Diabetes & Metabolism Journal

Volume 47(2); March 2023

Reviews

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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Abstract PDF PubReader ePub Crossref - TDM: 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.

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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Abstract PDF PubReader ePub Crossref - TDM

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.

Citations

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The Role of Increased Expression of Sirtuin 6 in the Prevention of Premature Aging Pathomechanisms
Adrianna Dzidek, Olga Czerwińska-Ledwig, Małgorzata Żychowska, Wanda Pilch, Anna Piotrowska
International Journal of Molecular Sciences.2023; 24(11): 9655. CrossRef
Exploring the Influence of Age, Gender and Body Mass Index on Colorectal Cancer Location
Dorel Popovici, Cristian Stanisav, Sorin Saftescu, Serban Negru, Radu Dragomir, Daniel Ciurescu, Razvan Diaconescu
Medicina.2023; 59(8): 1399. 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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Abstract PDF PubReader ePub Crossref - TDM

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

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.

Citations

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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

Editorial

Comparing the Mortality Risk between Metabolic Dysfunction-Associated Fatty Liver Disease and Non-Alcoholic Fatty Liver Disease: Han Na Jung, Chang Hee Jung; Diabetes Metab J. 2023;47(2):198-200. Published online March 15, 2023; DOI: https://doi.org/10.4093/dmj.2023.0038

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Original Articles

Guideline/Fact Sheet
Comparison of Operational Definition of Type 2 Diabetes Mellitus Based on Data from Korean National Health Insurance Service and Korea National Health and Nutrition Examination Survey: Jong Ha Baek, Yong-Moon Park, Kyung Do Han, Min Kyong Moon, Jong Han Choi, Seung-Hyun Ko; Diabetes Metab J. 2023;47(2):201-210. Published online February 8, 2023; DOI: https://doi.org/10.4093/dmj.2022.0375

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM: Background
We evaluated the validity and reliability of the operational definition of type 2 diabetes mellitus (T2DM) based on the Korean National Health Insurance Service (NHIS) database.
Methods
Adult subjects (≥40 years old) included in the Korea National Health and Nutrition Examination Survey (KNHANES) from 2008 to 2017 were merged with those from the NHIS health check-up database, producing a cross-sectional dataset. We evaluated the sensitivity, specificity, accuracy, and agreement of the NHIS criteria for defining T2DM by comparing them with the KNHANES criteria as a standard reference.
Results
In the study population (n=13,006), two algorithms were devised to determine from the NHIS dataset whether the diagnostic claim codes for T2DM were accompanied by prescription codes for anti-diabetic drugs (algorithm 1) or not (algorithm 2). Using these algorithms, the prevalence of T2DM was 14.9% (n=1,942; algorithm 1) and 20.8% (n=2,707; algorithm 2). Good reliability in defining T2DM was observed for both algorithms (Kappa index, 0.73 [algorithm 1], 0.63 [algorithm 2]). However, the accuracy (0.93 vs. 0.89) and specificity (0.96 vs. 0.90) tended to be higher for algorithm 1 than for algorithm 2. The validity (accuracy, ranging from 0.91 to 0.95) and reliability (Kappa index, ranging from 0.68 to 0.78) of defining T2DM by NHIS criteria were independent of age, sex, socioeconomic status, and accompanied hypertension or dyslipidemia.
Conclusion
The operational definition of T2DM based on population-based NHIS claims data, including diagnostic codes and prescription codes, could be a valid tool to identify individuals with T2DM in the Korean population.

Guideline/Fact Sheet
Insulin Fact Sheet in Type 1 and 2 Diabetes Mellitus and Trends of Antidiabetic Medication Use in Insulin Users with Type 2 Diabetes Mellitus: 2002 to 2019: Jiyun Park, Gyuri Kim, Bong-Sung Kim, Kyung-Do Han, So Yoon Kwon, So Hee Park, You-Bin Lee, Sang-Man Jin, Jae Hyeon Kim; Diabetes Metab J. 2023;47(2):211-219. Published online February 7, 2023; DOI: https://doi.org/10.4093/dmj.2022.0346

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM

Background
This study investigated the trends of insulin use among Korean patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Changes in prescription of antidiabetic medications in T2DM patients taking insulin therapy were evaluated.
Methods
We analyzed data from the National Health Insurance Service database in Korea to evaluate the prevalence of insulin users and trends of insulin use in T1DM and T2DM patients from January 2002 to December 2019. We also investigated numbers and types of antidiabetic medications in insulin users with T2DM.
Results
The overall total number of insulin users increased from 2002 to 2019, reaching 348,254 for T2DM and 20,287 for T1DM in 2019 compared with 109,974 for T2DM and 34,972 for T1DM in 2002. The proportion of patients using basal analogs and short acting analogs have increased and those using human insulin, premixed insulin, or biphasic human insulin have decreased (rapid acting analogs: 71.85% and 24.12% in T1DM and T2DM, respectively, in 2019; basal analogs: 76.75% and 75.09% in T1DM and T2DM, respectively, in 2019). The use of other antidiabetic medication in addition to insulin increased for T2DM, especially in dual therapy, reaching up to 52.35% in 2019 compared with 16.72% in 2002.
Conclusion
The proportion of the patients using basal or rapid acting analogs increased among all insulin users in both T1DM and T2DM patients. Among patients with T2DM, the proportion of patients using antidiabetic medications in addition to insulin was significantly increased compared to those who used insulin alone.

Citations

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Evaluation of pharmacokinetic interactions between lobeglitazone, empagliflozin, and metformin in healthy subjects
Heeyoung Kim, Choon Ok Kim, Hyeonsoo Park, Min Soo Park, Dasohm Kim, Taegon Hong, Yesong Shin, Byung Hak Jin
Translational and Clinical Pharmacology.2023; 31(1): 59. CrossRef

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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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM

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.

Citations

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Comparison of Outcomes Between Metabolic Dysfunction-Associated Fatty Liver Disease and Non-alcoholic Fatty Liver Disease: A Meta-Analysis
Ghazala S Virk, Jaahnavi Vajje, Nausheen K Virk, Raam Mannam, Wajeeh Rehman, Naglaa G Ghobriel , Irfan-ud-din Mian, Muhammad Usama
Cureus.2023;[Epub] CrossRef
Trends in prevalence and all-cause mortality of metabolic dysfunction-associated fatty liver disease among adults in the past three decades: Results from the NHANES study
Zhi-Qin Xie, Hong-Xia Li, Bing-Kun Wang, Zhao-Ming Yang, Zi-Yu Zhang, Wen-Liang Tan, Wen-Xin Li, Qing-Bin Wang, Lei Yang, Hong-Kai Zhuang, Chen-Wei Tang, Chang-Zhen Shang, Ya-Jin Chen
European Journal of Internal Medicine.2023; 110: 62. CrossRef
Comparing the Mortality Risk between Metabolic Dysfunction-Associated Fatty Liver Disease and Non-Alcoholic Fatty Liver Disease
Han Na Jung, Chang Hee Jung
Diabetes & Metabolism Journal.2023; 47(2): 198. CrossRef
Increased expression of sodium-glucose cotransporter 2 and O-GlcNAcylation in hepatocytes drives non-alcoholic steatohepatitis
Hye Jin Chun, Eun Ran Kim, Minyoung Lee, Da Hyun Choi, Soo Hyun Kim, Eugene Shin, Jin-Hong Kim, Jin Won Cho, Dai Hoon Han, Bong-Soo Cha, Yong-ho Lee
Metabolism.2023; 145: 155612. CrossRef
Current understanding and future perspectives on the impact of changing NAFLD to MAFLD on global epidemiology and clinical outcomes
Karl Vaz, Daniel Clayton-Chubb, Ammar Majeed, John Lubel, David Simmons, William Kemp, Stuart K. Roberts
Hepatology International.2023;[Epub] CrossRef

Complications
Non-Alcoholic Fatty Liver Disease with Sarcopenia and Carotid Plaque Progression Risk in Patients with Type 2 Diabetes Mellitus: Yongin Cho, Hye-Sun Park, Byung Wook Huh, Yong-ho Lee, Seong Ha Seo, Da Hea Seo, Seong Hee Ahn, Seongbin Hong, So Hun Kim; Diabetes Metab J. 2023;47(2):232-241. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0355

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM: Background
We aimed to evaluate whether non-alcoholic fatty liver disease (NAFLD) with or without sarcopenia is associated with progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).
Methods
We investigated 852 T2DM patients who underwent abdominal ultrasonography, bioelectrical impedance analysis, and carotid artery ultrasonography at baseline and repeated carotid ultrasonography after 6 to 8 years. NAFLD was confirmed by abdominal ultrasonography, and sarcopenia was defined as a sex-specific skeletal muscle mass index (SMI) value <2 standard deviations below the mean for healthy young adults. SMI was calculated by dividing the sum of appendicular skeletal mass by body weight. We investigated the association between NAFLD with or without sarcopenia and the progression of carotid atherosclerosis.
Results
Of the 852 patients, 333 (39.1%) were classified as NAFLD without sarcopenia, 66 (7.7%) were classified as sarcopenia without NAFLD, and 123 (14.4%) had NAFLD with sarcopenia at baseline. After 6 to 8 years, patients with both NAFLD and sarcopenia had a higher risk of atherosclerosis progression (adjusted odds ratio, 2.20; P<0.009) than controls without NAFLD and sarcopenia. When a subgroup analysis was performed on only patients with NAFLD, female sex, absence of central obesity, and non-obesity were significant factors related to increased risk of plaque progression risk in sarcopenic patients.
Conclusion
NAFLD with sarcopenia was significantly associated with the progression of carotid atherosclerosis in T2DM patients.

Complications
Association of Body Mass Index and Fracture Risk Varied by Affected Bones in Patients with Diabetes: A Nationwide Cohort Study: Se-Won Lee, Kyungdo Han, Hyuk-Sang Kwon; Diabetes Metab J. 2023;47(2):242-254. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2022.0001

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM

Background
Body mass index (BMI) is a risk factor for the type 2 diabetes (T2DM), and T2DM accompanies various complications, such as fractures. We investigated the effects of BMI and T2DM on fracture risk and analyzed whether the association varied with fracture locations.
Methods
This study is a nationwide population-based cohort study that included all people with T2DM (n=2,746,078) who received the National Screening Program during 2009–2012. According to the anatomical location of the fracture, the incidence rate and hazard ratio (HR) were analyzed by dividing it into four categories: vertebra, hip, limbs, and total fracture.
Results
The total fracture had higher HR in the underweight group (HR, 1.268; 95% CI, 1.228 to 1.309) and lower HR in the obese group (HR, 0.891; 95% CI, 0.882 to 0.901) and the morbidly obese group (HR, 0.873; 95% CI, 0.857 to 0.89), compared to reference (normal BMI group). Similar trends were observed for HR of vertebra fracture. The risk of hip fracture was most prominent, the risk of hip fracture increased in the underweight group (HR, 1.896; 95% CI, 1.178 to 2.021) and decreased in the obesity (HR, 0.643; 95% CI, 0.624 to 0.663) and morbidly obesity group (HR, 0.627; 95% CI, 0.591 to 0.665). Lastly, fracture risk was least affected by BMI for limbs.
Conclusion
In T2DM patients, underweight tends to increase fracture risk, and overweight tends to lower fracture risk, but association between BMI and fracture risk varied depending on the affected bone lesions.

Citations

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Dysuricemia—A New Concept Encompassing Hyperuricemia and Hypouricemia
Naoyuki Otani, Motoshi Ouchi, Einosuke Mizuta, Asuka Morita, Tomoe Fujita, Naohiko Anzai, Ichiro Hisatome
Biomedicines.2023; 11(5): 1255. CrossRef
Association of Body Mass Index and Fracture Risk Varied by Affected Bones in Patients with Diabetes: A Nationwide Cohort Study (Diabetes Metab J 2023;47:242-54)
Se-Won Lee, Kyungdo Han, Hyuk-Sang Kwon
Diabetes & Metabolism Journal.2023; 47(3): 439. CrossRef
Association of Body Mass Index and Fracture Risk Varied by Affected Bones in Patients with Diabetes: A Nationwide Cohort Study (Diabetes Metab J 2023;47:242-54)
So Young Park
Diabetes & Metabolism Journal.2023; 47(3): 437. CrossRef

Genetics
Genome-Wide Association Study on Longitudinal Change in Fasting Plasma Glucose in Korean Population: Heejin Jin, Soo Heon Kwak, Ji Won Yoon, Sanghun Lee, Kyong Soo Park, Sungho Won, Nam H. Cho; Diabetes Metab J. 2023;47(2):255-266. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0375

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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM: Background
Genome-wide association studies (GWAS) on type 2 diabetes mellitus (T2DM) have identified more than 400 distinct genetic loci associated with diabetes and nearly 120 loci for fasting plasma glucose (FPG) and fasting insulin level to date. However, genetic risk factors for the longitudinal deterioration of FPG have not been thoroughly evaluated. We aimed to identify genetic variants associated with longitudinal change of FPG over time.
Methods
We used two prospective cohorts in Korean population, which included a total of 10,528 individuals without T2DM. GWAS of repeated measure of FPG using linear mixed model was performed to investigate the interaction of genetic variants and time, and meta-analysis was conducted. Genome-wide complex trait analysis was used for heritability calculation. In addition, expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression project.
Results
A small portion (4%) of the genome-wide single nucleotide polymorphism (SNP) interaction with time explained the total phenotypic variance of longitudinal change in FPG. A total of four known genetic variants of FPG were associated with repeated measure of FPG levels. One SNP (rs11187850) showed a genome-wide significant association for genetic interaction with time. The variant is an eQTL for NOC3 like DNA replication regulator (NOC3L) gene in pancreas and adipose tissue. Furthermore, NOC3L is also differentially expressed in pancreatic β-cells between subjects with or without T2DM. However, this variant was not associated with increased risk of T2DM nor elevated FPG level.
Conclusion
We identified rs11187850, which is an eQTL of NOC3L, to be associated with longitudinal change of FPG in Korean population.

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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Abstract PDF Supplementary Material PubReader ePub Crossref - TDM

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

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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

Basic Research
N⁶-Methyladenosine Methyltransferase METTL3 Alleviates Diabetes-Induced Testicular Damage through Modulating TUG1/Clusterin Axis: Yuan Tian, Yue-Hai Xiao, Chao Sun, Bei Liu, Fa Sun; Diabetes Metab J. 2023;47(2):287-300. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0306

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Abstract PDF PubReader ePub Crossref - TDM: Background
The present study investigated the regulatory effects of N6-methyladenosine (m6A) methyltransferase like-3 (METTL3) in diabetes-induced testicular damage.
Methods
In vivo diabetic mice and high glucose (HG) treated GC-1 spg cells were established. The mRNA and protein expressions were determined by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence and immunohistochemistry staining. Levels of testosterone, blood glucose, cell viability, and apoptosis were detected by enzyme-linked immunosorbent assay, MTT, and flow cytometry, respectively. Molecular interactions were verified by RNA immunoprecipitation and RNA pull-down assay. Histopathological staining was performed to evaluate testicular injury.
Results
METTL3 and long non-coding RNA taurine up-regulated 1 (lncRNA TUG1) were downregulated in testicular tissues of diabetic mice and HG-treated GC-1 spg cells. METTL3 overexpression could reduce the blood glucose level, oxidative stress and testicular damage but enhance testosterone secretion in diabetic mouse model and HG-stimulated GC-1 spg cells. Mechanically, METTL3-mediated m6A methylation enhanced the stability of TUG1, then stabilizing the clusterin mRNA via recruiting serine and arginine rich splicing factor 1. Moreover, inhibition of TUG1/clusterin signaling markedly reversed the protective impacts of METTL3 overexpression on HG-stimulated GC-1 spg cells.
Conclusion
This study demonstrated that METTL3 ameliorated diabetes-induced testicular damage by upregulating the TUG1/clusterin signaling. These data further elucidate the potential regulatory mechanisms of m6A modification on diabetes-induced testicular injury.

Letter

Association of Myosteatosis with Nonalcoholic Fatty Liver Disease, Severity, and Liver Fibrosis Using Visual Muscular Quality Map in Computed Tomography (Diabetes Metab J 2023;47:104-17): Eun Roh; Diabetes Metab J. 2023;47(2):301-303. Published online March 15, 2023; DOI: https://doi.org/10.4093/dmj.2023.0051

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Response

Association of Myosteatosis with Nonalcoholic Fatty Liver Disease, Severity, and Liver Fibrosis Using Visual Muscular Quality Map in Computed Tomography (Diabetes Metab J 2023;47:104-17): Hwi Seung Kim, Hong-Kyu Kim, Chang Hee Jung; Diabetes Metab J. 2023;47(2):304-305. Published online March 15, 2023; DOI: https://doi.org/10.4093/dmj.2023.0058

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