Diabetes & Metabolism Journal

Original Articles

Cardiovascular Risk/Epidemiology
Oxidized Lipoproteins as Independent Predictors of Major Adverse Cardiovascular Events in Type 2 Diabetes Mellitus with Coronary Heart Disease: A Multicenter Prospective Cohort Study: Jun-Xu Gu, Juan Huang, Ai-Min Zhang, Yue Yin, Zi-Wei Wang, Hui-Zhang Bao, Shan-Shan Li, Na Zhang, Li Qin, Zhi-Hong Yue, Kun Wang, Mei Jia, Chun-Yan Wang, Lin Pei, Ming Su; Received October 15, 2025 Accepted February 6, 2026 Published online May 12, 2026; DOI: https://doi.org/10.4093/dmj.2025.1029 [Epub ahead of print]

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Oxidized lipoproteins contribute to atherosclerosis and metabolic dysfunction; however, their prognostic significance for major adverse cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM) and coexisting coronary heart disease (CHD) remains unclear.
Methods
This multicenter cohort included 3,733 patients with angiographically confirmed T2DM-CHD, followed for 5 years. Baseline circulating oxidized high-density lipoprotein cholesterol (ox-HDL-C), oxidized low-density lipoprotein cholesterol (ox- LDL-C), and oxidized lipoprotein(a) (ox-Lp(a)) were measured, and associations with coronary severity, β-cell function, and MACEs were analyzed using Cox regression, Kaplan-Meier, and restricted cubic spline models.
Results
Patients with MACEs had higher baseline ox-HDL-C, ox-LDL-C, and ox-Lp(a), correlating with greater coronary lesion burden and impaired β-cell function. Restricted cubic spline analyses revealed nonlinear, dose-dependent associations, with MACEs risk increasing above thresholds of 19.88 ng/mL (ox-HDL-C), 25.71 ng/mL (ox-LDL-C), and 19.96 μmol/L (ox-Lp(a)), with sexspecific differences observed. In Cox proportional hazards models, individuals in the highest quartile of oxidized lipoproteins had significantly elevated 5-year MACEs risk compared to those in the lowest quartile, and these associations remained robust after adjusting for confounders (ox-HDL-C: adjust hazard ratio [HR], 1.872; 95% confidence interval [CI], 1.408 to 2.489; P<0.001; ox- LDL-C: adjust HR, 2.239; 95% CI, 1.686 to 2.974; P<0.001; ox-Lp(a): adjust HR, 1.917; 95% CI, 1.442 to 2.549; P<0.001).
Conclusion
Oxidized lipoproteins are independent predictors of MACEs in patients with T2DM-CHD and reflect vascular and metabolic dysfunction. Incorporating oxidized lipoprotein profiling into clinical risk assessment may improve early identification of high-risk individuals and guide preventive strategies.

Complications
Characterizing the Immune Cell Infiltration in Renal Interstitium and Therapeutic Targets of Drugs in Diabetic Nephropathy by Multiomics Study: Chongbin Liu, Zurong Zhang, Yiyun Xi, Ming Yang, Huafeng Liu, Lin Sun; Received January 6, 2025 Accepted September 20, 2025 Published online January 30, 2026; DOI: https://doi.org/10.4093/dmj.2025.0016 [Epub ahead of print]

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Immune cell infiltration in the renal interstitium contributes to the progression of diabetic nephropathy (DN), yet the precise mechanisms remain incompletely unclear.
Methods
Public multi-omics datasets were integrated for comprehensive bioinformatic analyses. Interactions between infiltrating immune cells and damaged tubular epithelial cells (TECs) were analyzed with the CellChat, and key regulators were identified by machine learning. DN was modeled in C57BL/6 mice by high-fat diet/streptozotocin. Human kidney 2 (HK-2) cells were exposed to high glucose plus palmitic acid (HGPA). Gene function was validated by Western blotting, real-time quantitative polymerase chain reaction, immunohistochemistry and surface plasmon resonance (SPR).
Results
Renal interstitium from DN patients displayed markedly increased infiltration of M1 macrophages, regulatory T-cells, natural killer cells and other immune subsets, all correlating with indices of renal injury. CellChat analysis indicated that damaged TECs communicated with infiltrating immune cells primarily through chemokine networks centered on C-X-C motif chemokine ligand (CXCL), C-X3-C motif chemokine ligand (CX3CL), and C-C motif chemokine ligand 2 (CCL2). Retinoic acid-induced 2 (RAI2) was upregulated in DN kidneys and showed significant associations with immune infiltration and renal injury via these chemokine pathways. Consistently, RAI2 expression was elevated in kidneys of DN mice and in HGPA-treated HK-2 cells. SPR demonstrated direct, high-affinity binding of resveratrol to human RAI2 protein. Knockdown of RAI2 or treatment with resveratrol attenuated HGPA-induced apoptosis and suppressed CCL2, CXCL, and CX3CL expression levels.
Conclusion
RAI2 is a pivotal mediator of tubule injury and immune cell infiltration in DN, and resveratrol via direct binding to RAI2 and suppressed its function.

Pharmacotherapy
Efficacy and Safety of HD-6277, a Novel G Protein-Coupled Receptor 40 Agonist, in Individuals with Type 2 Diabetes Mellitus: A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 2 Clinical Trial: Yong-ho Lee, Kyung Wan Min, Jun Hwa Hong, Soo Lim, Jae Myung Yu, Choon Hee Chung, Jun Sung Moon, Jong Chul Won, Chul Woo Ahn, Jie-Eun Lee, Tae Nyun Kim, Byung-Wan Lee; Diabetes Metab J. 2026;50(3):576-586. Published online December 19, 2025; DOI: https://doi.org/10.4093/dmj.2025.0528

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Background
This study assessed the efficacy and safety of HD-6277, a novel oral G protein-coupled receptor 40 (GPR40) agonist in adults with inadequate control of type 2 diabetes mellitus (T2DM).
Methods
This double-blind, randomized, placebo-controlled phase 2 trial recruited 112 individuals aged 18–75 years with T2DM and glycosylated hemoglobin (HbA1c) levels between 7.0% and 10.0% while on diet and exercise alone for at least 8 weeks before screening. Parallel-group randomized trials of HD-6277 (50 and 100 mg groups vs. placebo) were conducted for 12 weeks. The primary outcome was the change in HbA1c levels from baseline to week 12. Secondary outcomes included changes in HbA1c, fasting plasma glucose (FPG), postprandial glucose, insulin, glycoalbumin, and C-peptide at weeks 4, 8, and 12.
Results
At week 12, HD-6277 at 50 and 100 mg demonstrated statistically significant reductions in HbA1c compared to placebo, with least square (LS) mean differences of –0.73% (95% confidence interval [CI], –1.11 to –0.35; P=0.0002) and –0.85% (95% CI, –1.21 to –0.50; P<0.0001), respectively. Both doses also produced clinically meaningful reductions in FPG. Additionally, HD- 6277 at 100 mg significantly increased the insulinogenic index compared to placebo, with an LS mean difference of 1.91 (95% CI, 0.34 to 3.48; P=0.0175). No clinically relevant treatment-related adverse events were observed.
Conclusion
HD-6277 at 50 and 100 mg improved glycemic control and was well-tolerated in adults with T2DM inadequately managed with diet and exercise. GPR40 agonists may offer a promising new therapeutic option for T2DM.

Citations

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Revisiting GPR40 Agonist in Type 2 Diabetes Mellitus: A Cautious but Meaningful Return
Eun-Hee Cho
Diabetes & Metabolism Journal.2026; 50(3): 472. CrossRef

Basic and Translational Research
Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation: Giang Nguyen, Ji Hee Yu, Phuc Thi Minh Pham, Thuy Linh Lai, So Young Park, Ki Woo Kim, Seung-Soon Im, Jeana Hong, Yong-ho Lee, Jae-Ho Lee, Seon Mee Kang, Dae-Hee Choi, Eun-Hee Cho; Diabetes Metab J. 2026;50(2):307-319. Published online November 27, 2025; DOI: https://doi.org/10.4093/dmj.2024.0531

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Background
Lactate, traditionally considered a metabolic byproduct, is increasingly recognized as a signaling molecule involved in metabolic regulation. Its role in hepatic steatosis, particularly through G-protein-coupled receptor 81 (GPR81)-mediated pathways, remains underexplored.
Methods
We investigated the effects of lactate on hepatic lipid metabolism using in vitro alpha mouse liver 12 (AML12) cells, zebrafish, and two diet-induced nonalcoholic fatty liver disease (NAFLD) mouse models. Lipid accumulation, gene/protein expression, and 5’ adenosine monophosphate-activated protein kinase (AMPK) signaling were assessed under lactate exposure, GPR81 knockdown, monocarboxylate transporter 1 (MCT1) inhibition, and AMPK activation conditions.
Results
Lactate treatment in hepatocytes increased de novo lipogenesis and fatty acid uptake while suppressing fatty acid oxidation and AMPK phosphorylation. These effects were reversed by GPR81 knockdown but not by MCT1 inhibition, suggesting a GPR81-dependent mechanism. AMPK activation with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced lactate-induced lipid accumulation. In zebrafish, 10 mM lactate treatment for 24 hours significantly increased hepatic lipid content. In mice fed high-fat diet (HFD) or high-fat high-cholesterol (HFHC) diets for 12 weeks, hepatic lactate levels and GPR81 expression were elevated. Interestingly, p-AMPK expression decreased in HFD livers but increased in the HFHC group, indicating dietspecific regulation.
Conclusion
Our findings demonstrate that lactate promotes hepatic steatosis primarily via the GPR81–AMPK signaling axis. GPR81 activation enhances lipogenesis and lipid uptake, independent of MCT1-mediated transport. These results position GPR81 as a promising therapeutic target for NAFLD.

Citations

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LncRNA LELE enhances lactate efflux and reduces lipid deposition via upregulating MCT1
Kang Xiao, Yingying Zhou, Qiyong Qiu, Chenguang Zhu, Xiaoxue Shen, Le Chang, Wei Qiang, Hengtong Liu, Guangzhen Jiang, Xiangfei Li, Wenbin Liu, Dingdong Zhang
Aquaculture.2026; 622: 744043. CrossRef

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

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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

Basic and Translational Research
Interactions between Tau Phosphorylation and Endoplasmic Reticulum Stress in Diabetic Nephropathy: Eun Soo Lee, Jeong Suk Kang, Seong-Woo Lee, Su Ho Jo, Ji-Hye Lee, Eun Young Lee, Choon Hee Chung; Received October 7, 2024 Accepted July 18, 2025 Published online November 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0618 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Tau is a microtubule-associated protein whose abnormal phosphorylation disrupts the cytoskeleton and induces cell death. While its role is well known in neuro degenerative diseases, its function in kidney pathology, particularly diabetic nephropathy (DN), is not well understood.
Methods
DN was induced in NADPH oxidase 5 (NOX5) pod⁺ mice through a high-fat diet (HFD; 60% kcal fat) for 3, 6, and 12 weeks. Kidney tissues and cultured mesangial cells were analyzed for tau phosphorylation at specific residues (Ser202 and Thr205), fibrosis markers (e.g., α-smooth muscle actin), and endoplasmic reticulum (ER) stress. Tau phosphorylation was modulated using thousand and one amino acid kinase inhibitor and ER stress inhibitors. Immunohistochemistry was also performed on human renal biopsy samples from DN patients.
Results
pTau Ser202 and Thr205 expression levels were elevated by 6 weeks of the HFD and remained persistently upregulated at 12 weeks. Human biopsy analysis further revealed elevated pTau Ser202 and Thr205 expression in the patients with DN, which correlated with proteinuria. In NOX5 pod⁺ mice, early metabolic changes developed by HFD led to tau phosphorylation and kidney damage. Transforming growth factor β-induced fibrosis or thapsigargin-induced ER stress increased tau phosphorylation, while inhibiting tau phosphorylation or ER stress alleviated mesangial cell damage.
Conclusion
Our findings demonstrate that site-specific tau phosphorylation is associated with renal injury in DN and may serve as a potential marker of disease severity. The interplay between tau phosphorylation and ER stress appears to contribute to disease progression. Targeting tau phosphorylation and its upstream stress pathways may offer new therapeutic strategies for DN.

Complications
4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the Efferocytosis-MCT1-Lactate-GPR132 Pathway and Macrophage-Independent Synergistic Effects: Mengqin Tu, Xiaoli Zou, Xiaozhen Tan, Yijun Liu, Xinxu Ge, Yu Hu, Qiuyue Peng, Linlin Huang, Yan Zeng, Chunxia Jia, Man Guo, Jiao Chen, Yang Long, Yong Xu; Received September 21, 2024 Accepted July 2, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2024.0579 [Epub ahead of print]

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Background
Diabetic foot ulcers are a severe diabetic complication causing poor healing. Itaconate, a tricarboxylicacid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis andmacrophage pro-resolving function to promote diabetic wound healing.
Methods
A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis.
Results
In diabetic mice, impaired apoptotic neutrophils clearance and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1 which, in turn, increased release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).
Conclusion
4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation.

Citations

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Roles of efferocytosis in wound repair: Process, cells, and signals
Yilin Sun, Haiying Guo, Yang Bai, Jin Chen, Yuhong Li
Genes & Diseases.2026; 13(3): 101937. CrossRef

Complications
STING Promotes Renal Fibrosis of Diabetic Kidney Disease via ID1-Dependent Epithelial-Mesenchymal Transition: Hongya Wang, Xiaobing Mao, Yuqing Huang, Xiaozhen Tan, Yuling Yang, Mengting Huang, Zongzhe Jiang, Yang Long, Xia Fang, Yong Xu; Received October 18, 2024 Accepted May 30, 2025 Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0645 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Tubulointerstitial fibrosis (TIF) due to epithelial-mesenchymal transition (EMT) is an inseparable feature of diabetic renal fibrosis. Although stimulator of interferon genes (STING) has been shown to have potential in regulating EMT, whether and how it modulates EMT in diabetic kidney disease (DKD) mice remains unclear. Here, we investigated the role and the underlying mechanisms of STING-mediated EMT on TIF in DKD.
Methods
STING expression was detected in human renal biopsy tissues and serum samples with DKD. Mouse models with genetic deletion of STING or inhibition by a STING inhibitor (C176) were established to further investigate the functions of STING in vivo. The in vitro roles of STING were analyzed in human renal tubular epithelial (HK2) cells with STING overexpression or STING knockdown. RNA sequencing was used to explore the underlying mechanisms.
Results
STING was upregulated in the kidneys and serum from patients with DKD and negatively correlated with kidney function. STING deletion or pharmacologic inhibition with C176 ameliorated pathological lesions, renal function and fibrosis in mouse models of DKD. STING deficiency alleviated renal fibrosis in DKD mice via inhibiting EMT. Mechanistically, by RNA sequencing, inhibitor of differentiation 1 (ID1) was found to a downstream molecule of STING. Inhibition of ID1 on the basis of overexpression of STING could suppress EMT and renal fibrosis.
Conclusion
Our study provides evidence that STING deficiency relieves renal fibrosis by inhibiting ID1-mediated EMT and that inhibition of STING and ID1 has the potential therapeutic prospects for patients with DKD.

Basic and Translational Research
Abnormally Elevated PKCδ Delays Diabetic Wound Healing by Inhibiting the GAD1-GABA Pathway: Peiliang Qin, Peng Zhou, Yating Huang, Binbin Long, Ruikang Gao, Bingjie Zhu, Yiqing Li, Qin Li; Received August 4, 2024 Accepted May 29, 2025 Published online September 8, 2025; DOI: https://doi.org/10.4093/dmj.2024.0450 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic foot ulcer (DFU) represents a challenging complication of diabetes mellitus, characterized by slow healing processes. Protein kinase C delta (PKCδ) has been identified as a significant factor in the pathogenesis of various diabetic complications, including DFU. However, the precise underlying mechanisms remain to be fully elucidated.
Methods
Human umbilical vein endothelial cells (HUVECs) were cultivated under high glucose conditions and PKCδ was knocked down by siRNA. The proliferation, migration, and tube formation of HUVECs were detected. A metabolomics sequencing was done to identify potential metabolites contributing to the changes. HUVECs proliferation, migration, tube formation, and apoptosis were detected after regulating the production of selected metabolite. And finally, the effect of the metabolite on diabetic wound healing was detected.
Results
In vitro, knockdown of PKCδ upregulated glutamate decarboxylase 1 (GAD1) expression and gamma-aminobutyric acid (GABA) levels, which enhanced proliferation, migration, and tube formation and suppressed apoptosis of HUVECs under high glucose conditions. Interestingly, inhibition of GAD1 in normal glucose-treated HUVECs resulted in decreased proliferation, migration, tube formation, and increased apoptosis. Furthermore, in vivo experiments demonstrated that topical administration of GABA accelerated the healing of diabetic wounds in streptozotocin-induced type 2 diabetes mellitus mice, manifested as higher angiogenesis and proliferation.
Conclusion
The inhibition of GAD1-GABA pathway by PKCδ suppresses the proliferation, migration, tube formation and promotes the apoptosis of endothelial cells under high glucose and leads to delayed diabetic wound healing.

Basic and Translational Research
High-Fat Diet-Fed Kcnq1 Mutant Mice Have Reduced Pancreatic β-Cell Mass via Gene-Environment Interaction: Shun-ichiro Asahara, Hiroyuki Inoue, Yuka Ihara, Kyoko Teruyama, Asuka Imai, Chisako Hara, Mizuki Hara, Masako Seike, Aisha Yokoi, Nozomi Kido, Hirotaka Suzuki, Ayumi Kanno, Yuka Inaba, Hitoshi Watanabe, Go Shioi, Maki Kimura-Koyanagi, Michihiro Matsumoto, Hiroshi Inoue, Keiichi I. Nakayama, Wataru Ogawa, Masato Kasuga, Yoshiaki Kido; Diabetes Metab J. 2026;50(1):77-89. Published online July 30, 2025; DOI: https://doi.org/10.4093/dmj.2024.0790

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Background
The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA ‘Kcnq1ot1,’ which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe.
Methods
We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass.
Results
In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass.
Conclusion
This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.

Citations

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Long noncoding RNAs in insulin signaling: mechanisms, metabolic roles, and therapeutic prospects
Soham Bhattacharyya, Debopriya Choudhury, Brahmachari Vedeshachaitanya, Pushkar Malakar
Diabetes Research and Clinical Practice.2026; 237: 113320. CrossRef

Complications
Targeting SLC25A33 Suppresses Vascular Smooth Muscle Cell Proliferation and Migration by Reducing Cytosolic mtDNA Levels: Implications for Occlusive Vascular Diseases: Daehoon Kim, Jieun Shin, Yeon-Kyung Choi, You Mie Lee, Keun-Gyu Park, Hyang Sook Kim, Jun-Kyu Byun; Diabetes Metab J. 2026;50(1):139-152. Published online July 30, 2025; DOI: https://doi.org/10.4093/dmj.2024.0632

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Abstract PDF Supplementary Material PubReader ePub: Background
Vascular smooth muscle cells (VSMCs) play a crucial role in the development of occlusive vascular diseases through abnormal proliferation and migration. This pathological behavior is closely associated with mitochondrial reactive oxygen species (ROS)-mediated mitochondrial DNA (mtDNA) damage. The mitochondrial carrier protein solute carrier family 25 member 33 (SLC25A33), essential for nucleoside transport, is integral to mtDNA production. This study aimed to investigate the effects of SLC25A33 inhibition on the proliferation and migration of VSMCs, as well as its impact on neointima formation.
Methods
VSMCs were isolated from the thoracic aorta of 4-week-old Sprague-Dawley rats. The effects of small interfering RNAinduced silencing of SLC25A33 mRNA on platelet-derived growth factor (PDGF)-induced proliferation and migration of VSMCs were analyzed. The in vivo effects of targeting the SLC25A33 gene on neointima formation were evaluated using a murine carotid artery ligation model by perivascularly applying Lenti-shSLC25A33 with Pluronic F-127 gel.
Results
First, we observed an upregulation of the SLC25A33 protein in the carotid artery ligation-induced neointima in mice. Silencing of SLC25A33 suppressed the PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Knockdown of SLC25A33 inhibited PDGF-induced production of mtDNA and ROS, consequently inactivating the cyclic GMP-AMP synthesis (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1)-nuclear factor kappa B (NF-κB) pathway. Furthermore, the downregulation of SLC25A33 reduced carotid artery ligation-induced neointima in mice.
Conclusion
This study suggests that targeting SLC25A33 in VSMCs could be a novel therapeutic strategy to prevent occlusive vascular diseases.

Basic and Translational Research
Construction of a Novel Secreted Protein Database and Identification of a New Adipokine CRELD2: Shu-Na Wang, Zhi-Yong Li, Qi-Sheng Ling, Peng-Fei Jing, Wen-Yu Liu, Yi-Jie Zhang, Xiu-Ping Zhang, Xi-Yuan Wang, Fu-Qiang Chang, Zhu-Wei Miao, Jing-Xin Zhao, Jin Chen, Chao-Yu Miao; Diabetes Metab J. 2025;49(5):1006-1023. Published online July 23, 2025; DOI: https://doi.org/10.4093/dmj.2024.0211

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Abstract PDF Supplementary Material PubReader ePub: Background
Secreted proteins may become therapeutic targets, drugs and biomarkers for aging and disease. This study aimed to establish a novel secreted protein database for adipose tissue under access to food ad libitum (AL) and caloric restriction (CR), and verify a novel adipokine.
Methods
Twelve rat chips were used for whole-genome expression in various adipose tissues from AL and CR rats, followed by bioinformatics analysis and experiments in mice, rats, and humans as well as in obesity and diabetes models.
Results
Adipose tissue expression profiles in rat different locations exhibited unique features, and enrichment analysis of differentially expressed genes between CR and AL groups showed CR effects on different adipose tissues. The 1,472 putative secreted proteins were identified, in which 200 genes were highly expressed, constructing a potential adipokines library. Cysteine rich with EGF like domains 2 (CRELD2, also named MESFATIN), whose gene was mesenteric adipose tissue specifically expressed and upregulated by CR in rat chips, was selected and verified as novel adipokine with proving its expression and secretion in in vivo mouse, rat and human and in vitro adipose tissue and adipocyte. CRELD2 secretion increased during adipocyte differentiation, and CRELD2 recombinant protein promoted adipogenesis. Although CRELD2 serum concentration showed no difference between wild-type mice and genetic ob/ob obesity mice or high fat diet induced obesity mice, CRELD2 expression decreased in white adipose tissues of ob/ob mice.
Conclusion
CRELD2 is a new adipokine involved in adipocyte differentiation and adipogenesis. A novel secreted protein database created from multiple adipose depots with CR intervention is helpful for future discovery and research of more secreted proteins.

Basic and Translational 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; Diabetes Metab J. 2025;49(3):407-420. Published online January 24, 2025; DOI: https://doi.org/10.4093/dmj.2024.0233

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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.

Citations

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Transient versican expression is required for β1-integrin accumulation during podocyte layer morphogenesis in amphibian developing kidney
Isabelle Buisson, Jean-François Riou, Muriel Umbhauer, Ronan Le Bouffant, Valérie Bello
Cells & Development.2026; 185: 204062. CrossRef
m6A Modified VCAN Promotes Glomerular Endothelial Cells Injury and Diabetic Nephropathy by SHH Pathway
Jie Jiang, Jicheng Zhang, Chao Wang, Feng Wang
Applied Biochemistry and Biotechnology.2026; 198(5): 3461. CrossRef
Multi-omics and machine learning identify FN1 and ALDH2 as diagnostic biomarkers and therapeutic targets in early and late diabetic kidney disease
Jingwei Lin, Yingying Zheng, Diman Mai, Fuxiang Fang, Zhuokun Wei, Mengyu Liu, Trung Hieu Pham, Ming Li, Jiawen Zhao
Renal Failure.2025;[Epub] CrossRef

Basic and Translational Research
Ras Guanine Nucleotide-Releasing Protein-4 Inhibits Erythropoietin Production in Diabetic Mice with Kidney Disease by Degrading HIF2A: Junmei Wang, Shuai Huang, Li Zhang, Yixian He, Xian Shao, A-Shan-Jiang A-Ni-Wan, Yan Kong, Xuying Meng, Pei Yu, Saijun Zhou; Diabetes Metab J. 2025;49(3):421-435. Published online January 23, 2025; DOI: https://doi.org/10.4093/dmj.2024.0398

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Background
In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes.
Methods
The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments.
Results
RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice.
Conclusion
RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

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Differential effects of prophylactic iron supplementation on physiological gestational anemia and post-IDA gestational anemia: a study based on a rat model
Zelin Zhang, Limin Lai, Ziping Liu, Sili Liu, Liping Qu, Wenjun Zou
Frontiers in Nutrition.2025;[Epub] CrossRef

Basic and Translational Research
Rbbp6-Mediated Bmal1 Ubiquitination Inhibits YAP1 Signaling Pathway to Promote Ferroptosis in Diabetes-Induced Testicular Damage: Yuan Tian, Zhiqiang Zhu, Jun Qiao, Bei Liu, Yuehai Xiao; Diabetes Metab J. 2025;49(2):210-224. Published online November 6, 2024; DOI: https://doi.org/10.4093/dmj.2024.0099

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Background
Diabetes-induced testicular damage (DITD) is a common complication of diabetes. We investigated underlying mechanism of retinoblastoma-binding protein 6 (Rbbp6)-mediated brain and muscle ARNT-like 1 (Bmal1) ubiquitination in modulating ferroptosis in DITD.
Methods
Spermatogenic cell apoptosis and viability were measured by flow cytometry and cell counting kit 8 (CCK-8), respectively. The impact of Rbbp6 and Bmal1 on ferroptosis was assessed by determining expression of ferroptosis markers glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and levels of malondialdehyde (MDA), glutathione (GSH), iron, and lipid peroxidation. Co-immunoprecipitation was performed to determine the interaction between Rbbp6 and Bmal1, as well as the ubiquitination level of Bmal1. The expression levels of Rbbp6, Bmal1, Yes-associated protein 1 (YAP1), ferroptosis markers, and testicular steroidogenic enzymes were tested by Western blot.
Results
Bmal1 protein expression was significantly downregulated, while Rbbp6 was upregulated in DITD mouse model and high glucose (HG)-induced GC-1 spg cells. Overexpression of Bmal1 improved testicular injury in diabetic mice, reduced 4-hydroxynonenal (4-HNE), MDA, iron levels, and increased expression levels of GPX4, SLC7A11, GSH, as well as testicular steroidogenic enzymes. Rbbp6 decreased Bmal1 level through promoting its ubiquitination. Meanwhile, Rbbp6 knockdown inhibited the ferroptosis of HG-induced GC-1 spg cells, which were abolished by silencing Bmal1. In addition, knockdown of YAP1 or treatment with ferroptosis inducer erastin blocked the above effects caused by Bmal1 overexpression.
Conclusion
Rbbp6-mediated Bmal1 ubiquitination suppressed YAP1 pathway, promoting ferroptosis in DITD. This study highlighted Rbbp6/Bmal1/YAP1 axis as a potential therapeutic target for mitigating DITD.

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Xiaoqiong Jiang, Yu Wang, Xuanlong Zhang, Huiming Deng, Liangyu Fang, Chaire Tafadzwa, Jiangnan Yao, Hao Chen, Anqi Ye, Kailiang Zhou, Xiangwei Ling, Jian Xiao
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GALNT3-mediated AKT1 glycosylation activates the AKT1/CREB signaling pathway to inhibit high glucose-induced spermatogenic cell apoptosis and mitochondrial dysfunction
Yong Zhao, Jia Luo, Lu Wu
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Resveratrol attenuates high-fat diet-induced testicular injury via the NRF2/GPX4 pathway: an integrated metabolomics and network pharmacology study
Yating Lai, Yuanyuan Wang, Wei Zeng, Jiayu Zhang, Jiamin Cao, Mengjia Sun, Hongxue Liang, Zhongxiang Zhao, Jing Jin
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METTL14 Aggravates Sepsis‐Induced Acute Kidney Injury by Promoting Ferroptosis Through m6A Modification of BMAL1
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E3 ubiquitin ligases and deubiquitinases: Promising therapeutic targets for diabetic kidney disease
Yun Wu, Huicheng Jia, Fei Sun, Yinan Yang, Zhengsheng Li, Wei Jing Liu
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Guilu Erxian glue mitigates spermatogenesis dysfunction through HIF-1α/SLC7A11-mediated ferroptosis inhibition: An integrated metabolomics and network pharmacology study
Chuying Tang, Wen Sheng, Xianrui Li, Wei Fu, Meixin Lin, Zheng Wen, Wei Luo, Zezheng Zhang, Qingxia Zheng, Xing Zhou, Jin Ding
Phytomedicine.2025; 148: 157321. CrossRef

Basic and Translational Research
Shionone Inhibits Glomerular Fibirosis by Suppressing NLRP3 Related Inflammasome though SESN2-NRF2/ HO-1 Pathway: Tian Xiao, Hanzhen Zhao, Yucong Wang, Mengyin Chen, Cong Wang, Chen Qiao; Diabetes Metab J. 2025;49(1):34-48. Published online August 28, 2024; DOI: https://doi.org/10.4093/dmj.2024.0024

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Background
Diabetic nephropathy (DN) is the most common and serious complication of diabetes mellitus. Shionone (SH), an important triterpenoid compound in the root extract of Aster, might exert a protective effect in DN mice and high glucose cultivated glomerular podocytes. The current study aimed to unravel the underlying mechanism by which SH mitigates DN. We postulate that SH stimulates the expression of sestrin-2 (SESN2), a pivotal stress-inducible protein in the anti-inflammasome machinery.
Methods
We utilized high-fat diet combined with streptozotocin (55 mg/kg intraperitoneal) for DN mice model, and high glucose (30 mM, 48 hours) cultured glomerular podocytes for DN cell model to evaluate the effect of SH. We also preformed experimentation on SESN2 deficiency models (SESN2 knockout mice and SESN2 siRNA in cells) to further prove our hypothesis.
Results
The results demonstrated that SH effectively suppressed glomerular fibrosis, induced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and inhibited NLR family pyrin domain containing 3 (NLRP3) activation. Furthermore, our findings revealed that SH exerted its anti-inflammatory effect through Sesn2-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and subsequent activation of its downstream target heme oxygenase-1 (HO-1).
Conclusion
In summary, our findings suggest that SH serves as a promising therapeutic agent for the treatment of DN-related glomerular fibrosis. SH enhances the expression of SESN2, attenuates α-smooth muscle actin accumulation, and suppresses NLRP3-related inflammation through the Nrf2/HO-1 signaling pathway.

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Shionone attenuates endoplasmic reticulum stress-associated ferroptosis in cardiomyocytes by reducing LCN2 and regulating PI3K/Akt signaling
Chunni Gao, Xingjuan Gao, Jinshuang Li
Journal of Bioenergetics and Biomembranes.2026;[Epub] CrossRef
Perillaldehyde inhibits oxidative stress, NLRP3-mediated inflammation and fibrosis in diabetic nephropathy through regulating HMOX1
Wen Hao, Chunhua Liu, Jing Feng, Zhanliang Ren
Hereditas.2026;[Epub] CrossRef
Sestrins as Biomarkers of Cellular Stress and Human Disease
Alexander Haidurov, Andrei Budanov
Cells.2026; 15(7): 651. CrossRef
Zinc deficiency exacerbates and supplementation attenuates early-stage obesity-related podocyte injury via Nrf2/HO-1-mediated pyroptosis
Yucan Guan, Yanling Li, Xiaoying Bai, Ping Luo, Manyu Luo
International Immunopharmacology.2026; 180: 116703. CrossRef
Advances in understanding the NLRP3 inflammasome‑mediated mechanisms and therapeutic targets in diabetic nephropathy (Review)
Xiwei Wang, Shuang Li, Xiaotian Ge, Tao Xie, Sainan Li, Ruiqi Yuan, Tianxi Li, Hui Yuan
International Journal of Molecular Medicine.2026; 58(1): 1. CrossRef
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Basic Research
PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca²⁺ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes: Yongxin Liu, Yongqing Wei, Xiaolong Jin, Hongyu Cai, Qianqian Chen, Xiujuan Zhang; Diabetes Metab J. 2024;48(6):1058-1072. Published online July 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0275

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Background
Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action.
Methods
High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic β-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca²⁺ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit.
Results
PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic β-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic β-cells. Additionally, PDZD8 knockdown alleviated Ca²⁺ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of β-cells.
Conclusion
PDZD8 knockdown inhibited pancreatic β-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca²⁺ into the mitochondria.

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Review

Pathophysiology
Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease: Yan Zhang, Shibo Wei, Eun-Ju Jin, Yunju Jo, Chang-Myung Oh, Gyu-Un Bae, Jong-Sun Kang, Dongryeol Ryu; Diabetes Metab J. 2024;48(4):487-502. Published online July 24, 2024; DOI: https://doi.org/10.4093/dmj.2023.0362

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Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

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Daphne de Korte, Menno Hoekstra
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Szumam Liu, Min Ma, Jun Qu, Joshua Muia, Zhijian Wu, Quintijn Bonnez, Karen Vanhoorelbeke, Liang Zheng, Xinyang Zhao, X. Long Zheng
Arteriosclerosis, Thrombosis, and Vascular Biology.2025; 45(4): 506. CrossRef
Protein Arginine N‐Methyltransferase 4 Activation Contributes to Glucose‐Induced Skeletal Muscle Atrophy
Pawan Kumar, Farah Gulzar, Nikita Chhikara, Arvind K. Maurya, Sushmita Singh, Ishbal Ahmad, Sanjeev Kanojiya, Akhilesh K. Tamrakar
The FASEB Journal.2025;[Epub] CrossRef
PRMT1 in Health and Disease: Emerging Perspectives From Molecular Mechanisms to Therapeutic Strategies
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MedComm.2025;[Epub] CrossRef

Original Articles

Basic Research
Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway: Shan-Shan Li, Lu Pan, Zhen-Ye Zhang, Meng-Dan Zhou, Xu-Fei Chen, Ling-Ling Qian, Min Dai, Juan Lu, Zhi-Ming Yu, Shipeng Dang, Ru-Xing Wang; Diabetes Metab J. 2024;48(4):716-729. Published online February 27, 2024; DOI: https://doi.org/10.4093/dmj.2023.0031

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Background
Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified.
Methods
In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed.
Results
In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation.
Conclusion
Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

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Kajetan Kiełbowski, Estera Bakinowska, Andrzej Pawlik
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Shan-Shan Li, Lu Pan, Shipeng Dang, Ru-Xing Wang
Diabetes & Metabolism Journal.2024; 48(6): 1181. CrossRef
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Cardiovascular risk/Epidemiology
Risk of Cardiovascular Disease according to Baseline Low-Density Lipoprotein Cholesterol Level in Different Age Groups in Korean Diabetes Population: A Cohort Study: Tae Kyung Yoo, Kyung-Do Han, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2024;48(2):265-278. Published online February 26, 2024; DOI: https://doi.org/10.4093/dmj.2022.0443

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Background
The association between low-density lipoprotein (LDL-C) levels and cardiovascular disease (CVD) risk in different age groups within the diabetes mellitus (DM) population remains unclear. The cohort study was conducted to investigate this relationship.
Methods
We assessed the 2009 to 2012 Korean National Health Screening and National Health Insurance Service records, with follow-up to the primary outcome (myocardial infarction [MI] or stroke) or December 2018. After excluding the participants with a history of MI or stroke, 2,227,394 participants with DM were included and categorized according to baseline LDL-C levels and age. Cox proportional hazards modeling was conducted. The CVD risk of age <40 years and LDL-C <70 mg/dL was set as the reference. In each age group, LDL-C <70 mg/dL was used as a reference for the subgroup analysis.
Results
The cut-off LDL-C value for increased MI risk in each age group varied (<40 years old, LDL-C ≥160 mg/dL: hazard ratios [HR], 2.03; 95% confidence interval [CI], 1.644 to 2.506) (40–49-year-old, LDL-C <115 mg/dL: HR, 1.245; 95% CI, 1.04 to 1.489) (50–59-year-old, LDL-C <115 mg/dL: HR, 1.21; 95% CI, 1.014 to 1.445) (60-69-year-old, LDL-C <145 mg/dL: HR, 1.229; 95% CI, 1.022 to 1.479) (≥70 years old group, LDL-C <100 mg/dL: HR, 1.238; 95% CI, 1.018 to 1.504). The cut-off LDL-C values for increased stroke risk varied in each age subgroup (<40 years old, LDL-C ≥160 mg/dL: HR, 1.395; 95% CI, 1.094 to 1.779) (40–49-year-old, LDL-C <145 mg/dL: HR, 1.13; 95% CI, 1.019 to 1.253) (50–59-year-old, LDL-C <160 mg/dL: HR, 1.079; 95% CI, 1.008 to 1.154) (60–69-year-old, LDL-C <130 mg/dL: HR, 1.07; 95% CI, 1.022 to 1.119) (≥70 years old, LDL-C <115 mg/dL: HR, 1.064; 95% CI, 1.019 to 1.112).
Conclusion
The effect of LDL-C on the risk of CVD differs depending on the age of the population with DM.

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Review

Pathophysiology
Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases: Songling Tang, Di Hao, Wen Ma, Lian Liu, Jiuyu Gao, Peng Yao, Haifang Yu, Lu Gan, Yu Cao; Diabetes Metab J. 2024;48(4):503-517. Published online February 15, 2024; DOI: https://doi.org/10.4093/dmj.2023.0213

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Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca²⁺ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.

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Original Articles

Metabolic Risk/Epidemiology
A Composite Blood Biomarker Including AKR1B10 and Cytokeratin 18 for Progressive Types of Nonalcoholic Fatty Liver Disease: Seung Joon Choi, Sungjin Yoon, Kyoung-Kon Kim, Doojin Kim, Hye Eun Lee, Kwang Gi Kim, Seung Kak Shin, Ie Byung Park, Seong Min Kim, Dae Ho Lee; Diabetes Metab J. 2024;48(4):740-751. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0189

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Background
We aimed to evaluate whether composite blood biomarkers including aldo-keto reductase family 1 member B10 (AKR1B10) and cytokeratin 18 (CK-18; a nonalcoholic steatohepatitis [NASH] marker) have clinically applicable performance for the diagnosis of NASH, advanced liver fibrosis, and high-risk NASH (NASH+significant fibrosis).
Methods
A total of 116 subjects including healthy control subjects and patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were analyzed to assess composite blood-based and imaging-based biomarkers either singly or in combination.
Results
A composite blood biomarker comprised of AKR1B10, CK-18, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) showed excellent performance for the diagnosis of, NASH, advanced fibrosis, and high-risk NASH, with area under the receiver operating characteristic curve values of 0.934 (95% confidence interval [CI], 0.888 to 0.981), 0.902 (95% CI, 0.832 to 0.971), and 0.918 (95% CI, 0.862 to 0.974), respectively. However, the performance of this blood composite biomarker was inferior to that various magnetic resonance (MR)-based composite biomarkers, such as proton density fat fraction/MR elastography- liver stiffness measurement (MRE-LSM)/ALT/AST for NASH, MRE-LSM+fibrosis-4 index for advanced fibrosis, and the known MR imaging-AST (MAST) score for high-risk NASH.
Conclusion
Our blood composite biomarker can be useful to distinguish progressive forms of NAFLD as an initial noninvasive test when MR-based tools are not available.

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Pathophysiology
Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity: Xiaorui Yu, Jiawang Tao, Yuhang Wu, Yan Chen, Penghui Li, Fan Yang, Miaoxiu Tang, Abdul Sammad, Yu Tao, Yingying Xu, Yin-Xiong Li; Diabetes Metab J. 2024;48(4):802-815. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0124

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Background
Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods
The constructed ASGR1 knockout mice and ASGR1^-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results
ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1^-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion
The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

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Review

Basic Research
Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases: Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong; Diabetes Metab J. 2024;48(1):1-18. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2023.0115

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Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPR^mt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPR^mt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.

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Original Articles

Basic Research
Extracellular Vimentin Alters Energy Metabolism And Induces Adipocyte Hypertrophy: Ji-Hae Park, Soyeon Kwon, Young Mi Park; Diabetes Metab J. 2024;48(2):215-230. Published online September 26, 2023; DOI: https://doi.org/10.4093/dmj.2022.0332

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Background
Previous studies have reported that oxidative stress contributes to obesity characterized by adipocyte hypertrophy. However, mechanism has not been studied extensively. In the current study, we evaluated role of extracellular vimentin secreted by oxidized low-density lipoprotein (oxLDL) in energy metabolism in adipocytes.
Methods
We treated 3T3-L1-derived adipocytes with oxLDL and measured vimentin which was secreted in the media. We evaluated changes in uptake of glucose and free fatty acid, expression of molecules functioning in energy metabolism, synthesis of adenosine triphosphate (ATP) and lactate, markers for endoplasmic reticulum (ER) stress and autophagy in adipocytes treated with recombinant vimentin.
Results
Adipocytes secreted vimentin in response to oxLDL. Microscopic evaluation revealed that vimentin treatment induced increase in adipocyte size and increase in sizes of intracellular lipid droplets with increased intracellular triglyceride. Adipocytes treated with vimentin showed increased uptake of glucose and free fatty acid with increased expression of plasma membrane glucose transporter type 1 (GLUT1), GLUT4, and CD36. Vimentin treatment increased transcription of GLUT1 and hypoxia-inducible factor 1α (Hif-1α) but decreased GLUT4 transcription. Adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), diacylglycerol O-acyltransferase 1 (DGAT1) and 2 were decreased by vimentin treatment. Markers for ER stress were increased and autophagy was impaired in vimentin-treated adipocytes. No change was observed in synthesis of ATP and lactate in the adipocytes treated with vimentin.
Conclusion
We concluded that extracellular vimentin regulates expression of molecules in energy metabolism and promotes adipocyte hypertrophy. Our results show that vimentin functions in the interplay between oxidative stress and metabolism, suggesting a mechanism by which adipocyte hypertrophy is induced in oxidative stress.

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Ruihuan Chen, Jianping Wu, Daniel Jafari, Annica K. B. Gad
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Cardiovascular Risk/Epidemiology
Two-Year Changes in Diabetic Kidney Disease Phenotype and the Risk of Heart Failure: A Nationwide Population-Based Study in Korea: Seung Eun Lee, Juhwan Yoo, Han Seok Choi, Kyungdo Han, Kyoung-Ah Kim; Diabetes Metab J. 2023;47(4):523-534. Published online April 25, 2023; DOI: https://doi.org/10.4093/dmj.2022.0096

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Background
Diabetic kidney disease (DKD) is a risk factor for hospitalization for heart failure (HHF). DKD could be classified into four phenotypes by estimated glomerular filtration rate (eGFR, normal vs. low) and proteinuria (PU, negative vs. positive). Also, the phenotype often changes dynamically. This study examined HHF risk according to the DKD phenotype changes across 2-year assessments.
Methods
The study included 1,343,116 patients with type 2 diabetes mellitus (T2DM) from the Korean National Health Insurance Service database after excluding a very high-risk phenotype (eGFR <30 mL/min/1.73 m2) at baseline, who underwent two cycles of medical checkups between 2009 and 2014. From the baseline and 2-year eGFR and PU results, participants were divided into 10 DKD phenotypic change categories.
Results
During an average of 6.5 years of follow-up, 7,874 subjects developed HHF. The cumulative incidence of HHF from index date was highest in the eGFR^lowPU– phenotype, followed by eGFR^norPU⁺ and eGFR^norPU^–. Changes in DKD phenotype differently affect HHF risk. When the persistent eGFR^norPU^– category was the reference, hazard ratios for HHF were 3.10 (95% confidence interval [CI], 2.73 to 3.52) in persistent eGFR^norPU⁺ and 1.86 (95% CI, 1.73 to 1.99) in persistent eGFR^lowPU^–. Among altered phenotypes, the category converted to eGFR^lowPU⁺ showed the highest risk. In the normal eGFR category at the second examination, those who converted from PU^– to PU⁺ showed a higher risk of HHF than those who converted from PU⁺ to PU^–.
Conclusion
Changes in DKD phenotype, particularly with the presence of PU, are more likely to reflect the risk of HHF, compared with DKD phenotype based on a single time point in patients with T2DM.

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Persistent proteinuria is associated with the occurrence of cardiovascular disease: a nationwide population-based cohort study
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Basic Research
Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes: Praise Chanmee Kim, Ji Seon Lee, Sung Soo Chung, Kyong Soo Park; Diabetes Metab J. 2023;47(3):382-393. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0156

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Background
Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)–peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues.
Methods
The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed in vivo using adipocyte-specific Senp2 knockout (Senp2-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (Cpt1b) and long-chain acyl-coenzyme A synthetase 1 (Acsl1) using transfection/reporter assays and chromatin immunoprecipitation.
Results
SENP2 mediated the increased expression of FAO-associated enzymes, CPT1b and ACSL1, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of Cpt1b and Acsl1 were increased by 2-fold 24 hours after leptin injection in control mice but not in Senp2-aKO mice. Leptin increased PPARα binding to the Cpt1b and Acsl1 promoters in adipocytes through SENP2.
Conclusion
These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

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Jing-Wen Zhang, Ling Weng, Yi Fu, Lou Liu, Jie Chen, Ju-Ying Zhou, Chen-Ying Ma
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Review

Basic Research
Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases: Byung Soo Kong, Changhan Lee, Young Min Cho; Diabetes Metab J. 2023;47(3):315-324. Published online February 24, 2023; DOI: https://doi.org/10.4093/dmj.2022.0333

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Mitochondria are complex metabolic organelles with manifold pathophysiological implications in diabetes. Currently published mitochondrial-encoded peptides, which are expressed from the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c), 16S rRNA (humanin and short humanin like peptide 1-6 [SHLP1-6]), or small human mitochondrial open reading frame over serine tRNA (SHMOOSE) are associated with regulation of cellular metabolism and insulin action in age-related diseases, such as type 2 diabetes mellitus. This review focuses mainly on recent advances in MOTS-c research with regards to diabetes, including both type 1 and type 2. The emerging understanding of MOTS-c in diabetes may provide insight into the development of new therapies for diabetes and other age or senescence-related diseases.

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Xinxin Liu, Yingqi Ma, Xuefeng Wang, Xiaowen Zhang, Chen Shen, Youzhu Su, Xing Chang, Hao Zhou, Jian-Ping Liu
Journal of Advanced Research.2026; 84: 937. CrossRef
MOTS-c is associated with oxidative stress and arterial stiffness in peritoneal dialysis patients: a pilot study
Michela Musolino, Athanasios Roumeliotis, Stefanos Roumeliotis, Mariateresa Zicarelli, Federico Ruosi, Marta Greco, Roberta Misiti, Daniela Patrizia Foti, Vasiliki Sgouropoulou, Gordana Kocic, Andrej Veljkovic, Ioannis E. Neofytou, Ioannis Alekos, Efthymi
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MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3
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Xin Shu, Jiying Liu, Bingjie Xu, Hui Wang, Li Liu, Xiaotong Zheng, Jianfei Chen
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Nada Borghol, Sozerko Yandiev, Julien Courchet
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Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes
Byung Soo Kong, Hyunsuk Lee, Sehi L’Yi, Serin Hong, Young Min Cho
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UPRmt-regulated mitokines: novel strategies for myocardial injury repair
Weinan Gao, Jia Liu, Wenda Zhang, Bin Liu, Luyan Shen
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Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives
Satadeepa Kal, Sumana Mahata, Suborno Jati, Sushil K. Mahata
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Benyuan Zhang, Joon Young Chang, Min Hee Lee, Sang-Hyeon Ju, Hyon-Seung Yi, Minho Shong
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Alejandra María Rivera Nieves, Brian Michael Wauford, Accalia Fu
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Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome
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Pyrroloquinoline Quinone Alleviates Mitochondria Damage in Radiation-Induced Lung Injury in a MOTS-c-Dependent Manner
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Original Article

Basic Research
Long Non-Coding RNA TUG1 Attenuates Insulin Resistance in Mice with Gestational Diabetes Mellitus via Regulation of the MicroRNA-328-3p/SREBP-2/ERK Axis: Xuwen Tang, Qingxin Qin, Wenjing Xu, Xuezhen Zhang; Diabetes Metab J. 2023;47(2):267-286. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0216

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Background
Long non-coding RNAs (lncRNAs) have been illustrated to contribute to the development of gestational diabetes mellitus (GDM). In the present study, we aimed to elucidate how lncRNA taurine upregulated gene 1 (TUG1) influences insulin resistance (IR) in a high-fat diet (HFD)-induced mouse model of GDM.
Methods
We initially developed a mouse model of HFD-induced GDM, from which islet tissues were collected for RNA and protein extraction. Interactions among lncRNA TUG1/microRNA (miR)-328-3p/sterol regulatory element binding protein 2 (SREBP-2) were assessed by dual-luciferase reporter assay. Fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), HOMA pancreatic β-cell function (HOMA-β), insulin sensitivity index for oral glucose tolerance tests (ISOGTT) and insulinogenic index (IGI) levels in mouse serum were measured through conducting gain- and loss-of-function experiments.
Results
Abundant expression of miR-328 and deficient expression of lncRNA TUG1 and SREBP-2 were characterized in the islet tissues of mice with HFD-induced GDM. LncRNA TUG1 competitively bound to miR-328-3p, which specifically targeted SREBP-2. Either depletion of miR-328-3p or restoration of lncRNA TUG1 and SREBP-2 reduced the FBG, FINS, HOMA-β, and HOMA-IR levels while increasing ISOGTT and IGI levels, promoting the expression of the extracellular signal-regulated kinase (ERK) signaling pathway-related genes, and inhibiting apoptosis of islet cells in GDM mice. Upregulation miR-328-3p reversed the alleviative effects of SREBP-2 and lncRNA TUG1 on IR.
Conclusion
Our study provides evidence that the lncRNA TUG1 may prevent IR following GDM through competitively binding to miR-328-3p and promoting the SREBP-2-mediated ERK signaling pathway inactivation.

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Reviews

Drug/Regimen
New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins: Kyuho Kim, Henry N. Ginsberg, Sung Hee Choi; Diabetes Metab J. 2022;46(4):517-532. Published online July 27, 2022; DOI: https://doi.org/10.4093/dmj.2022.0198; Correction in: Diabetes Metab J 2022;46(5):817

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Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

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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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Sulwon Lecture 2021

Basic Research
Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c): Tae Kwan Yoon, Chan Hee Lee, Obin Kwon, Min-Seon Kim; Diabetes Metab J. 2022;46(3):402-413. Published online May 25, 2022; DOI: https://doi.org/10.4093/dmj.2022.0092

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Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPR^mt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.

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MOTS-c Serum Concentration Positively Correlates with Lower-Body Muscle Strength and Is Not Related to Maximal Oxygen Uptake—A Preliminary Study
Remigiusz Domin, Michał Pytka, Mikołaj Żołyński, Jan Niziński, Marcin Rucinski, Przemysław Guzik, Jacek Zieliński, Marek Ruchała
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Original Articles

Complications
Fatty Acid-Binding Protein 4 in Patients with and without Diabetic Retinopathy: Ping Huang, Xiaoqin Zhao, Yi Sun, Xinlei Wang, Rong Ouyang, Yanqiu Jiang, Xiaoquan Zhang, Renyue Hu, Zhuqi Tang, Yunjuan Gu; Diabetes Metab J. 2022;46(4):640-649. Published online April 28, 2022; DOI: https://doi.org/10.4093/dmj.2021.0195

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Background
Fatty acid-binding protein 4 (FABP4) has been demonstrated to be a predictor of early diabetic nephropathy. However, little is known about the relationship between FABP4 and diabetic retinopathy (DR). This study explored the value of FABP4 as a biomarker of DR in patients with type 2 diabetes mellitus (T2DM).
Methods
A total of 238 subjects were enrolled, including 20 healthy controls and 218 T2DM patients. Serum FABP4 levels were measured using a sandwich enzyme-linked immunosorbent assay. The grade of DR was determined using fundus fluorescence angiography. Based on the international classification of DR, all T2DM patients were classified into the following three subgroups: non-DR group, non-proliferative diabetic retinopathy (NPDR) group, and proliferative diabetic retinopathy (PDR) group. Multivariate logistic regression analyses were employed to assess the correlation between FABP4 levels and DR severity.
Results
FABP4 correlated positively with DR severity (r=0.225, P=0.001). Receiver operating characteristic curve analysis was used to assess the diagnostic potential of FABP4 in identifying DR, with an area under the curve of 0.624 (37% sensitivity, 83.6% specificity) and an optimum cut-off value of 76.4 μg/L. Multivariate logistic regression model including FABP4 as a categorized binary variable using the cut-off value of 76.4 μg/L showed that the concentration of FABP4 above the cut-off value increased the risk of NPDR (odds ratio [OR], 3.231; 95% confidence interval [CI], 1.574 to 6.632; P=0.001) and PDR (OR, 3.689; 95% CI, 1.306 to 10.424; P=0.014).
Conclusion
FABP4 may be used as a serum biomarker for the diagnosis of DR.

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GMSCs‐Derived Exosome ZHX2 Improves Diabetes Nephropathy by Blocking AGEs/RAGE/NLRP3 Pathway to Inhibit Podocyte Pyroptosis and Inflammatory Response
Shaobo Wang, Xue Cai, Chanyan Weng, Miaozhu Su, Qunfeng Yang, Bo Chen, Jincheng Zeng
The FASEB Journal.2026;[Epub] CrossRef
Increased fatty acid-binding protein 4 levels are associated with the risk of developing retinopathy in type 2 diabetes mellitus patients
Yan Liu, Kaihui Ma, Aiying Zhang, Yun Cui, Hui Zhao, Xinhua Li, Ke Zhao
Diabetes & Metabolism.2025; 51(4): 101653. CrossRef
What do You Need to Know after Diabetes and before Diabetic Retinopathy?
Shiyu Zhang, Jia Liu, Heng Zhao, Yuan Gao, Changhong Ren, Xuxiang Zhang
Aging and disease.2025;[Epub] CrossRef
Proteome atlas for mechanistic discovery and risk prediction of diabetic retinopathy
Shaopeng Yang, Zhuoyao Xin, Ruilin Xiong, Ziyu Zhu, Huangdong Li, Yanping Chen, Zhenghao Zhong, Lanqi Du, Lisa Zhuoting Zhu, Xianwen Shang, Wenyong Huang, Lei Zhang, Shida Chen, Chang He, Shaoying Tan, Mingguang He, Nathan Congdon, Jost B. Jonas, Yih-Chun
Nature Communications.2025;[Epub] CrossRef
Circulating AFABP, FGF21, and PEDF Levels as Prognostic Biomarkers of Sight-threatening Diabetic Retinopathy
Chi-Ho Lee, David Tak-Wai Lui, Chloe Yu-Yan Cheung, Carol Ho-Yi Fong, Michele Mae-Ann Yuen, Yu-Cho Woo, Wing-Sun Chow, Ian Yat-Hin Wong, Aimin Xu, Karen Siu-Ling Lam
The Journal of Clinical Endocrinology & Metabolism.2023; 108(9): e799. CrossRef
A Prediction Model for Sight-Threatening Diabetic Retinopathy Based on Plasma Adipokines among Patients with Mild Diabetic Retinopathy
Yaxin An, Bin Cao, Kun Li, Yongsong Xu, Wenying Zhao, Dong Zhao, Jing Ke, Takayuki Masaki
Journal of Diabetes Research.2023; 2023: 1. CrossRef

Type 1 Diabetes
Identification of Key Genes and Pathways in Peripheral Blood Mononuclear Cells of Type 1 Diabetes Mellitus by Integrated Bioinformatics Analysis: Xing Li, Mingyu Liao, Jiangheng Guan, Ling Zhou, Rufei Shen, Min Long, Jiaqing Shao; Diabetes Metab J. 2022;46(3):451-463. Published online April 1, 2022; DOI: https://doi.org/10.4093/dmj.2021.0018

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Background
The onset and progression of type 1 diabetes mellitus (T1DM) is closely related to autoimmunity. Effective monitoring of the immune system and developing targeted therapies are frontier fields in T1DM treatment. Currently, the most available tissue that reflects the immune system is peripheral blood mononuclear cells (PBMCs). Thus, the aim of this study was to identify key PBMC biomarkers of T1DM.
Methods
Common differentially expressed genes (DEGs) were screened from the Gene Expression Omnibus (GEO) datasets GSE9006, GSE72377, and GSE55098, and PBMC mRNA expression in T1DM patients was compared with that in healthy participants by GEO2R. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses of DEGs were performed using the Cytoscape, DAVID, and STRING databases. The vital hub genes were validated by reverse transcription-polymerase chain reaction using clinical samples. The disease-gene-drug interaction network was built using the Comparative Toxicogenomics Database (CTD) and Drug Gene Interaction Database (DGIdb).
Results
We found that various biological functions or pathways related to the immune system and glucose metabolism changed in PBMCs from T1DM patients. In the PPI network, the DEGs of module 1 were significantly enriched in processes including inflammatory and immune responses and in pathways of proteoglycans in cancer. Moreover, we focused on four vital hub genes, namely, chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine ligand 1 (CXCL1), matrix metallopeptidase 9 (MMP9), and granzyme B (GZMB), and confirmed them in clinical PBMC samples. Furthermore, the disease-gene-drug interaction network revealed the potential of key genes as reference markers in T1DM.
Conclusion
These results provide new insight into T1DM pathogenesis and novel biomarkers that could be widely representative reference indicators or potential therapeutic targets for clinical applications.

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Identification of crucial extracellular genes as potential biomarkers in newly diagnosed Type 1 diabetes via integrated bioinformatics analysis
Ming Gao, Qing Liu, Lingyu Zhang, Fatema Tabak, Yifei Hua, Wei Shao, Yangyang Li, Li Qian, Yu Liu
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Integrative transcriptomic analysis identifies common biomarkers in type 1 and type 2 diabetes using WGCNA and machine learning
M R Rasyak, Turyadi, R Nirwantono, F S Mozar, A Imani, A Desandros, B Pardamean
IOP Conference Series: Earth and Environmental Science.2025; 1550(1): 012002. CrossRef
Single-cell and transcriptomic analyses reveal the influence of diabetes on ovarian cancer
Zhihao Zhao, Qilin Wang, Fang Zhao, Junnan Ma, Xue Sui, Hyok Chol Choe, Peng Chen, Xue Gao, Lin Zhang
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Bioinformatics analysis identifies TGF-β signaling pathway-associated molecular subtypes and gene signature in diabetic foot
Guanggang Du, Jie Chen, Xuezhu Zhu, Zongdong Zhu
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Shudeb Babu Sen Omit, Salma Akhter, Humayan Kabir Rana, A. R. M. Mahamudul Hasan Rana, Nitun Kumar Podder, Mahmudul Islam Rakib, Ashadun Nobi, Ali Imran
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Mingshu Huang, Weixing Chen, Min Wang, Yisheng Huang, Hongyu Liu, Yue Ming, Yuanxin Chen, Zhengming Tang, Bo Jia
BioDrugs.2023; 37(3): 331. CrossRef
Identification of the key genes of tuberculosis and construction of a diagnostic model via weighted gene co-expression network analysis
Baiying Li, Lifang Sun, Yaping Sun, Libo Zhen, Qi Qi, Ting Mo, Huijie Wang, Meihua Qiu, Qingshan Cai
Journal of Infection and Chemotherapy.2023; 29(11): 1046. CrossRef
Probing biological network in concurrent carcinomas and Type-2 diabetes for potential biomarker screening: An advanced computational paradigm
Abdullah Al Marzan, Shatila Shahi, Md Sakil Arman, Md Zafrul Hasan, Ajit Ghosh
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Transcriptional analysis of human peripheral blood mononuclear cells stimulated by Mycobacterium tuberculosis antigen
Jing Wei, Fangzheng Guo, Yamin Song, Kun Xu, Feiyang Lin, Kangsheng Li, Baiqing Li, Zhongqing Qian, Xiaojing Wang, Hongtao Wang, Tao Xu
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Combining bioinformatics and machine learning algorithms to identify and analyze shared biomarkers and pathways in COVID-19 convalescence and diabetes mellitus
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Transcriptome analysis of peripheral blood mononuclear cells in patients with type 1 diabetes mellitus
Zhaoxiang Wang, Li Zhang, Fengyan Tang, Zhongming Yang, Mengzhu Wang, Jue Jia, Dong Wang, Ling Yang, Shao Zhong, Guoyue Yuan
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Cardiovascular Risk/Epidemiology
Myocardial Infarction, Stroke, and All-Cause Mortality according to Low-Density Lipoprotein Cholesterol Level in the Elderly, a Nationwide Study: You-Bin Lee, Minji Koo, Eunjin Noh, Soon Young Hwang, Jung A Kim, Eun Roh, So-hyeon Hong, Kyung Mook Choi, Sei Hyun Baik, Geum Joon Cho, Hye Jin Yoo; Diabetes Metab J. 2022;46(5):722-732. Published online March 8, 2022; DOI: https://doi.org/10.4093/dmj.2021.0225

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Background
We assessed the myocardial infarction (MI), stroke, and all-cause death risks during follow-up according to the low-density lipoprotein cholesterol (LDL-C) levels among older adults.
Methods
The Korean National Health Insurance Service datasets (2002 to 2020) were used for this population-based cohort study. The hazards of MI, stroke, and all-cause mortality during follow-up were analyzed according to LDL-C level in individuals aged ≥65 years without baseline cardiovascular diseases (n=1,391,616).
Results
During a mean 7.55 years, 52,753 MIs developed; 84,224 strokes occurred over a mean 7.47 years. After a mean 8.50 years, 233,963 died. A decrease in LDL-C was associated with lower hazards of MI and stroke. The decreased hazard of stroke in lower LDL-C was more pronounced in statin users, and individuals with diabetes or obesity. The hazard of all-cause death during follow-up showed an inverted J-shaped pattern according to the LDL-C levels. However, the paradoxically increased hazard of mortality during follow-up in lower LDL-C was attenuated in statin users and individuals with diabetes, hypertension, or obesity. In statin users, lower LDL-C was associated with a decreased hazard of mortality during follow-up.
Conclusion
Among the elderly, lower LDL-C was associated with decreased risks of MI and stroke. Lower LDL-C achieved by statins in the elderly was associated with a decreased risk of all-cause death during follow-up, suggesting that LDL-C paradox for the premature death risk in the elderly should not be applied to statin users. Intensive statin therapy should not be hesitated for older adults with cardiovascular risk factors including diabetes.

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Short Communication

Basic Research
GPR40 Agonism Modulates Inflammatory Reactions in Vascular Endothelial Cells: Joo Won Kim, Eun Roh, Kyung Mook Choi, Hye Jin Yoo, Hwan-Jin Hwang, Sei Hyun Baik; Diabetes Metab J. 2022;46(3):506-511. Published online January 24, 2022; DOI: https://doi.org/10.4093/dmj.2021.0092

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Endothelial dysfunction is strongly linked with inflammatory responses, which can impact cardiovascular disease. Recently, G protein-coupled receptor 40 (GPR40) has been investigated as a modulator of metabolic stress; however, the function of GPR40 in vascular endothelial cells has not been reported. We analyzed whether treatment of GPR40-specific agonists modulated the inflammatory responses in human umbilical vein endothelial cells (HUVECs). Treatment with LY2922470, a GPR40 agonist, significantly reduced lipopolysaccharide (LPS)-mediated nuclear factor-kappa B (NF-κB) phosphorylation and movement into the nucleus from the cytosol. However, treatment with another GPR40 agonist, TAK875, did not inhibit LPS-induced NF-κB activation. LPS treatment induced expression of adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and attachment of THP-1 cells to HUVECs, which were all decreased by LY2922470 but not TAK875. Our results showed that ligand-dependent agonism of GPR40 is a promising therapeutic target for overcoming inflammatory reactions in the endothelium.

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Karen Esmeralda Sánchez-Pluma, Edgar Martínez-Romero, José Everardo Avelino-Cruz, Giorgia Scarpellino, Valentina Brunetti, Monica Savio, Luis G. Vázquez-de-Lara Cisneros, Francesco Moccia, Roberto Berra-Romani
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Adipose Triglyceride Lipase and Gpr40 Contribute to the Anti‐Contractile Effect of Perivascular Adipose Tissue
Miranda Hyatt, Rinaldo Rodrigues Dos Passos, Fenix A. Araujo, Emily W. Wilson, Emily W. Waigi, Tiago J. Costa, Darízy F. Silva, R. Clinton Webb, Camilla F. Wenceslau, Cameron G. McCarthy
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GPR40-full agonist AM1638 alleviates palmitate-induced oxidative damage in H9c2 cells via an AMPK-dependent pathway
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G Protein-Coupled Receptor 40 Agonist LY2922470 Alleviates Ischemic-Stroke-Induced Acute Brain Injury and Functional Alterations in Mice
Yingyu Lu, Wanlu Zhou, Qinghua Cui, Chunmei Cui
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Original Article

Basic Research
DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice: Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang; Diabetes Metab J. 2022;46(2):337-348. Published online January 21, 2022; DOI: https://doi.org/10.4093/dmj.2021.0056

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Background
We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo.
Methods
DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells.
Results
Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells.
Conclusion
These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

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Review

Basic Research
Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases: Jin-Ho Koh, Yong-Woon Kim, Dae-Yun Seo, Tae-Seo Sohn; Diabetes Metab J. 2021;45(6):853-865. Published online November 22, 2021; DOI: https://doi.org/10.4093/dmj.2021.0138

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Tissues actively involved in energy metabolism are more likely to face metabolic challenges from bioenergetic substrates and are susceptible to mitochondrial dysfunction, leading to metabolic diseases. The mitochondria receive signals regarding the metabolic states in cells and transmit them to the nucleus or endoplasmic reticulum (ER) using calcium (Ca²⁺) for appropriate responses. Overflux of Ca²⁺ in the mitochondria or dysregulation of the signaling to the nucleus and ER could increase the incidence of metabolic diseases including insulin resistance and type 2 diabetes mellitus. Mitochondrial transcription factor A (Tfam) may regulate Ca²⁺ flux via changing the mitochondrial membrane potential and signals to other organelles such as the nucleus and ER. Since Tfam is involved in metabolic function in the mitochondria, here, we discuss the contribution of Tfam in coordinating mitochondria-ER activities for Ca²⁺ flux and describe the mechanisms by which Tfam affects mitochondrial Ca²⁺ flux in response to metabolic challenges.

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Original Article

Cardiovascular Risk/Epidemiology
Mean and Variability of Lipid Measurements and Risk for Development of Subclinical Left Ventricular Diastolic Dysfunction: Jiyun Park, Mira Kang, Jiyeon Ahn, Min Young Kim, Min Sun Choi, You-Bin Lee, Gyuri Kim, Kyu Yeon Hur, Jae Hyeon Kim, Jeong Hoon Yang, Sang-Man Jin; Diabetes Metab J. 2022;46(2):286-296. Published online November 22, 2021; DOI: https://doi.org/10.4093/dmj.2021.0080

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Background
Subclinical left ventricular diastolic dysfunction (LVDD) is an emerging consequence of increased insulin resistance, and dyslipidemia is one of the few correctable risk factors of LVDD. This study evaluated the role of mean and visit-to-visit variability of lipid measurements in risk of LVDD in a healthy population.
Methods
This was a 3.7-year (interquartile range, 2.1 to 4.9) longitudinal cohort study including 2,817 adults (median age 55 years) with left ventricular ejection fraction >50% who underwent an annual or biannual health screening between January 2008 and July 2016. The mean, standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB), non-HDL-C, and triglycerides were obtained from three to six measurements during the 5 years preceding the first echocardiogram.
Results
Among the 2,817 patients, 560 (19.9%) developed LVDD. The mean of no component of lipid measurements was associated with risk of LVDD. CV (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.10 to 1.67), SD (HR, 1.27; 95% CI, 1.03 to 1.57), and VIM (HR, 1.26; 95% CI, 1.03 to 1.55) of LDL-C and all the variability parameters of apoB were significantly associated with development of LVDD. The association between CV-LDL and risk of LVDD did not have significant interaction with sex, increasing/decreasing trend at baseline, or use of stain and/or lipid-modifying agents.
Conclusion
The variability of LDL-C and apoB, rather than their mean, was associated with risk for LVDD.

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Sulwon Lecture 2020

Pathophysiology
Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases: Inês Sousa-Lima, Hyun Jeong Kim, John Jones, Young-Bum Kim; Diabetes Metab J. 2021;45(5):655-674. Published online September 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0197

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Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

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Original Article

Metabolic Risk/Epidemiology
Serum Retinol-Binding Protein Levels Are Associated with Nonalcoholic Fatty Liver Disease in Chinese Patients with Type 2 Diabetes Mellitus: A Real-World Study: Zhi-Hui Zhang, Jiang-Feng Ke, Jun-Xi Lu, Yun Liu, Ai-Ping Wang, Lian-Xi Li; Diabetes Metab J. 2022;46(1):129-139. Published online August 10, 2021; DOI: https://doi.org/10.4093/dmj.2020.0222

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Background
The association of serum retinol-binding protein (RBP) levels with nonalcoholic fatty liver disease (NAFLD) remains controversial. Furthermore, few studies have investigated their relationship in type 2 diabetes mellitus (T2DM) patients. Therefore, the aim of the present study was to explore the association between serum RBP levels and NAFLD in Chinese inpatients with T2DM.
Methods
This cross-sectional, real-world study included 2,263 Chinese T2DM inpatients. NAFLD was diagnosed by abdominal ultrasonography. The subjects were divided into four groups based on RBP quartiles, and clinical characteristics were compared among the four groups. The associations of both RBP levels and quartiles with the presence of NAFLD were also analyzed.
Results
After adjustment for sex, age, and diabetes duration, there was a significant increase in the prevalence of NAFLD from the lowest to the highest RBP quartiles (30.4%, 40.0%, 42.4%, and 44.7% for the first, second, third, and fourth quartiles, respectively, P<0.001 for trend). Fully adjusted multiple logistic regression analysis revealed that both increased RBP levels (odds ratio, 1.155; 95% confidence interval, 1.012 to 1.318; P=0.033) and quartiles (P=0.014 for trend) were independently associated with the presence of NAFLD in T2DM patients.
Conclusion
Increased serum RBP levels were independently associated with the presence of NAFLD in Chinese T2DM inpatients. Serum RBP levels may be used as one of the indicators to assess the risk of NAFLD in T2DM patients.

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Yi-Lin Ma, Chun-Hua Jin, Cui-Chun Zhao, Jiang-Feng Ke, Jun-Wei Wang, Yu-Jie Wang, Jun-Xi Lu, Gao-Zhong Huang, Lian-Xi Li
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GA/HbA1c ratio is a simple and practical indicator to evaluate the risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: an observational study
Jun-Wei Wang, Chun-Hua Jin, Jiang-Feng Ke, Yi-Lin Ma, Yu-Jie Wang, Jun-Xi Lu, Mei-Fang Li, Lian-Xi Li
Diabetology & Metabolic Syndrome.2022;[Epub] CrossRef
Decreased Serum Osteocalcin is an Independent Risk Factor for Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes
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Review

Basic Research
Brown Fat as a Regulator of Systemic Metabolism beyond Thermogenesis: Okamatsu-Ogura Yuko, Masayuki Saito; Diabetes Metab J. 2021;45(6):840-852. Published online June 25, 2021; DOI: https://doi.org/10.4093/dmj.2020.0291

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Brown adipose tissue (BAT) is a specialized tissue for nonshivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. Moreover, several remarkable advancements have been made in brown fat biology over the past decade: The molecular and functional analyses of inducible thermogenic adipocytes (socalled beige adipocytes) arising from a developmentally different lineage from classical brown adipocytes have been accelerated. In addition to a well-established thermogenic activity of uncoupling protein 1 (UCP1), several alternative thermogenic mechanisms have been discovered, particularly in beige adipocytes. It has become clear that BAT influences other peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator, other than for thermogenesis. This notion is supported by discovering that various paracrine and endocrine factors are secreted from BAT. We review the current understanding of BAT pathophysiology, particularly focusing on its role as a metabolic regulator in small rodents and also in humans.

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Original Articles

Basic Research
Sulforaphane Ameliorates Diabetes-Induced Renal Fibrosis through Epigenetic Up-Regulation of BMP-7: Lili Kong, Hongyue Wang, Chenhao Li, Huiyan Cheng, Yan Cui, Li Liu, Ying Zhao; Diabetes Metab J. 2021;45(6):909-920. Published online June 4, 2021; DOI: https://doi.org/10.4093/dmj.2020.0168

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Background
The dietary agent sulforaphane (SFN) has been reported to reduce diabetes-induced renal fibrosis, as well as inhibit histone deacetylase (HDAC) activity. Bone morphologic protein 7 (BMP-7) has been shown to reduce renal fibrosis induced by transforming growth factor-beta1. The aim of this study was to investigate the epigenetic effect of SFN on BMP-7 expression in diabetes-induced renal fibrosis.
Methods
Streptozotocin (STZ)-induced diabetic mice and age-matched controls were subcutaneously injected with SFN or vehicle for 4 months to measure the in vivo effects of SFN on the kidneys. The human renal proximal tubular (HK11) cell line was used to mimic diabetic conditions in vitro. HK11 cells were transfected to over-express HDAC2 and treated with high glucose/palmitate (HG/Pal) to explore the epigenetic modulation of BMP-7 in SFN-mediated protection against HG/Pal-induced renal fibrosis.
Results
SFN significantly attenuated diabetes-induced renal fibrosis in vivo. Among all of the HDACs we detected, HDAC2 activity was markedly elevated in the STZ-induced diabetic kidneys and HG/Pal-treated HK11 cells. SFN inhibited the diabetes-induced increase in HDAC2 activity which was associated with histone acetylation and transcriptional activation of the BMP-7 promoter. HDAC2 over-expression reduced BMP-7 expression and abolished the SFN-mediated protection against HG/Pal-induced fibrosis in vitro.
Conclusion
Our study demonstrates that the HDAC inhibitor SFN protects against diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7.

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Genetics
Association of Combined TCF7L2 and KCNQ1 Gene Polymorphisms with Diabetic Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus: Rujikorn Rattanatham, Nongnuch Settasatian, Nantarat Komanasin, Upa Kukongviriyapan, Kittisak Sawanyawisuth, Phongsak Intharaphet, Vichai Senthong, Chatri Settasatian; Diabetes Metab J. 2021;45(4):578-593. Published online March 22, 2021; DOI: https://doi.org/10.4093/dmj.2020.0101

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Background
Vascular complications are the major morbid consequences of type 2 diabetes mellitus (T2DM). The transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) are common T2DM susceptibility genes in various populations. However, the associations between polymorphisms in these genes and diabetic complications are controversial. This study aimed to investigate the effects of combined gene-polymorphisms within TCF7L2, KCNQ1, and KCNJ11 on vascular complications in Thai subjects with T2DM.
Methods
We conducted a case-control study comprising 960 T2DM patients and 740 non-diabetes controls. Single nucleotide polymorphisms in TCF7L2, KCNQ1, and KCNJ11 were genotyped and evaluated for their association with diabetic vascular complications.
Results
The gene variants TCF7L2 rs290487-T, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-C were associated with increased risk of T2DM. TCF7L2 rs7903146-C, TCF7L2 rs290487-C, KCNQ1 rs2237892-T, and KCNQ1 rs2237897-T revealed an association with hypertension. The specific combination of risk-alleles that have effects on T2DM and hypertension, TCF7L2 rs7903146-C, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-T, as genetic risk score (GRS), pronounced significant association with coronary artery disease (CAD), cumulative nephropathy and CAD, and cumulative microvascular and macrovascular complications (respective odds ratios [ORs] with 95% confidence interval [95% CI], comparing between GRS 2–3 and GRS 5–6, were 7.31 [2.03 to 26.35], 3.92 [1.75 to 8.76], and 2.33 [1.13 to 4.79]).
Conclusion
This study demonstrated, for the first time, the effect conferred by specific combined genetic variants in TCF7L2 and KCNQ1 on diabetic vascular complications, predominantly with nephropathy and CAD. Such a specific pattern of gene variant combination may implicate in the progression of T2DM and life-threatening vascular complications.

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Complications
Serum Levels of Adipocyte Fatty Acid-Binding Protein Are Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Preserved Renal Function: Da Hea Seo, Moonsuk Nam, Mihye Jung, Young Ju Suh, Seong Hee Ahn, Seongbin Hong, So Hun Kim; Diabetes Metab J. 2020;44(6):875-886. Published online July 10, 2020; DOI: https://doi.org/10.4093/dmj.2019.0221

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Background

Recent studies have demonstrated that the levels of adipocyte fatty acid-binding protein (A-FABP) are closely associated with diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). This study aimed to examine the association between serum A-FABP level and rapid renal function decline in patients with T2DM and preserved renal function.

Methods

This was a prospective observational study of 452 patients with T2DM and preserved renal function who had serial measurements of estimated glomerular filtration rate (eGFR). Rapid renal function decline was defined as an eGFR decline of >4% per year. The association between baseline serum A-FABP level and rapid renal function decline was investigated.

Results

Over a median follow-up of 7 years, 82 participants (18.1%) experienced rapid renal function decline. Median A-FABP levels were significantly higher in patients with rapid renal function decline, compared to non-decliners (20.2 ng/mL vs. 17.2 ng/mL, P=0.005). A higher baseline level of A-FABP was associated with a greater risk of developing rapid renal function decline, independent of age, sex, duration of diabetes, body mass index, systolic blood pressure, history of cardiovascular disease, baseline eGFR, urine albumin creatinine ratio, total cholesterol, glycosylated hemoglobin, high-sensitivity C-reactive protein and use of thiazolidinedione, insulin, angiotensin-converting-enzyme inhibitors and angiotensin II-receptor blockers and statin (odds ratio, 3.10; 95% confidence interval, 1.53 to 6.29; P=0.002).

Conclusion

A high level of serum A-FABP is associated with an increased risk of rapid renal function decline in patients with T2DM and preserved renal function. This suggests that A-FABP could play a role in the progression of DKD in the early stages.

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Sulwon Lecture 2019

Pathophysiology
The Role of Growth Differentiation Factor 15 in Energy Metabolism: Joon Young Chang, Hyun Jung Hong, Seul Gi Kang, Jung Tae Kim, Ben Yuan Zhang, Minho Shong; Diabetes Metab J. 2020;44(3):363-371. Published online June 29, 2020; DOI: https://doi.org/10.4093/dmj.2020.0087

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Growth differentiation factor 15 (GDF15) is receiving great interest beyond its role as an aging and disease-related biomarker. Recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), suggests a central role in appetite regulation. However, there is also considerable evidence that GDF15 may have peripheral activity through an as-of-yet undiscovered mode of action. This raises the question as to whether increased GDF15 induction during pathophysiologic conditions also suppresses appetite. The present review will briefly introduce the discovery of GDF15 and describe the different contexts under which GDF15 is induced, focusing on its induction during mitochondrial dysfunction. We will further discuss the metabolic role of GDF15 under various pathophysiological conditions and conclude with possible therapeutic applications.

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Original Article

Complications
Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice: Wenya Weng, Tingwen Ge, Yi Wang, Lulu He, Tinghao Liu, Wanning Wang, Zongyu Zheng, Lechu Yu, Chi Zhang, Xuemian Lu; Diabetes Metab J. 2020;44(4):566-580. Published online May 15, 2020; DOI: https://doi.org/10.4093/dmj.2019.0089

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Background

Fibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN.

Methods

Four-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups.

Results

The results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression.

Conclusion

Therefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.

Citations

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Review

Basic Research
Role of CRTC2 in Metabolic Homeostasis: Key Regulator of Whole-Body Energy Metabolism?: Hye-Sook Han, Yongmin Kwon, Seung-Hoi Koo; Diabetes Metab J. 2020;44(4):498-508. Published online March 5, 2020; DOI: https://doi.org/10.4093/dmj.2019.0200

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Cyclic adenosine monophosphate (cAMP) signaling is critical for regulating metabolic homeostasis in mammals. In particular, transcriptional regulation by cAMP response element-binding protein (CREB) and its coactivator, CREB-regulated transcription coactivator (CRTC), is essential for controlling the expression of critical enzymes in the metabolic process, leading to more chronic changes in metabolic flux. Among the CRTC isoforms, CRTC2 is predominantly expressed in peripheral tissues and has been shown to be associated with various metabolic pathways in tissue-specific manners. While initial reports showed the physiological role of CRTC2 in regulating gluconeogenesis in the liver, recent studies have further delineated the role of this transcriptional coactivator in the regulation of glucose and lipid metabolism in various tissues, including the liver, pancreatic islets, endocrine tissues of the small intestines, and adipose tissues. In this review, we discuss recent studies that have utilized knockout mouse models to delineate the role of CRTC2 in the regulation of metabolic homeostasis.

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Original Articles

Lifesytle
Combined Aerobic and Resistance Exercise Training Reduces Circulating Apolipoprotein J Levels and Improves Insulin Resistance in Postmenopausal Diabetic Women: Yun Kyung Jeon, Sang Soo Kim, Jong Ho Kim, Hyun Jeong Kim, Hyun Jun Kim, Jang Jun Park, Yuen Suk Cho, So Hee Joung, Ji Ryang Kim, Bo Hyun Kim, Sang Heon Song, In Joo Kim, Yong Ki Kim, Young-Bum Kim; Diabetes Metab J. 2020;44(1):103-112. Published online February 21, 2020; DOI: https://doi.org/10.4093/dmj.2018.0160

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Background

Circulating apolipoprotein J (ApoJ) is closely associated with insulin resistance; however, the effect of exercise on circulating ApoJ levels and the association of ApoJ with metabolic indices remain unknown. Here, we investigated whether a combined exercise can alter the circulating ApoJ level, and whether these changes are associated with metabolic indices in patients with type 2 diabetes mellitus.

Methods

Postmenopausal women with type 2 diabetes mellitus were randomly assigned into either an exercise (EXE, n=30) or control (CON, n=15) group. Participants in the EXE group were enrolled in a 12-week program consisting of a combination of aerobic and resistance exercises. At baseline, 4, 8, and 12 weeks, body composition and metabolic parameters including homeostatic model assessment of insulin resistance (HOMA-IR) and serum ApoJ levels were assessed.

Results

In the EXE group, ApoJ levels decreased 26.3% and 19.4%, relative to baseline, at 8 and 12 weeks, respectively. Between-group differences were significant at 8 and 12 weeks (P<0.05 and P<0.001, respectively). In the EXE group, 12 weeks of exercise resulted in significant decreases in body weight, percent body fat, and HOMA-IR indices. Concurrently, weight-adjusted appendicular skeletal muscle mass (ASM/wt) was increased in the EXE group compared with the CON group. Importantly, changes in the ApoJ level were significantly correlated with changes in ASM/wt.

Conclusion

Exercise training resulted in a significant decrease in the circulating ApoJ level, with changes in ApoJ associated with an improvement in some insulin resistance indices. These data suggest that circulating ApoJ may be a useful metabolic marker for assessing the effects of exercise on insulin resistance.

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Basic Research
Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men: Laura G.M. Janssen, Andrea D. van Dam, Mark J.W. Hanssen, Sander Kooijman, Kimberly J. Nahon, Hanneke Reinders, Ingrid M. Jazet, Wouter D. van Marken Lichtenbelt, Patrick C.N. Rensen, Natasha M. Appelman-Dijkstra, Mariëtte R. Boon; Diabetes Metab J. 2020;44(2):326-335. Published online October 31, 2019; DOI: https://doi.org/10.4093/dmj.2019.0031

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Background

South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is associated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians.

Methods

Ten Dutch South Asian men with prediabetes and overweight or obesity and 10 matched Dutch white Caucasians were included. Blood samples were assayed for the Wnt inhibitor sclerostin. Subcutaneous white adipose tissue (WAT) and skeletal muscle biopsies were assayed for Wnt and insulin signaling gene expression with quantitative reverse transcription polymerase chain reaction (Clinicaltrials.gov NCT02291458).

Results

Plasma sclerostin was markedly higher in South Asians compared with white Caucasians (+65%, P<0.01). Additionally, expression of multiple Wnt signaling genes and key insulin signaling genes were lower in WAT in South Asians compared with white Caucasians. Moreover, in WAT in both ethnicities, Wnt signaling gene expression strongly positively correlated with insulin signaling gene expression. In skeletal muscle, WNT10B expression in South Asians was lower, but expression of other Wnt signaling and insulin signaling genes was comparable between ethnicities. Wnt and insulin signaling gene expression also positively correlated in skeletal muscle, albeit less pronounced.

Conclusion

South Asian men with overweight or obesity and prediabetes have higher plasma sclerostin and lower Wnt signaling gene expression in WAT compared with white Caucasians. We interpret that reduced Wnt signaling could contribute to impaired insulin signaling in South Asians.

Citations

Citations to this article as recorded by

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