Diabetes & Metabolism Journal

Original Article

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

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

Citations

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Diabetes and diabetic associative diseases: An overview of epigenetic regulations of TUG1
Mohammed Ageeli Hakami
Saudi Journal of Biological Sciences.2024; 31(5): 103976. CrossRef
Effect of Tinospora cordifolia on gestational diabetes mellitus and its complications
Ritu Rani, Havagiray Chitme, Avinash Kumar Sharma
Women & Health.2023; 63(5): 359. CrossRef
Therapeutic Effect of Tinospora cordifolia (Willd) Extracts on Letrozole-Induced Polycystic Ovarian Syndrome and its Complications in Murine Model
Ritu Rani, Avinash Kumar Sharma, Havagiray R Chitme
Clinical Medicine Insights: Endocrinology and Diabetes.2023;[Epub] CrossRef
The role of ncRNA regulatory mechanisms in diseases—case on gestational diabetes
Dong Gao, Liping Ren, Yu-Duo Hao, Nalini Schaduangrat, Xiao-Wei Liu, Shi-Shi Yuan, Yu-He Yang, Yan Wang, Watshara Shoombuatong, Hui Ding
Briefings in Bioinformatics.2023;[Epub] CrossRef
lncRNA TUG1 as potential novel biomarker for prognosis of cardiovascular diseases
Habib Haybar, Narjes Sadat Sadati, Daryush Purrahman, Mohammad Reza Mahmoudian-Sani, Najmaldin Saki
Epigenomics.2023; 15(23): 1273. CrossRef

Reviews

Drug/Regimen
Machine Learning Approach to Drug Treatment Strategy for Diabetes Care: Kazuya Fujihara, Hirohito Sone; Diabetes Metab J. 2023;47(3):325-332. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0349

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Globally, the number of people with diabetes mellitus has quadrupled in the past three decades, and approximately one in 11 adults worldwide have diabetes mellitus. Since both microvascular and macrovascular diseases in patients with diabetes predispose them to a lower quality of life as well as higher rates of mortality, managing blood glucose levels is of clinical relevance in diabetes care. Many classes of antihyperglycemic drugs are currently approved to treat hyperglycemia in patients with type 2 diabetes mellitus, with several new drugs having been developed during the last decade. Diabetes-related complications have been reduced substantially worldwide. Prioritization of therapeutic agents varies according to national guidelines. However, since the characteristics of participants in clinical trials differ from patients in actual clinical practice, it is difficult to apply the results of such trials to clinical practice. Machine learning approaches became highly topical issues in medicine along with rapid technological innovations in the fields of information and communication in the 1990s. However, adopting these technologies to support decision-making regarding drug treatment strategies for diabetes care has been slow. This review summarizes data from recent studies on the choice of drugs for type 2 diabetes mellitus focusing on machine learning approaches.

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Exploring antioxidant activities and inhibitory effects against α‐amylase and α‐glucosidase of Elaeocarpus braceanus fruits: insights into mechanisms by molecular docking and molecular dynamics
Hong Li, Yuanyue Zhang, Zhijia Liu, Chaofan Guo, Maurizio Battino, Shengbao Cai, Junjie Yi
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3D Convolutional Neural Networks for Predicting Protein Structure for Improved Drug Recommendation
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Cardiovascular Risk/Epidemiology
Intensified Multifactorial Intervention in Patients with Type 2 Diabetes Mellitus: Takayoshi Sasako, Toshimasa Yamauchi, Kohjiro Ueki; Diabetes Metab J. 2023;47(2):185-197. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0325

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In the management of diabetes mellitus, one of the most important goals is to prevent its micro- and macrovascular complications, and to that end, multifactorial intervention is widely recommended. Intensified multifactorial intervention with pharmacotherapy for associated risk factors, alongside lifestyle modification, was first shown to be efficacious in patients with microalbuminuria (Steno-2 study), then in those with less advanced microvascular complications (the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care [ADDITION]-Europe and the Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases [J-DOIT3]), and in those with advanced microvascular complications (the Nephropathy In Diabetes-Type 2 [NID-2] study and Diabetic Nephropathy Remission and Regression Team Trial in Japan [DNETT-Japan]). Thus far, multifactorial intervention led to a reduction in cardiovascular and renal events, albeit not necessarily significant. It should be noted that not only baseline characteristics but also the control status of the risk factors and event rates during intervention among the patients widely varied from one trial to the next. Further evidence is needed for the efficacy of multifactorial intervention in a longer duration and in younger or elderly patients. Moreover, now that new classes of antidiabetic drugs are available, it should be addressed whether strict and safe glycemic control, alongside control of other risk factors, could lead to further risk reductions in micro- and macrovascular complications, thereby decreasing all-cause mortality in patients with type 2 diabetes mellitus.

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Exploring mechanisms underlying diabetes comorbidities and strategies to prevent vascular complications
Takayoshi Sasako
Diabetology International.2024; 15(1): 34. CrossRef
Targeting ERS-mitophagy in hippocampal neurons to explore the improvement of memory by tea polyphenols in aged type 2 diabetic rats
Wenjuan Feng, Chenhui Lv, Le Cheng, Xin Song, Xuemin Li, Haoran Xie, Shuangzhi Chen, Xi Wang, Lushan Xue, Cheng Zhang, Jie Kou, Lili Wang, Haifeng Zhao
Free Radical Biology and Medicine.2024; 213: 293. CrossRef
Risk of Dementia Among Patients With Diabetes in a Multidisciplinary, Primary Care Management Program
Kailu Wang, Shi Zhao, Eric Kam-Pui Lee, Susan Zi-May Yau, Yushan Wu, Chi-Tim Hung, Eng-Kiong Yeoh
JAMA Network Open.2024; 7(2): e2355733. CrossRef
Causes of In-Hospital Death and Pharmaceutical Associations with Age of Death during a 10-Year Period (2011–2020) in Individuals with and without Diabetes at a Japanese Community General Hospital
Minae Hosoki, Taiki Hori, Yousuke Kaneko, Kensuke Mori, Saya Yasui, Seijiro Tsuji, Hiroki Yamagami, Saki Kawata, Tomoyo Hara, Shiho Masuda, Yukari Mitsui, Kiyoe Kurahashi, Takeshi Harada, Shingen Nakamura, Toshiki Otoda, Tomoyuki Yuasa, Akio Kuroda, Itsur
Journal of Clinical Medicine.2024; 13(5): 1283. CrossRef
External validation of a minimal-resource model to predict reduced estimated glomerular filtration rate in people with type 2 diabetes without diagnosis of chronic kidney disease in Mexico: a comparison between country-level and regional performance
Camilla Sammut-Powell, Rose Sisk, Ruben Silva-Tinoco, Gustavo de la Pena, Paloma Almeda-Valdes, Sonia Citlali Juarez Comboni, Susana Goncalves, Rory Cameron
Frontiers in Endocrinology.2024;[Epub] CrossRef
Gut Microbiota Targeted Approach by Natural Products in Diabetes Management: An Overview
Priyanka Sati, Praveen Dhyani, Eshita Sharma, Dharam Chand Attri, Arvind Jantwal, Rajni Devi, Daniela Calina, Javad Sharifi-Rad
Current Nutrition Reports.2024;[Epub] CrossRef
Cardiovascular Risk Reduction in Type 2 Diabetes: Further Insights into the Power of Weight Loss and Exercise
Seung-Hwan Lee
Endocrinology and Metabolism.2023; 38(3): 302. CrossRef
Sarcopenia: Loss of mighty armor against frailty and aging
Takayoshi Sasako, Kohjiro Ueki
Journal of Diabetes Investigation.2023; 14(10): 1145. CrossRef

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.

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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

Basic Research
The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4: Min-Ji Kim, Ibotombi Singh Sinam, Zerwa Siddique, Jae-Han Jeon, In-Kyu Lee; Diabetes Metab J. 2023;47(2):153-163. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0305

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Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.

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Yue Zhang, Meiyan Sun, Hongxiang Zhao, Zhengyan Wang, Yanan Shi, Jianxin Dong, Kaifang Wang, Xi Wang, Xingyue Li, Haiyan Qi, Xiaoyong Zhao
International Journal of Nanomedicine.2023; Volume 18: 7559. CrossRef

Technology/Device
Advances in Continuous Glucose Monitoring and Integrated Devices for Management of Diabetes with Insulin-Based Therapy: Improvement in Glycemic Control: Jee Hee Yoo, Jae Hyeon Kim; Diabetes Metab J. 2023;47(1):27-41. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0271

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Continuous glucose monitoring (CGM) technology has evolved over the past decade with the integration of various devices including insulin pumps, connected insulin pens (CIPs), automated insulin delivery (AID) systems, and virtual platforms. CGM has shown consistent benefits in glycemic outcomes in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) treated with insulin. Moreover, the combined effect of CGM and education have been shown to improve glycemic outcomes more than CGM alone. Now a CIP is the expected future technology that does not need to be worn all day like insulin pumps and helps to calculate insulin doses with a built-in bolus calculator. Although only a few clinical trials have assessed the effectiveness of CIPs, they consistently show benefits in glycemic outcomes by reducing missed doses of insulin and improving problematic adherence. AID systems and virtual platforms made it possible to achieve target glycosylated hemoglobin in diabetes while minimizing hypoglycemia, which has always been challenging in T1DM. Now fully automatic AID systems and tools for diabetes decisions based on artificial intelligence are in development. These advances in technology could reduce the burden associated with insulin treatment for diabetes.

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Jee Hee Yoo, Jae Hyeon Kim
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Seung-Hwan Lee
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Ioannis T. Oikonomakos, Ranjit M. Anjana, Viswanathan Mohan, Charlotte Steenblock, Stefan R. Bornstein
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Basic Research
Multiple Roles of Sirtuin 6 in Adipose Tissue Inflammation: Eun Ju Bae, Byung-Hyun Park; Diabetes Metab J. 2023;47(2):164-172. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2022.0270

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Adipose tissue (AT) inflammation is strongly associated with obesity-induced insulin resistance. When subjected to metabolic stress, adipocytes become inflamed and secrete a plethora of cytokines and chemokines, which recruit circulating immune cells to AT. Although sirtuin 6 (Sirt6) is known to control genomic stabilization, aging, and cellular metabolism, it is now understood to also play a pivotal role in the regulation of AT inflammation. Sirt6 protein levels are reduced in the AT of obese humans and animals and increased by weight loss. In this review, we summarize the potential mechanism of AT inflammation caused by impaired action of Sirt6 from the immune cells’ point of view. We first describe the properties and functions of immune cells in obese AT, with an emphasis on discrete macrophage subpopulations which are central to AT inflammation. We then highlight data that links Sirt6 to functional phenotypes of AT inflammation. Importantly, we discuss in detail the effects of Sirt6 deficiency in adipocytes, macrophages, and eosinophils on insulin resistance or AT browning. In our closing perspectives, we discuss emerging issues in this field that require further investigation.

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International Journal of Molecular Sciences.2023; 24(11): 9655. CrossRef
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Original Article

Metabolic Risk/Epidemiology
Metabolic Dysfunction-Associated Fatty Liver Disease and Mortality: A Population-Based Cohort Study: Kyung-Soo Kim, Sangmo Hong, Hong-Yup Ahn, Cheol-Young Park; Diabetes Metab J. 2023;47(2):220-231. Published online January 12, 2023; DOI: https://doi.org/10.4093/dmj.2021.0327

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Background
We investigated whether metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with an elevated risk of all-cause and cardiovascular mortality using a large-scale health examination cohort.
Methods
A total of 394,835 subjects in the Kangbuk Samsung Health Study cohort were enrolled from 2002 to 2012. Participants were categorized by the presence of nonalcoholic fatty liver disease (NAFLD) and MAFLD as follows: normal subjects; patients with both NAFLD and MAFLD; patients with NAFLD only; and patients with MAFLD only. Cox proportional hazards models were used to analyze the risk of mortality.
Results
During a median 5.7 years of follow-up, 20.69% was patients with both NAFLD and MAFLD, 1.51% was patients with NAFLD only, and 4.29% was patients with MAFLD only. All-cause and cardiovascular death was higher in patients with MAFLD than those without MAFLD (P<0.001, respectively). In patients with MAFLD only, the hazard ratio (HR) of all-cause and cardiovascular death was 1.35 (95% confidence interval [CI], 1.13 to 1.60) and 1.90 (95% CI, 1.26 to 2.88) after adjusting for age, which lost its statistical significance by multivariable adjustments. Compared to patients with less than two components of metabolic dysfunction, patients with more than two components of metabolic dysfunction were a higher risk of cardiovascular death (HR, 2.05; 95% CI, 1.25 to 3.38) and only women with more than two components of metabolic dysfunction were a higher risk of all-cause death (HR, 1.44; 95% CI, 1.02 to 2.03).
Conclusion
MAFLD criteria could identify a high-risk group for all-cause and cardiovascular death.

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Response

Advanced Liver Fibrosis Is Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease (Diabetes Metab J 2022;46:630-9): Da Hea Seo, So Hun Kim; Diabetes Metab J. 2022;46(6):956-957. Published online November 24, 2022; DOI: https://doi.org/10.4093/dmj.2022.0381; [Original]

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Letter

Advanced Liver Fibrosis Is Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease (Diabetes Metab J 2022;46:630-9): Ji Hye Huh; Diabetes Metab J. 2022;46(6):953-955. Published online November 24, 2022; DOI: https://doi.org/10.4093/dmj.2022.0374; [Original]

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Editorial

Oldies but Goodies: Thiazolidinedione as an Insulin Sensitizer with Cardioprotection: Eun-Hee Cho; Diabetes Metab J. 2022;46(6):827-828. Published online November 24, 2022; DOI: https://doi.org/10.4093/dmj.2022.0372

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Diabetes: a review of its pathophysiology, and advanced methods of mitigation
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Current Medical Research and Opinion.2024; : 1. CrossRef
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Joonsang Yoo, Jimin Jeon, Minyoul Baik, Jinkwon Kim
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Julita Tokarek, Emilian Budny, Maciej Saar, Kamila Stańczak, Ewa Wojtanowska, Ewelina Młynarska, Jacek Rysz, Beata Franczyk
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Review

Guideline/Fact Sheet
Screening for Prediabetes and Diabetes in Korean Nonpregnant Adults: A Position Statement of the Korean Diabetes Association, 2022: Kyung Ae Lee, Dae Jung Kim, Kyungdo Han, Suk Chon, Min Kyong Moon, on Behalf of the Committee of Clinical Practice Guideline of Korean Diabetes Association; Diabetes Metab J. 2022;46(6):819-826. Published online November 24, 2022; DOI: https://doi.org/10.4093/dmj.2022.0364

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Diabetes screening serves to identify individuals at high-risk for diabetes who have not yet developed symptoms and to diagnose diabetes at an early stage. Globally, the prevalence of diabetes is rapidly increasing. Furthermore, obesity and/or abdominal obesity, which are major risk factors for type 2 diabetes mellitus (T2DM), are progressively increasing, particularly among young adults. Many patients with T2DM are asymptomatic and can accompany various complications at the time of diagnosis, as well as chronic complications develop as the duration of diabetes increases. Thus, proper screening and early diagnosis are essential for diabetes care. Based on reports on the changing epidemiology of diabetes and obesity in Korea, as well as growing evidence from new national cohort studies on diabetes screening, the Korean Diabetes Association has updated its clinical practice recommendations regarding T2DM screening. Diabetes screening is now recommended in adults aged ≥35 years regardless of the presence of risk factors, and in all adults (aged ≥19) with any of the risk factors. Abdominal obesity based on waist circumference (men ≥90 cm, women ≥85 cm) was added to the list of risk factors.

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Editorial

Asymptomatic Hypoglycemia after Metabolic Surgery: New Insights from Perioperative Continuous Glucose Monitoring: Sang-Man Jin; Diabetes Metab J. 2022;46(5):675-676. Published online September 19, 2022; DOI: https://doi.org/10.4093/dmj.2022.0307

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Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis (Diabetes Metab J 2022;46:781-802): Tianqi Zhang, Marnie Shaw, Nicolas Cherbuin; Diabetes Metab J. 2022;46(5):815-816. Published online September 19, 2022; DOI: https://doi.org/10.4093/dmj.2022.0296; [Original]

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Corrigendum

New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins: Kyuho Kim, Henry N. Ginsberg, Sung Hee Choi; Diabetes Metab J. 2022;46(5):817-818. Published online September 19, 2022; DOI: https://doi.org/10.4093/dmj.2022.0295; Corrects: Diabetes Metab J 2022;46(4):517

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