Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
LRRFIP1 Inhibits White Adipocyte Differentiation by Suppressing the E2F6/C/EBPα Axis: Lei Zhou, Yuwen Jiao, Jiaming Xue, Xiaoqiang Zhan, Dongmei Wang, Liming Tang; Received March 4, 2025 Accepted July 24, 2025 Published online November 12, 2025; DOI: https://doi.org/10.4093/dmj.2025.0178 [Epub ahead of print]

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Background
To investigate the biological functions of the transcription factor LRR binding FLII interacting protein 1 (LRRFIP1) in white adipocyte differentiation (WAD) and elucidate the underlying molecular regulatory mechanisms involved.
Methods
Consensus clustering, differential gene expression screening, and intersection analysis were used to identify transcription factors involved in WAD. Adipogenic differentiation experiments were conducted using C3H10T1/2 cells, and a diet-induced obesity model in C57BL/6J mice was established to investigate the function of LRRFIP1 in WAD in vitro and in vivo. Molecular mechanisms were examined through quantitative real-time polymerase chain reaction, Western blotting, luciferase assays, and chromatin immunoprecipitation.
Results
Bioinformatics analyses identified LRRFIP1 as a transcription factor associated with WAD. LRRFIP1 expression was downregulated in white adipose tissues from obese patients and in mature white adipocytes. Silencing LRRFIP1 significantly inhibited WAD in C3H10T1/2 cells and reduced differentiation biomarker expression; in contrast, overexpressing LRRFIP1 had the opposite effects. Mechanistically, LRRFIP1 bound to the E2F transcription factor 6 (E2F6) promoter to suppress E2F6 transcription, thereby downregulating a key differentiation regulator, CCAAT enhancer binding protein alpha (C/EBPα). Furthermore, in a diet-induced obesity model, LRRFIP1 could regulate the differentiation and maturation of inguinal white adipose tissue.
Conclusion
Our findings reveal that LRRFIP1 plays a crucial inhibitory role in WAD by negatively regulating the E2F6/C/EBPα axis. This discovery not only enriches our understanding of the molecular networks governing WAD but also holds great promise for creating targeted therapies for obesity and associated metabolic conditions.

Citations

Citations to this article as recorded by

C/EBPα plays a critical role in adipocyte differentiation and obesity
Xiao Li, Hui Li, Fang Peng, Jianhua Li, Xiaoli Hou, Shaoping Ji
Frontiers in Molecular Biosciences.2026;[Epub] CrossRef
Progress in Research on LRRFIP1 Regulation of Colorectal Cancer Cell Apoptosis and Related Signaling Pathways
恩德李
Advances in Clinical Medicine.2026; 16(05): 2533. CrossRef

Basic and Translational Research
E2F5 Accelerates Vascular Smooth Muscle Cells Phenotype Switching in Diabetic Atherosclerosis through Activating Wnt/β-Catenin Pathway: Mingxue Di, Jie Wang, Lin Sun, Guang Yang, Qun Xu; Diabetes Metab J. 2026;50(3):506-518. Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0588

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Background
We determined the precise function of E2F transcription factor 5 (E2F5) on the development of diabetic atherosclerosis (DAS) and the underlying mechanisms.
Methods
Apolipoprotein E-knockout mice were intraperitoneally injected with streptozotocin for 5 days and fed a high-fat diet for 12 weeks for establishing an in vivo DAS model. To establish a DAS vascular smooth muscle cells (VSMCs) model, VSMCs were stimulated with fresh medium containing glucose and oxidized low-density lipoprotein. After the final treatment, serum lipids were detected, and aorta tissues were collected for hematoxylin and eosin staining, Western blot, Oil red O staining, and quantitative reverse transcription polymerase chain reaction. The effect of E2F5 on the proliferation, migration, cell cycle, phenotype switching, and cell cycle-related markers of VSMCs were evaluated.
Results
In vivo, the expression of E2F5 was elevated in aortic tissues of DAS mice. The downregulation of E2F5 alleviated the symptoms of DAS in mice. Moreover, E2F5 downregulation inhibited the phenotypic transformation of VSMCs in DAS mice. In vitro, the knockdown of E2F5 inhibited the phenotypic transformation of VSMCs. CyclinE overexpression reversed the inhibitory effect of E2F5 silencing on phenotypic transformation of VSMCs. Additionally, we also found that the treatment of BML-284 significantly attenuated the inhibitory effect of E2F5 silencing on phenotypic transformation of VSMCs.
Conclusion
E2F5 is an injurious factor in the pathogenesis of DAS, and the downregulation of E2F5 could repress VSMCs phenotype switching through inactivating Wnt/β-catenin pathway, and ultimately inhibit the progression of DAS.

Citations

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Metabolic memory failure and the reprogramming of atherosclerosis in diabetes
M. Devi, S. Evelyn Sharon, N. Harikrishnan, N. Pavithra, L. Shakthi
Obesity Medicine.2026; 61: 100703. CrossRef
E2F5 Promotes Vascular Endothelial Cell Proliferation and Angiogenesis in Diabetic Lower Limb Ischemia via an Autophagy-Related Mechanism
Yuyan Zhan, Hongwei Shi, Xiaoying Miu, Xiaoping Peng, Jungang Nie, Dong Liu, Qiong Duan, Ting Kang
Circulation Journal.2026;[Epub] CrossRef
SPI1 Promotes Intracranial Aneurysm Formation by Inhibiting Wnt5a Transcription
ZengShi Li, WeiChen Wang, Wei Li, Jie Peng, JunXi Liu, Yi Wu
Frontiers in Bioscience-Landmark.2026;[Epub] CrossRef
Metabolic reprogramming in diabetic complications: mechanisms, pathologies, and molecular evidence from multi-organ studies
Qian Gong, Wei Zhao, Jing Xia, Zhiwei Nie, Ruifan Luo, Lingxiu Li, Changwu Dong, Yujiao Zheng
Frontiers in Immunology.2026;[Epub] CrossRef

Reviews

Basic Research
Roles of Histone Deacetylase 4 in the Inflammatory and Metabolic Processes: Hyunju Kang, Young-Ki Park, Ji-Young Lee, Minkyung Bae; Diabetes Metab J. 2024;48(3):340-353. Published online March 22, 2024; DOI: https://doi.org/10.4093/dmj.2023.0174

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Histone deacetylase 4 (HDAC4), a class IIa HDAC, has gained attention as a potential therapeutic target in treating inflammatory and metabolic processes based on its essential role in various biological pathways by deacetylating non-histone proteins, including transcription factors. The activity of HDAC4 is regulated at the transcriptional, post-transcriptional, and post-translational levels. The functions of HDAC4 are tissue-dependent in response to endogenous and exogenous factors and their substrates. In particular, the association of HDAC4 with non-histone targets, including transcription factors, such as myocyte enhancer factor 2, hypoxia-inducible factor, signal transducer and activator of transcription 1, and forkhead box proteins, play a crucial role in regulating inflammatory and metabolic processes. This review summarizes the regulatory modes of HDAC4 activity and its functions in inflammation, insulin signaling and glucose metabolism, and cardiac muscle development.

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Biomaterials.2026; 325: 123618. CrossRef
Redox-sensitive high mobility group box 1 (HMGB1) is a multifunctional regulator of cellular senescence, inflammation, and immunosuppression: Impact on the aging process
Antero Salminen
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Jimin Park, Chae Young Moon, Jinju Jo, Hyunju Kang
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Extracellular vesicles from adipose‐derived mesenchymal stem cells prevent high glucose‐induced retinal ganglion cell pyroptosis through a microRNA‐26a‐5p‐dependent mechanism
Lei Tang, Jian Zhang, Jianping Gao
Journal of Diabetes Investigation.2025; 16(9): 1597. CrossRef
Maternal Vitamin and Mineral Supplementation Affected Neonatal Gene Expression and Rewired Key Regulatory Genes Underlying Hepatic Metabolism
Audrey J. Craner, Carl R. Dahlen, Jennifer L. Hurlbert, Ana Clara B. Menezes, Priyanka Banerjee, Friederike Baumgaertner, Kerri A. Bochantin-Winders, Samat Amat, Kevin K. Sedivec, Kendall C. Swanson, Wellison J. S. Diniz
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Macrophage Histone Deacetylase 4 Has Sex‐Dependent Dimorphic Effects on the Pathogenesis of Alcohol‐Associated Hepatitis
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CRISPR-mediated engineering of mesenchymal stromal/stem cells: a summary of recent progress in immunological applications for regenerative medicine and cancer therapy
Mohammadreza Dashti, Morteza Mohammaddust Sarab, Faezeh Shad, Sajad Dehnavi
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Histones deacetylases in the epidermis: structure, functions and therapeutic implications
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Others
A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia: Yong Ho Ahn; Diabetes Metab J. 2018;42(6):465-471. Published online November 2, 2018; DOI: https://doi.org/10.4093/dmj.2018.0116

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My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.

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Physiological functions of glucose transporter-2: From cell physiology to links with diabetes mellitus
Zhean Shen, Yingze Hou, Guo Zhao, Libi Tan, Jili Chen, Ziqi Dong, Chunxiao Ni, Longying Pei
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Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes
Juan Zhang, Rong Zhang, Chanwei Liu, Xiaoxu Ge, Ying Wang, Fusong Jiang, Langen Zhuang, Tiantian Li, Qihan Zhu, Yanyan Jiang, Yating Chen, Ming Lu, Yanzhong Wang, Meisheng Jiang, Yanjun Liu, Limei Liu
Diabetologia.2024; 67(8): 1698. CrossRef
Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose
Zhen Qiao, Julia Sidorenko, Joana A. Revez, Angli Xue, Xueling Lu, Katri Pärna, Harold Snieder, Peter M. Visscher, Naomi R. Wray, Loic Yengo
Nature Communications.2023;[Epub] CrossRef
Umbilical Cord-Mesenchymal Stem Cell-Conditioned Medium Improves Insulin Resistance in C2C12 Cell
Kyung-Soo Kim, Yeon Kyung Choi, Mi Jin Kim, Jung Wook Hwang, Kyunghoon Min, Sang Youn Jung, Soo-Kyung Kim, Yong-Soo Choi, Yong-Wook Cho
Diabetes & Metabolism Journal.2021; 45(2): 260. CrossRef
Aging-related modifications to G protein-coupled receptor signaling diversity
Jaana van Gastel, Hanne Leysen, Jan Boddaert, Laura vangenechten, Louis M. Luttrell, Bronwen Martin, Stuart Maudsley
Pharmacology & Therapeutics.2021; 223: 107793. CrossRef
Glucose transporters in the small intestine in health and disease
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Original Articles

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

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Hafez R. Madkor, Mostafa K. Abd El-Aziz, Mostafa S. Abd El-Maksoud, Islam M. Ibrahim, Fares E.M. Ali
Current Diabetes Reviews.2025;[Epub] CrossRef
Insulin in Myenteric Neurons: Time-Dependent and Regional Changes in Type 1 Diabetic Rats
Abigél Egyed-Kolumbán, Benita Onhausz, Bence Pál Barta, Zita Szalai, Ildikó Huliák, Mónika Kiricsi, Mária Bagyánszki, Nikolett Bódi
Cells.2025; 14(11): 809. CrossRef
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 Role of Hypothalamic FoxO1 on Hyperphagia in Streptozotocin-Induced Diabetic Mice.: Il Seong Nam-Goong, Jae Geun Kim, Se Jin Kim, Seong Jae Hur, Jin Woo Lee, Eun Sook Kim, Chang Ho Yun, Byung Ju Lee, Young Il Kim; Korean Diabetes J. 2009;33(5):375-381. Published online October 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.5.375

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Abstract PDF: BACKGROUND
Streptozotocin-induced diabetic animals are characterized by hyperphagia due to deficiencies of insulin and leptin. Forkhead box-containing protein of the O subfamily-1 (FoxO1) regulates energy homeostasis by regulating energy expenditure and food intake as well as mediating insulin and leptin signals in the hypothalamus. To identify the mediator of diabetic hyperphagia, we examined the effects of insulin or leptin on hypothalamic FoxO1 expression in a diabetic animal model. METHODS: Diabetes was induced in mice (C57BL/6) by intraperitoneal administration of streptozotocin (200 mg/kg). Stainless steel cannula was implanted into the lateral ventricle of the brain in each mouse. After three weeks, the mice were administered saline, insulin or leptin via intracerebroventricular (ICV) route. The medial hypothalamus was isolated to evaluate the mRNA expressions of FoxO1 and neuropeptides. RESULTS: Streptozotocin-induced diabetic mice exhibited significant elevations of blood glucose and food intake and significantly low levels of serum insulin and leptin. The levels of hypothalamic FoxO1 mRNA were significantly increased in diabetic mice. The hypothalamic expression of neuropeptide Y (NPY) mRNA was increased, but the expression of preproopiomelanocortin (POMC) mRNA was decreased in diabetic mice. ICV administration of insulin or leptin attenuated the upregulation of hypothalamic FoxO1 mRNA, and resulted in downregulation of NPY mRNA and upregulation of POMC mRNA in diabetic mice. CONCLUSION: We observed that the expression of hypothalamic FoxO1 mRNA was increased in streptozotocin-induced diabetic mice, and that it was significantly attenuated by central administration of insulin or leptin. These results suggest that hypothalamic FoxO1 is the direct mediator of diabetic hyperphagia.

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