Daily Endocrinology Research Analysis
Three impactful endocrinology-adjacent studies advance metabolic liver disease care and mechanistic understanding. A UK Biobank cohort links MASLD to higher mortality and multimorbidity; a multinational cohort associates SGLT-2 inhibitors with reduced liver-related events in T2D with MASLD; and a mechanistic mouse study shows nori-derived porphyran prevents obesity, diabetes, steatohepatitis, and HCC via a microbiota–bile acid–ceramide axis.
Summary
Three impactful endocrinology-adjacent studies advance metabolic liver disease care and mechanistic understanding. A UK Biobank cohort links MASLD to higher mortality and multimorbidity; a multinational cohort associates SGLT-2 inhibitors with reduced liver-related events in T2D with MASLD; and a mechanistic mouse study shows nori-derived porphyran prevents obesity, diabetes, steatohepatitis, and HCC via a microbiota–bile acid–ceramide axis.
Research Themes
- Risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD)
- Antidiabetic agents and hepatoprotection in T2D with MASLD
- Microbiota–bile acid–ceramide signaling in metabolic disease prevention
Selected Articles
1. The relationships between MASLD, extrahepatic multimorbidity and all-cause mortality in UK Biobank cohort.
In 438,840 UK Biobank participants, MASLD (defined by FLI ≥60 plus cardiometabolic risk factors) was present in 29.9% and associated with greater extrahepatic multimorbidity and 16% higher all-cause mortality over 13 years. Mortality risk was stronger in women and those with fewer long-term conditions, and each additional condition further amplified mortality risk.
Impact: This very large, well-adjusted cohort quantifies the independent mortality burden of MASLD and highlights specific multimorbidity patterns, informing risk stratification and integrated care.
Clinical Implications: Clinicians should proactively screen for and manage extrahepatic long-term conditions in MASLD, particularly in women, and consider integrated cardio-renal-metabolic pathways to reduce mortality.
Key Findings
- MASLD prevalence was 29.9% and associated with higher extrahepatic multimorbidity (21.3% vs 14.4%).
- MASLD increased all-cause mortality by 16% over a median 13 years (HR 1.16, 95% CI 1.13–1.19).
- Mortality associations were stronger in females and those with fewer LTCs; each additional LTC increased mortality by 30% in MASLD.
- Sixteen of 47 extrahepatic long-term conditions were linked to increased mortality among MASLD patients.
Methodological Strengths
- Very large sample size with long-term (median 13 years) follow-up
- Adjusted Cox models with detailed multimorbidity profiling across 47 extrahepatic conditions
Limitations
- MASLD defined using FLI and risk factors, not imaging or histology
- Potential selection bias of UK Biobank and residual confounding inherent to observational design
Future Directions: Validate risk stratification using imaging- or biopsy-defined MASLD and test integrated management pathways in interventional studies, with sex-specific analyses.
BACKGROUND & AIMS: This study aimed to estimate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), with and without multimorbidity, on all-cause mortality. METHODS: We analysed data from the UK Biobank. MASLD was identified as a fatty liver index (FLI) ≥ 60 and presence of cardiometabolic risk factors. Multimorbidity was defined as ≥2 of the long-term conditions (LTCs) in a pre-specified list of 47 extrahepatic conditions. Hazard ratios (HRs) from adjusted Cox models quantified the association between MASLD, multimorbidity and all-cause mortality. RESULTS: Of the 438,840 participants, 131,020 (29.9%) had MASLD at baseline. The participants with MASLD at baseline had a higher prevalence of multimorbidity than those without (21.3% vs. 14.4%). In addition to cardiometabolic risk factors, MASLD was strongly associated with several LTCs, particularly metabolic, cardiovascular, cancers, kidney, mental/behavioural, and respiratory diseases. During a median follow-up of 13 years, MASLD was associated with higher mortality (HR 1.16 (95%CI: 1.13, 1.19)), with stronger associations in females and in those with low LTC counts (≤3 LTCs). Each additional LTC at baseline was associated with 30% and 38% higher mortality in MASLD (HR 1.30 (1.29, 1.32)) and non-MASLD (HR 1.38 (1.37, 1.40)) populations, respectively. Among the 47 LTCs, 16 were associated with increased mortality in people with MASLD. CONCLUSION: Those with MASLD exhibited a higher prevalence of extrahepatic multimorbidity and a 16% higher rate of mortality than those without, underscoring the impact of liver steatosis on mortality and highlighting the need to target LTCs to improve outcomes and reduce healthcare burdens.
2. Porphyran from discolored nori prevents metabolic syndrome through microbiota-bile acid-ceramide pathway.
In mouse models, porphyran from discolored nori prevented obesity, diabetes, MASH, and HCC, mechanistically linked to reduced secondary bile acids, suppressed intestinal FXR signaling, and decreased circulating ceramides. This positions porphyran as a promising nutraceutical candidate that also aligns with sustainability goals.
Impact: This work uncovers a microbiota–bile acid–FXR–ceramide axis by which a food-derived polysaccharide exerts broad metabolic and oncologic protection, suggesting a novel, sustainable prevention strategy.
Clinical Implications: While preclinical, the findings justify early-phase human trials of porphyran for metabolic disease prevention and support dietary strategies that modulate intestinal FXR and ceramides.
Key Findings
- Porphyran administration prevented obesity, diabetes, MASH, and HCC in mice.
- Protection correlated with decreased secondary bile acids and suppressed intestinal FXR signaling.
- Marked reductions in circulating ceramides accompanied metabolic and oncologic benefits.
- Discolored nori, typically discarded, is a rich, sustainable source of porphyran.
Methodological Strengths
- In vivo demonstration of multi-disease prevention with mechanistic linkage to FXR and ceramides
- Systems-level assessment of gut microbiota, bile acids, and lipid mediators
Limitations
- Findings are limited to mouse models; human translation unknown
- Dose, formulation, and long-term safety in humans are not established
Future Directions: Conduct dose-ranging, biomarker-driven human trials assessing FXR activity and ceramides; define microbial contributors and scalable food-grade formulations.
Nori is a component of the traditional Japanese diet. The Japanese have a low prevalence of obesity and cardiovascular disease worldwide, and components of nori may have disease-preventive effects. Here, we focused on porphyran, which is abundant in nori that is discarded due to discoloration, and investigated the effects of nori-derived porphyran on gut microbiota, bile acid composition, and ceramide synthesis. Administration of porphyran to mice prevented obesity, diabetes, metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC). This improvement correlates with a decrease in secondary bile acids, a decrease in intestinal farnesoid X receptor (FXR) signaling, and a marked decrease in blood ceramide. Porphyran, abundant in discolored nori, should be the subject of future translational research to prevent diseases with significant unmet medical needs and improve global environmental sustainability.
3. Effect of Antidiabetic Drug Classes on the Risk of Liver-Related Events in Individuals With T2D and MASLD.
In 7,867 T2D patients with MASLD across 16 centers, SGLT-2 inhibitor use was associated with markedly lower risks of liver-related events (sdHR 0.23) and slower progression of liver stiffness (HR 0.54) over a median of 5.1 years, after propensity matching and confounder adjustment.
Impact: This study links a widely used antidiabetic class to improved hepatic outcomes in T2D with MASLD, providing real-world evidence to inform drug selection while awaiting randomized trials.
Clinical Implications: For T2D patients with MASLD or elevated liver stiffness risk, clinicians may preferentially consider SGLT-2 inhibitors to potentially lower liver-related events, alongside comprehensive metabolic care.
Key Findings
- SGLT-2 inhibitor use was associated with lower liver-related events (sdHR 0.23, 95% CI 0.08–0.69).
- SGLT-2 inhibitor use was associated with slower liver stiffness progression (HR 0.54, 95% CI 0.35–0.86).
- Use of GLP-1RAs and SGLT-2 inhibitors increased over time, with higher adoption in Asian centers.
Methodological Strengths
- Multicenter cohort with propensity score matching and competing risk analyses
- Assessment of both clinical events and liver stiffness progression over >5 years
Limitations
- Observational design with potential residual confounding and channeling bias
- Medication adherence, dosing, and imaging modality heterogeneity were not fully controlled
Future Directions: Randomized trials comparing SGLT-2 inhibitors to other classes in MASLD with T2D, with standardized elastography and histologic endpoints, are warranted.
BACKGROUND: We investigated the use of type 2 diabetes (T2D) medications, including pioglitazone, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, in individuals with T2D and metabolic dysfunction-associated steatotic liver disease (MASLD), and explored the effect of these medications on long-term risk of liver-related events (LREs) and progression of liver stiffness in a retrospective cohort study. METHODS: We enrolled 7867 individuals with T2D and MASLD from 16 tertiary referral centers between February 2004 and January 2023. We recorded the use of pioglitazone, GLP-1RAs, and SGLT-2 inhibitors and analyzed the effects of these antihyperglycemic medications on the risk of developing incident LREs and the progression of liver stiffness over a median of 5.1 years of follow-up. RESULTS: Pioglitazone, GLP-1RAs and SGLT-2 inhibitors were prescribed to 1238 (15.7%), 863 (11.0%), and 2386 (30.3%) individuals with T2D and MASLD, respectively. A significant increase in the utilization of GLP-1RAs and SGLT-2 inhibitors was observed from 2010-2017 to 2017-2023, with pioglitazone and SGLT-2 inhibitors being prescribed more frequently in Asian countries than in Western countries (pioglitazone: 17.9% vs 3.8%; SGLT-2 inhibitors: 34.4% vs 7.3%; P < .001). After propensity score matching, in competing risk models, SGLT-2 inhibitor use was significantly associated with a lower risk of developing both LREs (subdistribution hazard ratio, 0.23; 95% confidence interval, 0.08-0.69, P = .009) and liver stiffness progression (hazard ratio, 0.54; 95% confidence interval, 0.35-0.86, P = .008) after adjusting for potential confounders. CONCLUSIONS: SGLT-2 inhibitor use is more prevalent among Asian than Western individuals. SGLT-2 inhibitors are associated with a lower risk of LREs in individuals with T2D and MASLD.