Diabetes & Metabolism Journal

Review

Basic and Translational Research
Metabolic Sparks in the Liver: Metabolic and Epigenetic Reprogramming in Hepatic Stellate Cells Activation and Its Implications for Human Metabolic Diseases: Yeon Jin Roh, Hyeonki Kim, Dong Wook Choi; Diabetes Metab J. 2025;49(3):368-385. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0195

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Abstract PDF: The liver plays a fundamental role in metabolic homeostasis, integrating systemic fuel utilization with the progression of various metabolic diseases. Hepatic stellate cells (HSCs) are a key nonparenchymal cell type in the liver, which is essential for maintaining hepatic architecture in their quiescent state. However, upon chronic liver injury or metabolic stress, HSCs become activated, leading to excessive extracellular matrix deposition and pro-fibrotic signaling, ultimately positioning them as key players in liver pathology. Emerging evidence highlights the critical roles of metabolic reprogramming and epigenetic regulation in HSCs activation. HSCs activation is driven by both intrinsic fuel metabolism reprogramming and extrinsic metabolic cues from the microenvironment, while the metabolic intermediates actively reshape the epigenetic landscape, reinforcing fibrogenic transcriptional programs. In this review, we summarize recent advances in understanding how metabolic and epigenetic alterations drive HSCs activation, thereby shaping transcriptional programs that sustain fibrosis, and discuss potential therapeutic strategies to target these interconnected pathways in human metabolic diseases.

Original Articles

Others
Fibroblast Growth Factor 21 Levels Are Associated With Perception and Neural Responses to Sweetness in Type 2 Diabetes Mellitus: Piao Kang, Ying Zhang, Dian Zeng, Dan Liu, Rui Han, Yuwei Lu, Di Cheng, Qinyi Wang, Silin Liu, Liang Wu, Qian Wu, Shujie Yu, Anran Chen, Jingyi Guo, Wenli Ge, Jiacheng Ni, Jingyi Yang, Xiaomeng Wu, Lifei Ma, Weiping Jia, Qichen Fang, Yuehua Li, Huating Li; Received July 17, 2024 Accepted December 3, 2024 Published online March 26, 2025; DOI: https://doi.org/10.4093/dmj.2024.0390 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The relationship between fibroblast growth factor 21 (FGF21) and sweet taste perception and preference in type 2 diabetes mellitus (T2DM) remains unclear. This study aims to investigate this relationship and examine the neural responses of T2DM patients to high-calorie sweet (HCS) food pictures, further exploring its correlation with FGF21 levels.
Methods
We assessed sweet taste perception and preference in 40 T2DM patients and 41 controls using classical scales. Subsequently, the neural responses of 11 T2DM patients and 11 controls to HCS pictures were examined using functional magnetic resonance imaging. FGF21 levels were measured using chemiluminescent immunoassay, and the correlations with taste perception and neural responses were analyzed.
Results
Increased FGF21 levels were associated with decreased sweet perception and increased sweet taste preference in T2DM patients. Compared to control, T2DM patients exhibited greater neural activations in the orbitofrontal cortex, anterior cingulate cortex (ACC), thalamus, and hippocampus (HCS vs. non-food) as well as the putamen (HCS vs. low-calorie food). Notable differences were observed in the parahippocampal gyrus, insula, ACC, and hippocampus in T2DM patients (HCS vs. high-calorie non-sweet). Additionally, FGF21 accounted for 30.39% and 32.4% of the associations between T2DM and ACC, and parahippocampal gyrus, respectively.
Conclusion
FGF21 levels were independently associated with changes in sweet taste perception and preference in T2DM patients and were significantly associated with activation in reward-related brain regions. This study reveals the potential role of FGF21 in regulating responses to sweet foods in T2DM and provides insight to develop new therapeutic strategies for diabetes.

Complications
Global, Regional, and National Temporal Trends in Incidence for Type 2 Diabetes Mellitus Related Chronic Kidney Disease from 1992 to 2021: Yu Cao, Huiting Chen, Hui Liu, Hao Wu, Wei Gao; Received September 26, 2024 Accepted November 21, 2024 Published online March 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0593 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) is a major cause of declining renal function.
Methods
Temporal trends in T2DM-related chronic kidney disease (CKD-T2DM) incidence across 204 countries and territories from 1992 to 2021 were analyzed using data from the Global Burden of Disease 2021. The impact of macro-factors (demographic change, age, period, and birth cohort) on CKD-T2DM incidence trends was assessed using decomposition analyses and age-period- cohort modeling, highlighting opportunities to improve incidence and reduce regional disparities.
Results
In 2021, global CKD-T2DM incidence cases reached 2.01 million, a 150.92% increase since 1992, with population growth and aging contributing to 80% of this rise. The age-standardized incidence rate (ASIR) ranged from 15.09 per 100,000 in low sociodemographic index (SDI) regions to 23.07 in high SDI regions. China, India, the United States, and Japan have the most incidence cases, accounted for 69% of incidence cases globally. With 175 countries showing an increasing ASIR trend. Unfavorable trend in ASIR increase were generally found in most high-middle and middle SDI countries, such as China and Mexico (net drift=0.15% and 1.17%, per year). Age-period-cohort analyses indicated a high incidence risk near age 80, with worsening risks for recent periods and birth cohorts, except in high SDI areas.
Conclusion
The CKD-T2DM incidence burden continues to rise globally, with significant variations between countries, posing major global health implications. CKD-T2DM is largely preventable and treatable, warranting greater attention in global health policy, particularly for older populations and in low and middle SDI regions.

Basic Research
Macrophage-Specific Progranulin Deficiency Prevents Diet-Induced Obesity through the Inhibition of Hypothalamic and Adipose Tissue Inflammation: Chan Hee Lee, Chae Beom Park, Hyun-Kyong Kim, Won Hee Jang, Se Hee Min, Jae Bum Kim, Min-Seon Kim; Received August 17, 2024 Accepted October 23, 2024 Published online March 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0486 [Epub ahead of print]

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Chronic low-grade inflammation in multiple metabolic organs contributes to the development of insulin resistance induced by obesity. Progranulin (PGRN) is an evolutionarily-conserved secretory protein implicated in immune modulation. The generalized deletion of the PGRN-encoded Grn gene improves insulin resistance and glucose intolerance in obese mice fed a high-fat diet (HFD). However, it remains unclear which cells or organs are responsible for the beneficial metabolic effect of Grn depletion.
Methods
Considering the critical role of macrophages in HFD-induced obesity and inflammation, we generated mice with a macrophage-specific Grn depletion (Grn-MΦKO mice) by mating lysozyme M (LysM)-Cre and Grn-floxed mice. Body weight, food intake, energy expenditure, and glucose and insulin tolerance were compared between Grn-MΦKO mice and their wildtype (WT) controls under normal chow diet (NCD)- or HFD-fed conditions. We also examined macrophage activation and inflammation- related gene expression in the visceral adipose tissue and hypothalamus along with insulin and leptin signaling.
Results
Grn-MΦKO mice showed no alteration in metabolic phenotypes under NCD-fed conditions. However, upon HFD feeding, these mice exhibited less weight gain and improved glucose and insulin tolerance compared to WT mice. Moreover, HFD-induced macrophage activation and proinflammatory cytokine expression were significantly reduced in both the adipose tissue and hypothalamus of Grn-MΦKO mice, while HFD-induced impairments in leptin and insulin signaling showed improvement.
Conclusion
Macrophage-derived PGRN and possibly other Grn products play a critical role in the development of HFD-induced obesity, tissue inflammation, and impaired hormonal signaling in both central and peripheral metabolic organs.

Metabolic Risk/Epidemiology
An Analysis of Age-Related Body Composition Changes and Metabolic Patterns in Korean Adults Using FDG-PET/CT Health Screening Data: Chang-Myung Oh, Ji-In Bang, Sang Yoon Lee, Jae Kyung Lee, Jee Won Chai, So Won Oh; Diabetes Metab J. 2025;49(1):92-104. Published online September 2, 2024; DOI: https://doi.org/10.4093/dmj.2024.0057

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F-18-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) can be used to measure bone mineral density (BMD), cross-sectional muscle area (CSMA), Hounsfield units (HU) of liver and muscle, subcutaneous adipose tissue (SAT), abdominal visceral adipose tissue (VAT), and glucose metabolism. The present study aimed to identify age-related changes in body composition and glucose metabolism in Korean using opportunistic FDG-PET/CT imaging.
Methods
We analyzed FDG-PET/CT, clinical history, and laboratory data abstracted from the medical records of patients who underwent health screening at a single institute between 2017 and 2022.
Results
In total, 278 patients were included in the analysis (male:female=140:138). Age and body mass index were positively correlated in female, but negatively correlated in male. BMD decreased with age more in female, and CSMA decreased with age more in male. Muscle HU decreased with age for both sexes. In female, SAT and VAT increased with age; and in male, SAT decreased slightly while VAT remained stable. Muscle glucose metabolism showed no association with age in male but increased with age in female. CSMA correlated positively with BMD overall; and positively correlated with VAT and SAT in male only. In female only, both SAT and VAT showed negative correlations with glucose metabolism and correlated positively with muscle glucose metabolism. Liver HU values were inversely correlated with VAT, especially in female; and positively correlated with muscle glucose metabolism in female only.
Conclusion
FDG-PET/CT demonstrated distinct patterns of age-related changes in body composition and glucose metabolism, with significant differences between sexes.

Complications
Glycemic Control and Retinal Microvascular Changes in Type 2 Diabetes Mellitus Patients without Clinical Retinopathy: Kangmin Lee, Ga Hye Lee, Seung Eun Lee, Jee Myung Yang, Kunho Bae; Diabetes Metab J. 2024;48(5):983-992. Published online March 13, 2024; DOI: https://doi.org/10.4093/dmj.2023.0149

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Background
To investigate the association of glycemic control and retinal microvascular changes in patients with type 2 diabetes mellitus (T2DM) without diabetic retinopathy (DR).
Methods
This retrospective, observational, cohort study included patients with T2DM without DR. The patients were categorized into intensive control (IC; mean glycosylated hemoglobin [HbA1c] ≤7.0%) and moderate control (MC; mean HbA1c >7.0%) groups. Optical coherence tomography (OCT) and swept-source OCT angiography (OCTA) image parameters were compared between three groups, including healthy controls.
Results
In total, 259 eyes of 259 participants (88 IC, 81 MC, and 90 controls) were included. The foveal avascular zone area was significantly larger in the MC group than IC and control groups (all P<0.05). The IC group had lower vessel density in the superficial retinal layer and deep retinal layer than the controls (all P<0.05). The choriocapillaris (CC) flow deficit (FD) was significantly greater in the MC group than in the IC and control groups (18.2%, 16.7%, and 14.2%, respectively; all P<0.01). In multivariate regression analysis, CC-FD was associated with the mean HbA1c level (P=0.008). There were no significant differences in OCT parameters among the groups.
Conclusion
OCTA revealed that early CC impairment is associated with HbA1c levels; the CC changes precede clinically apparent DR. The OCTA parameters differed among the groups according to the degree of glycemic control. Our results suggest that microvascular changes precede DR and are closely related to glycemic control.

Citations

Citations to this article as recorded by

Flow and ischemic changes in retina and choroid across diabetic retinopathy spectrum: a SS-OCTA study
Qianhui Yang, Kelvin Y. C. Teo, Yueheng Hong, Bingyao Tan, Leopold Schmetterer, Chui Ming Gemmy Cheung, Tien Yin Wong, Gavin Tan Siew Wei
Eye.2025;[Epub] CrossRef

Lifestyle
Associations of Ultra-Processed Food Intake with Body Fat and Skeletal Muscle Mass by Sociodemographic Factors: Sukyoung Jung, Jaehee Seo, Jee Young Kim, Sohyun Park; Diabetes Metab J. 2024;48(4):780-789. Published online February 2, 2024; DOI: https://doi.org/10.4093/dmj.2023.0335

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Background
The effects of excessive ultra-processed food (UPF) consumption on body composition measures or sociodemographic disparities are understudied in Korea. We aimed to investigate the association of UPF intake with percent body fat (PBF) and percent appendicular skeletal muscle mass (PASM) by sociodemographic status in adults.
Methods
This study used data from the Korea National Health and Nutrition Examination Survey 2008–2011 (n=11,123 aged ≥40 years). We used a NOVA system to classify all foods reported in a 24-hour dietary recall, and the percentage of energy intake (%kcal) from UPFs was estimated. PBF and PASM were measured by dual-energy X-ray absorptiometry. Tertile (T) 3 of PBF indicated adiposity and T1 of PASM indicated low skeletal muscle mass, respectively. Multinomial logistic regression models were used to estimate odds ratios (OR) with 95% confidence interval (CI) after adjusting covariates.
Results
UPF intake was positively associated with PBF-defined adiposity (OR_{per 10% increase}, 1.04; 95% CI, 1.002 to 1.08) and low PASM (OR_{per 10% increase}, 1.05; 95% CI, 1.01 to 1.09). These associations were stronger in rural residents (PBF: OR_{per 10% increase}, 1.14; 95% CI, 1.06 to 1.23; PASM: OR_{per 10% increase}, 1.15; 95% CI, 1.07 to 1.23) and not college graduates (PBF: OR_{per 10% increase}, 1.06; 95% CI, 1.02 to 1.11; PASM: OR_{per 10% increase}, 1.07; 95% CI, 1.03 to 1.12) than their counterparts.
Conclusion
A higher UPF intake was associated with higher adiposity and lower skeletal muscle mass among Korean adults aged 40 years and older, particularly in those from rural areas and with lower education levels.

Citations

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Food Allergy, Nutrition, Psychology, and Health
Elena Gupta, Alexandra E. Conway, Marylee Verdi, Marion Groetch, Aikaterini Anagnostou, Elissa M. Abrams, Anna Nowak-Wegrzyn, Don Bukstein, Juliette C. Madan, Matthew Hand, Sarah L. Garnaat, Marcus S. Shaker
The Journal of Allergy and Clinical Immunology: In Practice.2025; 13(4): 773. CrossRef
Ultra-processed foods and cardio-kidney-metabolic syndrome: A review of recent evidence
Mehmet Kanbay, Lasin Ozbek, Mustafa Guldan, Sama Mahmoud Abdel-Rahman, Arif E. Narin, Alberto Ortiz
European Journal of Internal Medicine.2025;[Epub] CrossRef
The association between ultra-processed food consumption and adiposity indexes in adults living in Tehran: a dose-response analysis within a cross-sectional study
Mahsa Ranjbar, Neda Asgari Avini, Sakineh Shab-Bidar
BMC Public Health.2025;[Epub] CrossRef
Navigating Ultra-Processed Foods with Insight
Ji A Seo
Diabetes & Metabolism Journal.2024; 48(4): 713. CrossRef

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
DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis: Dong-Keon Lee, Su Ho Jo, Eun Soo Lee, Kyung Bong Ha, Na Won Park, Deok-Hoon Kong, Sang-In Park, Joon Seok Park, Choon Hee Chung; Diabetes Metab J. 2024;48(1):97-111. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0367

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Background
Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.
Methods
Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.
Results
DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.
Conclusion
Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

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EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis
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Basic Research
Glucagon-Like Peptide Receptor Agonist Inhibits Angiotensin II-Induced Proliferation and Migration in Vascular Smooth Muscle Cells and Ameliorates Phosphate-Induced Vascular Smooth Muscle Cells Calcification: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2024;48(1):83-96. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0363

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Background
Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system.
Methods
To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide.
Results
Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs.
Conclusion
These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.

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Hui-Yu Bai, Xiao-Rui Lv, Hai-Bo Gu, Hui Li, Bao-Shuai Shan
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Basic Research
Alantolactone Attenuates Renal Fibrosis via Inhibition of Transforming Growth Factor β/Smad3 Signaling Pathway: Kyeong-Min Lee, Yeo Jin Hwang, Gwon-Soo Jung; Diabetes Metab J. 2024;48(1):72-82. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0231

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Background
Renal fibrosis is characterized by the accumulation of extracellular matrix proteins and interstitial fibrosis. Alantolactone is known to exert anticancer, anti-inflammatory, antimicrobial and antifungal effects; however, its effects on renal fibrosis remains unknown. Here, we investigated whether alantolactone attenuates renal fibrosis in mice unilateral ureteral obstruction (UUO) and evaluated the effect of alantolactone on transforming growth factor (TGF) signaling pathway in renal cells.
Methods
To evaluate the therapeutic effect of alantolactone, cell counting kit-8 (CCK-8) assay, histological staining, Western blot analysis, and real-time quantitative polymerase chain reaction were performed in UUO kidneys in vivo and in TGF-β-treated renal cells in vitro.
Results
Alantolactone (0.25 to 4 µM) did not affect the viability of renal cells. Mice orally administered 5 mg/kg of alantolactone daily for 15 days did not show mortality or liver toxicity. Alantolactone decreased UUO-induced blood urea nitrogen and serum creatinine levels. In addition, it significantly alleviated renal tubulointerstitial damage and fibrosis and decreased collagen type I, fibronectin, and α-smooth muscle actin (α-SMA) expression in UUO kidneys. In NRK-49F cells, alantolactone inhibited TGF-βstimulated expression of fibronectin, collagen type I, plasminogen activator inhibitor-1 (PAI-1), and α-SMA. In HK-2 cells, alantolactone inhibited TGF-β-stimulated expression of collagen type I and PAI-1. Alantolactone inhibited UUO-induced phosphorylation of Smad3 in UUO kidneys. In addition, it not only decreased TGF-β secretion but also Smad3 phosphorylation and translocation to nucleus in both kidney cell lines.
Conclusion
Alantolactone improves renal fibrosis by inhibiting the TGF-β/Smad3 signaling pathway in obstructive nephropathy. Thus, alantolactone is a potential therapeutic agent for chronic kidney disease.

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Chun Liu, Xiaoqin Liu, Junguo Duan
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Fernando T. Ogata, Sudhir Verma, Vivien J. Coulson-Thomas, Tarsis F. Gesteira
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Alantolactone alleviates epithelial-mesenchymal transition by regulating the TGF-β/STAT3 signaling pathway in renal fibrosis
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Review

Cardiovascular Risk/Epidemiology
The Role of Echocardiography in Evaluating Cardiovascular Diseases in Patients with Diabetes Mellitus: Sun Hwa Lee, Jae-Hyeong Park; Diabetes Metab J. 2023;47(4):470-483. Published online July 27, 2023; DOI: https://doi.org/10.4093/dmj.2023.0036

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Patients with diabetes mellitus are highly susceptible to cardiovascular complications, which are directly correlated with cardiovascular morbidity and mortality. In addition to coronary artery disease, there is growing awareness of the risk and prevalence of heart failure (HF) in patients with diabetes. Echocardiography is an essential diagnostic modality commonly performed in patients with symptoms suggestive of cardiovascular diseases (CVD), such as dyspnea or chest pain, to establish or rule out the cause of symptoms. Conventional echocardiographic parameters, such as left ventricular ejection fraction, are helpful not only for diagnosing CVD but also for determining severity, treatment strategy, prognosis, and response to treatment. Echocardiographic myocardial strain, a novel echocardiographic technique, enables the detection of early changes in ventricular dysfunction before HF symptoms develop. This article aims to review the role of echocardiography in evaluating CVD in patients with diabetes mellitus and how to use it in patients with suspected cardiac diseases.

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Original Article

Basic Research
Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis: Kyung Bong Ha, Eun Soo Lee, Na Won Park, Su Ho Jo, Soyeon Shim, Dae-Kee Kim, Chan Mug Ahn, Choon Hee Chung; Diabetes Metab J. 2023;47(4):500-513. Published online April 25, 2023; DOI: https://doi.org/10.4093/dmj.2022.0110

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Background
Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor β (TGF-β) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial.
Methods
Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-β (2 ng/mL). The cells were then treated with Cur5-8 (1 μM), EW-7197 (0.5 μM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks.
Results
TGF-β-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score.
Conclusion
Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.

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Reviews

Others
Current Trends of Big Data Research Using the Korean National Health Information Database: Mee Kyoung Kim, Kyungdo Han, Seung-Hwan Lee; Diabetes Metab J. 2022;46(4):552-563. Published online July 27, 2022; DOI: https://doi.org/10.4093/dmj.2022.0193

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Recently, medical research using big data has become very popular, and its value has become increasingly recognized. The Korean National Health Information Database (NHID) is representative of big data that combines information obtained from the National Health Insurance Service collected for claims and reimbursement of health care services and results obtained from general health examinations provided to all Korean adults. This database has several strengths and limitations. Given the large size, various laboratory data, and questionnaires obtained from medical check-ups, their longitudinal nature, and long-term accumulation of data since 2002, carefully designed studies may provide valuable information that is difficult to obtain from other forms of research. However, consideration of possible bias and careful interpretation when defining causal relationships is also important because the data were not collected for research purposes. After the NHID became publicly available, research and publications based on this database have increased explosively, especially in the field of diabetes and metabolism. This article reviews the history, structure, and characteristics of the Korean NHID. Recent trends in big data research using this database, commonly used operational diagnosis, and representative studies have been introduced. We expect further progress and expansion of big data research using the Korean NHID.

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

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

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