Diabetes & Metabolism Journal

Original Article

Basic and Translational Research
Lactate-Induced Lipid Accumulation in Hepatocytes through GPR81 Activation: Giang Nguyen, Ji Hee Yu, Phuc Thi Minh Pham, Thuy Linh Lai, So Young Park, Ki Woo Kim, Seung-Soon Im, Jeana Hong, Yong-ho Lee, Jae-Ho Lee, Seon Mee Kang, Dae-Hee Choi, Eun-Hee Cho; Diabetes Metab J. 2026;50(2):307-319. Published online November 27, 2025; DOI: https://doi.org/10.4093/dmj.2024.0531

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Abstract PDF Supplementary Material PubReader ePub: Background
Lactate, traditionally considered a metabolic byproduct, is increasingly recognized as a signaling molecule involved in metabolic regulation. Its role in hepatic steatosis, particularly through G-protein-coupled receptor 81 (GPR81)-mediated pathways, remains underexplored.
Methods
We investigated the effects of lactate on hepatic lipid metabolism using in vitro alpha mouse liver 12 (AML12) cells, zebrafish, and two diet-induced nonalcoholic fatty liver disease (NAFLD) mouse models. Lipid accumulation, gene/protein expression, and 5’ adenosine monophosphate-activated protein kinase (AMPK) signaling were assessed under lactate exposure, GPR81 knockdown, monocarboxylate transporter 1 (MCT1) inhibition, and AMPK activation conditions.
Results
Lactate treatment in hepatocytes increased de novo lipogenesis and fatty acid uptake while suppressing fatty acid oxidation and AMPK phosphorylation. These effects were reversed by GPR81 knockdown but not by MCT1 inhibition, suggesting a GPR81-dependent mechanism. AMPK activation with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced lactate-induced lipid accumulation. In zebrafish, 10 mM lactate treatment for 24 hours significantly increased hepatic lipid content. In mice fed high-fat diet (HFD) or high-fat high-cholesterol (HFHC) diets for 12 weeks, hepatic lactate levels and GPR81 expression were elevated. Interestingly, p-AMPK expression decreased in HFD livers but increased in the HFHC group, indicating dietspecific regulation.
Conclusion
Our findings demonstrate that lactate promotes hepatic steatosis primarily via the GPR81–AMPK signaling axis. GPR81 activation enhances lipogenesis and lipid uptake, independent of MCT1-mediated transport. These results position GPR81 as a promising therapeutic target for NAFLD.

Review

Guideline/Statement/Fact Sheet
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, Seon Mee Kang, Hyuk-Sang Kwon, Mi Kyung Kim, You-Bin Lee, Se Hee Min, Jung Hwan Park, Woo Je Lee, Bong-Soo Cha, Byung-Wan Lee; Diabetes Metab J. 2025;49(6):1155-1177. Published online November 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0978

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This Korean Diabetes Association (KDA) consensus statement bridges global evidence with the Korean clinical context, where large randomized and real-world data remain limited. Recommendations required ≥80% agreement by the committee of clinical practice guideline and approval by the board of directors. The statement comprises three domains: diabetes screening aligned with Korean epidemiology; pharmacologic management guided by pathophysiology and comorbidities; and a severity construct of “severe diabetes mellitus” that links complication-based staging with metabolic grading to match therapeutic intensity to disease complexity. Compared with prior KDA guidelines, this statement introduces substantive advances in three areas. First, screening recommendations are streamlined to emphasize risk-aligned, practical implementation rather than prescriptive test sequences. Second, pharmacologic management applies an individualized framework for drug selection that jointly considers pathophysiology and comorbidities. It operationalizes individualized selection by dominant pathophysiology (insulin resistance vs. insulin insufficiency) and coexisting conditions, and formalizes treatment dynamics—early combination, timely initiation of injectables, avoidance of overbasalization, and structured deintensification. It also prioritizes agents with proven cardiovascular and renal protection and elevates management of obesity and metabolic dysfunction-associated steatotic liver disease as central goals; clinically, insulin should be initiated promptly in hypercatabolic states or suspected islet failure, and technology-enabled care—including continuous glucose monitoring and automated insulin delivery—are integral across all stages. Third, the newly introduced severity construct underpins treatment-intensity decisions across domains without reiterating prescriptive algorithms. Collectively, these recommendations provide a coherent, context-appropriate framework for diabetes screening and management in Korea and identify priorities for future evidence generation.

Citations

Citations to this article as recorded by

Efficacy and safety of adding a fourth oral antidiabetic drug versus metformin dose escalation in patients with type 2 diabetes inadequately controlled on triple oral combination therapy (EFFORT): A 24‐week, randomized, open‐label, multicenter trial
So Ra Kim, Jun Hwa Hong, Sin Gon Kim, Soo‐Kyung Kim, Hyuk‐Sang Kwon, Jun Sung Moon, Jung Hwan Park, Jae Myung Yu, Bong‐Soo Cha, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2026;[Epub] CrossRef

Original Articles

Guideline/Statement/Fact Sheet
2025 Clinical Practice Guidelines for Diabetes Management in Korea: Recommendation of the Korean Diabetes Association: Shinae Kang, Seon Mee Kang, Jong Han Choi, Seung-Hyun Ko, Bo Kyung Koo, Hyuk-Sang Kwon, Mi Kyung Kim, Sang Yong Kim, Soo-Kyung Kim, Young-eun Kim, Eun Sook Kim, Jae Hyeon Kim, Chong Hwa Kim, Ji Min Kim, Hae Jin Kim, Min Kyong Moon, Sun Joon Moon, Jun Sung Moon, Joon Ho Moon, Se Hee Min, Jung Hwan Park, Jaehyun Bae, Keeho Song, Ji Yoon Ahn, Jae-Seung Yun, Woo Je Lee, You-Bin Lee, Suk Chon, Eonju Jeon, Sang-Man Jin, Eugene Han, You-Cheol Hwang, Jae Hyun Bae, YoonJu Song, Jeong Hyun Lim, Jae Won Cho, Ji Yeon Choi, Yong Hee Hong, Jieun Lee, Sung Eun Kim, Ji Yun Noh, Bong-Soo Cha, Byung-Wan Lee; Diabetes Metab J. 2025;49(4):582-783. Published online July 1, 2025; DOI: https://doi.org/10.4093/dmj.2025.0469

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Efficacy and safety of adding a fourth oral antidiabetic drug versus metformin dose escalation in patients with type 2 diabetes inadequately controlled on triple oral combination therapy (EFFORT): A 24‐week, randomized, open‐label, multicenter trial
So Ra Kim, Jun Hwa Hong, Sin Gon Kim, Soo‐Kyung Kim, Hyuk‐Sang Kwon, Jun Sung Moon, Jung Hwan Park, Jae Myung Yu, Bong‐Soo Cha, Byung‐Wan Lee
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Pathophysiology
Enavogliflozin, an SGLT2 Inhibitor, Improves Nonalcoholic Steatohepatitis Induced by High-Fat, High-Cholesterol Diet: Phuc Thi Minh Pham, Giang Nguyen, So Young Park, Thuy Linh Lai, Dae-Hee Choi, Jeana Hong, Seon Mee Kang, Eun-Hee Cho; Diabetes Metab J. 2026;50(1):165-177. Published online June 16, 2025; DOI: https://doi.org/10.4093/dmj.2024.0259

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Background
Nonalcoholic fatty liver disease, a progressive condition caused by the accumulation of fat in the liver, begins with simple steatosis and can potentially progress to metabolic dysfunction-associated steatohepatitis (MASH) in the presence of inflammation and fibrosis, ultimately leading to cirrhosis or hepatocellular carcinoma. Increasing evidence indicates that sodiumglucose cotransporter 2 (SGLT2) inhibitors effectively alleviate MASH in mouse models. However, there is a lack of research on the effects of enavogliflozin on liver disease. In the present study, we investigated the effects of SGLT2 inhibitors on MASH induced by a high-fat, high-cholesterol (HFHC) diet in mice.
Methods
Male C57BL/6 mice were fed a normal chow diet, HFHC diet, or HFHC diet with enavogliflozin for 12 weeks. LX-2 and HepG2 cells were treated with enavogliflozin in the presence of various pathological stimuli.
Results
The HFHC diet induced excessive hepatic lipid accumulation, inflammation, and severe fibrosis. Administration of enavogliflozin not only ameliorated hepatic steatosis and fibrotic conditions but also suppressed the production of inflammatory cytokines. Positive outcomes were also observed in in vitro experiments, where enavogliflozin demonstrated the ability to impede the activation of hepatic stellate cells and alleviate lipid accumulation in hepatocytes. The potential pathway through which enavogliflozin attenuated liver fibrosis development may be associated with the transforming growth factor β1/Smad signaling pathway.
Conclusion
Our results suggest that enavogliflozin is effective in a mouse model of MASH by attenuating hepatic steatosis, suppressing inflammation, and improving liver fibrosis.

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Guideline/Fact Sheet
2023 Clinical Practice Guidelines for Diabetes Management in Korea: Full Version Recommendation of the Korean Diabetes Association: Jun Sung Moon, Shinae Kang, Jong Han Choi, Kyung Ae Lee, Joon Ho Moon, Suk Chon, Dae Jung Kim, Hyun Jin Kim, Ji A Seo, Mee Kyoung Kim, Jeong Hyun Lim, Yoon Ju Song, Ye Seul Yang, Jae Hyeon Kim, You-Bin Lee, Junghyun Noh, Kyu Yeon Hur, Jong Suk Park, Sang Youl Rhee, Hae Jin Kim, Hyun Min Kim, Jung Hae Ko, Nam Hoon Kim, Chong Hwa Kim, Jeeyun Ahn, Tae Jung Oh, Soo-Kyung Kim, Jaehyun Kim, Eugene Han, Sang-Man Jin, Jaehyun Bae, Eonju Jeon, Ji Min Kim, Seon Mee Kang, Jung Hwan Park, Jae-Seung Yun, Bong-Soo Cha, Min Kyong Moon, Byung-Wan Lee; Diabetes Metab J. 2024;48(4):546-708. Published online July 26, 2024; DOI: https://doi.org/10.4093/dmj.2024.0249

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Response

Status of Diabetic Neuropathy in Korea: A National Health Insurance Service-National Sample Cohort Analysis (2006 to 2015) (Diabetes Metab J 2021;45:115-9): Seong-Su Moon, Chong Hwa Kim, Seon Mee Kang, Eun Sook Kim, Tae Jung Oh, Jae-Seung Yun, Ho Chan Cho, Dae Jung Kim, Tae Sun Park; Diabetes Metab J. 2021;45(3):459-460. Published online May 25, 2021; DOI: https://doi.org/10.4093/dmj.2021.0084

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Brief Report

Complications
Status of Diabetic Neuropathy in Korea: A National Health Insurance Service-National Sample Cohort Analysis (2006 to 2015): Seong-Su Moon, Chong Hwa Kim, Seon Mee Kang, Eun Sook Kim, Tae Jung Oh, Jae-Seung Yun, Ho Chan Cho, Dae Jung Kim, Tae Sun Park; Diabetes Metab J. 2021;45(1):115-119. Published online December 18, 2020; DOI: https://doi.org/10.4093/dmj.2020.0120

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This report presents the status of diabetic neuropathy (DN) in Korea as determined using a National Health Insurance ServiceNational Sample Cohort (NHIS-NSC). Annual prevalences of DN were estimated by age and gender using descriptive statistics. Pharmacological treatments for DN were also analyzed. The annual prevalence of DN increased from 24.9% in 2006 to 26.6% in 2007, and thereafter, gradually subsided to 20.8% in 2015. In most cases, pharmacological treatments involved a single drug, which accounted for 91.6% of total prescriptions in 2015. The most commonly used drugs (in decreasing order) were thioctic acid, an anti-convulsive agent, or a tricyclic antidepressant. In conclusion, the prevalence of DN decreased over the 10-year study period. Thioctic acid monotherapy was usually prescribed for DN. To reduce the socio-economic burden of DN, more attention should be paid to the diagnosis of this condition and to the appropriate management of patients.

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Original Articles

A Survey on Ubiquitous Healthcare Service Demand among Diabetic Patients: Soo Lim, So-Youn Kim, Jung Im Kim, Min Kyung Kwon, Sei Jin Min, Soo Young Yoo, Seon Mee Kang, Hong Il Kim, Hye Seung Jung, Kyong Soo Park, Jun Oh Ryu, Hayley Shin, Hak Chul Jang; Diabetes Metab J. 2011;35(1):50-57. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.50

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Background

Advanced information technology can be used when developing diagnostic and treatment strategies to provide better care for diabetic patients. However, the levels of need and demand for the use of technological advances have not been investigated in diabetic patients. We proposed and developed an individualized, ubiquitous (U)-healthcare service using advanced information technology for more effective glucose control. Prior to our service initiation, we surveyed patient needs and other pertinent information.

Methods

During August 2009, we conducted a 34-item questionnaire survey among patients with diabetes who were older than 40 years in two certain hospitals in Korea.

Results

The mean age of the 228 participants was 61.2±9 years, and males made up 49.1% of the sample. Seventy-one percent replied that they wanted individualized healthcare service, and they also wanted their health information to be delivered through mobile devices such as a cellular phone or a personal digital assistant (40.4%). Most patients had never heard of U-healthcare services (81.1%); however, after explaining the concept, 71.1% of participants responded that they would use the service if it was provided. Despite their willingness, participants were concerned about technical difficulty in using the service (26.3%) as well as the cost of the service (29.8%).

Conclusion

The current study suggests that more than 70% of diabetic patients are interested in using U-healthcare services. To encourage widespread use, the application program or device of U-healthcare services should be simple, easy to use and affordable while also including a policy for the protection of private information.

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The Correlation and Accuracy of Glucose Levels between Interstitial Fluid and Venous Plasma by Continuous Glucose Monitoring System: Young Ha Baek, Heung Yong Jin, Kyung Ae Lee, Seon Mee Kang, Woong Ji Kim, Min Gul Kim, Ji Hyun Park, Soo Wan Chae, Hong Sun Baek, Tae Sun Park; Korean Diabetes J. 2010;34(6):350-358. Published online December 31, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.6.350

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Background

Clinical experience with the continuous glucose monitoring systems (CGMS) is limited in Korea. The objective of this study is to evaluate the accuracy of the CGMS and the correlation between interstitial fluid and venous plasma glucose level in Korean healthy male subjects.

Methods

Thirty-two subjects were served with glucose solution contained same amount of test food's carbohydrate and test foods after separate overnight fasts. CGMS was performed over 3 days during hopitalization for each subjects. Venous plasma glucose measurements were carried out during 4 hours (0, 0.25, 0.5, 0.75, 1, 2, 4 hours) just before and after glucose solution and test food load. The performance of the CGMS was evaluated by comparing its readings to those obtained at the same time by the hexokinase method using the auto biochemistry machine (Hitachi 7600-110). Also, correlations between glucose recorded with CGMS and venous plasma glucose value were examined.

Results

CGMS slightly underestimated the glucose value as compared with the venous plasma glucose level (16.3 ± 22.2 mg/dL). Correlation between CGMS and venous plasma glucose values throughout sensor lifetime is 0.73 (regression analysis: slope = 1.08, intercept = 8.38 mg/dL). Sensor sensitivity can deteriorate over time, with correlations between venous blood glucose and CGMS values dropping from 0.77 during 1st day to 0.65 during 2nd and 3rd day.

Conclusion

The accuracy of data provided by CGMS may be less than expected. CGMS sensor sensitivity is decreased with the passage of time. But, from this study, CGMS can be used for glucose variability tendency monitoring conveniently to the Korean.

Citations

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