People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with the potential to progress into liver cirrhosis or hepatocellular carcinoma, has become a significant global health concern due to its increasing prevalence alongside obesity and metabolic syndrome. Despite the promise of existing therapies such as thyroid hormone receptor-β (THR-β) agonists, PPAR agonists, FXR agonists, and GLP-1 receptor agonists, their effectiveness is limited by the complexity of the metabolic, inflammatory, and fibrotic pathways that drive MASLD progression, encompassing steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and reversible liver fibrosis. Recent advances in targeted therapeutics, including RNA interference (RNAi), mRNA-based gene therapies, monoclonal antibodies, proteolysis-targeting chimeras (PROTAC), peptide-based strategies, cell-based therapies such as CAR-modified immune cells and stem cells, and extracellular vesicle-based approaches, have emerged as promising interventions. Alongside these developments, innovative drug delivery systems are being actively researched to enhance the stability, precision, and therapeutic efficacy of these biotherapeutics. These delivery strategies aim to optimize biodistribution, improve target-specific action, and reduce systemic exposure, thus addressing critical limitations of existing treatment modalities. This review provides a comprehensive exploration of the underlying biological mechanisms of MASLD and evaluates the potential of these cutting-edge biotherapeutics in synergy with advanced delivery approaches to address unmet clinical needs. By integrating fundamental disease biology with translational advancements, it aims to highlight future directions for the development of effective, targeted treatments for MASLD and its associated complications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, also considered a metabolic syndrome, and is associated with poor prognosis. eGDR (estimated glucose disposal rate) is a new biomarker to assessment insulin resistance (IR). The association between eGDR and MASLD and liver fibrosis is currently unclear.

The aim of this cross-sectional study is to appraise the association between eGDR and MASLD and liver fibrosis.

This study have enrolled 3,100 participants from the 2017-2018 National Health and Nutrition Examination Surveys (NHANES). Binary logistic regression analysis was used to assess the association between eGDR and MASLD and liver fibrosis. Receiver operating characteristic (ROC) was applied to estimate the ability of eGDR to identify MASLD.

The mean age of the subjects was 54.59 (17.29) years, and 49.26% were female. The prevalence of MASLD and liver fibrosis was 62.19% and 11.15%, respectively. In the fully adjusted models, there were negative associations of eGDR with the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), with βs of -15.18 and - 0.74 (all p < 0.01), respectively. There were negative associations of eGDR with MASLD and liver fibrosis, with odds ratios (ORs) and 95% confidence intervals of 0.53 (95% CI: 0.48-0.74) and 0.40 (95% CI: 0.28-0.57) (all p < 0.01). The area under the curve (AUC) of the eGDR for identifying MASLD and liver fibrosis is 0.74 and 0.75, respectively.

The study findings suggest a significant association between eGDR and MASLD as well as liver fibrosis. eGDR may serve as a biomarker for identifying MASLD.

The development of type 2 diabetes (T2D) is largely dependent on the maintenance of pancreatic islet function and mass. Sexual dimorphism in T2D is evident in many areas, such as pathophysiology, treatment, and prevention. Mitogen-activated protein kinase phosphatase-2 (MKP-2) has a distinct role in the regulation of cell proliferation and the development of metabolic disorders. However, whether there is a causal relationship between MKP-2 and diabetes onset is unclear. The aim of this study was to determine the role of MKP-2 in the regulation of whole-body glucose homeostasis and the impact on pancreatic islet function using streptozotocin-induced pancreatic injury. Here, we show that female mice with whole-body deletion of MKP-2 exhibit hyperglycemia in mouse models treated with multiple low doses of streptozotocin (STZ). In comparison, both male MKP-2 wild-type and knockout mice were hyperglycemic. Consistent with the hyperglycemia, female MKP-2-deficient mice exhibited reduced islet size. Under T2D conditions, MKP-2-deficient mice display enhanced pancreatic JNK and ERK phosphorylation that is associated with the downregulation of genes important for pancreatic islet development and function, Pdx-1 and MafA. Furthermore, we found impaired metabolic flux in adipose tissue that is consistent with hyperglycemia and dysfunctional pancreas. MKP-2 deletion results in reduced Akt activation that is associated with increased adiposity and insulin resistance in female MKP-2 KO mice. These studies demonstrate the critical role of MKP-2 in the development of T2D diabetes in vivo. This suggests that MKP-2 may have a gender-specific role in diabetes development. This discovery raises the possibility that postmenopausal prevention of T2D may benefit from the activation of MKP-2 activity in islet cells.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are associated with a multifactorial complicated aetiology that is often coexisting and has a strong and distinct connection with cardiovascular diseases (CVDs). In order to accomplish effective and appropriate therapeutic strategies, a deeper understanding of the bidirectional interaction between NAFLD patients, NAFLD patients with T2DM, and NAFLD patients with CVDs is required to control the concomitant rise in prevalence of these conditions worldwide. This article also aims to shed light on the epidemiology and mechanisms behind the relationship between T2DM, NAFLD and the related cardiovascular consequences.

Literature was collected from PubMed, Medline, Embase, Web of Science and Google scholar from inception to June, 2024. For surveying literature different combinations and formats of terms including NAFLD, NASH, T2DM and CVDs were used.

In the recent decade, clinical and epidemiological studies have been conducted and provide strong evidence that NAFLD is closely linked with CVD progression along with associated morbidity and mortality in both patients with and without T2DM. Several mechanistic approaches contribute to cardiovascular consequences and abnormalities in cardiac biomarkers in T2DM and NAFLD patients, including adipose tissue malfunction, mitochondrial dysfunction, the microbiota, genetic and epigenetic alterations contributing to insulin resistance, glucotoxicity and lipotoxicity.

The study reveals a complex interplay between diabetes, hepatic and cardiovascular complications, leading to significant morbidity and mortality in diabetic and NAFLD patients. This pandemic necessitates further research to identify mitigating variables and develop effective treatment approaches.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often overlooked in patients with type 1 diabetes mellitus (T1DM). Our study aims to provide a comprehensive overview of the burden of MASLD in T1DM by assessing the prevalence of MASLD and its advanced forms in individuals with T1DM.

We systematically searched PubMed and Embase databases (from inception to May 5, 2024) for original articles on the prevalence or characteristics of MASLD (as detected by blood biomarkers/scores, imaging techniques, or liver biopsy) in adults with T1DM. Data were extracted, and we performed a meta-analysis of proportions using generalized linear mixed model, and pairwise meta-analysis using the DerSimonian-Laird method. Heterogeneity was investigated with further subgroup and meta-regression analyses, and publication bias was assessed.

We identified 23 studies for a total of 13,006 individuals with T1DM. Of these, 22.24% (95% confidence interval [CI], 15.62-30.66; I2 = 99.2%) had MASLD. Significant fibrosis (≥F2) and advanced fibrosis (≥F3) were found in 13.25% (95% CI, 11.15-15.67; I2 = 0%) and 5.12% (95% CI, 3.78-6.91; I2 = 0%) of patients with T1DM and MASLD, respectively. Patients with MASLD and T1DM were more likely to be older, overweight, male, have a longer duration of diabetes, require higher daily doses of insulin, have metabolic dysfunction, and were at a higher risk of microvascular complications.

MASLD is relatively common in T1DM. Patients with MASLD-T1DM have a distinct clinical profile compared with those with T1DM, with only a small proportion having significant or advanced fibrosis.

The aim was to examine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a risk factor for atherosclerotic cardiovascular disease, and its association with glycaemic control metrics in children and adolescents with type 1 diabetes (T1D).

We enrolled 244 children and adolescents with T1D (115 girls, mean age: 16.2 ± 3.2 years). The diagnosis of MASLD was defined by the presence of hepatic steatosis on ultrasonography in combination with at least one of five common cardiometabolic risk factors. Metrics of short-term and long-term glycaemic control, blood pressure, lipids, anthropometric characteristics and three genetic variants strongly related to MASLD susceptibility (rs738409 [patatin-like phospholipase domain-containing 3], rs58542926 [transmembrane 6 superfamily member 2] and rs1260326 [glucokinase regulator]) were assessed. Characteristics of these subjects with and without MASLD were compared using the unpaired Student t test, Mann-Whitney test or χ2 test as appropriate. Logistic regression analyses were performed to determine the main independent predictors of MASLD.

The prevalence of MASLD was 27.5% in children and adolescents with T1D. Blood pressure, total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein cholesterol, HbA1c and time above range (TAR) were significantly higher in subjects with MASLD than in those without MASLD. Mean HbA1c values from diabetes onset (adjusted odds ratio [OR]: 1.703, 95% confidence interval [CI]: 1.040-2.787, p = 0.034), TAR (adjusted OR: 1.028, 95% CI: 1.009-1.047, p = 0.006) and plasma LDL cholesterol (adjusted OR: 1.045, 95% CI: 1.013-1.078, p = 0.004) were independently associated with the presence of MASLD.

MASLD is a common condition in children and adolescents with T1D. The mean HbA1c values from diabetes onset, TAR and LDL cholesterol levels were the independent predictors of MASLD.

Diabetes mellitus is one of the major causes of ischemic and nonischemic heart failure. While hypertension and coronary artery disease are frequent comorbidities in patients with diabetes, cardiac contractile dysfunction and remodeling occur in diabetic patients even without comorbidities, which is referred to as diabetic cardiomyopathy. Investigations in recent decades have demonstrated that the production of reactive oxygen species (ROS), impaired handling of intracellular Ca2+, and alterations in energy metabolism are involved in the development of diabetic cardiomyopathy. AMP deaminase (AMPD) directly regulates adenine nucleotide metabolism and energy transfer by adenylate kinase and indirectly modulates xanthine oxidoreductase-mediated pathways and AMP-activated protein kinase-mediated signaling. Upregulation of AMPD in diabetic hearts was first reported more than 30 years ago, and subsequent studies showed similar upregulation in the liver and skeletal muscle. Evidence for the roles of AMPD in diabetes-induced fatty liver, sarcopenia, and heart failure has been accumulating. A series of our recent studies showed that AMPD localizes in the mitochondria-associated endoplasmic reticulum membrane as well as the sarcoplasmic reticulum and cytosol and participates in the regulation of mitochondrial Ca2+ and suggested that upregulated AMPD contributes to contractile dysfunction in diabetic cardiomyopathy via increased generation of ROS, adenine nucleotide depletion, and impaired mitochondrial respiration. The detrimental effects of AMPD were manifested at times of increased cardiac workload by pressure loading. In this review, we briefly summarize the expression and functions of AMPD in the heart and discuss the roles of AMPD in diabetic cardiomyopathy, mainly focusing on contractile dysfunction caused by this disorder.

Diabetes mellitus, a metabolic syndrome characterized by hyperglycemia and insulin dysfunction, often leads to serious complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Incretins, gut peptide hormones released post-nutrient intake, have shown promising therapeutic effects on these complications due to their wide-ranging biological impacts on various body systems. This review focuses on the role of incretin-based therapies, particularly Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, in managing diabetes and its complications. We also discuss the potential of novel agents like semaglutide, a recently approved oral compound, and dual/triple agonists targeting GLP-1/GIP, GLP-1/glucagon, and GLP-1/GIP/glucagon receptors, which are currently under investigation. The review aims to provide a comprehensive understanding of the beneficial impacts of natural incretins and the therapeutic potential of incretin-based therapies in diabetes management.

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting >30% of the global population. Metabolic dysregulation, particularly insulin resistance and its subsequent manifestation as type 2 diabetes mellitus, serves as the fundamental pathogenesis of metabolic liver disease. Clinical evidence of the recent nomenclature evolution is accumulating. The interaction and impacts are bidirectional between MASLD and diabetes in terms of disease course, risk, and prognosis. Therefore, there is an urgent need to highlight the multifaceted links between MASLD and diabetes for both hepatologists and diabetologists. The surveillance strategy, risk stratification of management, and current therapeutic achievements of metabolic liver disease remain the major pillars in a clinical care setting. Therefore, the Taiwan Association for the Study of the Liver (TASL), Taiwanese Association of Diabetes Educators, and Diabetes Association of the Republic of China (Taiwan) collaboratively completed the first guidance in patients with diabetes and MASLD, which provides practical recommendations for patient care.

Non-alcoholic fatty liver disease (NAFLD) poses a global health challenge. While pyroptosis is implicated in various diseases, its specific involvement in NAFLD remains unclear. Thus, our study aims to elucidate the role and mechanisms of pyroptosis in NAFLD. Utilizing data from the Gene Expression Omnibus (GEO) database, we analyzed the expression levels of pyroptosis-related genes (PRGs) in NAFLD and normal tissues using the R data package. We investigated protein interactions, correlations, and functional enrichment of these genes. Key genes were identified employing multiple machine learning techniques. Immunoinfiltration analyses were conducted to discern differences in immune cell populations between NAFLD patients and controls. Key gene expression was validated using a cell model. Analysis of GEO datasets, comprising 206 NAFLD samples and 10 controls, revealed two key PRGs (TIRAP, and GSDMD). Combining these genes yielded an area under the curve (AUC) of 0.996 for diagnosing NAFLD. In an external dataset, the AUC for the two key genes was 0.825. Nomogram, decision curve, and calibration curve analyses further validated their diagnostic efficacy. These genes were implicated in multiple pathways associated with NAFLD progression. Immunoinfiltration analysis showed significantly lower numbers of various immune cell types in NAFLD patient samples compared to controls. Single sample gene set enrichment analysis (ssGSEA) was employed to assess the immune microenvironment. Finally, the expression of the two key genes was validated in cell NAFLD model using qRT-PCR. We developed a prognostic model for NAFLD based on two PRGs, demonstrating robust predictive efficacy. Our findings enhance the understanding of pyroptosis in NAFLD and suggest potential avenues for therapeutic exploration.

To investigate the relationship between continuous glucose monitoring (CGM)-derived glucometrics and metabolic dysfunction-associated steatotic liver disease (MASLD) in type 1 diabetes (T1D).

A cross-sectional study collecting data on anthropometrics, glucometrics and MASLD in adults with T1D using a CGM device was conducted. MASLD was assessed by abdominal ultrasound and the presence of at least one cardiometabolic criterion. Backward multivariable logistic regression models were applied to define variables independently associated with MASLD.

A total of 302 consecutive participants were included (median age 49 [34-61] years, male sex 58%, median diabetes duration 29 [17-38] years, mean time in range [TIR] 55% ± 16%). MASLD was present in 17% of cases, and 32% had metabolic syndrome (MetS). MetS was significantly more prevalent in the MASLD group (65% vs. 25%, P < .0001). TIR (P = .038) and time below range (TBR) (P = .032) were lower and time above range (TAR) was higher (P = .006), whereas HbA1c did not reach significance (P = .068). No differences were found for the glycaemia risk index. TIR (P = .028), TAR (P = .007), TBR (P = .036), waist circumference (P < .001) and systolic blood pressure (P = .029) were independently associated with MASLD, while sex, age, aspartate aminotransferase/alanine aminotransferase ratio, gamma-glutamyl transferase, high-density lipoprotein cholesterol and triglycerides were not.

TIR, TAR, TBR, waist circumference and systolic blood pressure were independently associated with MASLD.

To compare hepatic stiffness and fat fraction in patients with obesity and type 1 diabetes (T1D) with type 2 diabetes (T2D) with a similar body mass index (BMI).

In this prospective cross-sectional study, 90 participants with T1D (BMI 30.5 ± 4.5 kg/m2; diabetes duration 20.5 ± 9.8 years; HbA1c 8.2% ± 1.4%) and 69 with T2D (BMI: 30.8 ± 4.6 kg/m2; diabetes duration: 11.7 ± 7.8 years; HbA1c: 7.3% ± 1.4%) were included. Liver fat fraction and stiffness were examined by magnetic resonance imaging and elastography, respectively. Logistic regressions were used to evaluate associations with biomedical variables.

The mean liver stiffness score in patients with obesity and T1D was 2.2 ± 0.5 kPa, while in T2D it was 2.6 ± 0.8 kPa (P < .001). The liver fat fraction in patients with obesity and T1D was 3.7% ± 6.3%, and in T2D it was 10.6% ± 7.9% (P < .001). Metabolic dysfunction-associated steatotic liver disease (MASLD) was present in 13.3% of patients with T1D and in 69.6% of patients with T2D, whereas fibrosis was suggested in 7.8% of patients with T1D and in 27.5% of patients with T2D. Liver stiffness was four times higher in patients with T2D compared with those with T1D (odds ratio = 5.4, 95% confidence interval: 2.1-13.6, P < .001). Aspartate transaminase (AST), alanine transaminase, gamma-glutamyl transferase (GGT), triglycerides and the android-to-gynoid ratio were associated with elevated fat fraction in both cohorts. AST and GGT were associated with elevated liver stiffness in both cohorts.

Patients with obesity and T1D had lower liver fat and liver stiffness compared with those patients with T2D, despite similar levels of BMI, a longer duration of diabetes and worse glycaemic control.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (DM) are the most prevalent metabolic disorders globally. The numbers affected in both disorders are also rapidly increasing with alarming trends in children and young adults.

Insulin resistance (IR) and the subsequent metabolic dysregulation are the fundamental pathogenesis pathways of the prevalent metabolic disorders. The interaction and impacts are bidirectional between MASLD and DM in terms of disease mechanisms, disease course, risks, and prognosis. There's a pressing issue for highlighting the links between MASLD and DM for both care specialists and primary care providers. The review collected the scientific evidence addressing the mutual interactions between the two disorders. The strategies for surveillance, risk stratification, and management are discussed in a practical manner. It also provides individualized viewpoints of patient care in hepatology and diabetology.

Both MASLD and DM shared similar disease mechanisms, and affected the disease development and progression in a bidirectional manner. The high prevalence and the cross-link between the two disorders raise clinical issues from awareness, screening, risk stratification, optimal referral, to appropriate management for primary care providers.

To investigate the effect mechanism of electroacupuncture based on the AMP-activated protein kinase (AMPK) /acetyl-CoA carboxylase (ACC) signaling pathway to improve glycolipid metabolism disorders in db/db mice. 10 db/m mice with normal genotype were used as the normal control group without diabetes (Con), and 30 db/db mice were divided randomly into three groups: Pathological model mice (Mod), Acupuncture + ACC antagonist group (Acu + ACC), and Acupuncture + AMPK antagonist group (Acu + AMPK). Con and Mod did not receive any special treatment, only as a control observation. The latter two groups of mice received electroacupuncture treatment for 4 weeks. Mouse triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol(LDL-C), and cholesterin(CHO) levels were detected by colorimetric assay. Enzyme-linked immunoassay (ELISA) was used to detect insulin(INS) levels. Liver histopathologic changes and hepatic glycogen synthesis were observed by HE and PAS staining. The mRNA and protein expression of insulin receptor substrate-1(IRS1), Phosphatidylinositol 3-kinase(PI3K), protein kinase B (AKT), AMPK, and ACC were detected by Western blot and qRT-PCR.The results show that compared with Mod, TG, LDL, CHO, and INS levels of Acu + AMPK and Acu + ACC mice were significantly reduced (P < 0.05), and the HDL levels were significantly increased (P < 0.05), the steatotic degeneration of mice hepatocytes was reduced to different degrees, and the hepatocyte glycogen particles were increased, and the latter two groups had a decrease in AKT, ACC mRNA expression was reduced (P < 0.05), PI3K protein expression was increased, and AKT and ACC protein expression was reduced (P < 0.05), in addition, protein expression of AMPK was increased and IRS1 protein expression was reduced in Acu + ACC (P < 0.05). The study showed that electroacupuncture improves glucose-lipid metabolism disorders in db/db mice, and this mechanism is related to the AMPK/ACC signaling pathway.

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts.

The presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with diabetes mellitus (DM) is associated with a high risk of cardiovascular disease, but is often underdiagnosed.

To develop machine learning (ML) models for risk assessment of MASLD occurrence in patients with DM.

Feature selection determined the discriminative parameters, utilized to classify DM patients as those with and without MASLD. The performance of the multiple logistic regression model was quantified by sensitivity, specificity, and percentage of correctly classified patients, and receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) assessed the model's net benefit for alternative treatments.

We studied 2000 patients with DM (mean age 58.85 ± 17.37 years; 48% women). Eight parameters: age, body mass index, type of DM, alanine aminotransferase, aspartate aminotransferase, platelet count, hyperuricaemia, and treatment with metformin were identified as discriminative. The experiments for 1735 patients show that 744/991 (75.08%) and 586/744 (78.76%) patients with/without MASLD were correctly identified (sensitivity/specificity: 0.75/0.79). The area under ROC (AUC) was 0.84 (95% CI, 0.82-0.86), while DCA showed a higher clinical utility of the model, ranging from 30% to 84% threshold probability. Results for 265 test patients confirm the model's generalizability (sensitivity/specificity: 0.80/0.74; AUC: 0.81 [95% CI, 0.76-0.87]), whereas unsupervised clustering identified high-risk patients.

A ML approach demonstrated high performance in identifying MASLD in patients with DM. This approach may facilitate better risk stratification and cardiovascular risk prevention strategies for high-risk patients with DM at risk of MASLD.

Steatotic liver disease (SLD) displays a dynamic and complex disease phenotype. Consequently, the metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) therapeutic pipeline is expanding rapidly and in multiple directions. In parallel, noninvasive tools for diagnosing and monitoring responses to therapeutic interventions are being studied, and clinically feasible findings are being explored as primary outcomes in interventional trials. The realization that distinct subgroups exist under the umbrella of SLD should guide more precise and personalized treatment recommendations and facilitate advancements in pharmacotherapeutics. This review summarizes recent updates of pathophysiology-based nomenclature and outlines both effective pharmacotherapeutics and those in the pipeline for MASLD/MASH, detailing their mode of action and the current status of phase 2 and 3 clinical trials. Of the extensive arsenal of pharmacotherapeutics in the MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, have shown only marginal benefits and are now being tested as part of combination therapies, yet others are still in development as monotherapies. Although the Food and Drug Administration (FDA) has recently approved resmetirom, additional therapeutic approaches in development will ideally target MASH and fibrosis while improving cardiometabolic risk factors. Due to the urgent need for the development of novel therapeutic strategies and the potential availability of safety and tolerability data, repurposing existing and approved drugs is an appealing option. Finally, it is essential to highlight that SLD and, by extension, MASLD should be recognized and approached as a systemic disease affecting multiple organs, with the vigorous implementation of interdisciplinary and coordinated action plans. SIGNIFICANCE STATEMENT: Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, is the most prevalent chronic liver condition, affecting more than one-fourth of the global population. This review aims to provide the most recent information regarding SLD pathophysiology, diagnosis, and management according to the latest advancements in the guidelines and clinical trials. Collectively, it is hoped that the information provided furthers the understanding of the current state of SLD with direct clinical implications and stimulates research initiatives.

Recent studies have suggested a link between type 1 diabetes mellitus (T1D) and metabolic dysfunction associated steatotic liver disease (MASLD) in children and adolescent, but longitudinal evidence is lacking. This study aimed to investigate the potential association between poorly controlled T1D and elevated alanine aminotransferase (ALT), serving as a proxy for MASLD in children and adolescents over time.

The study included 32,325 children aged 2-17 years with T1D from Germany, Austria, and Switzerland who had undergone at least one assessment of liver enzyme levels recorded in the Diabetes-Patienten- Verlaufsdokumentation registry. Multivariable logistic and Cox regression models were calculated to show possible associations between T1D and elevated ALT values (>26 U/L in males, >22 U/L in females) as a proxy for MASLD.

Children with poorly controlled T1D (HbA1c > 11%) exhibited increased odds of elevated ALT values, after adjustment for age, sex, diabetes duration and overweight (odds ratio [OR] 2.54; 95% confidence interval [CI], 2.10-3.10; p < 0.01). This finding is substantiated by a longitudinal analysis, which reveals that inadequately controlled T1D was associated with a higher hazard ratio (HR) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 (HR: 1.54; 95% CI, 1.19-2.01; p < 0.01).

In conclusion, the current study strongly links poorly controlled T1D in children and adolescents to MASLD irrespective of overweight. This association is not only present cross-sectionally but also increases over time. The study underscores the critical role of effective diabetes management in reducing the risk of MASLD in this population.

Standards of care summarized in clinical practice guidelines for nonalcoholic fatty liver disease (NAFLD) offer clinicians a streamlined diagnostic and management approach based on the best available evidence. These recommendations have changed a great deal in recent years; today, there is a clear focus on screening for the early identification and risk stratification of patients at high risk of steatohepatitis and clinically significant fibrosis to promote timely referrals to specialty care when needed. This article reviews and provides the rationale for current guidelines for NAFLD screening, diagnosis, treatment, and monitoring and addresses barriers to providing evidence-based NAFLD care and how to overcome them. The current paradigm of care calls for primary care clinicians and specialists to work together, within a multidisciplinary care team familiar with obesity and diabetes care, to provide comprehensive management of these complex patients.

Metabolic associated fatty liver disease (MAFLD) is a novel terminology introduced in 2020 to provide a more accurate description of fatty liver disease associated with metabolic dysfunction. It replaces the outdated term nonalcoholic fatty liver disease (NAFLD) and aims to improve diagnostic criteria and tailored treatment strategies for the disease. NAFLD, the most prevalent liver disease in western industrialized nations, has been steadily increasing in prevalence and is associated with serious complications such as cirrhosis and hepatocellular carcinoma. It is also linked to insulin resistance syndrome and cardiovascular diseases. However, current studies on NAFLD have limitations in meeting necessary histological endpoints.

This literature review aims to consolidate recent knowledge and discoveries concerning MAFLD, integrating the diverse aspects of the disease. Specifically, it focuses on analyzing the diagnostic criteria for MAFLD, differentiating it from NAFLD and alcoholic fatty liver disease (AFLD), and exploring the epidemiology, clinical manifestations, pathogenesis, and management approaches associated with MAFLD. The review also explores the associations between MAFLD and other conditions. It discusses the heightened mortality risk associated with MAFLD and its link to chronic kidney disease (CKD), showing that MAFLD exhibits enhanced diagnostic accuracy for identifying patients with CKD compared to NAFLD. The association between MAFLD and incident/prevalent CKD is supported by cohort studies and meta-analyses.

This literature review highlights the importance of MAFLD as a distinct terminology for fatty liver disease associated with metabolic dysfunction. The review provides insights into the diagnostic criteria, associations with CKD, and management approaches for MAFLD. Further research is needed to develop more accurate diagnostic tools for advanced fibrosis in MAFLD and to explore the underlying mechanisms linking MAFLD with other conditions. This review serves as a valuable resource for researchers and healthcare professionals seeking a comprehensive understanding of MAFLD.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of liver disease, specifically chronic liver disease. Type 2 diabetes (T2DM) is associated with the risk of NAFLD given that patients usually have insulin resistance as one of the observed complications with NAFLD. Hypoglycemic agents, including sodium glucose cotransporter 2 (SGLT-2), have shown to improve NAFLD. The objective of this study is to evaluate the effect of SGLT-2 inhibitors on NAFLD patients' outcomes, whether they have T2DM or not. We conducted a comprehensive search using the PubMed and Ovid databases to identify published studies that addressed the use of SGLT-2 inhibitors in NAFLD patients. The outcomes assessed include changes in liver enzymes, lipid profiles, weight changes, the fibrosis-4-index (FIB4), and magnetic resonance imaging proton density-based fat fraction (MRI-PDFF). Only clinical trials that met the quality measures were included in this review. Out of 382 potential studies, we included 16 clinical trials that discussed the use of SGLT-2 inhibitors in NAFLD patients. A total of 753 patients were enrolled in these trials. The majority of the trials reported positive effects of SGLT-2 inhibitors on liver enzymes; alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase. All 10 trials that reported changes in body mass index (BMI) from baseline showed a statistically significant reduction with SGLT-2 inhibitor use, while 11 studies reported a significant increase in high density lipoprotein (HDL) levels, 3 studies reported a reduction in triglycerides (TG) levels, and 2 studies showed a decrease in low density lipoprotein (LDL) levels. The available evidence shows that the use of SGLT-2 inhibitors in NAFLD is associated with positive outcomes on liver enzymes, lipid profiles, and BMI. Further studies with larger sample size and longer follow-up time are warranted.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM.

MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies.

156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4).

This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD.

CRD42022360251.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a raising concern in type 1 diabetes (T1D) patients. We evaluated whether multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) may differentially affect NAFLD.

NAFLD was assessed by Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) in 659 T1D patients treated by MDI (n=414, 65% men) or CSII (n=245, 50% men) without alcohol abuse or other liver diseases. Clinical and metabolic differences between MDI and CSII participants were also evaluated according to sex.

Compared with the MDI cohort, CSII users had a significantly lower FLI (20.2±21.2 vs. 24.8±24.3; p=0.003), HSI (36.2±4.4 vs. 37.4±4.4; p=0.003), waist circumference (84.6±11.8 vs. 86.9±13.7 cm; p=0.026), plasma triglyceride (76.0±45.8 vs. 84.7±58.3 mg/dl; p=0.035), and daily insulin dose (0.53±0.22 vs. 0.64±0.25 IU/kg body weight; p<0.001). In CSII users, lower FLI and HSI were observed in women (p=0.009 and p=0.033, respectively) but not in men (p=0.676 and p=0.131, respectively). Women on CSII also had lower daily insulin doses, plasma triglyceride, and visceral adiposity index than women on MDI.

CSII is associated with lower NAFLD indices in women with T1D. This may relate to the lower peripheral insulin in the context of a permissive hormonal milieu.

We aimed to compare the risk of incident diabetes according to fatty liver disease (FLD) definition, focusing on the comparison between those who met criteria for either metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD) but not the other. This was a 5.0-year (interquartile range, 2.4-8.2) retrospective longitudinal cohort study of 21,178 adults who underwent at least two serial health checkup examinations. The presence of hepatic steatosis was determined by abdominal ultrasonography at the first health examination. Cox proportional hazard analyses were used to compare the risk of incident diabetes among five groups. Incident diabetes cases occurred in 1296 participants (6.1%). When non-FLD without metabolic dysfunction (MD) group was set as a reference, the risk of incident diabetes increased in the order of NAFLD-only, non-FLD with MD, both FLD, and MAFLD-only groups. The presence of excessive alcohol consumption and/or hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, FLD, and MD synergistically increased the risk of incident diabetes. MAFLD-only group showed a greater increase in incidence of diabetes than non-FLD with MD and NAFLD-only groups. The interaction among excessive alcohol consumption, HBV/HCV infection, MD, and hepatic steatosis on the development of diabetes should not be overlooked.

The epidemiology of non-alcoholic fatty liver disease (NAFLD) in people with type 1 diabetes (T1D) is not yet elucidated. This study aimed to assess the diagnostic accuracy of non-invasive tests for NAFLD, to investigate the prevalence and severity of NAFLD, and to search for factors contributing to NAFLD in people with T1D.

In this prospective cohort study, we consecutively screened 530 adults with T1D from a tertiary care hospital, using ultrasound (US), vibration-controlled transient elastography equipped with liver stiffness measurement (LSM) and controlled attenuation parameter, and the fatty liver index. Magnetic resonance spectroscopy (MRS) was performed in a representative subgroup of 132 individuals to validate the diagnostic accuracy of the non-invasive tests.

Based on MRS as reference standard, US identified individuals with NAFLD with an AUROC of 0.98 (95% CI 0.95-1.00, sensitivity: 1.00, specificity: 0.96). The controlled attenuation parameter was also accurate with an AUROC of 0.85 (95% CI 0.77-0.93). Youden cut-off was ≥270 dB/m (sensitivity: 0.90, specificity: 0.74). The fatty liver index yielded a similar AUROC of 0.83 (95% CI 0.74-0.91), but the conventional cut-off used to rule in (≥60) had low sensitivity and specificity (0.62, 0.78). The prevalence of NAFLD in the overall cohort was 16.2% based on US. Metabolic syndrome was associated with NAFLD (OR: 2.35 [1.08-5.12], p = 0.031). The overall prevalence of LSM ≥8.0 kPa indicating significant fibrosis was 3.8%, but reached 13.2% in people with NAFLD.

NAFLD prevalence in individuals with T1D is 16.2%, with approximately one in 10 featuring elevated LSM. US-based screening could be considered in people with T1D and metabolic syndrome.

We aimed to report on the prevalence, disease severity, and risk factors of NAFLD in type 1 diabetes (T1D), while also tackling which non-invasive test for NAFLD is the most accurate. We found that ultrasound is the best test to diagnose NAFLD. NAFLD prevalence is 16.2%, and is associated with metabolic syndrome and BMI. Elevated liver stiffness indicating fibrosis is overall not prevalent in people with T1D (3.8%), but it reaches 13.2% in those with T1D and NAFLD.

Tirzepatide is a promising drug with dual-acting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor activation that has revolutionized the treatment of type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise. In phase 3 clinical trials (SURPASS 1-5), the dose-dependent efficacy and safety of tirzepatide were assessed by once-weekly subcutaneous injection (5 mg, 10 mg, and 15 mg), as monotherapy or combination therapy, in individuals with T2DM. Tirzepatide has been shown to achieve better glycemic control in terms of glycosylated hemoglobin reduction and improved fasting and postprandial glucose levels as compared to other diabetic medications. Moreover, the studies demonstrate a reduction in body weight (-6.2 to -12.9 kg), and other cardiovascular benefits by altering the lipid profile, reducing blood pressure, and visceral adiposity. Tirzepatide has acceptable side effects and is well tolerated, with a low risk of hypoglycemia. The SURPASS 4 clinical trial has shown positive cardiovascular outcomes in people with T2DM and elevated cardiovascular risk. Additionally, encouraging results from SURMOUNT trials and ongoing SURPASS-CVOT studies will shed more light on cardiovascular safety in the future. In this review, we have summarized the clinical trials and their respective outcomes and highlighted the potential future indications for tirzepatide in the management of obesity, heart failure, and nonalcoholic steatohepatitis.

Hormonal signaling plays key roles in tissue and metabolic homeostasis. Accumulated evidence has revealed a great deal of insulin and estrogen signaling pathways and their interplays in the regulation of mitochondrial, cellular remodeling, and macronutrient metabolism. Insulin signaling regulates nutrient and mitochondrial metabolism by targeting the IRS-PI3K-Akt-FoxOs signaling cascade and PGC1α. Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism through its receptors (ERα, ERβ, and GPER). Insulin and estrogen signaling converge on Sirt1, mTOR, and PI3K in the joint regulation of autophagy and mitochondrial metabolism. Dysregulated insulin and estrogen signaling lead to metabolic diseases. This article reviews the up-to-date evidence that depicts the pathways of insulin signaling and estrogen-ER signaling in the regulation of metabolism. In addition, we discuss the cross-talk between estrogen signaling and insulin signaling via Sirt1, mTOR, and PI3K, as well as new therapeutic options such as agonists of GLP1 receptor, GIP receptor, and β3-AR. Mapping the molecular pathways of insulin signaling, estrogen signaling, and their interplays advances our understanding of metabolism and discovery of new therapeutic options for metabolic disorders.

Non-alcoholic fatty liver disease (NAFLD) has become a significant concern among people living with HIV (PLHIV), albeit its burden remains unclear. The primary objective of this systematic review (SR) and meta-analysis (MA) was to estimate the prevalence of NAFLD and significant fibrosis in PLHIV. The secondary objective was to determine the risk factors for NAFLD among PLHIV.

We searched MEDLINE and Scopus from inception to 30 December 2022 for peer-reviewed studies that included PLHIV and reported the prevalence of NAFLD. MA of proportions was used to estimate the pooled prevalence of NAFLD and significant fibrosis. MA of pre-calculated effect estimates examined risk factors for NAFLD in PLHIV.

We included 24 articles published between 2009 and 2022, encompassing 6326 PLHIV. The pooled prevalence of NAFLD was 38% (95% CI: 31-45%) with high heterogeneity (I2 = 96.3%). The pooled prevalence of significant fibrosis was 13% (95% CI: 8-18%) with high heterogeneity (I2 = 92.09%). Subgroup analyses showed a NAFLD prevalence of 40% (95% CI: 24-57%) in the United States, 33% (95% CI: 31-36) in Asia, 42% (95% CI: 24-61%) in Europe and 33% (95% CI: 29-37) in South America. When stratifying by income level, NAFLD was 39% (95% CI: 31-48) prevalent in PLHIV from high-income economies and 34% in both upper-middle-income (95% CI: 31-37%) and lower-middle-income economies (95% CI: 28-41%). Higher body mass index (BMI) (OR = 1.32, 95% CI: 1.13-1.55; I2 = 89.9%), increasing triglycerides (OR = 1.48, 95% CI: 1.22-2.79; I2 = 27.2%) and dyslipidaemia (OR = 1.89, 95% CI: 1.32-2.71; I2 = 15.5%) were all associated with higher risk-adjusted odds of NAFLD in PLHIV.

The burden of NAFLD and significant fibrosis in PLHIV is significant. Therefore, targeted efforts to screen and diagnose NAFLD in this population are needed. Health services for PLHIV could include ways to target NAFLD risk factors, screen for liver disease and implement interventions to treat those with significant fibrosis or more advanced stages of liver disease. Taking no action to address NAFLD in PLHIV should not be an option.

This SR and MA found a 38% NAFLD and 13% significant fibrosis prevalence in PLHIV. Increasing triglyceride levels, higher BMI values and dyslipidaemia were associated with higher risk-adjusted odds of NAFLD among PLHIV.

Metabolic associated fatty liver disease (MAFLD) has become the most common liver disease globally, yet no new drugs have been approved for clinical treatment. Therefore, we investigated the relationship between dietary intake of soy-derived daidzein and MAFLD, to find potentially effective treatments.

We conducted a cross-sectional study using data from 1,476 participants in National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018 and their associated daidzein intake from the flavonoid database in the USDA Food and Nutrient Database for Dietary Studies (FNDDS). We investigated the relationship between MAFLD status, controlled attenuation parameter (CAP), AST/Platelet Ratio Index (APRI), Fibrosis-4 Index (FIB-4), liver stiffness measurement (LSM), nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), hepatic steatosis index (HSI), fatty liver index (FLI), and daidzein intake by adjusting for confounding variables using binary logistic regression models and linear regression models.

In the multivariable-adjusted model II, there was a negative association between daidzein intake and the incidence of MAFLD (OR for Q4 versus Q1 was 0.65, 95% confidence interval [CI] = 0.46-0.91, p = 0.0114, p for trend was 0.0190). CAP was also negatively associated with daidzein intake, β = -0.37, 95% CI: -0.63 to -0.12, p = 0.0046 in model II after adjusting for age, sex, race, marital status, education level, family income-to-poverty ratio (PIR), smoking, and alcohol consumption. Stratified by quartiles of daidzein intake, trend analysis of the relationship between daidzein intake and CAP remained significant (p for trend = 0.0054). In addition, we also found that HSI, FLI, and NFS were negatively correlated with daidzein intake. LSM was negatively related to daidzein intake but had no statistical significance. The correlation between APRI, FIB-4, and daidzein intake was not strong (although p < 0.05, β values were all 0).

We found that MAFLD prevalence, CAP, HSI, and FLI, all decreased with increased daidzein intake, suggesting that daidzein intake may improve hepatic steatosis. Therefore, dietary patterns of soy food or supplement consumption may be a valuable strategy to reduce the disease burden and the prevalence of MAFLD.

To investigate the relationship between metabolic-associated fatty liver disease (MAFLD) and end-stage renal disease (ESRD) in patients with biopsy-confirmed diabetic nephropathy (DN).

A total of 316 participants with biopsy-confirmed DN between January 2008 and December 2019 were retrospectively assessed. Kaplan-Meier curve and Cox proportional hazard models were used to compare the risk of incident ESRD in 50 patients with MAFLD and 50 patients without MAFLD, after using propensity score matching (PSM) to address the imbalances of sex, age, baseline-estimated glomerular filtration rate, serum albumin, 24-h urine protein, hemoglobin and systolic blood pressure.

During the median follow-up period of 3 years, there were 19 ESRD outcome events (19%) in PSM cohort. Kaplan-Meier curve analysis suggested that renal survival significantly deteriorated in patients with MAFLD versus those without MAFLD (p = 0.021). Additionally, the hazard ratios (95% confidence interval) of MAFLD were 3.12 (1.09-8.95, p = 0.035), 3.36 (1.09-10.43, p = 0.036), 3.66 (1.22-10.98, p = 0.021), 4.25 (1.34-13.45, p = 0.014), 3.11 (1.08-8.96, p = 0.035) and 5.84 (1.94-18.5, p = 0.003) after adjustment for six models, including demographic, clinical and pathological characteristics as well as medication use at the time of renal biopsy, respectively. Besides, patients with higher liver fibrosis score had a greater possibility of ESRD, comparing to those with lower liver fibrosis score (p = 0.002).

MAFLD increases the risk of incident ESRD in patients with biopsy-proven DN. Further research is needed to determine whether treatment targeting MAFLD improves the prognosis of DN.