williams, Chitrabhanu Ballav, Atanu Dutta, Michelle Russell-Taylor, Rachel Besser, James Bursell, Shanthi Chandran, Sejal Patel, Anne Smith, Manohara Kenchaiah,
Clinical and Experimental Immunology.2022; 210(2): 151. CrossRef

Basic Research
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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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.

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Effects of hypoxia in the diabetic corneal stroma microenvironment
Purnima Sharma, Jian-Xing Ma, Dimitrios Karamichos
Experimental Eye Research.2024; 240: 109790. CrossRef
Visualizing hypoxic modulation of beta cell secretions via a sensor augmented oxygen gradient
Kai Duan, Mengyang Zhou, Yong Wang, Jose Oberholzer, Joe F. Lo
Microsystems & Nanoengineering.2023;[Epub] CrossRef
Pancreatic stellate cells promote pancreatic β-cell death through exosomal microRNA transfer in hypoxia
Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
Molecular and Cellular Endocrinology.2023; 572: 111947. CrossRef
Pancreatic stellate cells in pancreatic cancer: as potential targets for future therapy
Zhengfeng Wang, Ru He, Shi Dong, Wence Zhou
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Recent advances in the development of bioartificial pancreas using 3D bioprinting for the treatment of type 1 diabetes: a review
Anushikha Ghosh, Arka Sanyal, Abhik Mallick
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Sarah S. Malik, Diksha Padmanabhan, Rebecca L. Hull-Meichle
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Diabetic mellitus, vascular calcification and hypoxia: A complex and neglected tripartite relationship
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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Exosomal miR-140–3p and miR-143–3p from TGF-β1-treated pancreatic stellate cells target BCL2 mRNA to increase β-cell apoptosis
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
Mitochondria oxidative stress mediated nicotine-promoted activation of pancreatic stellate cells by regulating mitochondrial dynamics
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
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Le Li, Xing-jia Yu, Lei Gao, Long Cheng, Bei Sun, Gang Wang
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Review

Basic Research
The Role of CD36 in Type 2 Diabetes Mellitus: β-Cell Dysfunction and Beyond: Jun Sung Moon, Udayakumar Karunakaran, Elumalai Suma, Seung Min Chung, Kyu Chang Won; Diabetes Metab J. 2020;44(2):222-233. Published online April 23, 2020; DOI: https://doi.org/10.4093/dmj.2020.0053

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Impaired β-cell function is the key pathophysiology of type 2 diabetes mellitus, and chronic exposure of nutrient excess could lead to this tragedy. For preserving β-cell function, it is essential to understand the cause and mechanisms about the progression of β-cells failure. Glucotoxicity, lipotoxicity, and glucolipotoxicity have been suggested to be a major cause of β-cell dysfunction for decades, but not yet fully understood. Fatty acid translocase cluster determinant 36 (CD36), which is part of the free fatty acid (FFA) transporter system, has been identified in several tissues such as muscle, liver, and insulin-producing cells. Several studies have reported that induction of CD36 increases uptake of FFA in several cells, suggesting the functional interplay between glucose and FFA in terms of insulin secretion and oxidative metabolism. However, we do not currently know the regulating mechanism and physiological role of CD36 on glucolipotoxicity in pancreatic β-cells. Also, the downstream and upstream targets of CD36 related signaling have not been defined. In the present review, we will focus on the expression and function of CD36 related signaling in the pancreatic β-cells in response to hyperglycemia and hyperlipidemia (ceramide) along with the clinical studies on the association between CD36 and metabolic disorders.

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Original Articles

Basic Research
Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes: Young Sil Eom, A-Ryeong Gwon, Kyung Min Kwak, Jin-Young Youn, Heekyoung Park, Kwang-Won Kim, Byung-Joon Kim; Diabetes Metab J. 2021;45(1):86-96. Published online February 26, 2020; DOI: https://doi.org/10.4093/dmj.2019.0160

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Background

Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS).

Methods

Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and β-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion.

Results

NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and β-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice.

Conclusion

Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and β-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in β-cell mass determination and diabetes.

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N6-methylation of RNA-bound adenosine regulator HNRNPC promotes vascular endothelial dysfunction in type 2 diabetes mellitus by activating the PSEN1-mediated Notch pathway
Ying Cai, Tao Chen, Mingzhu Wang, Lihua Deng, Cui Li, Siqian Fu, Kangling Xie
Diabetes Research and Clinical Practice.2023; 197: 110261. CrossRef
Single‐cell RNA sequencing: Inhibited Notch2 signalling underlying the increased lens fibre cells differentiation in high myopia
Yunqian Yao, Ling Wei, Zhenhua Chen, Hao Li, Jiao Qi, Qingfeng Wu, Xingtao Zhou, Yi Lu, Xiangjia Zhu
Cell Proliferation.2023;[Epub] CrossRef
Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus
Yu‐Huan Peng, Ping Wang, Xiao‐Qun He, Ming‐Zhao Hong, Feng Liu
Journal of Diabetes Investigation.2022; 13(2): 236. CrossRef
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Pathophysiology
Metformin Ameliorates Lipotoxic β-Cell Dysfunction through a Concentration-Dependent Dual Mechanism of Action: Hong Il Kim, Ji Seon Lee, Byung Kook Kwak, Won Min Hwang, Min Joo Kim, Young-Bum Kim, Sung Soo Chung, Kyong Soo Park; Diabetes Metab J. 2019;43(6):854-866. Published online June 27, 2019; DOI: https://doi.org/10.4093/dmj.2018.0179

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Background

Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress.

Methods

NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis.

Results

We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK.

Conclusion

This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.

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Islet Studies and Transplantation
Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5: Udayakumar Karunakaran, Suma Elumalai, Jun Sung Moon, Jae-Han Jeon, Nam Doo Kim, Keun-Gyu Park, Kyu Chang Won, Jaechan Leem, In-Kyu Lee; Diabetes Metab J. 2019;43(2):192-205. Published online January 16, 2019; DOI: https://doi.org/10.4093/dmj.2018.0052

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Background

Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced β-cell apoptosis and explored the relationship between myricetin and CDK5.

Methods

To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis.

Results

Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to β-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Δψm) loss.

Conclusion

Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.

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Review

Clinical Diabetes & Therapeutics
Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management: Silvia Pieralice, Paolo Pozzilli; Diabetes Metab J. 2018;42(6):451-464. Published online December 17, 2018; DOI: https://doi.org/10.4093/dmj.2018.0190

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Abstract PDF PubReader

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

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Original Article

Obesity and Metabolic Syndrome
In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic β-Cells: Claudia Velasquez, Juan Sebastian Vasquez, Norman Balcazar; Diabetes Metab J. 2017;41(4):303-315. Published online May 24, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.4.303

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Background

The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic β-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]).

Methods

From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated.

Results

The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion.

Conclusion

These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of β-cells and the possible development of type 2 diabetes mellitus.

Citations

Citations to this article as recorded by

The reversible effects of free fatty acids on sulfonylurea-stimulated insulin secretion are related to the expression and dynamin-mediated endocytosis of KATP channels in pancreatic β cells
Chenmin Wei, Zichen Zhang, Qi Fu, Yunqiang He, Tao Yang, Min Sun
Endocrine Connections.2023;[Epub] CrossRef
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Axel Römer, Divya Rawat, Thomas Linn, Sebastian F Petry
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Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review
Axel Römer, Thomas Linn, Sebastian F. Petry
Antioxidants.2021; 10(2): 293. CrossRef
Contribution of Oxidative Stress and Impaired Biogenesis of Pancreatic β-Cells to Type 2 Diabetes
Petr Ježek, Martin Jabůrek, Lydie Plecitá-Hlavatá
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Habtamu Wondifraw Baynes, Seifu Mideksa, Sintayehu Ambachew
Adipocyte.2018; : 1. CrossRef
Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity
Petr Ježek, Martin Jabůrek, Blanka Holendová, Lydie Plecitá-Hlavatá
Molecules.2018; 23(6): 1483. CrossRef

Review

Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block: Jun Sung Moon, Kyu Chang Won; Diabetes Metab J. 2015;39(1):1-9. Published online February 16, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.1.1

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Type 2 diabetes (T2D) has been known as 'bi-hormonal disorder' since decades ago, the role of glucagon from α-cell has languished whereas β-cell taking center stage. Recently, numerous findings indicate that the defects of glucagon secretion get involve with development and exacerbation of hyperglycemia in T2D. Aberrant α-cell responses exhibit both fasting and postprandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production, and to postprandial hyperglycemia owing to blunted α-cell suppression. During hypoglycemia, insufficient counter-regulation response is also observed in advanced T2D. Though many debates still remained for exact mechanisms behind the dysregulation of α-cell in T2D, it is clear that the blockade of glucagon receptor or suppression of glucagon secretion from α-cell would be novel therapeutic targets for control of hyperglycemia. Whereas there have not been remarkable advances in developing new class of drugs, currently available glucagon-like peptide-1 and dipeptidyl peptidase-IV inhibitors could be options for treatment of hyperglucagonemia. In this review, we focus on α-cell dysfunction and therapeutic potentials of targeting α-cell in T2D.

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Original Article

The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition: Min Jeong Kwon, Hye Suk Chung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Mi Kyung Kim, Jeong Hyun Park; Diabetes Metab J. 2011;35(5):480-488. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.480

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Abstract PDF PubReader

Background

β-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of β-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes.

Methods

Apoptosis was induced by adding various concentrations of GB (0.001 to 200 µM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated.

Results

Addition of any concentration of GB in 150 µM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2α) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly.

Conclusion

GB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2α may attenuate ER stress for adaptation to increased ER protein load.

Citations

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Review

Autophagy in Diabetes.: Hye Seung Jung, Myung Shik Lee; Korean Diabetes J. 2009;33(6):453-457. Published online December 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.6.453

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25 Download

Abstract PDF: Diabetes mellitus is characterized by decreased insulin secretion and action. Decreased insulin secretion results from a reduction in mass and/or function of pancreatic beta-cells. Apoptosis, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress responses have been suggested as mechanisms for the changes in beta-cells in type 2 diabetes; however, the underlying causes have not been clearly elucidated. Autophagy is an intracellular process that maintains cellular homeostasis through degradation and recycling of organelles. Recently, we reported reduction of beta-cell mass in autophagy-deficient mice. Pancreatic insulin content was also decreased due to the decreased beta-cell mass and the reduced number of insulin granules. Morphological analysis of these beta-cells revealed an accumulation of ubiquitinated proteins, swollen mitochondria, and distended ER. Insulin secretory function ex vivo was also impaired. As a result, autophagy-deficient mice showed hypoinsulinemia and hyperglycemia. These results suggested that autophagy is necessary to maintain the structure, mass and function of beta-cells. In addition, as autophagy may play a protective role against ER stress and rejuvenate organelle function, impaired autophagy may lead to mitochondrial dysfunction and ER stress, which have been implicated as causes of insulin resistance. Therefore, in addition to beta-cell homeostasis, dysregulated autophagy may possibly be involved in insulin resistance.

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