Diabetes & Metabolism Journal

Review

Basic and Translational Research
Extracellular Vesicle-Mediated Network in the Pathogenesis of Obesity, Diabetes, Steatotic Liver Disease, and Cardiovascular Disease: Joonyub Lee, Won Gun Choi, Marie Rhee, Seung-Hwan Lee; Diabetes Metab J. 2025;49(3):348-367. Published online May 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0184

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Abstract PDF PubReader ePub: Extracellular vesicles (EVs) are lipid bilayer-enclosed particles carrying bioactive cargo, including nucleic acids, proteins, and lipids, facilitating intercellular and interorgan communication. In addition to traditional mediators such as hormones, metabolites, and cytokines, increasing evidence suggests that EVs are key modulators in various physiological and pathological processes, particularly influencing metabolic homeostasis and contributing to the progression of cardiometabolic diseases. This review provides an overview of the most recent insights into EV-mediated mechanisms involved in the pathogenesis of obesity, insulin resistance, diabetes mellitus, steatotic liver disease, atherosclerosis, and cardiovascular disease. EVs play a critical role in modulating insulin sensitivity, glucose homeostasis, systemic inflammation, and vascular health by transferring functional molecules to target cells. Understanding the EV-mediated network offers potential for identifying novel biomarkers and therapeutic targets, providing opportunities for EV-based interventions in cardiometabolic disease management. Although many challenges remain, this evolving field highlights the need for further research into EV biology and its translational applications in cardiovascular and metabolic health.

Original Article

Metabolic Risk/Epidemiology
The Impact of Obesity on the Association between Parity and Risk of Type 2 Diabetes Mellitus: Yuki Gen, Kyuho Kim, Joonyub Lee, Junyoung Jung, Sang-Hyuk Jung, Hong-Hee Won, Dokyoon Kim, Yun-Sung Jo, Yu-Bae Ahn, Seung-Hyun Ko, Jae-Seung Yun; Received September 5, 2024 Accepted November 15, 2024 Published online February 14, 2025; DOI: https://doi.org/10.4093/dmj.2024.0536 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Most studies focus solely on the relationship between parity and type 2 diabetes mellitus (T2DM) risk, providing limited insights into other contributing or protective factors. This study aims to explore the complex relationship between parity and T2DM risk, considering additional factors such as obesity, race, and body composition.
Methods
This prospective cohort study used data from 242,159 women aged 40 to 69 from the UK Biobank, none of whom had T2DM at baseline. Multivariable Cox proportional hazard models were applied to assess the association between parity and T2DM. Subgroup analyses were performed based on body mass index (BMI), waist circumference (WC), and race.
Results
The hazard ratio for T2DM per additional child was 1.16 (95% confidence interval, 1.13 to 1.16). Subgroup analysis revealed that Asian women and those with obesity or abdominal obesity had a higher risk of T2DM associated with multiparity. No increased risk was observed in women with normal BMI or WC. Mediation analysis showed that WC and BMI significantly mediated the parity-T2DM relationship, accounting for 49% and 38% of the effect, respectively.
Conclusion
There is a clear positive association between multiparity and T2DM risk, particularly in Asian women and those with obesity. Maintaining normal BMI and WC appears to mitigate this risk, highlighting the importance of weight management for women at higher parity levels. These findings offer crucial insights for public health interventions aimed at reducing T2DM risk among women.

Brief Report

Complications
Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights: Han-Sang Baek, Chaiho Jeong, Yeoree Yang, Joonyub Lee, Jeongmin Lee, Seung-Hwan Lee, Jae Hyoung Cho, Tae-Seo Sohn, Hyun-Shik Son, Kun-Ho Yoon, Eun Young Lee; Diabetes Metab J. 2024;48(6):1169-1175. Published online June 10, 2024; DOI: https://doi.org/10.4093/dmj.2024.0036

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One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

Citations

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Original Article

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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Abstract PDF Supplementary Material PubReader ePub: 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.

Sulwon Lecture 2022

Others
Opening the Precision Diabetes Care through Digital Healthcare: Joonyub Lee, Jin Yu, Kun-Ho Yoon; Diabetes Metab J. 2023;47(3):307-314. Published online March 29, 2023; DOI: https://doi.org/10.4093/dmj.2022.0386

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The national healthcare systems of every country in the world cannot sustain the rise in healthcare expenditure caused by chronic diseases and their complications. To sustain the national healthcare system, a novel system should be developed to improve the quality of care and minimize healthcare costs. For 20 years, our team developed patient-communicating digital healthcare platforms and proved their efficacy. National scale randomized control trials are underway to systematically measure the efficacy and economic benefits of this digital health care system. Precision medicine aims to maximize effectiveness of disease management by considering individual variability. Digital health technologies enable precision medicine at a reasonable cost that was not available before. The government launched the “National Integrated Bio-big Data Project” which will collect diverse health data from the participants. Individuals will share their health information to physicians or researchers at their will by gateway named “My-Healthway.’ Taken together, now we stand in front of the evolution of medical care, so-called “Precision medicine.” led by various kinds of technologies and a huge amount of health information exchange. We should lead these new trends as pioneers, not as followers, to establish and implement the best care for our patients that can help them to withstand their devastating diseases.

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Journal of Diabetes Investigation.2025; 16(6): 971. CrossRef
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Corrigendum

Early Glycosylated Hemoglobin Target Achievement Predicts Clinical Outcomes in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: Joonyub Lee, Jae Hyoung Cho; Diabetes Metab J. 2021;45(4):621-621. Published online July 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0119; Corrects: Diabetes Metab J 2021;45(3):337

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Editorial

Early Glycosylated Hemoglobin Target Achievement Predicts Clinical Outcomes in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: Joonyub Lee, Jae Hyoung Cho; Diabetes Metab J. 2021;45(3):337-338. Published online May 25, 2021; DOI: https://doi.org/10.4093/dmj.2021.0078; Correction in: Diabetes Metab J 2021;45(4):621

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Effects of nurse-led telephone interventions on HbA1c levels in patients with type 2 diabetes: a Meta-analysis-based evaluation of follow-up protocols
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Time to Reach Target Glycosylated Hemoglobin Is Associated with Long-Term Durable Glycemic Control and Risk of Diabetic Complications in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A 6-Year Observational Study (Diabetes Metab J 2021;45:368-78)
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Original Article

Pathophysiology
Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3: Kanghoon Lee, Hyunki Kim, Joonyub Lee, Chang-Myung Oh, Heein Song, Hyeongseok Kim, Seung-Hoi Koo, Junguee Lee, Ajin Lim, Hail Kim; Diabetes Metab J. 2019;43(5):649-658. Published online April 8, 2019; DOI: https://doi.org/10.4093/dmj.2018.0232

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Abstract PDF PubReader

Background

Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.

Methods

Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.

Results

Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.

Conclusion

PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

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Arginine 65 Methylation of Neurogenin 3 by PRMT1 Is Required for Pancreatic Endocrine Development of hESCs
Gahyang Cho, Kwangbeom Hyun, Jieun Choi, Eun Ji Shin, Bumsoo Kim, Hail Kim, Jaehoon Kim, Yong-Mahn Han
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Protein Arginine Methyltransferase 1 Is Essential for the Meiosis of Male Germ Cells
Sahar Waseem, Sudeep Kumar, Kanghoon Lee, Byoung-Ha Yoon, Mirang Kim, Hail Kim, Keesook Lee
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Proteome-Wide Alterations of Asymmetric Arginine Dimethylation Associated With Pancreatic Ductal Adenocarcinoma Pathogenesis
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