Diabetes & Metabolism Journal

Original Articles

Basic Research
Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes: Junfei Gu, Jiajia Jin, Xiaoyu Ren, Xinjie Zhang, Jiaxuan Li, Xiaowei Wang, Shucui Zhang, Xianlun Yin, Qunye Zhang, Zhe Wang; Received August 16, 2023 Accepted February 7, 2024 Published online May 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0278 [Epub ahead of print]

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

Type 1 Diabetes
A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms: Sophie Welsch, Antoine Harvengt, Paola Gallo, Manon Martin, Dominique Beckers, Thierry Mouraux, Nicole Seret, Marie-Christine Lebrethon, Raphaël Helaers, Pascal Brouillard, Miikka Vikkula, Philippe A. Lysy; Received May 26, 2023 Accepted November 25, 2023 Published online March 22, 2024; DOI: https://doi.org/10.4093/dmj.2023.0166 [Epub ahead of print]

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Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort.
Methods
We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion.
Results
The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies.
Conclusion
We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

Review

Metabolic Risk/Epidemiology
One-Carbon Metabolism Nutrients, Genetic Variation, and Diabetes Mellitus: Jie Zhu, Gunjana Saikia, Xiaotao Zhang, Xiaoxi Shen, Ka Kahe; Diabetes Metab J. 2024;48(2):170-183. Published online March 12, 2024; DOI: https://doi.org/10.4093/dmj.2023.0272

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Diabetes mellitus (DM) affects about 9.3% of the population globally. Hyperhomocysteinemia (HHcy) has been implicated in the pathogenesis of DM, owing to its promotion of oxidative stress, β-cell dysfunction, and insulin resistance. HHcy can result from low status of one-carbon metabolism (OCM) nutrients (e.g., folate, choline, betaine, vitamin B6, B12), which work together to degrade homocysteine by methylation. The etiology of HHcy may also involve genetic variation encoding key enzymes in OCM. This review aimed to provide an overview of the existing literature assessing the link between OCM nutrients status, related genetic factors, and incident DM. We also discussed possible mechanisms underlying the role of OCM in DM development and provided recommendations for future research and practice. Even though the available evidence remains inconsistent, some studies support the potential beneficial effects of intakes or blood levels of OCM nutrients on DM development. Moreover, certain variants in OCM-related genes may influence metabolic handling of methyl-donors and presumably incidental DM. Future studies are warranted to establish the causal inference between OCM and DM and examine the interaction of OCM nutrients and genetic factors with DM development, which will inform the personalized recommendations for OCM nutrients intakes on DM prevention.

Citations

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Alterations in Choline Metabolism in Non-Obese Individuals with Insulin Resistance and Type 2 Diabetes Mellitus
Haya Al-Sulaiti, Najeha Anwardeen, Sara S. Bashraheel, Khaled Naja, Mohamed A. Elrayess
Metabolites.2024; 14(8): 457. CrossRef
Association between oxidative balance score and diabetic kidney disease, low estimated glomerular filtration rate and albuminuria in type 2 diabetes mellitus patients: a cross-sectional study
Cong Liu, Jiju Yang, Hongdian Li, Yuanyuan Deng, Pengfei He, Jiao Zhang, Mianzhi Zhang
Frontiers in Endocrinology.2024;[Epub] CrossRef

Original Article

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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Abstract PDF Supplementary Material PubReader ePub: 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.

Brief Report

Genetics
Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea: Eun Hoo Rho, Sang Ik Baek, Heerah Lee, Moon-Woo Seong, Jong-Hee Chae, Kyong Soo Park, Soo Heon Kwak; Diabetes Metab J. 2024;48(3):482-486. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0078

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Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial disorder primarily resulting from m.3243A>G mutation. The clinical characteristics of MIDD exhibit significant heterogeneity. Our study aims to delineate these characteristics and determine the potential correlation with m.3243A>G heteroplasmy levels. This retrospective, descriptive study encompassed patients with confirmed m.3243A>G mutation and diabetes mellitus at Seoul National University Hospital. Our cohort comprises 40 patients with MIDD, with a mean age at study enrollment of 33.3±12.9 years and an average % of heteroplasmy of 30.0%± 14.6% in the peripheral blood. The most prevalent comorbidity was hearing loss (90%), followed by albuminuria (61%), seizure (38%), and stroke (33%). We observed a significant negative correlation between % of heteroplasmy and age at diabetes diagnosis. These clinical features can aid in the suspicion of MIDD and further consideration of genetic testing for m.3243A>G mutation.

Citations

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Clinical Characteristics of Diabetes in People with Mitochondrial DNA 3243A>G Mutation in Korea (Diabetes Metab J 2024;48:482-6)
Eun Hoo Rho, Soo Heon Kwak
Diabetes & Metabolism Journal.2024; 48(4): 818. CrossRef
MIDD Patients Should Not Be Confused with MELAS Patients, Even Though Both Carry the m.3243A>G Variant
Josef Finsterer, Sounira Mehri
Diabetes & Metabolism Journal.2024; 48(4): 816. CrossRef

Original Article

Basic Research
Effects Of Exercise Training And Chlorogenic Acid Supplementation On Hepatic Lipid Metabolism In Prediabetes Mice: Samaneh Shirkhani, Sayyed Mohammad Marandi, Mohammad Hossein Nasr-Esfahani, Seung Kyum Kim; Diabetes Metab J. 2023;47(6):771-783. Published online September 8, 2023; DOI: https://doi.org/10.4093/dmj.2022.0265

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Background
Since prediabetes is a risk factor for metabolic syndromes, it is important to promote a healthy lifestyle to prevent prediabetes. This study aimed to determine the effects of green coffee (GC), chlorogenic acid (CGA) intake, and exercise training (EX) on hepatic lipid metabolism in prediabetes male C57BL/6 mice.
Methods
Forty-nine mice were randomly divided into two groups feeding with a normal diet (n=7) or a high-fat diet (HFD, n=42) for 12 weeks. Then, HFD mice were further divided into six groups (n=7/group): control (pre-D), GC, CGA, EX, GC+EX, and CGA+EX. After additional 10 weeks under the same diet, plasma, and liver samples were obtained.
Results
HFD-induced prediabetes conditions with increases in body weight, glucose, insulin, insulin resistance, and lipid profiles were alleviated in all treatment groups. Acsl3, a candidate gene identified through an in silico approach, was lowered in the pre-D group, while treatments partly restored it. HFD induced adverse alterations of de novo lipogenesis- and β oxidation-associated molecules in the liver. However, GC and CGA supplementation and EX reversed or ameliorated these changes. In most cases, GC or CGA supplementation combined with EX has no synergistic effect and the GC group had similar results to the CGA group.
Conclusion
These findings suggest that regular exercise is an effective non-therapeutic approach for prediabetes, and CGA supplementation could be an alternative to partially mimic the beneficial effects of exercise on prediabetes.

Citations

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TFEB activator tanshinone IIA and derivatives derived from Salvia miltiorrhiza Bge. Attenuate hepatic steatosis and insulin resistance
Lulu Zheng, Beiyan Li, Anlei Yuan, Shijie Bi, Harrison Puscher, Chaoqun Liu, Liansheng Qiao, Yanjiang Qiao, Shifeng Wang, Yanling Zhang
Journal of Ethnopharmacology.2024; 335: 118662. CrossRef
Research progress on the pharmacological activity and mechanism of chlorogenic acid in alleviating acute kidney injury in sepsis patients

Perioperative Precision Medicine.2023;[Epub] CrossRef

Reviews

Basic Research
Adipose Tissue and Metabolic Health: Sung-Min An, Seung-Hee Cho, John C. Yoon; Diabetes Metab J. 2023;47(5):595-611. Published online July 24, 2023; DOI: https://doi.org/10.4093/dmj.2023.0011

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In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health and highlight some recent developments in understanding and exploiting adipocyte biology. Adipose tissue plays critical roles in the regulation of systemic glucose and lipid metabolism and secretes bioactive molecules possessing endocrine, paracrine, and autocrine functions. Dysfunctional adipose tissue has a detrimental impact on metabolic health and is intimately involved in key aspects of metabolic diseases such as insulin resistance, lipid overload, inflammation, and organelle stress. Differences in the distribution of fat depots and adipose characteristics relate to divergent degrees of metabolic dysfunction found in metabolically healthy and unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning as a metabolic sink and participating in crosstalk with other metabolic organs. Manipulation of adipose tissue provides a wealth of opportunities to intervene and combat the progression of associated metabolic diseases. We discuss current treatment modalities for obesity including incretin hormone analogs and touch upon emerging strategies with therapeutic potential including exosome-based therapy, pharmacological activation of brown and beige adipocyte thermogenesis, and administration or inhibition of adipocyte-derived factors.

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Pharmacological targets at the lysosomal autophagy–NLRP3 inflammasome crossroads
Srinivasa Reddy Bonam, Dylan Mastrippolito, Philippe Georgel, Sylviane Muller
Trends in Pharmacological Sciences.2024; 45(1): 81. CrossRef
Senescent adipocytes and type 2 diabetes – current knowledge and perspective concepts
Weronika Kruczkowska, Julia Gałęziewska, Mateusz Kciuk, Adrianna Gielecińska, Elżbieta Płuciennik, Zbigniew Pasieka, Lin-Yong Zhao, Yi-Jin Yu, Damian Kołat, Żaneta Kałuzińska-Kołat
Biomolecular Concepts.2024;[Epub] CrossRef
Visceral Adipose Tissue: The Hidden Culprit for Type 2 Diabetes
Sneha Dhokte, Krzysztof Czaja
Nutrients.2024; 16(7): 1015. CrossRef
Beyond the Cold: Activating Brown Adipose Tissue as an Approach to Combat Obesity
Cristina Elena Negroiu, Iulia Tudorașcu, Cristina Maria Bezna, Sanziana Godeanu, Marina Diaconu, Raluca Danoiu, Suzana Danoiu
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Lena Hong, Peter Zahradka, Carla G. Taylor
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Ivona Mitu, Roxana Popescu, Cristina-Daniela Dimitriu, Radu-Ștefan Miftode, Irina-Iuliana Costache, Ovidiu Mitu
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White-to-Beige and Back: Adipocyte Conversion and Transcriptional Reprogramming
Stanislav Boychenko, Vera S. Egorova, Andrew Brovin, Alexander D. Egorov
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Obesity and Obesity-Related Disorders—Editorial
Grażyna Nowicka
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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 & Metabolism Journal.2024; 48(4): 487. CrossRef
Butyric acid reduced lipid deposition in immortalized chicken preadipocyte by inhibiting cell proliferation and differentiation
Xiaoying Liu, Kailong Qin, Chaohui Wang, Xi Sun, Yun Li, Yanli Liu, Xiaojun Yang
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Bin Zhang, Wei Zhao, Dong Song, Xiaomei Lyu
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Cholesterol Efflux Decreases TLR4-Target Gene Expression in Cultured Macrophages Exposed to T. brucei Ghosts
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Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities
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Stem Cell Research & Therapy.2024;[Epub] CrossRef
Assessment of energy balance in nutritional counseling – fact or myth?
Mirosław Kiedrowski
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Basic Research
Heterogeneity of Islet Cells during Embryogenesis and Differentiation: Shugo Sasaki, Takeshi Miyatsuka; Diabetes Metab J. 2023;47(2):173-184. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0324

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

Citations

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Newly discovered knowledge pertaining to glucagon and its clinical applications
Dan Kawamori, Shugo Sasaki
Journal of Diabetes Investigation.2023; 14(7): 829. CrossRef

Complications
Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions: Md Jakir Hossain, Michael D. Kendig, Meg E. Letton, Margaret J. Morris, Ria Arnold; Diabetes Metab J. 2022;46(2):198-221. Published online March 24, 2022; DOI: https://doi.org/10.4093/dmj.2021.0347

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Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the ‘Neurodiab’ criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.

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SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a‐PINK1‐Parkin signaling pathway to activate mitophagy
Jing Yang, Zhuoying Yu, Ye Jiang, Zixian Zhang, Yue Tian, Jie Cai, Min Wei, Yanhan Lyu, Dongsheng Yang, Shixiong Shen, Guo‐Gang Xing, Min Li
CNS Neuroscience & Therapeutics.2024;[Epub] CrossRef
Long-term sensorimotor changes after a sciatic nerve block with bupivacaine and liposomal bupivacaine in a high-fat diet/low-dose streptozotocin rodent model of diabetes
Susanna C. Byram, Krista M. Lotesto, Michael Volyanyuk, Jacob E. Exline, Elizabeth A. Sager, Eileen M. Foecking
Frontiers in Anesthesiology.2024;[Epub] CrossRef
The impact of gut microbial dysbiosis on the atrophy of the hippocampus and abnormal metabolism of N-acetyl aspartate in type 2 diabetic rats
Zhenyang Zhu, Qingqing Chen, Gege Jiang, Yuan Liang, Jing Shen, Jianlin Wu
Heliyon.2024; 10(12): e33152. CrossRef
Advances in the treatment of diabetic peripheral neuropathy by modulating gut microbiota with traditional Chinese medicine
Ye-Yao Li, Rui-Qian Guan, Zhi-Bo Hong, Yao-Lei Wang, Li-Min Pan
World Journal of Diabetes.2024; 15(8): 1712. CrossRef
Compound Qiying Granules alleviates diabetic peripheral neuropathy by inhibiting endoplasmic reticulum stress and apoptosis
Yan Hu, Chen Chen, Zhengting Liang, Tao Liu, Xiaoling Hu, Guanying Wang, Jinxia Hu, Xiaolin Xie, Zhiyan Liu
Molecular Medicine.2023;[Epub] CrossRef
HCV affects KATP channels through GnT-IVa-mediated N-glycosylation of GLUT2 on the surface of pancreatic β-cells leading to impaired insulin secretion
Ben Niu, Lijing Ma, Lixuan Yao, Yating Zhang, Heng Su
Endocrine.2023; 84(2): 427. CrossRef
Multimodal Comparison of Diabetic Neuropathy in Aged Streptozotocin-Treated Sprague–Dawley and Zucker Diabetic Fatty Rats
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Biomedicines.2022; 11(1): 20. CrossRef

Original Article

Metabolic Risk/Epidemiology
Sex Differences in the Effects of CDKAL1 Variants on Glycemic Control in Diabetic Patients: Findings from the Korean Genome and Epidemiology Study: Hye Ah Lee, Hyesook Park, Young Sun Hong; Diabetes Metab J. 2022;46(6):879-889. Published online February 8, 2022; DOI: https://doi.org/10.4093/dmj.2021.0265

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Background
Using long-term data from the Korean Genome and Epidemiology Study, we defined poor glycemic control and investigated possible risk factors, including variants related to type 2 diabetes mellitus (T2DM). In addition, we evaluated interaction effects among risk factors for poor glycemic control.
Methods
Among 436 subjects with newly diagnosed diabetes, poor glycemic control was defined based on glycosylated hemoglobin trajectory patterns by group-based trajectory modeling. For the variants related to T2DM, genetic risk scores (GRSs) were calculated and divided into quartiles. Risk factors for poor glycemic control were assessed using a logistic regression model.
Results
Of the subjects, 43% were in the poor-glycemic-control group. Body mass index (BMI) and triglyceride (TG) were associated with poor glycemic control. The risk for poor glycemic control increased by 11.0% per 1 kg/m² increase in BMI and by 3.0% per 10 mg/dL increase in TG. The risk for GRS with poor glycemic control was sex-dependent (P_interaction=0.07), and a relationship by GRS quartiles was found in females but not in males. Moreover, the interaction effect was found to be significant on both additive and multiplicative scales. The interaction effect was evident in the variants of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like (CDKAL1).
Conclusion
Females with risk alleles of variants in CDKAL1 associated with T2DM had a higher risk for poor glycemic control than males.

Citations

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Hepatic Cdkal1 deletion regulates HDL catabolism and promotes reverse cholesterol transport
Dan Bi An, Soo-jin Ann, Seungmin Seok, Yura Kang, Sang-Hak Lee
Atherosclerosis.2023; 375: 21. CrossRef

Review

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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Graphical Abstract Abstract PDF PubReader ePub

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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Higher Genetic Risk for Type 2 Diabetes Is Associated With a Faster Decline of β-Cell Function in an East Asian Population
Hyunsuk Lee, Jaewon Choi, Jong-Il Kim, Richard M. Watanabe, Nam H. Cho, Kyong Soo Park, Soo Heon Kwak
Diabetes Care.2024; 47(8): 1386. CrossRef
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 & Metabolism Journal.2024; 48(4): 487. CrossRef
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Heba A. Mubarak, Manal M. Kamal, Yossra Mahmoud, Fatma S. Abd‐Elsamea, Eman Abdelbary, Marwa G. Gamea, Reham I. El‐Mahdy
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Leptin Rs7799039 polymorphism is associated with type 2 diabetes mellitus Egyptian patients
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Chemical Compounds and Ambient Factors Affecting Pancreatic Alpha-Cells Mass and Function: What Evidence?
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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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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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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 Article

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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