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Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance
Yajie Fan, Zhipeng Yan, Tingting Li, Aolin Li, Xinbiao Fan, Zhongwen Qi, Junping Zhang
Diabetes Metab J. 2024;48(1):19-36.   Published online January 3, 2024
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AbstractAbstract PDFPubReader   ePub   
Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.
Original Article
Basic Research
Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition
Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong
Diabetes Metab J. 2023;47(6):784-795.   Published online August 23, 2023
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  • 149 Download
  • 2 Crossref
AbstractAbstract PDFPubReader   ePub   
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors.
Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice.
Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus.
This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.


Citations to this article as recorded by  
  • Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
    Jae Hyun Bae
    Diabetes & Metabolism Journal.2024; 48(1): 157.     CrossRef
  • Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition (Diabetes Metab J 2023;47:784-95)
    Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong
    Diabetes & Metabolism Journal.2024; 48(1): 159.     CrossRef
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
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  • 504 Download
  • 14 Crossref
Graphical AbstractGraphical Abstract AbstractAbstract PDFPubReader   ePub   
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.


Citations to this article as recorded by  
  • Brown adipose tissue evaluation using water and triglyceride as indices by diffuse reflectance spectroscopy
    Tomomi Iida, Yukio Ueda, Hideo Tsukada, Dai Fukumoto, Takafumi Hamaoka
    Journal of Biophotonics.2024;[Epub]     CrossRef
  • White-brown adipose tissue interplay in polycystic ovary syndrome: Therapeutic avenues
    Khadijeh Abbasi, Reza Zarezadeh, Amir Valizadeh, Amir Mehdizadeh, Hamed Hamishehkar, Mohammad Nouri, Masoud Darabi
    Biochemical Pharmacology.2024; 220: 116012.     CrossRef
  • Brown Adipose Tissue, Batokines, and Bioactive Compounds in Foods: An Update
    Fabiane Ferreira Martins, Bruna Cadete Martins, Ananda Vitoria Silva Teixeira, Matheus Ajackson, Vanessa Souza‐Mello, Julio Beltrame Daleprane
    Molecular Nutrition & Food Research.2024;[Epub]     CrossRef
  • Thermogenic Brown Fat in Humans: Implications in Energy Homeostasis, Obesity and Metabolic Disorders
    Masayuki Saito, Yuko Okamatsu-Ogura
    The World Journal of Men's Health.2023; 41(3): 489.     CrossRef
  • Interplay of skeletal muscle and adipose tissue: sarcopenic obesity
    Min Jeong Park, Kyung Mook Choi
    Metabolism.2023; 144: 155577.     CrossRef
  • White adipose tissue undergoes browning during preweaning period in association with microbiota formation in mice
    Anju Tsukada, Yuko Okamatsu-Ogura, Emi Futagawa, Yuki Habu, Natsumi Takahashi, Mira Kato-Suzuki, Yuko Kato, Satoshi Ishizuka, Kei Sonoyama, Kazuhiro Kimura
    iScience.2023; 26(7): 107239.     CrossRef
  • In situ fluorescence-photoacoustic measurement of the changes of brown adipose tissue in mice under hindlimb unloading
    Baojie Gong, Jianxin Tang, Xiaoxiao Jiang, Zhe Zhang, Shiying Li, Hongjun Jin, Liming Nie, Guojia Huang
    Journal of Applied Physiology.2023; 135(2): 251.     CrossRef
  • Age-Related Expression Dynamics of Uncoupling Protein 1 in Adipose Tissues of ICR Outbred Mice during Postnatal Ontogenesis
    A. V. Yakunenkov, E. I. Elsukova, I. O. Natochy
    Journal of Evolutionary Biochemistry and Physiology.2023; 59(4): 1020.     CrossRef
  • Antibodies Regulate Dual-Function Enzyme IYD to Induce Functional Synergy between Metabolism and Thermogenesis
    Sunghyun Kang, Hwan-Woo Park, Kyung Ho Han
    International Journal of Molecular Sciences.2022; 23(14): 7834.     CrossRef
  • Machine learning-featured Secretogranin V is a circulating diagnostic biomarker for pancreatic adenocarcinomas associated with adipopenia
    Yunju Jo, Min-Kyung Yeo, Tam Dao, Jeongho Kwon, Hyon‐Seung Yi, Dongryeol Ryu
    Frontiers in Oncology.2022;[Epub]     CrossRef
  • Possible roles of exercise and apelin against pregnancy complications
    Hamed Alizadeh Pahlavani
    Frontiers in Endocrinology.2022;[Epub]     CrossRef
  • Relationships between the expression of adipose genes and profiles of hospitalized dogs
    Yukina Sugiyama, Fumie Shimokawa, Kazutoshi Sugiyama, Takashi Kobayashi, Yusuke Yamashita, Kei Kazama, Ken Onda, Masayuki Funaba, Masaru Murakami
    Veterinary Research Communications.2022; 46(4): 1239.     CrossRef
  • Garlic (Allium sativum L.) in diabetes and its complications: Recent advances in mechanisms of action
    Yayi Jiang, Rensong Yue, Guojie Liu, Jun Liu, Bo Peng, Maoyi Yang, Lianxue Zhao, Zihan Li
    Critical Reviews in Food Science and Nutrition.2022; : 1.     CrossRef
  • Fruit of Gardenia jasminoides Induces Mitochondrial Activation and Non-Shivering Thermogenesis through Regulation of PPARγ
    Woo Yong Park, Gahee Song, Ja Yeon Park, Kwan-Il Kim, Kwang Seok Ahn, Hyun Jeong Kwak, Jungtae Leem, Jae-Young Um, Jinbong Park
    Antioxidants.2021; 10(9): 1418.     CrossRef
Basic Research
Revisiting the Bacterial Phylum Composition in Metabolic Diseases Focused on Host Energy Metabolism
Yeonmi Lee, Hui-Young Lee
Diabetes Metab J. 2020;44(5):658-667.   Published online July 9, 2020
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  • 130 Download
  • 19 Web of Science
  • 19 Crossref
AbstractAbstract PDFPubReader   ePub   

Over a hundred billion bacteria are found in human intestines. This has emerged as an environmental factor in metabolic diseases, such as obesity and related diseases. The majority of these bacteria belong to two dominant phyla, Bacteroidetes and Firmicutes. Since the ratio of Firmicutes to Bacteroidetes increases in people with obesity and in various animal models, it has been assumed that phylum composition causes the increase in occurrence of metabolic diseases over the past decade. However, this assumption has been challenged by recent studies that have found even an opposite association of phylum composition within metabolic diseases. Moreover, the gut microbiota affects host energy metabolism in various ways including production of metabolites and interaction with host intestinal cells to regulate signaling pathways that affect energy metabolism. However, the direct effect of gut bacteria on host energy intake, such as energy consumption by the bacteria itself and its effects on intestinal energy absorption, has been underestimated. This review aims to discuss whether increased ratio of Firmicutes to Bacteroidetes is associated with the development of metabolic diseases, and whether energy competition between the bacteria and host is a missing part of the mechanism linking gut microbiota to metabolic diseases.


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    Peng Ding, Yushi Yu, Zihe Zhao, Xiang Li, Xiajing Wang, Huiyan Wang, Xiyuan Huang, Jun Ding, Chong Zhao
    Marine Environmental Research.2024; 193: 106300.     CrossRef
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  • Identification of oncogenic signatures in the inflammatory colon of C57BL/6 mice fed a high-fat diet
    Huawei Zeng, Bryan D. Safratowich, Wen-Hsing Cheng, Michael R. Bukowski
    The Journal of Nutritional Biochemistry.2023; 111: 109188.     CrossRef
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    Xinyi Zhu, Henghui Li, Liuzhu Zhou, Huijun Jiang, Minghui Ji, Jin Chen
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  • Microplastic-induced gut microbiota and serum metabolic disruption in Sprague-Dawley rats
    Nan Zhao, Meirong Zhao, Hangbiao Jin
    Environmental Pollution.2023; 320: 121071.     CrossRef
  • Effects of neutral polysaccharide from Platycodon grandiflorum on high-fat diet-induced obesity via the regulation of gut microbiota and metabolites
    Jing Song, Qin liu, Mengqi Hao, Xiaohu Zhai, Juan Chen
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
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    Yan Zhang, Rui Chen, DuoDuo Zhang, Shuang Qi, Yan Liu
    Biomedicine & Pharmacotherapy.2023; 160: 114295.     CrossRef
  • Connecting Gut Microbial Diversity with Plasma Metabolome and Fecal Bile Acid Changes Induced by the Antibiotics Tobramycin and Colistin Sulfate
    Aishwarya Murali, Varun Giri, Franziska Maria Zickgraf, Philipp Ternes, Hunter James Cameron, Saskia Sperber, Volker Haake, Peter Driemert, Hennicke Kamp, Dorothee Funk-Weyer, Shana J. Sturla, Ivonne M.C.M. Rietjens, Bennard van Ravenzwaay
    Chemical Research in Toxicology.2023; 36(4): 598.     CrossRef
  • Short-Term Alternate Feeding between Terrestrially Sourced Oil- and Fish Oil-Based Diets Modulates the Intestinal Microecology of Juvenile Turbot
    Xiuhua Ma, Yaoyao Kong, Houguo Xu, Qingzhu Bi, Mengqing Liang, Kangsen Mai, Yanjiao Zhang
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  • Effects and action mechanisms of lotus leaf (Nelumbo nucifera) ethanol extract on gut microbes and obesity in high-fat diet-fed rats
    Zhang Yanan, Ma Lu, Zhang Lu, Huo Jinhai, Wang Weiming
    Frontiers in Nutrition.2023;[Epub]     CrossRef
  • Effects of coffee with different roasting degrees on obesity and related metabolic disorders
    Claudia I. Gamboa-Gómez, Laura J. Barragán-Zúñiga, Fernando Guerrero-Romero, Gerardo Martínez-Aguilar, José Luis Gónzalez, Almendra A. Valenzuela-Ramírez, Juan A. Rojas-Contreras, Monica Anese, Maribel Cervantes Flores, Marilisa Alongi
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  • Gut Microbiota and Bacterial Translocation in the Pathogenesis of Liver Fibrosis
    Roman Maslennikov, Elena Poluektova, Oxana Zolnikova, Alla Sedova, Anastasia Kurbatova, Yulia Shulpekova, Natyia Dzhakhaya, Svetlana Kardasheva, Maria Nadinskaia, Elena Bueverova, Vladimir Nechaev, Anna Karchevskaya, Vladimir Ivashkin
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  • Eugenol, A Major Component of Clove Oil, Attenuates Adiposity, and Modulates Gut Microbiota in High‐Fat Diet‐Fed Mice
    Mengjie Li, Yuhan Zhao, Yanan Wang, Ruixuan Geng, Jingjing Fang, Seong‐Gook Kang, Kunlun Huang, Tao Tong
    Molecular Nutrition & Food Research.2022;[Epub]     CrossRef
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    Yu Wang, Ting Li, Yueyue Liu, Chengcheng Yang, Lei Liu, Xiangnan Zhang, Xingbin Yang
    Food & Function.2022; 13(24): 13014.     CrossRef
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    Fernanda Pace, Paula I. Watnick
    Trends in Microbiology.2021; 29(9): 849.     CrossRef
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    Amlan Kumar Patra, Indrajit Kar
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    Hye Rim Jang, Hui-Young Lee
    World Journal of Diabetes.2021; 12(6): 730.     CrossRef
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Original Article
Basic Research
Effects of Microbiota on the Treatment of Obesity with the Natural Product Celastrol in Rats
Weiyue Hu, Lingling Wang, Guizhen Du, Quanquan Guan, Tianyu Dong, Ling Song, Yankai Xia, Xinru Wang
Diabetes Metab J. 2020;44(5):747-763.   Published online May 11, 2020
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  • 136 Download
  • 16 Web of Science
  • 17 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   

Obesity has become one of the most serious issues threatening the health of humankind, and we conducted this study to examine whether and how celastrol protects against obesity.


We fed male Sprague-Dawley rats a high-fat diet and administered celastrol to obese rats for 3 weeks. By recording body weight (BW) and other measures, we identified the effective dose of celastrol for obesity treatment. Feces were collected to perform 16S rRNA sequencing, and hypothalami were extracted for transcriptome sequencing. We then treated leptin knockout rats with celastrol and explored the changes in energy metabolism. Male Institute of Cancer Research (ICR) mice were used to test the acute toxicity of celastrol.


We observed that celastrol reduced BW and promoted energy expenditure at a dose of 500 µg/kg BW but that food intake was not changed after administration. The diversity of the gut microbiota was improved, with an increased ratio of Bacteroidetes to Firmicutes, and the gut microbiota played an important role in the anti-obesity effects of celastrol. Hypothalamic transcriptome analysis showed a significant enrichment of the leptin signaling pathway, and we found that celastrol significantly enhanced energy expenditure, which was mediated by the leptin signaling pathway. Acute lethal toxicity of celastrol was not observed at doses ranging from 0 to 62.5 mg/kg BW.


Our study revealed that celastrol decreased the BW of obese rats by enhancing energy expenditure but not by suppressing food intake and that this effect was mediated by the improvement of the gut microbiota and the activation of the hypothalamic leptin signaling pathway.


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    Jia Gu, Ya-Ning Shi, Neng Zhu, Hong-Fang Li, Chan-Juan Zhang, Li Qin
    Biomedicine & Pharmacotherapy.2023; 164: 114981.     CrossRef
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    Jianghui HU, Jimin NI, Junping ZHENG, Yanlei GUO, Yong YANG, Cheng YE, Xiongjie SUN, Hui XIA, Yanju LIU, Hongtao LIU
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  • Celastrol: An Update on Its Hepatoprotective Properties and the Linked Molecular Mechanisms
    Mengzhen Li, Faren Xie, Lu Wang, Guoxue Zhu, Lian-Wen Qi, Shujun Jiang
    Frontiers in Pharmacology.2022;[Epub]     CrossRef
  • Celastrol inhibits the proliferation and migration of MCF-7 cells through the leptin-triggered PI3K/AKT pathway
    Pingping Chen, Bin Wang, Meng Li, Chunxue Cui, Fei Liu, Yonggang Gao
    Computational and Structural Biotechnology Journal.2022; 20: 3173.     CrossRef
  • Investigating Celastrol’s Anti-DCM Targets and Mechanisms via Network Pharmacology and Experimental Validation
    Rui Xi, Yongxin Wan, Lihong Yang, Jingying Zhang, Liu Yang, Shuai Yang, Rui Chai, Fengchen Mu, Qiting Sun, Rui Yan, Zhifang Wu, Sijin Li, Zhijun Liao
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  • Celastrol inhibits TXNIP expression to protect pancreatic β cells in diabetic mice
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  • Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion
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  • In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates
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  • Celastrol alleviates metabolic disturbance in high‐fat diet‐induced obese mice through increasing energy expenditure by ameliorating metabolic inflammation
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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
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  • 162 Download
  • 14 Web of Science
  • 16 Crossref
AbstractAbstract PDFPubReader   ePub   

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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Obesity and Metabolic Syndrome
Two Faces of White Adipose Tissue with Heterogeneous Adipogenic Progenitors
Injae Hwang, Jae Bum Kim
Diabetes Metab J. 2019;43(6):752-762.   Published online December 26, 2019
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AbstractAbstract PDFPubReader   

Chronic energy surplus increases body fat, leading to obesity. Since obesity is closely associated with most metabolic complications, pathophysiological roles of adipose tissue in obesity have been intensively studied. White adipose tissue is largely divided into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). These two white adipose tissues are similar in their appearance and lipid storage functions. Nonetheless, emerging evidence has suggested that SAT and VAT have different characteristics and functional roles in metabolic regulation. It is likely that there are intrinsic differences between VAT and SAT. In diet-induced obese animal models, it has been reported that adipogenic progenitors in VAT rapidly proliferate and differentiate into adipocytes. In obesity, VAT exhibits elevated inflammatory responses, which are less prevalent in SAT. On the other hand, SAT has metabolically beneficial effects. In this review, we introduce recent studies that focus on cellular and molecular components modulating adipogenesis and immune responses in SAT and VAT. Given that these two fat depots show different functions and characteristics depending on the nutritional status, it is feasible to postulate that SAT and VAT have different developmental origins with distinct adipogenic progenitors, which would be a key determining factor for the response and accommodation to metabolic input for energy homeostasis.


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AbstractAbstract PDF
Metabolic syndrome and diabetes are associated with increased risk of cardiac dysfunction independently of underlying coronary artery disease. The underlying pathogenesis is partially understood but accumulating evidence suggests that alterations of cardiac energy metabolism might contribute to the development of contractile dysfunction. Recent findings suggest that myocardial mitochondrial dysfunction may play an important role in the pathogenesis of cardiac contractile dysfunction in type 2 diabetes. This review is focused on evaluating mechanisms for the mitochondrial abnormalities that may be involved in the development and progression of cardiac dysfunction in diabetes.

Diabetes Metab J : Diabetes & Metabolism Journal