Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Inflammatory Milieu by Crosstalk between Glomerulus and Proximal Tubular Cells in Type 2 Diabetes Mellitus Kidney Disease: Peong Gang Park, Juhyeon Hwang, Yongjun Kim, Minki Hong, Donghwan Yun, Haein Yoon, Chaelin Kang, Sohyun Bae, Soo Heon Kwak, Yong Chul Kim, Kyung Chul Moon, Dong-Sup Lee, Yon Su Kim, Hee Gyung Kang, Hyun Je Kim, Seung Seok Han; Received September 4, 2024 Accepted December 12, 2024 Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0535 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Due to the limited availability of therapeutic agents for type 2 diabetic kidney disease (T2DKD), there is a need for further knowledge derived from experimental models and innovative techniques. In addressing this issue, single-cell RNA sequencing (scRNA-seq) has been exclusively applied to a genetically modified diabetic kidney disease model, but not to an induced model representing T2DKD. Herein, we analyzed scRNA-seq and other experiments from an induced T2DKD model and validated the results in human-derived biospecimens.
Methods
The model was induced by combining a high-fat diet with streptozotocin to simulate induced T2DKD. scRNA-seq, histological, and flow cytometric analyses were conducted, and the results were compared with control mice. The findings were then applied to human T2DKD kidneys.
Results
Biochemical and histological analyses unveiled early-stage T2DKD features, such as hyperfiltration, increased proteinuria, glomerulomegaly, and interstitial fibrosis. scRNA-seq identified that proximal tubules secreted a variety of chemokines, potentially in response to crosstalk with glomeruli. Notably, C-X-C motif chemokine 12 (CXCL12) emerged as a key player in potentially promoting T-cell recruitment. Flow cytometry substantiated T-cell infiltration into the kidney of the T2DKD model. This finding was further corroborated in human biopsied kidney tissues, showing a correlation between elevated CXCL12 levels and T2DKD progression.
Conclusion
The induced T2DKD model highlights the pivotal role of CXCL12-mediated T-cell infiltration, stemming from the crosstalk between proximal tubules and glomeruli. This data serves as a foundation for future studies, promising a therapeutic target for T2DKD.

Basic Research
Revealing VCAN as a Potential Common Diagnostic Biomarker of Renal Tubules and Glomerulus in Diabetic Kidney Disease Based on Machine Learning, Single-Cell Transcriptome Analysis and Mendelian Randomization: Li Jiang, Jie Jian, Xulin Sai, Xiai Wu; Received May 5, 2024 Accepted September 7, 2024 Published online January 24, 2025; DOI: https://doi.org/10.4093/dmj.2024.0233 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic kidney disease (DKD) is recognized as a significant complication of diabetes mellitus and categorized into glomerular DKDs and tubular DKDs, each governed by distinct pathological mechanisms and biomarkers.
Methods
Through the identification of common features observed in glomerular and tubular lesions in DKD, numerous differentially expressed gene were identified by the machine learning, single-cell transcriptome and mendelian randomization.
Results
The diagnostic markers versican (VCAN) was identified, offering supplementary options for clinical diagnosis. VCAN significantly highly expressed in glomerular parietal epithelial cell and proximal convoluted tubular cell. It was mainly involved in the up-regulation of immune genes and infiltration of immune cells like mast cell. Mendelian randomization analysis confirmed that serum VCAN protein levels were a risky factor for DKD, while there was no reverse association. It exhibited the good diagnostic potential for estimated glomerular filtration rate and proteinuria in DKD.
Conclusion
VCAN showed the prospects into DKD pathology and clinical indicator.

Basic Research
Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes: Junfei Gu, Jiajia Jin, Xiaoyu Ren, Xinjie Zhang, Jiaxuan Li, Xiaowei Wang, Shucui Zhang, Xianlun Yin, Qunye Zhang, Zhe Wang; Diabetes Metab J. 2024;48(5):885-900. Published online May 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0278

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Abstract PDF Supplementary Material PubReader ePub

Background
Metabolic dysregulation is a hallmark of type 2 diabetes mellitus (T2DM), in which the abnormalities in brown adipose tissue (BAT) play important roles. However, the cellular composition and function of BAT as well as its pathological significance in diabetes remain incompletely understood. Our objective is to delineate the single-cell landscape of BAT-derived stromal vascular fraction (SVF) and their characteristic alterations in T2DM rats.
Methods
T2DM was induced in rats by intraperitoneal injection of low-dose streptozotocin and high-fat diet feeding. Single-cell mRNA sequencing was then performed on BAT samples and compared to normal rats to characterize changes in T2DM rats. Subsequently, the importance of key cell subsets in T2DM was elucidated using various functional studies.
Results
Almost all cell types in the BAT-derived SVF of T2DM rats exhibited enhanced inflammatory responses, increased angiogenesis, and disordered glucose and lipid metabolism. The multidirectional differentiation potential of adipose tissue-derived stem cells was also reduced. Moreover, macrophages played a pivotal role in intercellular crosstalk of BAT-derived SVF. A novel Rarres2+macrophage subset promoted the differentiation and metabolic function of brown adipocytes via adipose-immune crosstalk.
Conclusion
BAT SVF exhibited strong heterogeneity in cellular composition and function and contributed to T2DM as a significant inflammation source, in which a novel macrophage subset was identified that can promote brown adipocyte function.

Citations

Citations to this article as recorded by

Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)
Yea Eun Kang, Ju Hee Lee
Diabetes & Metabolism Journal.2025; 49(1): 160. CrossRef
Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)
Junfei Gu, Xinjie Zhang, Qunye Zhang, Zhe Wang
Diabetes & Metabolism Journal.2025; 49(1): 162. CrossRef
Engineered stromal vascular fraction for tissue regeneration
Jianfeng Liu, Yiwei Li, Yanan Zhang, Zhiwei Zhao, Bin Liu
Frontiers in Pharmacology.2025;[Epub] CrossRef

Review

Basic Research
Heterogeneity of Islet Cells during Embryogenesis and Differentiation: Shugo Sasaki, Takeshi Miyatsuka; Diabetes Metab J. 2023;47(2):173-184. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0324

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Abstract PDF PubReader ePub

Diabetes is caused by insufficient insulin secretion due to β-cell dysfunction and/or β-cell loss. Therefore, the restoration of functional β-cells by the induction of β-cell differentiation from embryonic stem (ES) and induced-pluripotent stem (iPS) cells, or from somatic non-β-cells, may be a promising curative therapy. To establish an efficient and feasible method for generating functional insulin-producing cells, comprehensive knowledge of pancreas development and β-cell differentiation, including the mechanisms driving cell fate decisions and endocrine cell maturation is crucial. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies have opened a new era in pancreas development and diabetes research, leading to clarification of the detailed transcriptomes of individual insulin-producing cells. Such extensive high-resolution data enables the inference of developmental trajectories during cell transitions and gene regulatory networks. Additionally, advancements in stem cell research have not only enabled their immediate clinical application, but also has made it possible to observe the genetic dynamics of human cell development and maturation in a dish. In this review, we provide an overview of the heterogeneity of islet cells during embryogenesis and differentiation as demonstrated by scRNA-seq studies on the developing and adult pancreata, with implications for the future application of regenerative medicine for diabetes.

Citations

Citations to this article as recorded by

Investigation of the motif activity of transcription regulators in pancreatic β-like cell subpopulations differentiated from human induced pluripotent stem cells
Eric Leclerc, Mikhail Pachkov, Lisa Morisseau, Fumiya Tokito, Cecile Legallais, Rachid Jellali, Masaki Nishikawa, Amar Abderrahmani, Yasuyuki Sakai
Molecular Omics.2024; 20(10): 654. CrossRef
Newly discovered knowledge pertaining to glucagon and its clinical applications
Dan Kawamori, Shugo Sasaki
Journal of Diabetes Investigation.2023; 14(7): 829. CrossRef

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