Endocrinology and Metabolism

Review Article

Diabetes, obesity and metabolism
SGLT2 Inhibitors as Systemic Metabolic Modulators: Linking Glucose Excretion to Liver Function Restoration: Seung Wan Noh, Han Sol Ryu, Yong-Ho Kim, Byung-Chul Oh; Endocrinol Metab. 2025;40(6):851-865. Published online December 24, 2025; DOI: https://doi.org/10.3803/EnM.2025.2786

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as paradigm-shifting therapeutics that extend beyond glycemic regulation, to conferring profound hepatometabolic benefits. This review delineates the multifaceted mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD), with an emphasis on systemic metabolic remodeling, mitochondrial protection, and intracellular calcium restoration. By promoting glucosuria-induced energy depletion, SGLT2 inhibition alleviates insulin resistance, suppresses hepatic lipogenesis, and activates adenosine monophosphate-activated protein kinase (AMPK)–sirtuin 1 (SIRT1)–peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α pathways that reprogram hepatocellular metabolism toward achieving lipid oxidation and autophagy. Mechanistically, SGLT2 inhibitors restore intracellular Ca²⁺ homeostasis via sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activation, mitigating endoplasmic reticulum (ER) stress and normalizing Ca²⁺–phosphoinositide (PIP)–protein kinase B (AKT) signaling, collectively reinforcing insulin responsiveness and ER-mitochondrial crosstalk. Clinically, these effects translate into consistently reducing hepatic fat, aminotransferases, and fibrosis markers in both diabetic and nondiabetic patients with MASLD. Furthermore, SGLT2 inhibitors uniquely integrate renal energy regulation with hepatic resilience through the Ca²⁺–PIP–SERCA axis, positioning them as prototype systemic modulators of metabolic homeostasis. Future translational efforts should refine patient stratification using metabolomic and Ca²⁺-imaging biomarkers to delineate therapeutic responders and advance next-generation SGLT2 analogs targeting Ca²⁺-dependent metabolic signaling. Collectively, SGLT2 inhibitors represent a new metabolic therapeutic class that unify glucose, lipid, and Ca²⁺ regulation to restore hepatocellular functions in metabolic liver diseases.

Citations

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Original Article

Trends in Prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Nationwide Survey in Korea: Junhyun Kwon, Hanbit Shin, Dae Ho Lee, Eunji Kim; Received July 24, 2025 Accepted October 15, 2025 Published online December 24, 2025; DOI: https://doi.org/10.3803/EnM.2025.2578 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub

Background
The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD), which is associated with higher risks of obesity, type 2 diabetes mellitus, cardiovascular disease, chronic kidney disease, and extrahepatic cancer, is increasing. This study aimed to examine the temporal trends in MASLD prevalence among Korean adults, with a focus on age-stratified patterns and related health conditions.
Methods
This secondary analysis of Korea National Health and Nutrition Examination Survey data included data of 90,912 adults aged ≥19 years from 2007 to 2023. MASLD was defined as having the presence of at least one cardiometabolic risk factor and no heavy alcohol consumption. Temporal trends in MASLD prevalence and associated cardiometabolic risk factors were examined across age groups using weighted prevalence estimates and log-linear regression models.
Results
The overall prevalence of MASLD increased from 25.0% in 2007–2009 to 31.0% in 2022–2023 (annual percent change [APC], 1.36%). The most substantial increase was observed in young adults aged 19–44 years (22.3% to 30.5%; APC=2.09%), particularly among men. Middle-aged (45–64 years) and older (≥65 years) adults showed relatively stable or modest increases over time. Among young adults with MASLD, chronic kidney disease prevalence increased from 2.1% to 5.7%.
Conclusion
This nationwide study revealed a significant and continuous increase in MASLD prevalence among Korean adults, particularly in younger age groups. The disproportionate burden in these populations, along with high rates of metabolic comorbidities, underscores an emerging public health concern that may place considerable strain on future healthcare systems.

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Impact of probiotics and prebiotics on glucose/lipid metabolism in metabolic dysfunction-associated steatotic liver disease: mechanisms and implications
Yinan Zhao, Ziyan Li, Guoying Yu
Frontiers in Nutrition.2026;[Epub] CrossRef

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