Foreword: Diabetes and liver disease are common chronic diseases in China. They interact with each other in terms of pathogenesis, clinical manifestations, and therapeutic targets, often serving as mutual risk factors. Effective co-management can help reduce the disease burden. To support the development of diabetes and liver disease co-management in China, this journal, in collaboration with the China Diabetes and Liver Disease Co-Management Initiative (CDL), presents the CDL Literature Monthly Review. Each month, we share relevant literature on the mechanisms of disease, diagnostic and therapeutic advancements concerning diabetes combined with liver disease, and invite experts in the field to provide commentary. We hope this review offers valuable insights and assistance to researchers, clinical practitioners, and front-line medical workers engaged in scientific research and clinical treatment.This issue of the CDL Literature Monthly Review will feature six clinical research articles related to diabetes and fatty liver disease. The invited commentators for this issue are Professor Ling Yang from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Professor Li Zhu from Suzhou Fifth People’s Hospital; and Professor Na Fu from Hebei Medical University Third Hospital.
Commentary Experts
Professor Ling Yang Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Professor, Chief Physician, Doctoral Supervisor, and Director of the Liver Disease Research Laboratory at the Department of Gastroenterology, Union Hospital.
01 Prevalence and Predictive Features of Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 1 Diabetes Fuhri Snethlage CM, Meijnikman AS, Mak AL, et al. Eur J Endocrinol, 2024, 190(5): 391-400.
The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 1 diabetes remain unclear. This study explores the prevalence and severity of MASLD in patients with type 1 diabetes and evaluates which clinical features are most important in predicting the severity of MASLD. The results indicate that individuals with type 1 diabetes who also have hypertension, are older, have a high BMI, and a longer duration of diabetes are at higher risk for MASLD.
The study evaluated 453 patients with type 1 diabetes [average age 41.6 ± 15.0 years, 64% female, BMI 25.4 ± 4.2 kg/m², HbA1c 55.6 ± 12 mmol/mol] using vibration-controlled transient elastography (VCTE). Hepatic steatosis and fibrosis were assessed using controlled attenuation parameter (CAP) scores (≥280.0 dB/m) and liver stiffness measurements (LSM) (≥8.0 kPa). The predictive ability of clinical features related to type 1 diabetes for steatosis and fibrosis was evaluated using a machine learning Extra-Trees classifier model. The results showed that the prevalence of hepatic steatosis and fibrosis was 9.5% and 3.5%, respectively. Higher liver stiffness values were associated with longer duration of type 1 diabetes, older age, higher BMI, and higher CAP scores. The most important factors predicting fibrosis in patients with type 1 diabetes were the duration of diabetes, age, and systolic blood pressure.
Commentary
In this cross-sectional study from the GUTDM1 cohort of Amsterdam University Medical Center, researchers first included factors such as residual β-cell function and continuous glucose monitoring (CGM) indicators as potential risk factors for MASLD. They found that the prevalence of MASLD in patients with type 1 diabetes was lower than in the general population. Among patients with type 1 diabetes, the prevalence of MASLD was significantly associated with known MASLD-related factors (such as obesity and elevated triglycerides) but not with hyperglucagonemia. Hepatic steatosis and fibrosis were strongly correlated with type 1 diabetes characteristics, including reduced TIR, increased daily insulin dose, and residual β-cell function, suggesting that type 1 diabetes-specific factors may promote MASLD, or MASLD may affect the progression of type 1 diabetes. However, these factors were not significant predictors of steatosis or fibrosis prevalence. The most important predictors of fibrosis were the duration of type 1 diabetes, age, and systolic blood pressure. Future studies should explore whether MASLD screening can reduce the disease burden in patients with type 1 diabetes.
02 Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors in Improvement of Fatty Liver Index in Patients with Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Retrospective Nationwide Claims Database Study in Japan Shikamura M, Takayama A, Takeuchi M, et al. Diabetes Obes Metab, 2024. doi: 10.1111/dom.15632.
To date, there is limited clinical research and evidence on whether sodium-glucose cotransporter-2 inhibitors (SGLT-2is) can improve hepatic steatosis. This study aimed to evaluate the effectiveness of SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) in improving the fatty liver index (FLI) in patients with type 2 diabetes (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). The results indicate that SGLT2is are more effective than DPP4is in improving FLI in patients with T2DM and MASLD. Using real-world data in the absence of direct clinical comparative studies may support clinical decision-making.
This retrospective cohort study included new users of SGLT2i or DPP4i for T2DM and MASLD from a large claims database (JMDC claims database). The primary endpoint was the incidence of FLI improvement. Propensity score-weighted estimates were used to predict treatment initiation time, and Cox proportional hazards models assessed the 95% confidence intervals (CI) and hazard ratios. The study included 9127 new users of SGLT2i and 12286 new users of DPP4i. Compared with DPP4i, SGLT2i showed higher incidences of FLI improvement (≥30%, ≥40%, and ≥50% reduction from baseline FLI), with weighted hazard ratios of 1.27 (95% CI: 1.18-1.38), 1.24 (95% CI: 1.13-1.37), and 1.19 (95% CI: 1.05-1.33), respectively. SGLT2i showed greater reductions in FLI values over up to three years of follow-up compared to DPP4i.
Commentary
MASLD often coexists with T2DM. Although recent clinical information suggests a potential role for SGLT2i in treating hepatic steatosis, current evidence remains limited, and further studies are needed to determine the therapeutic effects and benefits of SGLT2i. This large cohort study shows that in patients with T2DM and MASLD, using SGLT2i for one year can significantly improve the fatty liver index, hepatic biochemical markers, and the effects become more pronounced with prolonged use. Additionally, compared with DPP4i, SGLT2i showed superior improvement in BMI, WC, GGT, ALT, and HbA1c. This study demonstrates the unique benefits of SGLT2i in improving hepatic steatosis in MASLD patients.
This study uses FLI as a non-invasive objective scoring index for hepatic steatosis, calculated based on clinical parameters BMI, waist circumference, triglycerides, and gamma-glutamyl transferase, with the advantage of repeatable measurements, facilitating long-term monitoring of MASLD. However, its consistency with liver biopsy remains to be validated.
Although the long-term effects of SGLT2i treatment on liver histology require further study, substantial evidence supports the use of SGLT2i in the treatment of T2DM combined with MASLD. Pharmacological studies have shown that SGLT2is have anti-inflammatory effects, reduce insulin resistance, and promote weight loss, helping to reduce and improve hepatic fat accumulation, inflammatory cytokines, blood pressure, lipid imbalances, and liver enzymes. Further prospective clinical studies based on liver biopsies are needed to draw definitive conclusions and support their clinical application in MASLD/MASH.
Commentary Expert
Professor Li Zhu Suzhou Fifth People’s Hospital Ph.D., Chief Physician, and Master’s Supervisor at Suzhou Fifth People’s Hospital.
03 A Secondary Analysis of Indices of Hepatic and Beta Cell Function Following 12 Weeks of Carbohydrate and Energy Restriction vs. Free-Living Control in Adults with Type 2 Diabetes Durrer C, Islam H, Cen HH, et al. Nutr Metab (Lond), 2024, 21(1): 29.
Significant weight loss in patients with type 2 diabetes (T2DM) can reduce the need for antidiabetic medications and lower blood glucose levels below the diagnostic threshold for the disease. Furthermore, weight loss interventions have been shown to improve the underlying pathophysiological mechanisms related to ectopic liver fat and pancreatic β-cell function. Therefore, this study explored the extent to which low-carbohydrate and energy restriction (LCER) dietary interventions improve β-cell stress/function, hepatic fat accumulation, and metabolically related liver function in patients with T2DM. The results indicate that a 12-week LCER diet did not improve β-cell stress markers; however, hepatic fat accumulation and liver function markers improved, suggesting that the LCER diet may improve the underlying pathophysiological mechanisms of T2DM.
In a large community parallel randomized controlled trial, patients underwent 12 weeks of LCER diet intervention (Pharm TCR: <50 g carbohydrates; 850-1100 kcal/day; n=20) versus usual care (TAU; n=16). This study conducted a secondary analysis of their blood samples. The subjects were T2DM patients using at least one antidiabetic medication and had a BMI ≥30 kg/m². The primary endpoints were C-peptide to proinsulin ratio, circulating microRNA 375 (miR375), homeostasis model assessment (HOMA) β-cell function (B), fatty liver index (FLI), hepatic steatosis index (HSI), HOMA insulin resistance (IR), circulating fetuin-A, and fibroblast growth factor 21 (FGF21). The results showed no significant changes in miR375 (P=0.42), C-peptide to proinsulin ratio (P=0.17), and HOMA B (P=0.15). FLI and HSI decreased by 25.1 (P<0.0001) and 4.9 (P<0.0001), respectively. HOMA IR decreased by 46.5% (P=0.011). FGF21 decreased by 161.2 pg/mL (P=0.035), and fetuin-A showed a similar trend (mean difference: -16.7 ng/mL; P=0.11). In the Pharm TCR group, these improvements in liver function markers were accompanied by reductions in circulating metabolites associated with hepatic insulin resistance (e.g., diacylglycerols, ceramides).
Commentary
Globally, T2DM is one of the most common lifestyle-related diseases, imposing a significant economic burden on healthcare systems worldwide. Risk factors for T2DM are often related to an unhealthy diet, including long-term high sugar, high fat, and high-calorie diets. Existing data suggest that the prevalence of MASLD and non-alcoholic steatohepatitis (NASH) in the T2DM population is as high as 65.04% and 46.88%, respectively. Therefore, lifestyle interventions, particularly dietary changes, are fundamental to treating T2DM and MASLD.
This study conducted a secondary analysis of blood indicators (at 0 and 12 weeks) in two groups of subjects (LCER group and TAU group) from a randomized parallel controlled trial. The experimental data showed that patients in the LCER diet intervention group had significantly reduced weight and BMI at 12 weeks, while the fatty liver index and hepatic steatosis index improved. Fibroblast growth factor 21 decreased, and fetuin-A showed a downward trend. Additionally, various metabolites contributing to hepatic insulin resistance significantly reduced, including various glycerides (e.g., diacylglycerols, triglycerides) and ceramides. In summary, the LCER dietary intervention not only significantly reduced weight in T2DM patients but also effectively reduced hepatic fat accumulation and improved hepatic fat metabolic function.
This study preliminarily demonstrated through the analysis of various metabolic indicators that limiting high-calorie diet interventions can improve hepatic steatosis and related metabolic indicators in MASLD. The study’s limitations include the lack of research and analysis on hepatic fibrosis changes. Additionally, future studies can explore LCER dietary interventions in MASLD patients without concomitant T2DM to observe whether LCER dietary interventions can prevent the development of diabetes in MASLD patients.
04 Effect of Sustained Decreases in Sedentary Time and Increases in Physical Activity on Liver Enzymes and Indices in Type 2 Diabetes Haxhi J, Vitale M, Mattia L, et al. Front Endocrinol (Lausanne), 2024, 15: 1393859.
Current MASLD guidelines recommend high volumes and/or intensities of physical activity (PA), typically requiring participation in supervised exercise programs, which can be challenging to implement in routine clinical practice. Instead, counseling interventions may be more appropriate but may not significantly increase moderate to vigorous PA (MVPA). This study evaluated whether counseling interventions aimed at increasing PA and reducing sedentary time (SED-time) could effectively improve MASLD markers in patients with T2DM. The results showed that even if the recommended MVPA targets were not met, behavioral changes involving all domains of PA lifestyle could have beneficial effects on MASLD markers in patients with T2DM.
Three hundred inactive and sedentary patients were randomly assigned to theoretical and practical counseling once a year for one month each year (intervention group) or standard care for three years (control group). AST, ALT, and γGT levels, as well as FLI, HSI, and visceral adiposity index (VAI), were measured in each group. Total PA, light-intensity PA (LPA), MVPA, and SED-time were objectively measured using accelerometers.
Over the three-year period, MASLD markers did not change in the control group, while ALT, γGT, FLI, and HSI decreased in the intervention group, with significant differences between the groups. Although MVPA moderately increased, it was related to significant reductions in SED-time and increases in LPA. The mean changes in MASLD markers varied with (and were associated with) changes in MVPA, SED-time, LPA, and PA. The mean changes in MVPA or PA were independent predictors of changes in MASLD markers. When included in the model, changes in cardiorespiratory fitness and lower limb muscle strength were independently associated with some MASLD markers.
Commentary
Adjusting dietary structure and increasing exercise are fundamental treatments for MASLD. There is a dose-response relationship between exercise volume and the reduction of hepatic fat content. Aerobic exercise of moderate intensity for more than 150 minutes per week and adherence for more than three months can reduce hepatic MRI-PDFF by more than 30% in MASLD patients. However, long-term adherence to moderate-intensity exercise can be challenging without supervision. Exercise can reduce hepatic fat content and improve insulin resistance regardless of weight loss. Therefore, this study targeted inactive and sedentary populations, intervening with more acceptable lifestyle changes by reducing sedentary time, thereby increasing exercise time without specifying exercise intensity. A three-year long-term study was conducted.
The study showed that through regular behavioral practical counseling, the intervention group achieved changes in exercise patterns, with significant reductions in ALT, γGT, FLI, and HSI, while the control group showed no significant changes. Further analysis revealed that changes in ALT, γGT, and HSI were significantly positively correlated with changes in SED-time and inversely correlated with changes in MVPA, LPA, and total PA, while changes in FLI and VAI were only significantly correlated with changes in MVPA. The study demonstrates that in patients with T2DM, counseling interventions to increase PA and reduce SED-time effectively improve MASLD. Even small increases in MVPA through maintaining a more active lifestyle can benefit MASLD/NASH in patients with T2DM. Furthermore, MVPA levels are an efficient independent predictor of improvements in MASLD markers, reaffirming the concept that more MVPA is better.
Combined treatment with reasonable diet and moderate exercise is more effective in improving MASLD than diet or exercise alone, so relying solely on exercise to improve hepatic inflammation and fibrosis has limited effect. The study’s experimental design did not include dietary changes, which may affect the results. Additionally, the lack of research analysis on hepatic fibrosis-related evaluation indicators means that the impact of reducing sedentary time and increasing exercise time on hepatic fibrosis changes still requires further in-depth research.
Commentary Expert
Professor Na Fu Hebei Medical University Third Hospital
05 Air Pollution, Life’s Essential 8, and Risk of Severe Non-Alcoholic Fatty Liver Disease Among Individuals with Type 2 Diabetes Aimuzi R, Xie Z, Qu Y, et al. BMC Public Health, 2024, 24(1): 1350.
The long-term impact of air pollution on the risk of secondary metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with type 2 diabetes (T2DM) is unclear. The regulatory role of Life’s Essential 8 (LE8) is also unclear. This study included 23,129 T2DM patients from the UK Biobank database. The annual averages of nitrogen dioxide (NO2), nitrogen oxides (NOX), and particulate matter (PM2.5, PM2.5-10, PM10) for each participant were estimated using a land-use regression model. Cox proportional hazards models were used to assess the relationship between exposure to air pollution and the risk of severe MASLD, with stratified analyses to evaluate the effect of LE8. The results indicate that long-term exposure to air pollution is associated with an increased risk of severe MASLD in T2DM participants. Lower LE8 levels may increase the adverse impact of air pollution on MASLD.
During a median follow-up period of 13.6 years, 1123 cases of severe MASLD were recorded. After adjusting for potential confounders, higher levels of PM2.5 (HR=1.12), NO2 (HR=1.15), and NOX (HR=1.08) were associated with an increased risk of severe MASLD. In addition, LE8 scores were negatively correlated with MASLD risk (HR=0.97). Compared to participants with low air pollution exposure and high LE8 levels, those with high air pollution exposure and low LE8 levels had a significantly higher risk of severe MASLD.
Commentary
Environmental factors and unhealthy lifestyles play crucial roles in the occurrence of MASLD. This study analyzed the risk of severe MASLD in T2DM patients under long-term exposure to air pollution and explored the significant role of LE8, which encompasses four lifestyle and four metabolic factors, in reducing the risk of MASLD in patients with T2DM.
The UK Biobank study is an ongoing prospective cohort study that includes over 500,000 adults recruited from 22 centers in the UK between 2006 and 2010. This study included 23,129 T2DM patients for analysis, estimating annual average air pollutant levels using a land-use regression model and using Cox proportional hazards models to assess the relationship between air pollutants and the risk of severe MASLD. The results showed: (1) Long-term exposure to high levels of PM2.5, NO2, and NOX is associated with an increased risk of severe MASLD in T2DM patients. Specifically, the hazard ratios (HR) for PM2.5, NO2, and NOX were 1.12, 1.15, and 1.08, respectively. (2) LE8 scores were negatively correlated with MASLD risk, with an HR of 0.97, suggesting that higher LE8 scores may offer some protection against the adverse effects of air pollution.
Overall, this study highlights the potential impact of air pollution on the risk of severe MASLD in T2DM patients and the important role of Life’s Essential 8 in reducing this risk. The study’s conclusions have significant implications for public health policy and individual health management.
06 Effects of Once-Weekly Semaglutide on Cardiovascular Risk Factors and Metabolic Dysfunction-Associated Steatotic Liver Disease in Japanese Patients with Type 2 Diabetes: A Retrospective Longitudinal Study Based on Real-World Data A Katsuyama H, Hakoshima M, Kaji E, et al. Biomedicines, 2024, 12(5): 1001.
Semaglutide is a GLP-1 receptor agonist widely used in the treatment of type 2 diabetes (T2DM). Clinical trials have shown that semaglutide significantly improves glycemia and obesity and reduces the risk of adverse cardiovascular events. However, studies on its effectiveness in real-world settings among Asian T2DM patients, particularly its relationship with various lipid metabolism abnormalities or MASLD, are still relatively scarce. This study confirms that once-weekly semaglutide significantly improves weight, glycemic control, and atherosclerotic lipid metabolism abnormalities, as well as MASLD.
This retrospective cohort study included 75 T2DM patients receiving once-weekly semaglutide treatment, comparing metabolic parameter changes before and after starting semaglutide. The study results showed that during semaglutide treatment, these patients’ HbA1c decreased by 0.7%-0.9%, and weight decreased by 1.4-1.7 kg. Additionally, non-HDL cholesterol significantly decreased at 3, 6, and 12 months after starting treatment, LDL cholesterol significantly decreased at 3 and 6 months, and HDL cholesterol increased at 12 months. Particularly, in patients newly starting GLP-1RA treatment, semaglutide had more pronounced effects on weight loss, HbA1c reduction, and lipid metabolism improvement; in those previously treated with other GLP-1RAs, HbA1c also improved. Additionally, during the 12 months of semaglutide treatment, hepatic steatosis index (HSI) decreased. Notably, APRI significantly decreased in patients newly starting GLP-1RA treatment.
Commentary
This study provides valuable real-world data on the effects of the GLP-1 receptor agonist (GLP-1RA) semaglutide on cardiovascular risk factors and MASLD in T2DM patients. Researchers conducted a retrospective cohort study, including 75 T2DM patients treated with once-weekly semaglutide at Kohnodai Hospital in Japan from June 2020 to June 2022, with treatment lasting at least three months. They observed changes in various metabolic factors before and after treatment, including blood and urine test results, anthropometric parameters, and changes in HSI and non-invasive hepatic fibrosis diagnostic markers (APRI, FIB-4). The results indicate that once-weekly semaglutide significantly improves weight, glycemic control, and important risk factors for cardiovascular disease and MASLD. In patients newly starting GLP-1RA treatment, semaglutide showed more pronounced effects on weight loss, HbA1c reduction, and lipid metabolism improvement, with more significant reductions in APRI. In patients previously treated with other GLP-1RAs, HbA1c and HSI also improved. This study emphasizes the potential value of semaglutide in routine clinical practice and MASLD prevention in Asian T2DM patients, which may significantly impact medication choices and treatment strategies for T2DM patients. However, the limited number of patients included in the study means it cannot completely avoid the influence of confounding factors. Expanding the study population can increase the credibility of the results and provide strong scientific evidence for future clinical decision-making.
