Diabetes & Metabolism Journal

Review

Pharmacotherapy
Sodium-Glucose Cotransporter 2 Inhibitors as Emerging Anticancer Agents: Yun Kyung Cho, Chang Hee Jung; Diabetes Metab J. 2026;50(1):1-18. Published online January 1, 2026; DOI: https://doi.org/10.4093/dmj.2025.0964

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Abstract PDF PubReader ePub: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are established treatments for type 2 diabetes mellitus, heart failure, and chronic kidney disease, with well-documented metabolic and cardiorenal benefits. Emerging evidence indicates that these agents may also exert anticancer effects through mechanisms independent of glucose lowering. Preclinical studies have demonstrated functional SGLT2 expression in tumors such as prostate, pancreatic, breast, colorectal, and bone cancers. Inhibition of SGLT2 decreases tumor glucose uptake, disrupts mitochondrial respiration with subsequent adenosine monophosphate-activated protein kinase activation, and induces endoplasmic reticulum stress and autophagy. Immunomodulatory effects, including programmed death-ligand 1 (PD-L1) degradation and stimulator of interferon genes (STING)–interferon regulatory factor 3 (IRF3)–interferon-β (IFN-β) pathway activation, further illustrate their pleiotropic effects. Observational cohort studies, particularly from nationwide Korean databases, report reduced risks of pancreatic and prostate cancer among new users of SGLT2 inhibitors. In contrast, randomized controlled trials and meta-analyses focused on cardiovascular outcomes demonstrate neutral effects on overall cancer risk, providing reassurance regarding safety. Early translational studies suggest that combining SGLT2 inhibitors with chemotherapy is feasible and tolerable. In this review, we summarize the biological rationale and mechanistic insights underlying the anticancer effects of SGLT2 inhibitors, highlight preclinical and clinical evidence across different cancer types, and discuss challenges and future directions for their integration into oncology.

Original Articles

Guideline/Statement/Fact Sheet
Health Effects of Sugar-Sweetened and Artificially Sweetened Beverages: Umbrella Review and Evidence-Based Consensus Statement of the Korean Diabetes Association and the Korean Nutrition Society: Jong Han Choi, SuJin Song, Soo Kyoung Kim, Jae Won Cho, Jae Hyun Bae, Shinje Moon, Jeong Hyun Lim, YeonHee Lee, Ji-Yun Hwang, YoonJu Song, Sang Soo Kim; Diabetes Metab J. 2026;50(1):32-46. Published online January 1, 2026; DOI: https://doi.org/10.4093/dmj.2025.0848

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Abstract PDF Supplementary Material PubReader ePub: Background
Excess intake of added sugars contributes to obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and premature mortality. Sugar-sweetened beverages (SSBs), the main source of added sugars, are consistently linked to adverse outcomes. Artificially sweetened beverages (ASBs) have been suggested as short-term substitutes, but evidence regarding benefits and harms remains inconclusive, and guidance is lacking.
Methods
This consensus statement draws on a structured evidence review combining two approaches: an updated meta-analysis of randomized controlled trials (RCTs) assessing short- to intermediate-term effects of replacing SSBs with ASBs on weight and metabolic outcomes; and an umbrella review of systematic reviews of cohort studies evaluating long-term associations of SSBs and ASBs with major outcomes, including mortality, CVD, and T2DM.
Results
In 14 RCTs (3–76 weeks), replacing SSBs with ASBs produced modest reductions in body weight (–0.73 kg) and body fat (–0.72%), with inconsistent effects on glycemic and cardiometabolic markers. Evidence from 20 systematic reviews of cohorts (up to 34 years follow-up) showed that higher intake of both SSBs and ASBs was associated with increased risks of T2DM, CVD, and mortality, with relative risks for ASBs similar to those for SSBs.
Conclusion
ASBs may serve as a short-term substitution for individuals with high SSB intake, particularly those at elevated metabolic risk. However, regular or long-term use is not recommended due to uncertain safety and potential reinforcement of sweet preference. Public health strategies should emphasize reducing both SSBs and ASBs, prioritizing water and unsweetened beverages as the ultimate goal.

Pharmacotherapy
Efficacy and Safety of Enavogliflozin as Add-on in Adults with Type 2 Diabetes Mellitus Inadequately Controlled with Insulin or Insulin with Other Antidiabetic Drugs: Jun Hwa Hong, Kyung Wan Min, Chang Beom Lee, Parinya Chamnan, Thanitha Sirirak, Kiran Sony, Sarinya Sattanon, Hae Jin Kim, Sang-Yong Kim, Younghee Kim, Jung A Heo, Jae Min Cho, Jae Jin Nah, Mi Hee Park, Jae Hyeon Kim; Received May 30, 2025 Accepted October 14, 2025 Published online December 15, 2025; DOI: https://doi.org/10.4093/dmj.2025.0477 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The study evaluated the efficacy and safety of enavogliflozin, a novel, promising selective sodium-glucose cotransporter 2 inhibitor, as an add-on in adults with type 2 diabetes mellitus (T2DM) inadequately controlled with insulin alone or combined with other antidiabetic drugs (OADs).
Methods
The double-blind, placebo-controlled, multicenter trial was conducted in South Korea and Thailand. Individuals with glycosylated hemoglobin (HbA1c) ≥7.5% after ≥8-week treatment with background insulin alone or combined with ≤2 OADs were randomized to receive enavogliflozin 0.3 mg or placebo (n=116 each) for 24 weeks. The primary outcome was a change in HbA1c at week 24. Secondary outcomes included, among others, changes in body weight, blood pressure, and other measures of glycemic control. Adverse events (AEs) were investigated throughout the study (Clinical trial registration number: NCT05466643).
Results
At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was –0.9% (P<0.001). Also, placebo-adjusted mean changes in fasting plasma glucose (–32.4 mg/dL, P<0.001), body weight (–1.3 kg, P<0.001), and total daily dose of insulin (–1.3 units, P=0.010) at week 24 were statistically significant. In addition, a significant decrease in blood pressure and fasting C-peptide was observed in the enavogliflozin group, along with a significant increase in homeostasis model assessment of β-cell function, yet without a concomitant change in homeostasis model assessment of insulinresistance. No significant increase in treatment-related AEs was observed for enavogliflozin.
Conclusion
Enavogliflozin 0.3 mg/day is an efficacious and safe add-on treatment option in T2DM patients controlled inadequately with insulin alone or combined with OADs.

Complications
4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the Efferocytosis-MCT1-Lactate-GPR132 Pathway and Macrophage-Independent Synergistic Effects: Mengqin Tu, Xiaoli Zou, Xiaozhen Tan, Yijun Liu, Xinxu Ge, Yu Hu, Qiuyue Peng, Linlin Huang, Yan Zeng, Chunxia Jia, Man Guo, Jiao Chen, Yang Long, Yong Xu; Received September 21, 2024 Accepted July 2, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2024.0579 [Epub ahead of print]

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Background
Diabetic foot ulcers are a severe diabetic complication causing poor healing. Itaconate, a tricarboxylicacid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis andmacrophage pro-resolving function to promote diabetic wound healing.
Methods
A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis.
Results
In diabetic mice, impaired apoptotic neutrophils clearance and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1 which, in turn, increased release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).
Conclusion
4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation.

Citations

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Roles of efferocytosis in wound repair: Process, cells, and signals
Yilin Sun, Haiying Guo, Yang Bai, Jin Chen, Yuhong Li
Genes & Diseases.2025; : 101937. CrossRef

Reviews

Lifestyle and Behavioral Interventions
Optimizing Physical Activity Strategies for Older Adults with Diabetes: Hyeon-Jin Yu, Doyoun Hong, Kyuho Kim, Ji Hye Heo, Dong-Hyeok Cho, Yoshitaka Hashimoto, Jae-Seung Yun; Diabetes Metab J. 2025;49(6):1178-1197. Published online November 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0967

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Abstract PDF PubReader ePub: The increasing prevalence of diabetes among older adults has emerged as a major socioeconomic burden. This population is highly heterogeneous, ranging from functionally independent to severely impaired individuals, making it difficult to establish standardized recommendations. Physical activity (PA) is a cornerstone of diabetes management; however, current exercise guidelines do not adequately address the wide spectrum of functional capacities observed in older adults. For those with physical limitations, relatively simple activities such as walking, breaking up sedentary time, incorporating movement into daily routines, and aquatic exercise have been proposed, yet supporting evidence remains limited. This review summarizes the pathophysiologic mechanisms of metabolic and functional changes associated with aging and diabetes—including sarcopenia, altered body composition, and cardiovascular decline—and comprehensively discusses the benefits and precautions of various exercise modalities, tailored recommendations according to diabetes-related complications, and key clinical considerations. We further classified older adults with diabetes into three functional levels, individuals in good health, those with some comorbidities or mild disabilities, and those with high comorbidities and/or functional impairment, and proposed corresponding physical activity strategies for each level. Finally, we highlight practical and feasible approaches, including walking, interrupting sedentary behavior, daily functional movements, and aquatic exercise, to enhance clinical applicability for individuals with reduced physical capacity. These tailored, function-based strategies may help older adults with diabetes achieve safer, more effective, and sustainable improvements in glycemic control and overall health.

Guideline/Statement/Fact Sheet
Defining Severe Diabetes Mellitus: A Consensus Framework for Grading and Staging Diabetes Based on Pathophysiology and Complications: Jae Hyun Bae, Hun Jee Choe, Ye Seul Yang, Mi Hae Seo, Jong Han Choi, Gyuri Kim, Young Sang Lyu, Jeung Hun Han, Shinae Kang, Won Jun Kim, Kyung-Soo Kim, Young Min Cho, Bong Soo Cha, for the Severe Diabetes Mellitus Task Force of the Korean Diabetes Association; Diabetes Metab J. 2025;49(6):1141-1154. Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2025.0739

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Diabetes mellitus comprises a heterogeneous group of metabolic disorders differing in etiology, clinical course, and outcomes. Traditional classifications, such as type 1 and type 2 diabetes mellitus, fail to capture the full heterogeneity, including variation in insulin deficiency, insulin resistance, and complication burden. To address these limitations, we propose the Diabetes Grade–Stage Classification, an integrated system that combines pathophysiology-based grading with complication-based staging. Grading quantifies metabolic dysfunction through the assessment of insulin deficiency and insulin resistance. In parallel, staging assesses the extent of target organ damage, particularly in the cardiovascular, renal, ocular, and nervous systems. Together, this framework enables a comprehensive assessment of disease status, identification of vulnerable or high-risk phenotypes, and implementation of risk-adapted management strategies. Clinically, it facilitates personalized care, promotes collaborative coordination, and strengthens physician–patient communication. Furthermore, this framework provides a scalable structure for integrating disease severity into both individual- and population-level interventions. Although the current criteria for grading and staging are based on expert consensus and selected clinical indicators, such as low C-peptide levels and advanced complications, further validation and refinement are needed. In conclusion, the grading and staging system provides an operational tool for classifying the severity of diabetes mellitus and has the potential to extend life expectancy and improve quality of life for people living with diabetes mellitus.

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Bridging Evidence and Practice: A Consensus Statement from the Korean Diabetes Association on Diabetes Screening, Pharmacological Treatment and Severe Diabetes
Jong Han Choi, Shinae Kang, Soo-Kyung Kim, Won Jun Kim, Ji Min Kim, Jaehyun Bae, Jae-Seung Yun, Eonju Jeon, Young-Eun Kim, Jae Hyun Bae, Hun Jee Choe, Young Min Cho, Seung-Hyun Ko, Sang Yong Kim, Hae Jin Kim, You-Cheol Hwang, Min Kyong Moon, Suk Chon, Seo
Diabetes & Metabolism Journal.2025; 49(6): 1155. CrossRef

Original Article

Others
The Concurrent Challenges of Sarcopenia and Frailty: A 5-Year Mortality Risk Evaluation in Geriatric Patients with Type 2 Diabetes Mellitus: Burcu Eren Cengiz, Nurhayat Tugra Ozer, Celil Barlas Cengiz, Yavuz Sultan Selim Akgul, Sibel Akın; Received January 30, 2025 Accepted June 12, 2025 Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0077 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) is common among older adults and may increase the risk of sarcopenia and frailty. This study evaluates the impact of sarcopenia and frailty on 5-year mortality in older adults with T2DM.
Methods
We assessed a cohort study of 447 adults with T2DM who were more than 60 years old. To follow the guidelines set by the European Working Group on Sarcopenia in Older People 2 (EWGSOP 2), we used bioelectrical impedance analysis to measure muscle mass and a handgrip dynamometer to measure muscle strength. We assessed frailty using the Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight (FRAIL) Scale. We categorised the patients into four groups: isolated sarcopenic, isolated alone, both conditions (sarcopenia and frailty), or neither.
Results
The mean age of the patients was 69 years, with 71.6% female. Isolated sarcopenic was present in 11.0%, isolated frail in 22.4%, and sarcopenia and frailty in 9.8%. After adjusting for variables such as age, sex, comorbidities, activities of daily living, glycemic control, and nutritional status, sarcopenia and frailty were found to be significantly associated with an increased risk of 5-year mortality. Isolated frail also significantly predicted mortality (hazard ratio, 2.59; 95% confidence interval, 1.34 to 5.03; P=0.005).
Conclusion
Sarcopenia and frailty are significant predictors of increased mortality risk in older adults with T2DM. Sarcopenia and frailty pose the highest risk. Early identification and targeted interventions for these conditions in older T2DM patients are crucial to improving outcomes.

Review

Others
Differences between Type 2 Diabetes Mellitus and Obesity Management: Medical, Social, and Public Health Perspectives: Soo Lim, Ga Eun Nam, Arya M. Sharma; Diabetes Metab J. 2025;49(4):565-579. Published online June 11, 2025; DOI: https://doi.org/10.4093/dmj.2025.0278

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Obesity and type 2 diabetes mellitus (T2DM) are among the most urgent global public health challenges, yet differ markedly in recognition and management across medical, social, infrastructure, and policy domains. T2DM is supported by clear diagnostic criteria, defined treatment targets, and broad acceptance as a chronic disease. In contrast, obesity is assessed using imprecise metrics like body mass index, lacks standardized treatment goals, and is often misunderstood as a lifestyle issue rather than a chronic, relapsing disease. This misconception contributes to stigma, discrimination, and unrealistic patient expectations. T2DM receives substantial research funding, comprehensive clinical guidelines, and structured medical education, with strong support from large professional societies and multidisciplinary care models. Obesity care remains underfunded, inconsistently delivered, and underrepresented in medical training. Public health and policy efforts strongly favor T2DM, providing coordinated programs, insurance coverage, and regulatory oversight. Conversely, obesity is marginalized, with limited policy influence and a largely unregulated commercial weight-loss industry. Bridging these disparities requires adopting lessons from T2DM management—such as evidence-based guidelines, improved provider training, expanded insurance coverage, and public health strategies—to enhance obesity care and recognize it as a chronic disease requiring long-term, structured management.

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GLP-1 Receptor Agonists: Advances in Mechanism, Therapeutic Applications, and Future Perspectives
Megha Pawar, Chandrashekhar Patil, Zubershaha Fakir, Durgesh Pagar, Sunil Mahajan
BioMed Target Journal.2025; : 2. CrossRef

Original Articles

Pharmacotherapy
Novel Insights into the Causal Relationship between Antidiabetic Drugs and Adverse Perinatal Outcomes: A Mendelian Randomization Study: Chang Su, Xueqing He, Xiaona Chang, Juan Tian, Guang Wang, Jia Liu; Diabetes Metab J. 2025;49(6):1242-1251. Published online June 2, 2025; DOI: https://doi.org/10.4093/dmj.2024.0521

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Abstract PDF Supplementary Material PubReader ePub: Background
Hyperglycemia during pregnancy increases the risk of adverse perinatal outcomes and birth defects. Evidence regarding the long-term safety of antidiabetic drugs during pregnancy is still lacking.
Methods
A two-sample Mendelian randomization (MR) study was performed to assess the causal association between six antidiabetic drug targets (ABCC8, DPP4, INSR, GLP1R, PPARG, and SLC5A2) and seven adverse perinatal outcomes and five congenital malformation outcomes. Inverse variance weighted (IVW) was adopted as the main MR method, and sensitivity analysis using traditional MR methods was performed to evaluate the robustness of the results.
Results
We observed strong evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors (odds ratio [OR], 0.084; 95% confidence interval [CI], 0.009 to 0.834; P=0.034) reduces the risk of preterm birth; genetic variation in sulfonylurea drug targets (OR, 0.015; 95% CI, 2.50E-04 to 0.919; P=0.045) and genetic variation in thiazolidinedione drug targets (OR, 0.007; 95% CI, 4.16E-04 to 0.121; P=0.001) reduced the risk of eclampsia/preeclampsia; glucagon-like peptide 1 (GLP-1) analogues target (β=–0.549; 95% CI, –0.958 to –0.140; P=0.009) was inversely associated with fetal birth weight; thiazolidinedione target was inversely associated with gestational age (β=–0.952; 95% CI, –1.785 to –0.118; P=0.025); SGLT2 inhibitors reduced the risk of cardiocirculatory malformations (OR, 0.001; 95% CI, 8.75E-06 to 0.126; P=0.005).
Conclusion
Most antidiabetic drugs are safe when used during the perinatal period. Of note, GLP-1 analogues may lead to a risk of low birth weight, while thiazolidinediones may lead to a reduction in fetal gestational age.

Basic and Translational Research
Phosphodiesterase 5 Inhibitor Improves Insulin Sensitivity by Regulating Adipose Tissue Macrophage Polarization in Diet-Induced Obese Mice: Dan-Gyeong Song, Seongwon Pak, Dae-Chul Shin, Shindy Soedono, Kae Won Cho, Yejin Park, Subin Moon, Sooyeon Jang, Saeha Kim, Sang-Won Han, Keunwook Lee, Jong-Hee Sohn, Chan Hee Lee; Received June 14, 2024 Accepted February 25, 2025 Published online May 22, 2025; DOI: https://doi.org/10.4093/dmj.2024.0308 [Epub ahead of print]

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Background
Obesity is a rapidly increasing global health issue, which is associated with glucose and insulin resistance. Phosphodiesterase type 5 (PDE5) inhibitors (PDE5i) are known for their ability to enhance blood flow and vascular stability and are widely used to treat conditions such as erectile dysfunction, pulmonary hypertension, heart failure, and cancer. However, studies investigating the role of PDE5i in alleviating obesity and metabolic diseases remains unclear. Therefore, we investigated the effects of PDE5i on obesity and metabolic disorders in diet-induced obese mice and its underlying mechanisms.
Methods
PDE5i was administered to high-fat diet (HFD)-fed C57BL/6J mice for 6 to 7 weeks. Body weight and food intake were measured weekly, and baseline metabolic rates, physical activity, and glucose and insulin tolerance tests were assessed during PDE5i administration. Macrophages and T-cells in the gonadal white adipose tissue (gWAT) were analyzed by flow cytometry. Vascular stability and blood flow in gWAT were analyzed via immunostaining and in vivo live imaging. RAW264.7 cells and bone marrow-derived macrophages were used to determine immunoregulatory effects of PDE5i.
Results
In HFD-fed mice, PDE5i administration significantly enhanced systemic insulin sensitivity and AKT phosphorylation in gWAT. PDE5i reduced the M1/M2 ratio of gWAT macrophages of obese mice. These phenomena were associated with enhanced blood flow to the gWAT. In vitro experiments revealed that PDE5i suppressed lipopolysaccharide-induced proinflammatory cytokine production and increased the mRNA expression of genes associated with M2 polarization.
Conclusion
PDE5i plays a role in regulating adipose tissue inflammation and thus holds promise as a therapeutic agent for metabolic enhancement.

Citations

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Beyond Cyclic Nucleotides: Emerging Roles of Phosphodiesterases in Metabolic Disorders
Nicole Bertani, Maria Rita Assenza, Francesca Sciarra, Giorgia D’Addato, Francesca Gioia Klinger, Mary Anna Venneri, Andrea M. Isidori, Federica Campolo
Frontiers in Bioscience-Landmark.2025;[Epub] CrossRef

Pharmacotherapy
Initial Pharmacological Strategies in People with Early Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis: Jong Han Choi, Bo Kyung Koo, Ye Seul Yang, Se Hee Min, Jong Suk Park, Sang Youl Rhee, Hyun Jung Kim, Min Kyong Moon; Diabetes Metab J. 2025;49(6):1252-1261. Published online April 29, 2025; DOI: https://doi.org/10.4093/dmj.2024.0660

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Abstract PDF Supplementary Material PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) requires stringent glycemic control from an early stage to prevent complications. The most effective treatment regimen for early T2DM remains unclear. The study aimed to compare the efficacy and safety of monotherapies and combination therapies for early T2DM.
Methods
A systematic review and network meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized controlled trials focused on glycemic control, body weight, and adverse events were included. The primary outcomes were changes in glycosylated hemoglobin (HbA1c) and odds of achieving the target HbA1c after 6 months.
Results
All combination therapies were more effective than monotherapy. Metformin+glucagon-like peptide-1 receptor agonists (GLP-1RA) (weighted mean difference [WMD] –1.50%; 95% confidence interval [CI] –2.04 to –0.96) and metformin+dipeptidyl peptidase-4 inhibitors (WMD –1.46%; 95% CI, –1.96 to –0.95) were the most effective for change in HbA1c. GLP-1RA and sodium- glucose cotransporter-2 inhibitors led to weight reduction. Apart from the increased risk of hypoglycemia with sulfonylureas, no significant differences in adverse events were observed across regimens.
Conclusion
Early combination therapy effectively improved glycemic control in patients with early T2DM without significantly increasing adverse risks. Future studies should explore new combinations, including potent GLP-1RA.

Basic and Translational Research
Macrophage-Specific Progranulin Deficiency Prevents Diet-Induced Obesity through the Inhibition of Hypothalamic and Adipose Tissue Inflammation: Chan Hee Lee, Chae Beom Park, Hyun-Kyong Kim, Won Hee Jang, Se Hee Min, Jae Bum Kim, Min-Seon Kim; Diabetes Metab J. 2025;49(4):784-797. Published online March 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0486

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

Citations

Citations to this article as recorded by

Role of Macrophage-Derived Progranulin in Energy and Glucose Metabolism
Do Kyeong Song
Diabetes & Metabolism Journal.2025; 49(4): 580. CrossRef
The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction
Milton Packer
JACC.2025; 86(16): 1269. CrossRef
Serum Granulin Concentrations Are Elevated in Prediabetes and Newly Diagnosed Diabetes: A Cross-Sectional Study
Yu-Hsuan Chou, Yuan Kao, Ka Chon Chan, Hsuan-Wen Chou, Yu-Cheng Liang, Hung-Tsung Wu, Horng-Yih Ou
Journal of Clinical Medicine.2025; 14(18): 6566. CrossRef

Guideline/Statement/Fact Sheet
Older Adults with Diabetes in Korea: Latest Clinical and Epidemiologic Trends: Kyuho Kim, Bongseong Kim, Kyuna Lee, Yu-Bae Ahn, Seung-Hyun Ko, Sung Hee Choi, Kyungdo Han, Jae-Seung Yun, on Behalf of the Committee of Public Relation of the Korean Diabetes Association; Diabetes Metab J. 2025;49(2):183-193. Published online March 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0836

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Background
Diabetes in older adults is becoming a significant public burden to South Korea. However, a comprehensive understanding of epidemiologic trends and the detailed clinical characteristics of older adults with diabetes is lacking. Therefore, we evaluated epidemiologic trends and the metabolic and lifestyle characteristics of diabetes in Korean older adults.
Methods
We analyzed data from the Korea National Health and Nutrition Examination Survey to assess diabetes prevalence according to diabetes duration and lifestyle behaviors. In addition, we drew upon the National Health Information Database of the National Health Insurance System to assess physical activity levels, antidiabetic medication use, polypharmacy, medication adherence, and major comorbidities.
Results
The absolute number of newly diagnosed cases of diabetes among older adults doubled over the past decade. Management rates of metabolic indicators were higher in older adults with diabetes compared to those without diabetes. The proportion of older adults with diabetes meeting the minimum recommended physical activity increased over the years. Compared to 10 years before, the use of dipeptidyl peptidase-4 inhibitor or sodium-glucose cotransporter-2 inhibitor had increased, as had comorbidities such as dyslipidemia, dementia, cancer, heart failure, atrial fibrillation, and chronic kidney disease. Initial medication adherence was significantly lower in those with end-stage kidney disease or dementia, insulin use, high-risk alcohol use, and living alone. Continuing insulin use 1 year after diagnosis of diabetes was significantly higher in those who initiated insulin therapy at diagnosis, had retinopathy, were on triple antidiabetic medications, and had a history of cancer.
Conclusion
Comprehensive management of metabolic indicators and physical activity is essential for older adults with diabetes. Improvements in prescribing guidelines, personalized management of age-related comorbidities, and individualized approaches that consider the heterogeneous nature of older adults with diabetes are desirable. Further research, such as high-quality cohort and intervention studies specific to older adults, is needed to establish evidence-based management for older adults with diabetes.

Citations

Citations to this article as recorded by

Rising mortality from electrolyte and acid–base imbalances in the United States (1999–2020): a joinpoint regression analysis of national trends and disparities
Zaima Afzaal, Asma Chaudhary, Inshal Uddin Khattak, Saba Aliha, Asad Khan, Anas M Din Bashir, Hameer Ali, Amnah Khan, Aizaz Anwar Khalid, Wania Khan, Touqeer Rehman, Maryam Atif, Areen Zia, Mazia Mahnoor, Rumman Javed, Saad Ahmed Waqas, Raheel Ahmed, Soma
Annals of Medicine & Surgery.2026; 88(1): 362. CrossRef
Exploring the Lack of Physical Activity among Adolescents Worldwide
Dalmacito A. Cordero Jr.
Diabetes & Metabolism Journal.2025; 49(3): 513. CrossRef
Clinical Considerations for Safe Use of SGLT2 Inhibitors
Jae-Seung Yun, Eonju Jeon
The Journal of Korean Diabetes.2025; 26(2): 60. CrossRef
A Position Statement on Management of Diabetes in Older Adults
Jae-Seung Yun, Jin Hwa Kim, Sung Hoon Yu, Kyung Ae Lee, Hye Seung Jung, Ji Hye Heo, Jong-Ha Baek, Dong Hyeok Cho
The Journal of Korean Diabetes.2025; 26(3): 141. CrossRef
Optimizing Physical Activity Strategies for Older Adults with Diabetes
Hyeon-Jin Yu, Doyoun Hong, Kyuho Kim, Ji Hye Heo, Dong-Hyeok Cho, Yoshitaka Hashimoto, Jae-Seung Yun
Diabetes & Metabolism Journal.2025; 49(6): 1178. CrossRef

Guideline/Statement/Fact Sheet
Prevalence, Incidence, and Metabolic Characteristics of Young Adults with Type 2 Diabetes Mellitus in South Korea (2010–2020): Ji Yoon Kim, Jiyoon Lee, Joon Ho Moon, Se Eun Park, Seung-Hyun Ko, Sung Hee Choi, Nam Hoon Kim; Diabetes Metab J. 2025;49(2):172-182. Published online March 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0826

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Background
This study aimed to examine trends in the prevalence, incidence, metabolic characteristics, and management of type 2 diabetes mellitus (T2DM) among young adults in South Korea.
Methods
Young adults with T2DM were defined as individuals aged 19 to 39 years who met the diagnostic criteria for T2DM. Data from the Korean National Health Insurance Service-Customized Database (2010–2020, n=225,497–372,726) were analyzed to evaluate trends in T2DM prevalence, incidence, metabolic profiles, comorbidities, and antidiabetic drug prescription. Additional analyses were performed using the Korea National Health and Nutrition Examination Survey.
Results
The prevalence of T2DM in young adults significantly increased from 1.02% in 2010 to 2.02% in 2020 (P<0.001), corresponding to 372,726 patients in 2020. Over the same period, the incidence rate remained stable within the range of 0.36% to 0.45%. Prediabetes prevalence steadily increased from 15.53% to 20.92%, affecting 3.87 million individuals in 2020. The proportion of young adults with T2DM who were obese also increased, with 67.8% having a body mass index (BMI) ≥25 kg/m² and 31.6% having a BMI ≥30 kg/m² in 2020. The prevalence of hypertension, dyslipidemia, and fatty liver disease also increased, reaching 34.2%, 79.8%, and 78.9%, respectively, in 2020. Although the overall pharmacological treatment rate remained low, the prescription of antidiabetic medications with weight-reducing properties increased over the study period.
Conclusion
The prevalence of T2DM among young adults in South Korea nearly doubled over the past decade. The strong association with obesity and metabolic comorbidities emphasizes the urgent need for targeted prevention and management strategies tailored to this population.

Citations

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Guideline/Statement/Fact Sheet
Diabetes Fact Sheets in Korea 2024: Se Eun Park, Seung-Hyun Ko, Ji Yoon Kim, Kyuho Kim, Joon Ho Moon, Nam Hoon Kim, Kyung Do Han, Sung Hee Choi, Bong Soo Cha; Diabetes Metab J. 2025;49(1):24-33. Published online January 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0818; Correction in: Diabetes Metab J 2025;49(3):524

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Background
This study aimed to investigate the prevalence, management, and comorbidities of diabetes mellitus among Korean adults.
Methods
Data from the Korea National Health and Nutrition Examination Survey (2019–2022) were analyzed to assess the prevalence, treatment, risk factors, and comorbidities of diabetes. Comparisons between young and older adults with diabetes were emphasized.
Results
Among Korean adults aged ≥30 years, the prevalence of diabetes is 15.5% during 2021–2022. Of these, 74.7% were aware of their condition, 70.9% received antidiabetic treatment, and only 32.4% achieved glycosylated hemoglobin (HbA1c) <6.5%. Moreover, 15.9% met the integrated management targets, which included HbA1c <6.5%, blood pressure <140/85 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL. In young adults aged 19 to 39 years, the prevalence of diabetes was 2.2%. Among them, 43.3% were aware of their condition, 34.6% received treatment, and 29.6% achieved HbA1c <6.5%. Obesity affected 87.1%, and 26.9% had both hypertension and hypercholesterolemia. Among adults aged ≥65 years, the prevalence of diabetes was 29.3%, with awareness, treatment, and control rates of 78.8%, 75.7%, and 31.2%, respectively. Integrated management targets (HbA1c <7.5%, hypertension, and lipids) were achieved by 40.1%.
Conclusion
Diabetes mellitus remains highly prevalent among Korean adults, with significant gaps in integrated glycemic, blood pressure, and lipid control. Older adults with diabetes show higher awareness and treatment rates but limited integrated management outcomes. Young adults with diabetes bear a significant burden of obesity and comorbidities, alongside low awareness and treatment rates. Therefore, early intervention programs, education, and strategies tailored to younger populations are urgently required.

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Reviews

Drug/Regimen
Benefit and Safety of Sodium-Glucose Co-Transporter 2 Inhibitors in Older Patients with Type 2 Diabetes Mellitus: Ja Young Jeon, Dae Jung Kim; Diabetes Metab J. 2024;48(5):837-846. Published online September 1, 2024; DOI: https://doi.org/10.4093/dmj.2024.0317

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People with type 2 diabetes mellitus (T2DM) are at higher risk of developing cardiovascular disease, heart failure, chronic kidney disease, and premature death than people without diabetes. Therefore, treatment of diabetes aims to reduce these complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown beneficial effects on cardiorenal and metabolic health beyond glucose control, making them a promising class of drugs for achieving the ultimate goals of diabetes treatment. However, despite their proven benefits, the use of SGLT2 inhibitors in eligible patients with T2DM remains suboptimal due to reports of adverse events. The use of SGLT2 inhibitors is particularly limited in older patients with T2DM because of the lack of treatment experience and insufficient long-term safety data. This article comprehensively reviews the risk-benefit profile of SGLT2 inhibitors in older patients with T2DM, drawing on data from prospective randomized controlled trials of cardiorenal outcomes, original studies, subgroup analyses across different age groups, and observational cohort studies.

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Others
Holistic and Personalized Strategies for Managing in Elderly Type 2 Diabetes Patients: Jae-Seung Yun, Kyuho Kim, Yu-Bae Ahn, Kyungdo Han, Seung-Hyun Ko; Diabetes Metab J. 2024;48(4):531-545. Published online July 26, 2024; DOI: https://doi.org/10.4093/dmj.2024.0310

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Due to increased life expectancy and lifestyle changes, the prevalence of diabetes among the elderly in Korea is continuously rising, as is the associated public health burden. Diabetes management in elderly patients is complicated by age-related physiological changes, sarcopenia characterized by loss of muscle mass and function, comorbidities, and varying levels of functional, cognitive, and mobility abilities that lead to frailty. Moreover, elderly patients with diabetes frequently face multiple chronic conditions that elevate their risk of cardiovascular diseases, cancer, and mortality; they are also prone to complications such as hyperglycemic hyperosmolar state, diabetic ketoacidosis, and severe hypoglycemia. This review examines the characteristics of and management approaches for diabetes in the elderly, and advocates for a comprehensive yet personalized strategy.

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The effect of multidisciplinary team and experience-based co-design on the care of older adult patients with type 2 diabetes: A randomized controlled trial
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Diabetes Research and Clinical Practice.2025; 221: 112028. CrossRef
Older Adults with Diabetes in Korea: Latest Clinical and Epidemiologic Trends
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Hyeon-Jin Yu, Doyoun Hong, Kyuho Kim, Ji Hye Heo, Dong-Hyeok Cho, Yoshitaka Hashimoto, Jae-Seung Yun
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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; Diabetes Metab J. 2024;48(5):885-900. Published online May 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0278

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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.

Citations

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Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)
Yea Eun Kang, Ju Hee Lee
Diabetes & Metabolism Journal.2025; 49(1): 160. CrossRef
Single-Cell Landscape and a Macrophage Subset Enhancing Brown Adipocyte Function in Diabetes (Diabetes Metab J 2024;48:885-900)
Junfei Gu, Xinjie Zhang, Qunye Zhang, Zhe Wang
Diabetes & Metabolism Journal.2025; 49(1): 162. CrossRef
Engineered stromal vascular fraction for tissue regeneration
Jianfeng Liu, Yiwei Li, Yanan Zhang, Zhiwei Zhao, Bin Liu
Frontiers in Pharmacology.2025;[Epub] CrossRef

Drug/Regimen
Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial: Ji-Yeon Park, Joonyub Lee, Yoon-Hee Choi, Kyung Wan Min, Kyung Ah Han, Kyu Jeung Ahn, Soo Lim, Young-Hyun Kim, Chul Woo Ahn, Kyung Mook Choi, Kun-Ho Yoon, the Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) study investigators; Diabetes Metab J. 2024;48(5):915-928. Published online April 23, 2024; DOI: https://doi.org/10.4093/dmj.2023.0259

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Background
Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy.
Methods
The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety.
Results
After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were –1.38%±0.08%, –1.03%±0.08%, and –0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy.
Conclusion
Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

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Metabolic Risk/Epidemiology
Harnessing Metabolic Indices as a Predictive Tool for Cardiovascular Disease in a Korean Population without Known Major Cardiovascular Event: Hyun-Jin Kim, Byung Sik Kim, Yonggu Lee, Sang Bong Ahn, Dong Wook Kim, Jeong-Hun Shin; Diabetes Metab J. 2024;48(3):449-462. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0197

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Background
This study evaluated the usefulness of indices for metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and insulin resistance (IR), as predictive tools for cardiovascular disease in middle-aged Korean adults.
Methods
The prospective data obtained from the Ansan-Ansung cohort database, excluding patients with major adverse cardiac and cerebrovascular events (MACCE). The primary outcome was the incidence of MACCE during the follow-up period.
Results
A total of 9,337 patients were included in the analysis, of whom 1,130 (12.1%) experienced MACCE during a median follow-up period of 15.5 years. The metabolic syndrome severity Z-score, metabolic syndrome severity score, hepatic steatosis index, and NAFLD liver fat score were found to significantly predict MACCE at values above the cut-off point and in the second and third tertiles. Among these indices, the hazard ratios of the metabolic syndrome severity score and metabolic syndrome severity Z-score were the highest after adjusting for confounding factors. The area under the receiver operating characteristic curve (AUC) of the 10-year atherosclerotic cardiovascular disease (ASCVD) score for predicting MACCE was 0.716, and the metabolic syndrome severity Z-score had an AUC of 0.619.
Conclusion
The metabolic syndrome severity score is a highly reliable indicator and was closely associated with the 10-year ASCVD risk score in predicting MACCE in the general population. Given the specific characteristics and limitations of metabolic syndrome severity scores as well as the indices of NAFLD and IR, a more practical scoring system that considers these factors is essential to achieve greater accuracy in forecasting cardiovascular outcomes.

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Comparing non-alcoholic fatty liver disease indices in predicting the prevalence and incidence of metabolic syndrome in middle-aged adults
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Others
Comparative Effect of Glucose-Lowering Drugs for Type 2 Diabetes Mellitus on Stroke Prevention: A Systematic Review and Network Meta-Analysis: Ji Soo Kim, Gyeongsil Lee, Kyung-Il Park, Seung-Won Oh; Diabetes Metab J. 2024;48(2):312-320. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2022.0421

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Background
There is still a lack of research on which diabetic drugs are more effective in preventing stroke. Our network metaanalysis aimed to compare cerebrovascular benefits among glucose-lowering treatments.
Methods
We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry for clinical trials from inception through May 25, 2021. We included both prespecified cerebrovascular outcomes and cerebrovascular events reported as severe adverse events. Subgroup analyses were conducted by stroke subtype, publication type, age of patients, baseline glycosylated hemoglobin (HbA1c), duration of type 2 diabetes mellitus, and cardiovascular risks.
Results
Of 2,861 reports and 1,779 trials screened, 79 randomized controlled trials comprising 206,387 patients fulfilled the inclusion criteria. In the pairwise meta-analysis, the use of glucagon-like peptide-1 (GLP-1) agonist was associated with a lower risk of total stroke compared with placebo (relative risk [RR], –0.17; 95% confidence interval [CI], –0.27 to –0.07). In the network meta- analysis, only the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitor was associated with a reduction of total stroke, compared with placebo (RR, 0.81; 95% CI, 0.67 to 0.98). In the subgroup analyses, the use of SGLT-2 inhibitor and GLP-1 agonist was associated with a lower risk of stroke in those with high HbA1c (≥8.0) and low-risk of cardiovascular disease, respectively.
Conclusion
SGLT-2 inhibitors and GLP-1 agonists were shown to be beneficial for stroke prevention in patients with type 2 diabetes mellitus.

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Zhiqing Chen, Hongmei Meng, Yujin Guo, Huaiyu Sun, Wuqiong Zhang, Yu Guo, Shuai Hou
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Basic Research
A New Concept in Antidiabetic Therapeutics: A Concerted Removal of Labile Iron and Intracellular Deposition of Zinc: Vladimir Vinokur, Eduard Berenshtein, Mordechai Chevion, Dror Chevion; Diabetes Metab J. 2024;48(1):59-71. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0292; Retraction in: Diabetes Metab J 2024;48(2):325

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Guideline/Fact Sheet
Dyslipidemia Fact Sheet in South Korea, 2022: Eun-Sun Jin, Jee-Seon Shim, Sung Eun Kim, Jae Hyun Bae, Shinae Kang, Jong Chul Won, Min-Jeong Shin, Heung Yong Jin, Jenny Moon, Hokyou Lee, Hyeon Chang Kim, In-Kyung Jeong, on Behalf of the Committee of Public Relation of the Korean Society of Lipid and Atherosclerosis; Diabetes Metab J. 2023;47(5):632-642. Published online August 2, 2023; DOI: https://doi.org/10.4093/dmj.2023.0135

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Background
This study aimed to investigate the prevalence and status of dyslipidemia management among South Korean adults, as performed by the Korean Society of Lipid and Atherosclerosis under the name Dyslipidemia Fact Sheet 2022.
Methods
We analyzed the lipid profiles, age-standardized and crude prevalence, management status of hypercholesterolemia and dyslipidemia, and health behaviors among Korean adults aged ≥20 years, using the Korea National Health and Nutrition Examination Survey data between 2007 and 2020.
Results
In South Korea, the crude prevalence of hypercholesterolemia (total cholesterol ≥240 mg/dL or use of a lipid-lowering drug) in 2020 was 24%, and the age-standardized prevalence of hypercholesterolemia more than doubled from 2007 to 2020. The crude treatment rate was 55.2%, and the control rate was 47.7%. The crude prevalence of dyslipidemia—more than one out of three conditions (low-density lipoprotein cholesterol ≥160 or the use of a lipid-lowering drug, triglycerides ≥200, or high-density lipoprotein cholesterol [HDL-C] [men and women] <40 mg/dL)—was 40.2% between 2016 and 2020. However, it increased to 48.2% when the definition of hypo-HDL-cholesterolemia in women changed from <40 to <50 mg/dL.
Conclusion
Although the prevalence of hypercholesterolemia and dyslipidemia has steadily increased in South Korea, the treatment rate remains low. Therefore, continuous efforts are needed to manage dyslipidemia through cooperation between the national healthcare system, patients, and healthcare providers.

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Drug Regimen
Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus: A 24-Week, Double-Blind, Randomized Trial: Kyung Ah Han, Yong Hyun Kim, Doo Man Kim, Byung Wan Lee, Suk Chon, Tae Seo Sohn, In Kyung Jeong, Eun-Gyoung Hong, Jang Won Son, Jae Jin Nah, Hwa Rang Song, Seong In Cho, Seung-Ah Cho, Kun Ho Yoon; Diabetes Metab J. 2023;47(6):796-807. Published online February 9, 2023; DOI: https://doi.org/10.4093/dmj.2022.0315

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Background
Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin.
Methods
In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500).
Results
Adjusted mean change of HbA1c at week 24 was –0.80% with enavogliflozin and –0.75% with dapagliflozin (difference, –0.04%; 95% confidence interval, –0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was –32.53 and –29.14 mg/dL. An increase in urine glucose-creatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (–1.85 vs. –1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (–3.77 kg vs. –3.58 kg) and blood pressure (systolic/diastolic, –5.93/–5.41 mm Hg vs. –6.57/–4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated.
Conclusion
Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was non-inferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone.

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Leqing Xu, Yike Wu, Jiyifan Li, Yanan Ding, Junwei Chow, Longzhou Li, Haiyang Liu, Zihan Wang, Tingting Gong, Yue Li, Guo Ma
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Reverse translational approach to clarify the strong potency of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor
Sun-Hwa Park, Hye-Young Ji, Ji-Soo Choi, Kyung Seok Oh, Jihoon Lee, Minyeong Pang, Im-Sook Song, Joon Seok Park
The Journal of Pharmacology and Experimental Therapeutics.2025; 392(8): 103650. CrossRef
Combined effects of Yupingfeng and metformin on blood glucose levels and intestinal tissue in high-fat diet-induced type 2 diabetic rats
Hui Liu, Yuan Guan, Like Xu, Ji Hu
Frontiers in Endocrinology.2025;[Epub] CrossRef
Comparison of safety profile of DPP4 inhibitors with SGLT2 inhibitors in type 2 diabetes mellitus: systematic review
Zeel R. Nimavat, Ankit N. Patel, Alpa P. Gor, Barna Ganguly
International Journal of Basic & Clinical Pharmacology.2025;[Epub] CrossRef
Weight-independent amelioration of adipokine profile by enavogliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes
Young Sang Lyu, Hansol Lee, Kyung-Soo Kim, Sangmo Hong, Cheol-Young Park
Cardiovascular Diabetology.2025;[Epub] CrossRef
Pharmacokinetics and Safety of Fixed‐Dose Versus Separate Enavogliflozin/Gemigliptin Combinations, and Food Effect on Enavogliflozin in Healthy Korean Subjects
Young‐Sim Choi, JAEJIN NA, Seo Yeong Park, Jae Min Cho, Yoonhye Jeong, Jun Gi Hwang
Clinical and Translational Science.2025;[Epub] CrossRef
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Francois Alhenc-Gelas
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Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials
Young Sang Lyu, Sangmo Hong, Si Eun Lee, Bo Young Cho, Cheol-Young Park
Cardiovascular Diabetology.2024;[Epub] CrossRef
A 52‐week efficacy and safety study of enavogliflozin versus dapagliflozin as an add‐on to metformin in patients with type 2 diabetes mellitus: ENHANCE‐M extension study
Tae Seo Sohn, Kyung‐Ah Han, Yonghyun Kim, Byung‐Wan Lee, Suk Chon, In‐Kyung Jeong, Eun‐Gyoung Hong, Jang Won Son, JaeJin Na, Jae Min Cho, Seong In Cho, Wan Huh, Kun‐Ho Yoon
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The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium‐glucose cotransporter‐2 inhibitor, in type 2 diabetes
Sae Im Jeong, Mu Seong Ban, Jun‐Gi Hwang, Min‐Kyu Park, Soo Lim, Sejoong Kim, Soon Kil Kwon, Yoonjin Kim, Jae Min Cho, Jae Jin Na, Wan Huh, Jae‐Yong Chung
Diabetes, Obesity and Metabolism.2024; 26(7): 2588. CrossRef
Long‐term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52‐week extension of a Phase 3 randomized controlled trial
Soo Heon Kwak, Kyung Ah Han, Eun Sook Kim, Sung Hee Choi, Jong Chul Won, Jae Myung Yu, Seungjoon Oh, Hye Jin Yoo, Chong Hwa Kim, Kyung‐Soo Kim, SungWan Chun, Yong Hyun Kim, Seung Ah Cho, Da Hye Kim, Kyong Soo Park
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Role of novel sodium glucose co-transporter-2 inhibitor enavogliflozin in type-2 diabetes: A systematic review and meta-analysis
Deep Dutta, B.G. Harish, Beatrice Anne, Lakshmi Nagendra
Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2023; 17(8): 102816. CrossRef
Characteristics of the Latest Therapeutic Agent for Diabetes
Nuri Yun
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Iryna Kostitska, Nadia Protas, Liliia Petrovska
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Navigating the Future of Diabetes Treatment with New Drugs: Focusing on the Possibilities and Prospects of Enavogliflozin
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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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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.

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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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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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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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Original Articles

Drug/Regimen
Safety and Effectiveness of Empagliflozin in Korean Patients with Type 2 Diabetes Mellitus: Results from a Nationwide Post-Marketing Surveillance: Jun Sung Moon, Nam Hoon Kim, Jin Oh Na, Jae Hyoung Cho, In-Kyung Jeong, Soon Hee Lee, Ji-Oh Mok, Nan Hee Kim, Dong Jin Chung, Jinhong Cho, Dong Woo Lee, Sun Woo Lee, Kyu Chang Won; Diabetes Metab J. 2023;47(1):82-91. Published online June 20, 2022; DOI: https://doi.org/10.4093/dmj.2021.0356

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Background
To evaluate the safety and effectiveness of empagliflozin in routine clinical settings, we collected and assessed the clinical profiles of Korean patients with type 2 diabetes mellitus.
Methods
This was a post-marketing surveillance study of empagliflozin 10 and 25 mg. Information on adverse events and adverse drug reactions (ADRs) was collected as safety data sets. Available effectiveness outcomes, including glycosylated hemoglobin (HbA1c) level, fasting plasma glucose, body weight, and blood pressure, were assessed.
Results
The incidence rate of ADRs was 5.14% in the safety dataset (n=3,231). Pollakiuria, pruritis genital, and weight loss were the most common ADRs. ADRs of special interest accounted for only 1.18%, and there were no serious events that led to mortality or hospitalization. In the effectiveness data set (n=2,567), empagliflozin significantly reduced the mean HbA1c level and body weight during the study period by –0.68%±1.39% and –1.91±3.37 kg (both P<0.0001), respectively. In addition, shorter disease duration, absence of dyslipidemia, and higher baseline HbA1c levels were identified as the clinical features characteristic of a “responder” to empagliflozin therapy.
Conclusion
Empagliflozin is a safe and potent glucose-lowering drug in routine use among Korean patients with type 2 diabetes mellitus. It is expected to have better glycemic efficacy in Korean patients with poorly controlled type 2 diabetes mellitus.

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Mohammad Saifuddin, Ajit K. Paul, Sultana M. Shefin, Md. Jahangir Alam, Shahjada Selim, Sunjida Islam, Tanjina Hossain, Sadiqa Tuqan, Nusrat Sultana, Marufa Mustari, Ramen C. Basak, Kazi A. Aftab, Indrajit Prasad, Mohammad R. Uddin, Shoma Sharker, Md. Abu
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Guideline/Fact Sheet
Diabetes Fact Sheet in Korea 2021: Jae Hyun Bae, Kyung-Do Han, Seung-Hyun Ko, Ye Seul Yang, Jong Han Choi, Kyung Mook Choi, Hyuk-Sang Kwon, Kyu Chang Won, on Behalf of the Committee of Media-Public Relation of the Korean Diabetes Association; Diabetes Metab J. 2022;46(3):417-426. Published online May 25, 2022; DOI: https://doi.org/10.4093/dmj.2022.0106

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Background
This study aimed to investigate the prevalence and management of diabetes mellitus, risk-factor control, and comorbidities among Korean adults.
Methods
We conducted a cross-sectional analysis of data from the Korea National Health and Nutrition Examination Survey to assess the prevalence, treatment, risk factors, comorbidities, and self-management behaviors of diabetes mellitus from 2019 to 2020. We also analyzed data from the Korean National Health Insurance Service to evaluate the use of antidiabetic medications in people with diabetes mellitus from 2002 through 2018.
Results
Among Korean adults aged 30 years or older, the estimated prevalence of diabetes mellitus was 16.7% in 2020. From 2019 through 2020, 65.8% of adults with diabetes mellitus were aware of the disease and treated with antidiabetic medications. The percentage of adults with diabetes mellitus who achieved glycosylated hemoglobin (HbA1c) <6.5% was 24.5% despite the increased use of new antidiabetic medications. We found that adults with diabetes mellitus who achieved all three goals of HbA1c <6.5%, blood pressure (BP) <140/85 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL were 9.7%. The percentage of self-management behaviors was lower in men than women. Excess energy intake was observed in 16.7% of adults with diabetes mellitus.
Conclusion
The prevalence of diabetes mellitus among Korean adults remained high. Only 9.7% of adults with diabetes mellitus achieved all glycemic, BP, and lipid controls from 2019 to 2020. Continuous evaluation of national diabetes statistics and a national effort to increase awareness of diabetes mellitus and improve comprehensive diabetes care are needed.

Citations

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2023 Clinical Practice Guidelines for Diabetes Management in Korea: Full Version Recommendation of the Korean Diabetes Association
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Journal of Korean Gerontological Nursing.2024; 26(3): 257. CrossRef
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Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial
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Diabetes, Metabolic Syndrome and Obesity.2024; Volume 17: 3917. CrossRef
Association between the duration of oral contraceptive use and the prevalence of type 2 diabetes mellitus: Korea National Health and Nutrition Examination Survey (KNHANES) 2007–2021
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종한 최, 민경 문
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Respiratory Research.2024;[Epub] CrossRef
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Cardiovascular Disease & Diabetes Statistics in Korea: Nationwide Data 2010 to 2019
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Adherence to ADA Clinical Guidelines in Type 2 Diabetes Management in Public Health Clinics in Palestine
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Risk of Pancreatic Cancer and Use of Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes: A Propensity Score-Matching Analysis
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Response to Letter to the Editor From Han and Xu: “Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients With Diabetes”
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Lipid Management in Korean People With Type 2 Diabetes Mellitus: Korean Diabetes Association and Korean Society of Lipid and Atherosclerosis Consensus Statement
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Lipid Management in Korean People with Type 2 Diabetes Mellitus: Korean Diabetes Association and Korean Society of Lipid and Atherosclerosis Consensus Statement
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Evaluation and Management of Patients with Diabetes and Heart Failure: A Korean Diabetes Association and Korean Society of Heart Failure Consensus Statement
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Diabetes and Skin Disease
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The Journal of Korean Diabetes.2023; 24(1): 29. CrossRef
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Cardiovascular Risk/Epidemiology
Myocardial Infarction, Stroke, and All-Cause Mortality according to Low-Density Lipoprotein Cholesterol Level in the Elderly, a Nationwide Study: You-Bin Lee, Minji Koo, Eunjin Noh, Soon Young Hwang, Jung A Kim, Eun Roh, So-hyeon Hong, Kyung Mook Choi, Sei Hyun Baik, Geum Joon Cho, Hye Jin Yoo; Diabetes Metab J. 2022;46(5):722-732. Published online March 8, 2022; DOI: https://doi.org/10.4093/dmj.2021.0225

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Background
We assessed the myocardial infarction (MI), stroke, and all-cause death risks during follow-up according to the low-density lipoprotein cholesterol (LDL-C) levels among older adults.
Methods
The Korean National Health Insurance Service datasets (2002 to 2020) were used for this population-based cohort study. The hazards of MI, stroke, and all-cause mortality during follow-up were analyzed according to LDL-C level in individuals aged ≥65 years without baseline cardiovascular diseases (n=1,391,616).
Results
During a mean 7.55 years, 52,753 MIs developed; 84,224 strokes occurred over a mean 7.47 years. After a mean 8.50 years, 233,963 died. A decrease in LDL-C was associated with lower hazards of MI and stroke. The decreased hazard of stroke in lower LDL-C was more pronounced in statin users, and individuals with diabetes or obesity. The hazard of all-cause death during follow-up showed an inverted J-shaped pattern according to the LDL-C levels. However, the paradoxically increased hazard of mortality during follow-up in lower LDL-C was attenuated in statin users and individuals with diabetes, hypertension, or obesity. In statin users, lower LDL-C was associated with a decreased hazard of mortality during follow-up.
Conclusion
Among the elderly, lower LDL-C was associated with decreased risks of MI and stroke. Lower LDL-C achieved by statins in the elderly was associated with a decreased risk of all-cause death during follow-up, suggesting that LDL-C paradox for the premature death risk in the elderly should not be applied to statin users. Intensive statin therapy should not be hesitated for older adults with cardiovascular risk factors including diabetes.

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COVID-19
Effects of Social Distancing on Diabetes Management in Older Adults during COVID-19 Pandemic: Soo Myoung Shin, Tae Jung Oh, Sung Hee Choi, Hak Chul Jang; Diabetes Metab J. 2021;45(5):765-772. Published online August 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0096

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Background
On March 22, 2020, intense social distancing (SD) was implemented in Korea to prevent the spread of coronavirus disease 19 (COVID-19). This study examined the impact of SD on diabetes control in older adults with diabetes.
Methods
Adults aged 60 to 90 years with type 2 diabetes mellitus who were physically and mentally independent were recruited. Participants who had complete blood chemistry data from April to July 2019 (pre-SD era) and April to July 2020 (SD era) were enrolled. Data were obtained about physical activity, nutrition, sarcopenia, and psychological and mental health from questionnaires in April to July 2020. Calf circumference was measured.
Results
In total, 246 people (100 men, 146 women; mean age, 73.8±5.7 years) participated in this study. The levels of glycated hemoglobin (HbA1c, 7.4%±1.0% vs. 7.1%±0.8%, P<0.001), fasting glucose (142.2±16.7 mg/dL vs. 132.0±27.7 mg/dL, P<0.001), and body weight (62.6±9.4 kg vs. 61.8±10.1 kg, P<0.01) were higher in the SD era than in the pre-SD era. Total physical activity was lower in the SD era (2,584.6±2,624.1 MET-min/week^–1 vs. 1,987.3±2,295.0 MET-min/week^–1, P<0.001). A larger increase in HbA1c level was associated with increased body weight and decreased physical activity.
Conclusion
SD had negative effects on diabetes management in older adults with diabetes. Fasting glucose and HbA1c levels and body weight increased during the SD era. Participants with reduced physical activity gained more weight and had higher blood glucose levels. Given that the COVID-19 pandemic is ongoing, health professionals and diabetes educators should monitor changes in lifestyle factors in older adults with diabetes.

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Drug/Regimen
Effects of Teneligliptin on HbA1c levels, Continuous Glucose Monitoring-Derived Time in Range and Glycemic Variability in Elderly Patients with T2DM (TEDDY Study): Ji Cheol Bae, Soo Heon Kwak, Hyun Jin Kim, Sang-Yong Kim, You-Cheol Hwang, Sunghwan Suh, Bok Jin Hyun, Ji Eun Cha, Jong Chul Won, Jae Hyeon Kim; Diabetes Metab J. 2022;46(1):81-92. Published online June 16, 2021; DOI: https://doi.org/10.4093/dmj.2021.0016

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Background
To evaluate the effects of teneligliptin on glycosylated hemoglobin (HbA1c) levels, continuous glucose monitoring (CGM)-derived time in range, and glycemic variability in elderly type 2 diabetes mellitus patients.
Methods
This randomized, double-blinded, placebo-controlled study was conducted in eight centers in Korea (clinical trial registration number: NCT03508323). Sixty-five participants aged ≥65 years, who were treatment-naïve or had been treated with stable doses of metformin, were randomized at a 1:1 ratio to receive 20 mg of teneligliptin (n=35) or placebo (n=30) for 12 weeks. The main endpoints were the changes in HbA1c levels from baseline to week 12, CGM metrics-derived time in range, and glycemic variability.
Results
After 12 weeks, a significant reduction (by 0.84%) in HbA1c levels was observed in the teneligliptin group compared to that in the placebo group (by 0.08%), with a between-group least squares mean difference of –0.76% (95% confidence interval [CI], –1.08 to –0.44). The coefficient of variation, standard deviation, and mean amplitude of glycemic excursion significantly decreased in participants treated with teneligliptin as compared to those in the placebo group. Teneligliptin treatment significantly decreased the time spent above 180 or 250 mg/dL, respectively, without increasing the time spent below 70 mg/dL. The mean percentage of time for which glucose levels remained in the 70 to 180 mg/dL time in range (TIR70–180) at week 12 was 82.0%±16.0% in the teneligliptin group, and placebo-adjusted change in TIR70–180 from baseline was 13.3% (95% CI, 6.0 to 20.6).
Conclusion
Teneligliptin effectively reduced HbA1c levels, time spent above the target range, and glycemic variability, without increasing hypoglycemia in our study population.

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Drug/Regimen
Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors: Sangmo Hong, Chang Hee Jung, Song Han, Cheol-Young Park; Diabetes Metab J. 2022;46(1):63-70. Published online April 19, 2021; DOI: https://doi.org/10.4093/dmj.2020.0253

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Background
It is not known which type 2 diabetes mellitus (T2DM) patients would most benefit from dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. We aimed to investigate the predictors of response to DPP-4 inhibitors considering degree of DPP-4 inhibition.
Methods
This study is a post hoc analysis of a 24-week, randomized, double-blind, phase III trial that compared the efficacy and safety of a DPP-4 inhibitor (gemigliptin vs. sitagliptin) in patients with T2DM. Subjects were classified into tertiles of T1 <65.26%, T2=65.26%–76.35%, and T3 ≥76.35% by DPP-4 inhibition. We analyzed the change from baseline in glycosylated hemoglobin (HbA1c) according to DPP-4 inhibition with multiple linear regression adjusting for age, ethnicity, body mass index, baseline HbA1c, and DPP-4 activity at baseline.
Results
The mean age was greater in the high tertile group compared with the low tertile group (T1: 49.8±8.3 vs. T2: 53.1±10.5 vs. T3: 55.3±9.5, P<0.001) of DPP-4 inhibition. Although HbA1c at baseline was not different among tertiles of DPP-4 inhibition (P=0.398), HbA1c after 24-week treatment was lower in the higher tertile compares to the lower tertile (T1: 7.30%±0.88% vs. T2: 7.12%±0.78% vs. T3: 7.00%±0.78%, P=0.021). In multiple regression analysis, DPP-4 enzyme inhibition rate was not a significant determent for HbA1c reduction due to age. In subgroup analysis by tertile of DPP-4 inhibition, age was the only significant predictor and only in the highest tertile (R²=0.281, B=–0.014, P=0.024).
Conclusion
This study showed that HbA1c reduction by DPP-4 inhibitor was associated with increasing age, and this association was linked with higher DPP-4 inhibition.

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Basic Research
The Effects of Exercise and Restriction of Sugar-Sweetened Beverages on Muscle Function and Autophagy Regulation in High-Fat High-Sucrose-Fed Obesity Mice: Didi Zhang, Ji Hyun Lee, Hyung Eun Shin, Seong Eun Kwak, Jun Hyun Bae, Liang Tang, Wook Song; Diabetes Metab J. 2021;45(5):773-786. Published online March 25, 2021; DOI: https://doi.org/10.4093/dmj.2020.0157

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Background
Autophagy maintains muscle mass and healthy skeletal muscles. Several recent studies have associated sugar-sweetened beverage (SSB) consumption with diseases. We investigated whether muscle dysfunction due to obesity could be restored by SSB restriction (SR) alone or in combination with exercise (EX) training.
Methods
Obese mice were subjected to SR combined with treadmill EX. Intraperitoneal glucose tolerance test, grip strength test, hanging time test, and body composition analysis were performed. Triglyceride (TG) and total cholesterol (TC) serum concentrations and TG concentrations in quadriceps muscles were analyzed. Western blot and reverse transcription-quantitative polymerase chain reaction helped analyze autophagy-related protein and mRNA expression, respectively.
Results
SR alone had no significant effect on fasting blood glucose levels, glucose tolerance, and muscle function. However, it had effect on serum TC, serum TG, and BCL2 interacting protein 3 expression. SR+EX improved glucose tolerance and muscle function and increased serum TC utilization than SR alone. SR+EX reduced P62 levels, increased glucose transporter type 4 and peroxisome proliferator-activated receptor γ coactivator-1α protein expression, and improved grip strength relative to the high-fat and high-sucrose liquid (HFHS) group, and this was not observed in the HFHS+EX group.
Conclusion
SR induced mitophagy-related protein expression in quadriceps, without affecting muscle function. And, the combination of SR and EX activated mitophagy-related proteins and improved muscle function.

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Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression
Rajakrishnan Veluthakal, Diana Esparza, Joseph M. Hoolachan, Rekha Balakrishnan, Miwon Ahn, Eunjin Oh, Chathurani S. Jayasena, Debbie C. Thurmond
International Journal of Molecular Sciences.2024; 25(3): 1504. CrossRef
The association between healthy beverage index and sarcopenia in Iranian older adults: a case-control study
Marzieh Mahmoodi, Zainab Shateri, Mehran Nouri, Mohebat Vali, Nasrin Nasimi, Zahra Sohrabi, Mohammad Hossein Dabbaghmanesh, Maede Makhtoomi
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Shanhu Qiu, Xue Cai, Yang Yuan, Bo Xie, Zilin Sun, Duolao Wang, Tongzhi Wu
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Review

Type 1 Diabetes
Non-Insulin Antidiabetes Treatment in Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis: Xiaoling Cai, Chu Lin, Wenjia Yang, Lin Nie, Linong Ji; Diabetes Metab J. 2021;45(3):312-325. Published online March 15, 2021; DOI: https://doi.org/10.4093/dmj.2020.0171

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In order to evaluate the efficacy and side effects of the non-insulin antidiabetes medications as an adjunct treatment in type 1 diabetes mellitus (T1DM), we conducted systematic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between the date of inception and March 2020 to produce a systematic review and meta-analysis. Overall, 57 studies were included. Compared with placebo, antidiabetes agents in adjunct to insulin treatment resulted in significant reduction in glycosylated hemoglobin (weighted mean difference [WMD], –0.30%; 95% confidence interval [CI], –0.34 to –0.25%; P<0.01) and body weight (WMD, –2.15 kg; 95% CI, –2.77 to –1.53 kg; P<0.01), and required a significantly lower dosage of insulin (WMD, –5.17 unit/day; 95% CI, –6.77 to –3.57 unit/day; P<0.01). Compared with placebo, antidiabetes agents in adjunct to insulin treatment increased the risk of hypoglycemia (relative risk [RR], 1.04; 95% CI, 1.01 to 1.08; P=0.02) and gastrointestinal side effects (RR, 1.99; 95% CI, 1.61 to 2.46; P<0.01) in patients with T1DM. Compared with placebo, the use of non-insulin antidiabetes agents in addition to insulin could lead to glycemic improvement, weight control and lower insulin dosage, while they might be associated with increased risks of hypoglycemia and gastrointestinal side effects in patients with T1DM.

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Glycemic Management Across the Lifespan for People With Type 1 Diabetes: A Clinical Practice Guideline
Ilana J. Halperin, Brandy Wicklow, Shazhan Amed, Alanna Chambers, Charlotte Courage, Elizabeth Cummings, Patricia Kirkland, Dylan MacKay, Meranda Nakhla, Zubin Punthakee, Paul M. Ryan, Lindsay Sawatsky, Peter A. Senior, Bikrampal S. Sidhu, Alanna Weisman
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Rameez Raja Bhagadurshah, Subbiah Eagappan, Raghavan Kasthuri Santharam, Sridhar Subbiah
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Original Articles

Drug/Regimen
Efficacy and Safety of Treatment with Quadruple Oral Hypoglycemic Agents in Uncontrolled Type 2 Diabetes Mellitus: A Multi-Center, Retrospective, Observational Study: Jun Sung Moon, Sunghwan Suh, Sang Soo Kim, Heung Yong Jin, Jeong Mi Kim, Min Hee Jang, Kyung Ae Lee, Ju Hyung Lee, Seung Min Chung, Young Sang Lyu, Jin Hwa Kim, Sang Yong Kim, Jung Eun Jang, Tae Nyun Kim, Sung Woo Kim, Eonju Jeon, Nan Hee Cho, Mi-Kyung Kim, Hye Soon Kim, Il Seong Nam-Goong, Eun Sook Kim, Jin Ook Chung, Dong-Hyeok Cho, Chang Won Lee, Young Il Kim, Dong Jin Chung, Kyu Chang Won, In Joo Kim, Tae Sun Park, Duk Kyu Kim, Hosang Shon; Diabetes Metab J. 2021;45(5):675-683. Published online August 12, 2020; DOI: https://doi.org/10.4093/dmj.2020.0107

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Background

Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM).

Methods

From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated.

Results

In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, −1.1%±1.2%; P<0.001). The number of patients with HbA1c <7% increased significantly from 5 to 68 (P<0.005). In addition, lipid profiles and liver enzyme levels were also improved whereas no changes in body weight. There was no significant safety issue in patients treated with quadruple OHA therapy.

Conclusion

This study shows the therapeutic efficacy of the quadruple OHA regimen T2DM and demonstrates that it can be an option for the management of T2DM patients who cannot use insulin or reject injectable therapy.

Citations

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Empagliflozin-based quadruple oral therapy for type 2 diabetes: a prospective cohort study
Fatemeh Moosaie, Shiva Abedinzadeh, Soghra Rabizadeh, Kimia Daneshvar, Mohammadamin Noorafrooz, Fatemeh Alsadat Mojtahedi, Niloofar Deravi, Seyede Marzie Fatemi Abhari, Akam Ramezani, Alipasha Meysamie, Marzieh Hajibabaei, Sahar Karimpour Reyhan, Mahsa Ab
Scientific Reports.2025;[Epub] CrossRef
Estimating Type 2 Diabetes Prevalence: A Model of Drug Consumption Data
Rita Oliveira, Matilde Monteiro-Soares, José Pedro Guerreiro, Rúben Pereira, António Teixeira-Rodrigues
Pharmacy.2024; 12(1): 18. CrossRef
Disease burden and symptom management in type 2 diabetic patients: A phenomenological study
Sevgi Demir Çam, Sevda Uzun
Public Health Nursing.2024; 41(6): 1291. CrossRef
Comparing dual oral agents plus insulin vs. Triple oral agents in uncontrolled type II diabetes: A pilot study
Nadia Gul, Inayat Ur Rehman, Yasar shah, Arbab Muhammad Ali, Zahid Ali, Omer Shehzad, Khang Wen Goh, Long Chiau Ming, Amal K. Suleiman, Nimesh Lageju
PLOS ONE.2024; 19(11): e0311435. CrossRef
Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study
Kyung-Soo Kim, Kyung Ah Han, Tae Nyun Kim, Cheol-Young Park, Jung Hwan Park, Sang Yong Kim, Yong Hyun Kim, Kee Ho Song, Eun Seok Kang, Chul Sik Kim, Gwanpyo Koh, Jun Goo Kang, Mi Kyung Kim, Ji Min Han, Nan Hee Kim, Ji Oh Mok, Jae Hyuk Lee, Soo Lim, Sang S
Diabetes & Metabolism.2023; 49(4): 101440. CrossRef
Effectiveness and safety of teneligliptin added to patients with type 2 diabetes inadequately controlled by oral triple combination therapy: A multicentre, randomized, double‐blind, and placebo‐controlled study
Minyoung Lee, Woo‐je Lee, Jae Hyeon Kim, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2022; 24(6): 1105. CrossRef
A double‐blind, Randomized controlled trial on glucose‐lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase‐4 inhibitor therapy: REFIND study
Soree Ryang, Sang Soo Kim, Ji Cheol Bae, Ji Min Han, Su Kyoung Kwon, Young Il Kim, Il Seong Nam‐Goong, Eun Sook Kim, Mi‐kyung Kim, Chang Won Lee, Soyeon Yoo, Gwanpyo Koh, Min Jeong Kwon, Jeong Hyun Park, In Joo Kim
Diabetes, Obesity and Metabolism.2022; 24(9): 1800. CrossRef
Glycaemic control with add‐on thiazolidinedione or a sodium‐glucose co‐transporter‐2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24‐week, randomized controlled trial
Jaehyun Bae, Ji Hye Huh, Minyoung Lee, Yong‐Ho Lee, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2021; 23(2): 609. CrossRef

Lifestyle
Reducing Carbohydrate from Individual Sources Has Differential Effects on Glycosylated Hemoglobin in Type 2 Diabetes Mellitus Patients on Moderate Low-Carbohydrate Diets: Hajime Haimoto, Shiho Watanabe, Keiko Maeda, Takashi Murase, Kenji Wakai; Diabetes Metab J. 2021;45(3):390-403. Published online July 21, 2020; DOI: https://doi.org/10.4093/dmj.2020.0033

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Background

We evaluated decreases in glycosylated hemoglobin (HbA1c) achieved by reducing carbohydrate from various sources in type 2 diabetes mellitus patients.

Methods

We followed up 138 male and 107 female outpatients on a moderate low-carbohydrate diet without diabetic medication for 6 months. Changes in carbohydrate sources (Δcarbohydrate) were assessed from 3-day dietary records at baseline and 6 months, and associations with changes in HbA1c (ΔHbA1c) were examined with Spearman's correlation coefficients (r_s) and multiple regression analysis.

Results

ΔHbA1c was −1.5%±1.6% in men and −0.9%±1.3% in women, while Δtotal carbohydrate was −115.3±103.7 g/day in men and −63.6±71.1 g/day in women. Positive associations with ΔHbA1c were found for Δtotal carbohydrate (r_s=0.584), Δcarbohydrate from soft drinks (0.368), confectionery (0.361), rice (0.325), bread (0.221), Chinese soup noodles (0.199) in men, and Δtotal carbohydrate (0.547) and Δcarbohydrate from rice (0.376) and confectionery (0.195) in women. Reducing carbohydrate sources by 50 g achieved decreases in HbA1c of 0.43% for total carbohydrate, 1.33% for soft drinks, 0.88% for confectionery, 0.63% for bread, 0.82% for Chinese soup noodles and 0.34% for rice in men and 0.45% for total carbohydrate, 0.67% for confectionery and 0.34% for rice in women, although mean reductions in carbohydrate from these sources were much smaller than that from rice.

Conclusion

Decreases in HbA1c achieved by reducing carbohydrate from soft drinks, confectionery, bread and Chinese soup noodles were 2- to 4-fold greater than that for rice. Our results will enable patients to decrease HbA1c efficiently (UMIN000009866).

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Zihe Guan, Yang Liu, Xinming Chen, Xiwei Yang
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Jong Han Choi, Jee-Hyun Kang, Suk Chon
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Associations of Dietary Salt and Its Sources with Hemoglobin A1c in Patients with Type 2 Diabetes Not Taking Anti-Diabetic Medications: Analysis Based on 6-Month Intervention with a Moderate Low-Carbohydrate Diet
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Complications
The Risk of Diabetes on Clinical Outcomes in Patients with Coronavirus Disease 2019: A Retrospective Cohort Study: Seung Min Chung, Yin Young Lee, Eunyeong Ha, Ji Sung Yoon, Kyu Chang Won, Hyoung Woo Lee, Jian Hur, Kyung Soo Hong, Jong Geol Jang, Hyun Jung Jin, Eun Young Choi, Kyeong-Cheol Shin, Jin Hong Chung, Kwan Ho Lee, June Hong Ahn, Jun Sung Moon; Diabetes Metab J. 2020;44(3):405-413. Published online May 21, 2020; DOI: https://doi.org/10.4093/dmj.2020.0105

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Background

To determine the role of diabetes mellitus (DM) in the coronavirus disease 2019 (COVID-19), we explored the clinical characteristics of patients with DM and compared risk factors such as age, glycemic control, and medications to those without DM.

Methods

This was a retrospective cohort study of 117 confirmed patients with COVID-19 which conducted at a tertiary hospital in Daegu, South Korea. The primary outcome was defined as the severe and critical outcome (SCO), of which the composite outcomes of acute respiratory distress syndrome, septic shock, intensive care unit care, and 28-day mortality. We analyzed what clinical features and glycemic control-related factors affect the prognosis of COVID-19 in the DM group.

Results

After exclusion, 110 participants were finally included. DM patients (n=29) was older, and showed higher blood pressure compared to non-DM patients. DM group showed higher levels of inflammation-related biomarkers and severity score, and highly progressed to SCO. After adjustment with other risk factors, DM increased the risk of SCO (odds ratio [OR], 10.771; P<0.001). Among the DM patients, SCO was more prevalent in elderly patients of ≥70 years old and age was an independent risk factor for SCO in patients with DM (OR, 1.175; P=0.014), while glycemic control was not. The use of medication did not affect the SCO, but the renin-angiotensin system inhibitors showed protective effects against acute cardiac injury (OR, 0.048; P=0.045).

Conclusion

The COVID-19 patients with DM had higher severity and resulted in SCO. Intensive and aggressive monitoring of COVID-19 clinical outcomes in DM group, especially in elderly patients is warranted.

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Genetics
Metagenomic Analysis of the Gut Microbiome Reveals Enrichment of Menaquinones (Vitamin K2) Pathway in Diabetes Mellitus: Nihar Ranjan Dash, Mohammad Tahseen Al Bataineh; Diabetes Metab J. 2021;45(1):77-85. Published online May 11, 2020; DOI: https://doi.org/10.4093/dmj.2019.0202

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Background

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with a high prevalence worldwide, especially among overweight and obese populations. T2DM is multifactorial with several genetic and acquired risk factors that lead to insulin resistance. Mounting evidence indicates that alteration of gut microbiome composition contribute to insulin resistance and inflammation. However, the precise link between T2DM and gut microbiome role and composition remains unknown.

Methods

We evaluated the metabolic capabilities of the gut microbiome of twelve T2DM and six healthy individuals through shotgun metagenomics using MiSeq platform.

Results

We identified no significant differences in the overall taxonomic composition between healthy and T2DM subjects when controlling for differences in diet. However, results showed that T2DM enriched in metabolic pathways involved in menaquinone (vitamin K2) superpathway biosynthesis (PWY-5838) as compared to healthy individuals. Covariance analysis between the bacterial genera and metabolic pathways displaying difference in abundance (analysis of variance P<0.05) in T2DM as compared to healthy subjects revealed that genera belonging Firmicutes, Actinobacteria, and Bacteroidetes phyla contribute significantly to vitamin K2 biosynthesis. Further, the microbiome corresponding to T2DM with high glycosylated hemoglobin (HbA1c) (>6.5%) exhibit high abundance of genes involved in lysine biosynthesis and low abundance of genes involved in creatinine degradation as compared to T2DM with lower HbA1c (<6.5%).

Conclusion

The identified differences in metabolic capabilities provide important information that may eventually lead to the development of novel biomarkers and more effective management strategies to treat T2DM.

Citations

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Basic Research
Role of Intestinal Microbiota in Metabolism of Voglibose In Vitro and In Vivo: Mahesh Raj Nepal, Mi Jeong Kang, Geon Ho Kim, Dong Ho Cha, Ju-Hyun Kim, Tae Cheon Jeong; Diabetes Metab J. 2020;44(6):908-918. Published online April 6, 2020; DOI: https://doi.org/10.4093/dmj.2019.0147

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Background

Voglibose, an α-glucosidase inhibitor, inhibits breakdown of complex carbohydrates into simple sugar units in intestine. Studies showed that voglibose metabolism in the liver might be negligible due to its poor intestinal absorption. Numerous microorganisms live in intestine and have several roles in metabolism and detoxification of various xenobiotics. Due to the limited information, the possible metabolism of voglibose by intestinal microbiota was investigated in vitro and in vivo.

Methods

For the in vitro study, different concentrations of voglibose were incubated with intestinal contents, prepared from both vehicle- and antibiotics-treated mice, to determine the decreased amount of voglibose over time by using liquid chromatography-mass spectrometry. Similarly, in vivo pharmacodynamic effect of voglibose was determined following the administration of voglibose and starch in vehicle- and antibiotic-pretreated non-diabetic and diabetic mice, by measuring the modulatory effects of voglibose on blood glucose levels.

Results

The in vitro results indicated that the remaining voglibose could be significantly decreased when incubated with the intestinal contents from normal mice compared to those from antibiotic-treated mice, which had less enzyme activities. The in vivo results showed that the antibiotic pretreatment resulted in reduced metabolism of voglibose. This significantly lowered blood glucose levels in antibiotic-pretreated mice compared to the control animals.

Conclusion

The present results indicate that voglibose would be metabolized by the intestinal microbiota, and that this metabolism might be pharmacodynamically critical in lowering blood glucose levels in mice.

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Pharmacomicrobiomics: Exploring the role of gut microbiota in type 2 diabetes and antidiabetic drug mechanisms
Dingsheng Wen, Xiangyue Wang, Yanping He, Xiaoqing Hao, Weihua Huang, Honghao Zhou, Wei Zhang, Xiong Li
Nutrition, Metabolism and Cardiovascular Diseases.2025; : 104379. CrossRef
A Novel Stability Indicating Analytical Development and Validation of an RP-HPLC Assay Method for the Quantification of Voglibose in Bulk and its Formulation
Md. Nazmul Sardar, Ekhlass Uddin, Md. Shahin Reza, Shajahan Talukdar Sunny, Md. Faysal Khan Shuvo, Md. Mamun Hossain, Md. Faruk Hossen, Md. Ali Asraf, Md. Kudrat-E-Zahan
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Lifesytle
Changes in the Quality of Life in Patients with Type 2 Diabetes Mellitus According to Physician and Patient Behaviors: Young-Joo Kim, In-Kyung Jeong, Sin-Gon Kim, Dong Hyeok Cho, Chong-Hwa Kim, Chul-Sik Kim, Won-Young Lee, Kyu-Chang Won, Jin-Hye Cha, Juneyoung Lee, Doo-Man Kim; Diabetes Metab J. 2020;44(1):91-102. Published online October 23, 2019; DOI: https://doi.org/10.4093/dmj.2018.0251

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Background

Diabetes mellitus (DM) is the most common chronic metabolic disorder with an increasing prevalence worldwide. According to a previous study, physicians' treatment patterns or patients' behaviors change when they become aware of the risk for cardiovascular (CV) disease in patients with DM. However, there exist controversial reports from previous studies in the impact of physicians' behaviors on the patients' quality of life (QoL) improvements. So we investigate the changes in QoL according to physicians and patients' behavioral changes after the awareness of CV risks in patients with type 2 DM.

Methods

Data were obtained from a prospective, observational study where 799 patients aged ≥40 years with type 2 DM were recruited at 24 tertiary hospitals in Korea. Changes in physicians' behaviors were defined as changes in the dose/type of antihypertensive, lipid-lowering, and anti-platelet therapies within 6-month after the awareness of CV risks in patients. Changes in patients' behaviors were based on lifestyle modifications. Audit of Diabetes Dependent Quality of Life comprising 19-life-domains was used.

Results

The weighted impact score change for local or long-distance journey (P=0.0049), holidays (P=0.0364), and physical health (P=0.0451) domains significantly differed between the two groups; patients whose physician's behaviors changed showed greater improvement than those whose physician's behaviors did not change.

Conclusion

This study demonstrates that changes in physicians' behaviors, as a result of perceiving CV risks, improve QoL in some domains of life in DM patients. Physicians should recognize the importance of understanding CV risks and implement appropriate management.

Citations

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Pathophysiology
Low-Frequency Intermittent Hypoxia Suppresses Subcutaneous Adipogenesis and Induces Macrophage Polarization in Lean Mice: Yan Wang, Mary Yuk Kwan Lee, Judith Choi Wo Mak, Mary Sau Man Ip; Diabetes Metab J. 2019;43(5):659-674. Published online April 23, 2019; DOI: https://doi.org/10.4093/dmj.2018.0196

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Background

The relationship between obstructive sleep apnoea (OSA) and metabolic disorders is complex and highly associated. The impairment of adipogenic capacity in pre-adipocytes may promote adipocyte hypertrophy and increase the risk of further metabolic dysfunction. We hypothesize that intermittent hypoxia (IH), as a pathophysiologic feature of OSA, may regulate adipogenesis by promoting macrophage polarization.

Methods

Male C57BL/6N mice were exposed to either IH (240 seconds of 10% O₂ followed by 120 seconds of 21% O₂, i.e., 10 cycles/hour) or intermittent normoxia (IN) for 6 weeks. Stromal-vascular fractions derived from subcutaneous (SUB-SVF) and visceral (VIS-SVF) adipose tissues were cultured and differentiated. Conditioned media from cultured RAW 264.7 macrophages after air (Raw) or IH exposure (Raw-IH) were incubated with SUB-SVF during adipogenic differentiation.

Results

Adipogenic differentiation of SUB-SVF but not VIS-SVF from IH-exposed mice was significantly downregulated in comparison with that derived from IN-exposed mice. IH-exposed mice compared to IN-exposed mice showed induction of hypertrophic adipocytes and increased preferential infiltration of M1 macrophages in subcutaneous adipose tissue (SAT) compared to visceral adipose tissue. Complementary in vitro analysis demonstrated that Raw-IH media significantly enhanced inhibition of adipogenesis of SUB-SVF compared to Raw media, in agreement with corresponding gene expression levels of differentiation-associated markers and adipogenic transcription factors.

Conclusion

Low frequency IH exposure impaired adipogenesis of SAT in lean mice, and macrophage polarization may be a potential mechanism for the impaired adipogenesis.

Citations

Citations to this article as recorded by

In-depth proteomics and Phosphoproteomics reveal biomarkers and molecular pathways of chronic intermittent hypoxia in mice
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Inhibition of NSUN6 protects against intermittent hypoxia-induced oxidative stress and inflammatory response in adipose tissue through suppressing macrophage ferroptosis and M1 polarization
Xinyu Wang, Linjing Gong, Chang Wei, Yuean Zhao, Longyi Ran, Peijun Li, Wenyu Gu, Xu Wu, Zongan Liang, Xinyuan Wang
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Low-frequency, mild-gradient chronic intermittent hypoxia still induces liver fibrogenesis in mice on a high-fat diet
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Yu Xue, Ruonan Tang, Zanhua Liu
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology.2025; 329(6): R859. CrossRef
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Short Communication

Clinical Diabetes & Therapeutics
Effects of Dapagliflozin on Endothelial Function, Renal Injury Markers, and Glycemic Control in Drug-Naïve Patients with Type 2 Diabetes Mellitus: Sung Hye Kong, Bo Kyung Koo, Min Kyong Moon; Diabetes Metab J. 2019;43(5):711-717. Published online March 20, 2019; DOI: https://doi.org/10.4093/dmj.2018.0208

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Background

The study aimed to evaluate the effects of dapagliflozin and metformin on vascular endothelial function and renal injury markers.

Methods

This prospective, randomized, open-label, crossover study included drug-naïve patients with type 2 diabetes mellitus, who were randomized to receive 8 weeks of initial treatment using metformin or dapagliflozin and crossed over for another 8 weeks of treatment after a 1-week washout period. Systemic endothelial function was evaluated via the reactive hyperemic index (RHI).

Results

The 22 participants included 10 males (45.5%) and had a median age of 58 years. The RHI values were not significantly changed during both 8-week treatment periods and there was no significant difference between the treatments. Relative to the metformin group, 8 weeks of dapagliflozin treatment produced significantly higher median N-acetyl-beta-D-glucosaminidase levels (10.0 ng/mL [interquartile range (IQR), 6.8 to 12.1 ng/mL] vs. 5.6 ng/mL [IQR, 3.8 to 8.0 ng/mL], P=0.013). Only the dapagliflozin group exhibited improved homeostatic model assessment of insulin resistance and body weight, while serum ketone and β-hydroxybutyrate levels increased.

Conclusion

Dapagliflozin treatment did not affect systemic endothelial function or renal injury markers except N-acetyl-beta-D-glucosaminidase.

Citations

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Dapagliflozin protects the kidney in a non-diabetic model of cardiorenal syndrome
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Renoprotection by Dapagliflozin in a Non-Diabetic Model of Cardiorenal Syndrome
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Letter: Effects of Dapagliflozin on Endothelial Function, Renal Injury Markers, and Glycemic Control in Drug-Naïve Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2019:43:711–7)
Dimitrios Patoulias, Michael Doumas
Diabetes & Metabolism Journal.2019; 43(6): 906. CrossRef
Response: Effects of Dapagliflozin on Endothelial Function, Renal Injury Markers, and Glycemic Control in Drug-Naïve Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2019:43:711–7)
Sung Hye Kong, Bo Kyung Koo, Min Kyong Moon
Diabetes & Metabolism Journal.2019; 43(6): 913. CrossRef

Review

Clinical Diabetes & Therapeutics
Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management: Silvia Pieralice, Paolo Pozzilli; Diabetes Metab J. 2018;42(6):451-464. Published online December 17, 2018; DOI: https://doi.org/10.4093/dmj.2018.0190

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Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.

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Original Article

Complications
Higher Prevalence and Progression Rate of Chronic Kidney Disease in Elderly Patients with Type 2 Diabetes Mellitus: Kyung-Soo Kim, Seok Won Park, Yong-Wook Cho, Soo-Kyung Kim; Diabetes Metab J. 2018;42(3):224-232. Published online May 31, 2018; DOI: https://doi.org/10.4093/dmj.2017.0065

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Background

To evaluate the prevalence of chronic kidney disease (CKD) and progression rate to CKD in elderly patients with type 2 diabetes mellitus (T2DM).

Methods

We investigated the medical records of 190 elderly patients (65 years or older) with T2DM from 2005 to 2011 in 6-month increments. Mean follow-up duration was 64.5 months. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² and/or the presence of albuminuria.

Results

The mean age was 70.4 years and mean diabetes duration was 10.6 years. Among all the participants, 113 patients (59.5%) had CKD. The eGFR was significantly decreased between baseline (65.7±15.0 mL/min/1.73 m²) and the end of follow-up (52.7±17.5 mL/min/1.73 m², P<0.001). At the end of follow-up, the prevalence of eGFR <60 mL/min/1.73 m² had increased by 61.6% (at baseline, 44.2%). Furthermore, in patients with eGFR ≥60 mL/min/1.73 m², the progression rate to more than CKD stage 3 was 39.6% at the end of follow-up; 30.2% of elderly diabetic patients had progressed to albuminuria from normoalbuminuria. Kaplan-Meier analysis showed that the time interval to worsening nephropathy was significantly shorter in elderly patients with diabetes duration ≥10 years than in those with diabetes duration <5 years (P=0.018).

Conclusion

CKD was commonly observed in older patients with T2DM, and the progression rate to CKD is also high. Consequently, it is important to identify and manage CKD as early as possible in elderly patients with T2DM, especially in those with diabetes duration ≥10 years.

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Short Communication

Others
Synthesis of a New Zinc-Mixed Ligand Complex and Evaluation of Its Antidiabetic Properties in High Fat Diet: Low Dose Streptozotocin Induced Diabetic Rats: Muruganantham Koothappan, Roshana Devi Vellai, Iyyam Pillai Subramanian, Sorimuthu Pillai Subramanian; Diabetes Metab J. 2018;42(3):244-248. Published online April 24, 2018; DOI: https://doi.org/10.4093/dmj.2018.0002

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Due to the multifactorial and multisystemic nature of diabetes mellitus, it is often treated with a combination of therapeutic agents having different mode of action. Earlier, we have synthesized several organozinc complexes and evaluated their safety and antidiabetic properties in experimental type 2 diabetes mellitus (T2DM). More recently, we have synthesized a metformin-3-hydroxyflavone complex and studied its antidiabetic efficacy in experimental rats. In the present study, a new zinc-mixed ligand (metformin-3-hydroxyflavone) was synthesized, characterized by spectral studies and its antidiabetic properties was evaluated in HFD fed—low dose streptozotocin induced T2DM in rats. The hypoglycemic efficacy of the complex was evaluated through oral glucose tolerance test, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index and by determining the status of important biochemical parameters. Oral administration of the complex at a concentration of 10 mg/kg body weight/rat/day for 30 days significantly improved the glucose homeostasis. The complex possesses significant antidiabetic properties relatively at a less concentration than metformin-3-hydroxyflavone complex in ameliorating hyperglycemia.

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Original Article

Others
Clinical Implications of Using Post-Challenge Plasma Glucose Levels for Early Diagnosis of Type 2 Diabetes Mellitus in Older Individuals: Kyong Hye Joung, Sang Hyun Ju, Ji Min Kim, Sorim Choung, Jae Min Lee, Kang Seo Park, Hyun Jin Kim, Bon Jeong Ku; Diabetes Metab J. 2018;42(2):147-154. Published online February 13, 2018; DOI: https://doi.org/10.4093/dmj.2018.42.2.147

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Background

The aim of this study was to explore the differences in the clinical characteristics and diagnostic rates of diabetes mellitus (DM) according to various criteria in different age groups and to evaluate the efficacy of each criterion for screening older patients.

Methods

We studied 515 patients and measured the fasting plasma glucose level (FPG), 2-hour plasma glucose level after the 75 g oral glucose tolerance test (2-hour postload glucose [2-h PG]), and glycosylated hemoglobin (HbA1c) for re-evaluation of hyperglycemia without a history of diabetes. Patients with newly diagnosed DM were grouped by age as younger (<65 years) or older (≥65 years).

Results

Older patients had significantly lower HbA1c, FPG, and 2-h PG levels and a higher homeostatic level of pancreatic β-cell function compared with younger patients (P<0.001). The older group had the lowest diagnostic rate when using the FPG level (45.5%) and the highest diagnostic rate when using the 2-h PG level (84.6%). These results were mostly due to the higher frequency of isolated post-challenge hyperglycemia in the older patients than in the younger group (28.8% vs. 9.2%). The use of both the FPG and HbA1c levels significantly enhanced the low diagnostic power when employing only the FPG levels in the older group (71.2% vs. 45.5%).

Conclusion

In the older patients, the 2-h PG level was the most accurate diagnostic criterion. When we consider the costs and convenience, a combination of the FPG and HbA1c criteria may be recommended as a screening test for DM in older people.

Citations

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Reviews

Clinical Diabetes & Therapeutics
Insulin Therapy for Adult Patients with Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association, 2017: Byung-Wan Lee, Jin Hwa Kim, Seung-Hyun Ko, Kyu-Yeon Hur, Nan-Hee Kim, Sang Youl Rhee, Hyun Jin Kim, Min Kyong Moon, Seok-O Park, Kyung Mook Choi; Diabetes Metab J. 2017;41(5):367-373. Published online October 24, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.5.367

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Abstract PDF PubReader ePub

The Korean Diabetes Association (KDA) has regularly updated its Clinical Practice Guidelines. In 2017, the KDA published a position statement on the use of antihyperglycemic agents for patients with type 2 diabetes mellitus (T2DM). Growing evidence from new multinational clinical trials using novel and traditional insulin analogues has also been accumulated. Following global trends, many results of clinical trials, especially concerning the clinical efficacy and safety of insulin therapy, have been published about Korean patients with T2DM. After a systematic search of recent evidence, the KDA updated and modified its clinical practice recommendations regarding the initiation, choice, and intensification of insulin and created an insulin treatment algorithm for the first time to guide physicians caring for adult Korean patients with T2DM.

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Clinical Diabetes & Therapeutics
Combination Therapy of Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus: Min Kyong Moon, Kyu-Yeon Hur, Seung-Hyun Ko, Seok-O Park, Byung-Wan Lee, Jin Hwa Kim, Sang Youl Rhee, Hyun Jin Kim, Kyung Mook Choi, Nan-Hee Kim; Diabetes Metab J. 2017;41(5):357-366. Published online October 24, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.5.357

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The Korean Diabetes Association (KDA) recently updated the Clinical Practice Guidelines on antihyperglycemic agent therapy for adult patients with type 2 diabetes mellitus (T2DM). In combination therapy of oral hypoglycemic agents (OHAs), general recommendations were not changed from those of the 2015 KDA guidelines. The Committee on Clinical Practice Guidelines of the KDA has extensively reviewed and discussed the results of meta-analyses and systematic reviews of effectiveness and safety of OHAs and many clinical trials on Korean patients with T2DM for the update of guidelines. All OHAs were effective when added to metformin or metformin and sulfonylurea, although the effects of each agent on body weight and hypoglycemia were different. Therefore, selection of a second agent as a metformin add-on therapy or third agent as a metformin and sulfonylurea add-on therapy should be based on the patient's clinical characteristics and the efficacy, side effects, mechanism of action, risk of hypoglycemia, effect on body weight, patient preference, and combined comorbidity. In this review, we address the results of meta-analyses and systematic reviews, comparing the effectiveness and safety among OHAs. It will help to choose the appropriate drug for an individual patient with T2DM.

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