Diabetes & Metabolism Journal

Original Articles

Complications
Association of Muscle Mass Loss with Diabetes Development in Liver Transplantation Recipients: Sejeong Lee, Minyoung Lee, Young-Eun Kim, Hae Kyung Kim, Sook Jung Lee, Jiwon Kim, Yurim Yang, Chul Hoon Kim, Hyangkyu Lee, Dong Jin Joo, Myoung Soo Kim, Eun Seok Kang; Diabetes Metab J. 2024;48(1):146-156. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0100

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Abstract PDF Supplementary Material PubReader ePub: Background
Post-transplant diabetes mellitus (PTDM) is one of the most significant complications after transplantation. Patients with end-stage liver diseases requiring transplantation are prone to sarcopenia, but the association between sarcopenia and PTDM remains to be elucidated. We aimed to investigate the effect of postoperative muscle mass loss on PTDM development.
Methods
A total of 500 patients who underwent liver transplantation at a tertiary care hospital between 2005 and 2020 were included. Skeletal muscle area at the level of the L3–L5 vertebrae was measured using computed tomography scans performed before and 1 year after the transplantation. The associations between the change in the muscle area after the transplantation and the incidence of PTDM was investigated using a Cox proportional hazard model.
Results
During the follow-up period (median, 4.9 years), PTDM occurred in 165 patients (33%). The muscle mass loss was greater in patients who developed PTDM than in those without PTDM. Muscle depletion significantly increased risk of developing PTDM after adjustment for other confounding factors (hazard ratio, 1.50; 95% confidence interval, 1.23 to 1.84; P=0.001). Of the 357 subjects who had muscle mass loss, 124 (34.7%) developed PTDM, whereas of the 143 patients in the muscle mass maintenance group, 41 (28.7%) developed PTDM. The cumulative incidence of PTDM was significantly higher in patients with muscle loss than in patients without muscle loss (P=0.034).
Conclusion
Muscle depletion after liver transplantation is associated with increased risk of PTDM development.

Lifestyle
Clinical Effects of a Home Care Pilot Program for Patients with Type 1 Diabetes Mellitus: A Retrospective Cohort Study: Sejeong Lee, KyungYi Kim, Ji Eun Kim, Yura Hyun, Minyoung Lee, Myung-Il Hahm, Sang Gyu Lee, Eun Seok Kang; Diabetes Metab J. 2023;47(5):693-702. Published online June 22, 2023; DOI: https://doi.org/10.4093/dmj.2022.0170

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Background
Given the importance of continuous self-care for people with type 1 diabetes mellitus (T1DM), the Ministry of Health and Welfare of Korea launched a pilot program for chronic disease management. Herein, we applied a home care pilot program to people with T1DM to investigate its effects.
Methods
This retrospective cohort study was conducted at a single tertiary hospital (January 2019 to October 2021). A multidisciplinary team comprising doctors, nurses, and clinical nutritionists provided specialized education and periodically assessed patients’ health status through phone calls or text messages. A linear mixed model adjusting for age, sex, and body mass index was used to analyze the glycemic control changes before and after implementing the program between the intervention and control groups.
Results
Among 408 people with T1DM, 196 were enrolled in the intervention group and 212 in the control group. The reduction in glycosylated hemoglobin (HbA1c) after the program was significantly greater in the intervention group than in the control group (estimated marginal mean, –0.57% vs. –0.23%, P=0.008); the same trend was confirmed for glycoalbumin (GA) (–3.2% vs. –0.39%, P<0.001). More patients achieved the target values of HbA1c (<7.0%) and GA (<20%) in the intervention group than in the control group at the 9-month follow-up (34.5% vs. 19.6% and 46.7% vs. 28.0%, respectively).
Conclusion
The home care program for T1DM was clinically effective in improving glycemic control and may provide an efficient care option for people with T1DM, and positive outcomes are expected to expand the program to include more patients.

Citations

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Glycemic outcomes and patient satisfaction and self-management improves in transition from standard to virtual multidisciplinary care
Noga Minsky, Liat Arnon Klug, Tatyana Kolobov, Elizabeth Tarshish, Yuval Shalev Many, Aviva Lipsitz, Amna Jabarin, Nicole Morozov, Dania Halperin, Moshe Shalom, Rachel Nissanholtz-Gannot, Genya Aharon-Hananel, Amir Tirosh, Orly Tamir
Diabetes Research and Clinical Practice.2024; 209: 111587. CrossRef

Complications
Renal Tubular Damage Marker, Urinary N-acetyl-β-D-Glucosaminidase, as a Predictive Marker of Hepatic Fibrosis in Type 2 Diabetes Mellitus: Hae Kyung Kim, Minyoung Lee, Yong-ho Lee, Eun Seok Kang, Bong-Soo Cha, Byung-Wan Lee; Diabetes Metab J. 2022;46(1):104-116. Published online July 13, 2021; DOI: https://doi.org/10.4093/dmj.2020.0273

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Background
Non-alcoholic steatohepatitis is closely associated with the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). We investigated whether urinary N-acetyl-β-D-glucosaminidase (u-NAG), an early renal tubular damage biomarker in DKD, could be related to the degree of hepatic fibrosis in patients with T2DM.
Methods
A total of 300 patients with T2DM were enrolled in this study. Hepatic steatosis and fibrosis were determined using transient elastography. The levels of urinary biomarkers, including u-NAG, albumin, protein, and creatinine, and glucometabolic parameters were measured.
Results
Based on the median value of the u-NAG to creatinine ratio (u-NCR), subjects were divided into low and high u-NCR groups. The high u-NCR group showed a significantly longer duration of diabetes, worsened hyperglycemia, and a more enhanced hepatic fibrosis index. A higher u-NCR was associated with a greater odds ratio for the risk of higher hepatic fibrosis stage (F2: odds ratio, 1.99; 95% confidence interval [CI], 1.04 to 3.82). Also, u-NCR was an independent predictive marker for more advanced hepatic fibrosis, even after adjusting for several confounding factors (β=1.58, P<0.01).
Conclusion
The elevation of u-NAG was independently associated with a higher degree of hepatic fibrosis in patients with T2DM. Considering the common metabolic milieu of renal and hepatic fibrosis in T2DM, the potential use of u-NAG as an effective urinary biomarker reflecting hepatic fibrosis in T2DM needs to be validated in the future.

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Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial
Xiao Tong Teong, Kai Liu, Andrew D. Vincent, Julien Bensalem, Bo Liu, Kathryn J. Hattersley, Lijun Zhao, Christine Feinle-Bisset, Timothy J. Sargeant, Gary A. Wittert, Amy T. Hutchison, Leonie K. Heilbronn
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Significance of Diabetic Kidney Disease Biomarkers in Predicting Metabolic-Associated Fatty Liver Disease
Jaehyun Bae, Byung-Wan Lee
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Abdominal adipose tissue and type 2 diabetic kidney disease: adipose radiology assessment, impact, and mechanisms
Fei Lu, Jinlei Fan, Fangxuan Li, Lijing Liu, Zhiyu Chen, Ziyu Tian, Liping Zuo, Dexin Yu
Abdominal Radiology.2023; 49(2): 560. CrossRef
β‐Amyrin ameliorates diabetic nephropathy in mice and regulates the miR‐181b‐5p/HMGB2 axis in high glucose‐stimulated HK‐2 cells
Wenhua Xu, Hongwu Zhang, Qinfeng Zhang, Jialan Xu
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High Glycated Hemoglobin Instead of High Body Mass Index Might Increase the Urine N-Acetyl-β-D-glucosaminidase Con-Centration in Children and Adolescents with Diabetes Mellitus
Jin-Soon Suh, Kyoung Soon Cho, Seul Ki Kim, Shin-Hee Kim, Won Kyoung Cho, Min Ho Jung, Moon Bae Ahn
Life.2022; 12(6): 879. CrossRef

Review

Drug/Regimen
Lobeglitazone: A Novel Thiazolidinedione for the Management of Type 2 Diabetes Mellitus: Jaehyun Bae, Taegyun Park, Hyeyoung Kim, Minyoung Lee, Bong-Soo Cha; Diabetes Metab J. 2021;45(3):326-336. Published online April 19, 2021; DOI: https://doi.org/10.4093/dmj.2020.0272

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Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and β-cell dysfunction. Among available oral antidiabetic agents, only the thiazolidinediones (TZDs) primarily target insulin resistance. TZDs improve insulin sensitivity by activating peroxisome proliferator-activated receptor γ. Rosiglitazone and pioglitazone have been used widely for T2DM treatment due to their potent glycemic efficacy and low risk of hypoglycemia. However, their use has decreased because of side effects and safety issues, such as cardiovascular concerns and bladder cancer. Lobeglitazone (Chong Kun Dang Pharmaceutical Corporation), a novel TZD, was developed to meet the demands for an effective and safe TZD. Lobeglitazone shows similar glycemic efficacy to pioglitazone, with a lower effective dose, and favorable safety results. It also showed pleiotropic effects in preclinical and clinical studies. In this article, we summarize the pharmacologic, pharmacokinetic, and clinical characteristics of lobeglitazone.

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Islam H. Ali, Rasha M. Hassan, Ahmed M. El Kerdawy, Mahmoud T. Abo-Elfadl, Heba M.I. Abdallah, Francesca Sciandra, Iman A.Y. Ghannam
European Journal of Medicinal Chemistry.2024; 269: 116279. CrossRef
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European Journal of Medicinal Chemistry.2024; 273: 116364. CrossRef
Thiazolidinedione an auspicious scaffold as PPAR-γ agonist: its possible mechanism to Manoeuvre against insulin resistant diabetes mellitus
Sourav Basak, Anjali Murmu, Balaji Wamanrao Matore, Partha Pratim Roy, Jagadish Singh
European Journal of Medicinal Chemistry Reports.2024; 11: 100160. CrossRef
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A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties
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Indian Journal of Endocrinology and Metabolism.2023; 27(4): 286. CrossRef
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Efficacy and safety of lobeglitazone, a new Thiazolidinedione, as compared to the standard of care in type 2 diabetes mellitus: A systematic review and meta-analysis
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Synthesis, Characterization, and Pharmacokinetic Studies of Thiazolidine-2,4-Dione Derivatives
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Will lobeglitazone rival pioglitazone? A systematic review and critical appraisal
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Evaluation of pharmacokinetic interactions between lobeglitazone, empagliflozin, and metformin in healthy subjects
Heeyoung Kim, Choon Ok Kim, Hyeonsoo Park, Min Soo Park, Dasohm Kim, Taegon Hong, Yesong Shin, Byung Hak Jin
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Lobeglitazone, a novel thiazolidinedione, for secondary prevention in patients with ischemic stroke: a nationwide nested case-control study
Joonsang Yoo, Jimin Jeon, Minyoul Baik, Jinkwon Kim
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Complementary effects of dapagliflozin and lobeglitazone on metabolism in a diet-induced obese mouse model
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Hye-Young Seo, So-Hee Lee, Ji Yeon Park, Eugene Han, Sol Han, Jae Seok Hwang, Mi Kyung Kim, Byoung Kuk Jang, Kenji Fujiwara
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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
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A Real-World Study of Long-Term Safety and Efficacy of Lobeglitazone in Korean Patients with Type 2 Diabetes Mellitus
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Original Articles

Basic Research
Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway: Ji-Yeon Lee, Minyoung Lee, Ji Young Lee, Jaehyun Bae, Eugene Shin, Yong-ho Lee, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha; Diabetes Metab J. 2021;45(6):921-932. Published online February 22, 2021; DOI: https://doi.org/10.4093/dmj.2020.0187

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Background
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.
Methods
Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.
Results
The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.
Conclusion
SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.

Citations

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SGLT2 inhibitors and AMPK: The road to cellular housekeeping?
Nasser Safaie, Shahab Masoumi, Shaban Alizadeh, Pourya Mirzajanzadeh, Hamid Reza Nejabati, Mobasher Hajiabbasi, Vahid Alivirdiloo, Neda Chobdari Basmenji, Aysan Derakhshi Radvar, Ziba Majidi, Yousef Faridvand
Cell Biochemistry and Function.2024;[Epub] CrossRef
Proximal tubule hypertrophy and hyperfunction: a novel pathophysiological feature in disease states
Mehmet Kanbay, Sidar Copur, Mustafa Guldan, Lasin Ozbek, Alper Hatipoglu, Adrian Covic, Francesca Mallamaci, Carmine Zoccali
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Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value
Yafei Xie, Yujie Wei, Dan Li, Jie Pu, Hong Ding, Xiaowei Zhang
Journal of Cardiovascular Pharmacology.2023; 81(1): 4. CrossRef
Current Treatment Options, Including Diet, Exercise, and Medications
Mazen Noureddin, Manal F. Abdelmalek
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SGLT2 Inhibitors and Kidney Diseases: A Clinical Perspective
Panagiotis Theofilis, Rigas G. Kalaitzidis
Current Medicinal Chemistry.2023; 30(23): 2595. CrossRef
Treatment of obesity-related diabetes: significance of thermogenic adipose tissue and targetable receptors
Ruping Pan, Jiadai Liu, Yong Chen
Frontiers in Pharmacology.2023;[Epub] CrossRef
Immunomodulatory Effects of SGLT2 Inhibitors—Targeting Inflammation and Oxidative Stress in Aging
Ema Schönberger, Vjera Mihaljević, Kristina Steiner, Sandra Šarić, Tomislav Kurevija, Ljiljana Trtica Majnarić, Ines Bilić Ćurčić, Silvija Canecki-Varžić
International Journal of Environmental Research and Public Health.2023; 20(17): 6671. CrossRef
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Manal Moustafa Mahmoud, Laila Ahmed Rashed, Somia Abdulatif Soliman, Safaa Mostafa Sayed, Omneya Kamel, Samaa Samir Kamar, Rania El Sayed Hussien
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Xiang Xiao, Shuming Ji, Junlin Zhang, Deying Kang, Fang Liu
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Zhicheng Gao, Jiaqi Bao, Yilan Hu, Junjie Tu, Lifang Ye, Lihong Wang
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SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1
Weijie Wang, Yilan Li, Yanxiu Zhang, Tao Ye, Kui Wang, Shuijie Li, Yao Zhang
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Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling
Ke Lin, Na Yang, Wu Luo, Jin-fu Qian, Wei-wei Zhu, Shi-ju Ye, Chen-xin Yuan, Di-yun Xu, Guang Liang, Wei-jian Huang, Pei-ren Shan
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Pleiotropic effects of SGLT2 inhibitors and heart failure outcomes
Panagiotis Theofilis, Marios Sagris, Evangelos Oikonomou, Alexios S. Antonopoulos, Gerasimos Siasos, Kostas Tsioufis, Dimitris Tousoulis
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Sandra Feijóo-Bandín, Alana Aragón-Herrera, Manuel Otero-Santiago, Laura Anido-Varela, Sandra Moraña-Fernández, Estefanía Tarazón, Esther Roselló-Lletí, Manuel Portolés, Oreste Gualillo, José Ramón González-Juanatey, Francisca Lago
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Clinical Diabetes & Therapeutics
Predictors of the Therapeutic Efficacy and Consideration of the Best Combination Therapy of Sodium-Glucose Co-transporter 2 Inhibitors: Ji-Yeon Lee, Yongin Cho, Minyoung Lee, You Jin Kim, Yong-ho Lee, Byung-Wan Lee, Bong-Soo Cha, Eun Seok Kang; Diabetes Metab J. 2019;43(2):158-173. Published online January 25, 2019; DOI: https://doi.org/10.4093/dmj.2018.0057

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Background

We investigated the predictive markers for the therapeutic efficacy and the best combination of sodium-glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin, dapagliflozin, and ipragliflozin) therapy in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 804 patients with T2DM who had taken SGLT2 inhibitor as monotherapy or an add-on therapy were analyzed. Multivariate regression analyses were performed to identify the predictors of SGLT2 inhibitor response including the classes of baseline anti-diabetic medications.

Results

After adjusting for age, sex, baseline body mass index (BMI), diabetes duration, duration of SGLT2 inhibitor use, initial glycosylated hemoglobin (HbA1c) level, estimated glomerular filtration rate (eGFR), and other anti-diabetic agent usage, multivariate analysis revealed that shorter diabetes duration, higher initial HbA1c and eGFR were associated with better glycemic response. However, baseline BMI was inversely correlated with glycemic status; lean subjects with well-controlled diabetes and obese subjects with inadequately controlled diabetes received more benefit from SGLT2 inhibitor treatment. In addition, dipeptidyl peptidase 4 (DPP4) inhibitor use was related to a greater reduction in HbA1c in patients with higher baseline HbA1c ≥7%. Sulfonylurea users experienced a larger change from baseline HbA1c but the significance was lost after adjustment for covariates and metformin and thiazolidinedione use did not affect the glycemic outcome.

Conclusion

A better response to SGLT2 inhibitors is expected in Korean T2DM patients who have higher baseline HbA1c and eGFR with a shorter diabetes duration. Moreover, the add-on of an SGLT2 inhibitor to a DPP4 inhibitor is likely to show the greatest glycemic response.

Citations

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Complications
Glycated Albumin Is a More Useful Glycation Index than HbA1c for Reflecting Renal Tubulopathy in Subjects with Early Diabetic Kidney Disease: Ji Hye Huh, Minyoung Lee, So Young Park, Jae Hyeon Kim, Byung-Wan Lee; Diabetes Metab J. 2018;42(3):215-223. Published online May 2, 2018; DOI: https://doi.org/10.4093/dmj.2017.0091

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Background

The aim of this study was to investigate which glycemic parameters better reflect urinary N-acetyl-β-D-glucosaminidase (uNAG) abnormality, a marker for renal tubulopathy, in subjects with type 2 diabetes mellitus (T2DM) subjects with normoalbuminuria and a normal estimated glomerular filtration rate (eGFR).

Methods

We classified 1,061 participants with T2DM into two groups according to uNAG level—normal vs. high (>5.8 U/g creatinine)—and measured their biochemical parameters.

Results

Subjects with high uNAG level had significantly higher levels of fasting and stimulated glucose, glycated albumin (GA), and glycosylated hemoglobin (HbA1c) and lower levels of homeostasis model assessment of β-cell compared with subjects with normal uNAG level. Multiple linear regression analyses showed that uNAG was significantly associated with GA (standardized β coefficient [β]=0.213, P=0.016), but not with HbA1c (β=−0.137, P=0.096) or stimulated glucose (β=0.095, P=0.140) after adjusting confounding factors. In receiver operating characteristic analysis, the value of the area under the curve (AUC) for renal tubular injury of GA was significantly higher (AUC=0.634; 95% confidence interval [CI], 0.646 to 0.899) than those for HbA1c (AUC=0.598; 95% CI, 0.553 to 0.640), stimulated glucose (AUC=0.594; 95% CI, 0.552 to 0.636), or fasting glucose (AUC=0.558; 95% CI, 0.515 to 0.600). The optimal GA cutoff point for renal tubular damage was 17.55% (sensitivity 59%, specificity 62%).

Conclusion

GA is a more useful glycation index than HbA1c for reflecting renal tubulopathy in subjects with T2DM with normoalbuminuria and normal eGFR.

Citations

Citations to this article as recorded by

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