In recent years, therapeutic approaches against diabetes-induced liver damage have attracted great interest. Studies indicate the anticarcinogenic, anti-inflammatory, antioxidant, and lipid-lowering potential of hesperidin (HESP), a flavonoid in citrus fruits. This study examined how HESP prevented streptozotocin (STZ)-induced diabetic liver damage. Four groups of seven rats each were created: Control, HESP (100 mg/kg/day), STZ (45 mg/kg), and STZ + HESP (45 mg/kg and 100 mg/kg/day, respectively). Serum AST, ALT, LDH, LDL, triglyceride, total cholesterol levels, and the TNF-α, IL-1β, and caspase-3 expression levels of liver tissue in the STZ group were higher than the other groups (p < 0.05). However, these values were significantly lower (p < 0.05) in the STZ + HESP group compared to the STZ group. Furthermore, administering HESP together with STZ reduced liver expression levels of caspase-3, TNF-α, and IL-1β, as well as blood levels of AST, ALT, LDH, LDL, triglyceride, and total cholesterol. HESP against diabetes-induced hepatic damage reduced proinflammatory cytokine levels, and returned the lipid profile, and apoptotic indicators to normal levels. These findings suggested that HESP therapy may be an important therapeutic role against diabetes-induced liver damage.

In this investigation, the significance of purple potato (Solanum tuberosum L.) extract treatment was assessed against oxidative stress and fat metabolizing transcription factors in the liver of high-fat (HF) diet-fed rats.

Wistar (male) rats were arranged into several groups and provided with a control and HF diet along with the purple potato extract. Body weights, oral glucose tolerance test (OGTT), insulin, plasma lipids, and oxidative stress-related indicators were analyzed in plasma and tissue samples. Additionally, real-time PCR was performed to evaluate the gene expression for oxidative stress and fat metabolism in the liver. Histological staining was also performed on pancreatic and hepatic tissues.

Purple potato extract lowered body weights and improved glucose utilization in the OGTT test in HF diet-fed rats. Purple potato extract also suppressed HF-diet-induced oxidative stress in plasma and hepatic tissues. Purple potato extract also restored the Nrf-2 expression in the liver, followed by the improved expression of HO-1, HO-2, and other antioxidant genes in HF diet-fed rats. In addition, genes involved in lipid metabolism were also positively modulated due to purple potato extract treatment. Furthermore, histological examination revealed the reduction of lipid accumulation and amelioration of inflammation due to the consumption of purple potato extract.

This investigation revealed that antioxidant-rich purple potato extract can modulate the antioxidant and fat metabolizing genes expression, ameliorated oxidative stress and glucose intolerance as well as lowered blood lipids in male rats.

Oxidative stress acts as a major underlying cause of liver dysfunction in individuals with uncontrolled diabetes mellitus. However, the role of NOX-4 (nicotinamide adenine dinucleotide phosphate oxidase-4) enzymes remains poorly understood. Furthermore, the potential benefits of Sitagliptin in addressing this issue are unclear. Therefore, this experimental study aimed to explore the role of the NOX-4 enzyme and evaluate the potential benefits of Sitagliptin in diabetes-associated impaired liver tests.

Male Wistar rats were randomly assigned to four groups: normal, normal-treated, diabetic, and diabetic-treated. Diabetes was induced by a single dose of Streptozotocin (45 mg/kg). Treated animals received Sitagliptin (20 mg/day, orally) for five weeks. Blood and tissue samples were collected at the end of the five-week period, and the required data were obtained using biochemical and genetic analysis methods.

In untreated rats, STZ-induced diabetes led to increased NOX-4 enzyme expression in the liver and a reduction in the antioxidant enzymes SOD, CAT, and GLT, collectively contributing to heightened oxidative damage, as indicated by elevated MDA levels. These alterations were associated with elevated circulating levels of SGOT, SGPT, and ALP. However, Sitagliptin reversed these alterations in diabetic animals. It enhanced the activity of antioxidant enzymes, reduced NOX-4 enzyme expression and oxidative damage in liver tissues, and subsequently improved liver function test results.

NOX-4 oxidant enzyme appears to play a critical role in diabetes-induced oxidative stress and subsequent liver failure. However, Sitagliptin may offer extra-glycemic benefits by normalizing NOX-4 enzyme activity levels, thereby improving liver function test results.

Type 2 diabetes mellitus (T2DM) exhibits a bidirectional relationship with periodontitis, wherein each condition influences the progression of the other. Arachidonic acid (AA) exerts an anti-diabetic effect, while showing a protective effect by regulating the inflammatory response independently of its metabolites. However, its impact on periodontitis with T2DM remains poorly understood.

The T2DM mouse model was established by combining a high-sugar and high-fat diet with streptozotocin injection, followed by silk ligation to induce periodontitis. Alterations in diabetes-associated symptoms were evaluated. Micro-computed tomography was used to measure bone-related parameters, including the distance from the cementoenamel junction to the alveolar bone crest, bone volume/total volume and bone mineral density. Targeted metabolomics analysis was conducted to evaluate the impact of exogenous AA on serum metabolite levels of AA in mice with type 2 diabetic periodontitis. 16S rRNA gene sequencing was utilized to analyze the microbial diversity. The activity of osteoclasts, levels of inflammatory factors and gene expression related to osteoclasts were investigated using TRAP staining and real-time quantitative PCR.

The periodontitis mouse model with T2DM was successfully established. Following two weeks of exogenous AA treatment, a reduction in fasting blood glucose levels was observed in the diabetic periodontitis mice. Exogenous AA alleviated alveolar bone loss in type 2 diabetic periodontitis mice. However, it had no substantial effect on the contents of serum AA-targeted metabolites. Exogenous AA reduced Staphylococcus in subgingival flora of type 2 diabetic periodontitis mice, but had no significant impact on microbial community structure or diversity. Furthermore, it decreased the number of osteoclasts in the alveolar bone of periodontitis with T2DM mice and increased IL-10 mRNA expression in its gingival tissue.

Exogenous AA may alleviate alveolar bone loss in T2DM mice with periodontitis by reducing the number of osteoclasts and increasing the expression of IL-10 mRNA in periodontal tissues, rather than the change of AA-targeted metabolites in serum or the composition and diversity of microorganisms in subgingival plaque. These findings may provide a potential therapeutic approach for the prevention and treatment of periodontitis with T2DM.

Observational studies have reported a bidirectional correlation between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), but the shared genetic basis between the two conditions remains unclear. Using genome-wide association study (GWAS) summary data from European-ancestry populations, we examined the cross-trait genetic correlation and identified genomic overlaps and shared risk loci. We employed a latent causal variable model and Mendelian randomization (MR) analysis to infer causal relationships. Colocalization analysis and conditional/conjunctional false discovery rate (condFDR/conjFDR) were used to identify genomic overlaps and shared risk loci. Two-step MR analysis was utilized to identify potential mediators. We observed a strong positive genomic correlation between NAFLD and T2D (rg = 0.652, P = 5.67 × 10-6) and identified tissue-specific transcriptomic correlations in the pancreas, liver, skeletal muscle, subcutaneous adipose, and blood. Genetic enrichment was observed in NAFLD conditional on associations with T2D and vice versa, indicating significant polygenic overlaps. We found robust evidence for the causal effect of NAFLD on T2D, particularly insulin-related T2D, rather than vice versa. Colocalization analysis identified shared genomic regions between NAFLD and T2D, including GCKR, FTO, MAU2-TM6SF2, and PNPLA3-SAMM50. High-density lipoprotein cholesterol and insulin were partly mediated the association between NAFLD and T2D. These findings unveil a close genetic link between NAFLD and T2D, shedding light on the biological mechanisms connecting NAFLD progression to T2D.

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.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most widespread chronic liver disease that poses significant threats to public health due to changes in dietary habits and lifestyle patterns. The transition from simple steatosis to nonalcoholic steatohepatitis (NASH) markedly increases the risk of developing cirrhosis, hepatocellular carcinoma, and liver failure in patients. However, there is only one Food and Drug Administration-approved therapeutic drug in the world, and the clinical demand is huge. There is significant clinical heterogeneity among patients with NAFLD, and it is challenging to fully understand human NAFLD using only a single animal model. Interestingly, felines, like humans, are particularly prone to spontaneous fatty liver disease. This review summarized and compared the etiology, clinical features, pathological characteristics, and molecular pathogenesis between human fatty liver and feline hepatic lipidosis (FHL). We analyzed the key similarities and differences between those two species, aiming to provide theoretical foundations for developing effective strategies for the treatment of NAFLD in clinics.

Previous studies have identified a positive link between the visceral adiposity index (VAI) and diabetes in specific populations. Our investigation focused on examining this association in normoglycemic adults in Japan.

A cohort study of NAGALA (NAfld in the Gifu Area Longitudinal Analysis) was undertaken from 2004 to 2015 in Japan. The link between VAI and diabetes was evaluated using multivariate Cox proportional hazards regression and restricted cubic spline (RCS) regression models. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of the VAI for incident diabetes.

Our study included 15,452 participants, with 8,418 men (54.48%) and 7,034 women (45.52%). The average age was 43.71 ± 8.90, and 373 participants (2.41%) developed diabetes. VAI was positively related to diabetes (HR=1.13, 95% CI 1.08-1.18). The inflection point of the non-linear relationship was observed at a VAI value of 4.67. For the VAI values up to 4.67, one unit increase in the VAI related to a 24% increase in new-onset diabetes (HR=1.24, 95% CI 1.12-1.37, p<0.0001). Subgroup analysis detected a more robust relationship in women (HR=1.40, 95% CI 1.14-1.70, p=0.0010). ROC analysis indicated that VAI, with an AUC of 0.7479 (95% CI: 0.7237-0.7720), had good predictive power.

Our cohort study validated the positive and non-linear relationship between the VAI and diabetes in normoglycemic adults in Japan. The relevance was more marked in women than in men. For those with a VAI below 4.67, a further reduction in the VAI could potentially lead to a significant decrease in diabetes risk.

The purpose of this research was to investigate the main active components, potential targets of action, and pharmacological mechanisms of Erhuang Quzhi Formula (EHQZF) against NAFLD using network pharmacology, molecular docking, and experimental validation. The main active chemical components of EHQZF and the potential targets for treating NAFLD were extracted and analyzed. The PPI network diagram of "Traditional Chinese Medicine-Active Ingredients-Core Targets" was constructed and the GO, KEGG, and molecular docking analysis were carried out. Identification of components in traditional Chinese medicine compounds was conducted by LC-MS. NAFLD models were established and relevant pathologic indicators and Western blot were analyzed in vivo and ex vivo. Totally 8 herbs attributed to the liver meridian and 20 corresponding targets of NAFLD were obtained from EHQZF. Flavonoids and phenolic acids as the main components of EHQZF treated NAFLD through the MAPK/AKT signaling pathway. Pathway enrichment analysis focused on the MAPK/AKT signaling pathway and apoptosis signaling pathway. Molecular docking showed that Quercetin and Luteolin had stable binding structures with AKT1, STAT3, and other targets. Experiments showed that EHQZF reduced lipid accumulation, regulated changes in adipose tissue, inhibited the MAPK/AKT signaling pathway and exert multiple components, several targets, and multiple pathway interactions to treat NAFLD.

Diabetes mellitus type 2 (DM2) is the most common chronic disease worldwide, characterized mainly by increased glucose concentration in the blood and affecting several organs' functionality. The daily consumption of probiotic bacteria can help control diabetes and reduce the damage caused. Cell immobilization techniques are a powerful tool that provides physical cell protection to such probiotic bacteria against gastrointestinal conditions. We suggest that cell immobilization could be a significant vector for delivering a high quantity of viable probiotics to the gut, helping attenuate hyperglycemia in diabetic rats. Seventy male Wistar rats were used in this work. Nicotinamide was administrated via intraperitoneal injection 15 minutes before inducing type 2 diabetes (DM2), followed by a second intraperitoneal injection of streptozotocin to induce DM2. Rats were divided into seven groups. For 45 days, a specific treatment was applied to each group. The group of rats, supplied with immobilized Lactobacillus casei, showed a serum glucose concentration of 137 mg/dL, which was close to the one observed in the groups of healthy rats (117 mg/dL) and rats treated with metformin (155 mg/dL). The diabetic rats without treatment presented a higher serum glucose concentration (461 mg/dL). In the rats treated with immobilized L. casei, there was no biochemical parameter alteration, and the cell morphology of the analyzed tissues was similar to those of the healthy group. The consumption of immobilized L. casei could allow a high quantity of viable probiotics to be delivered to the gut, reducing serum glucose concentration by up to 70% compared to diabetic rats and reducing organ damage caused by diabetes.

Background/Objectives: Abnormalities in lipid metabolism and endoplasmic reticulum (ER) stress are strongly associated with the development of a multitude of pathological conditions, including nonalcoholic fatty liver disease (NAFLD), diabetes mellitus, and obesity. Previous studies have indicated a potential connection between thyroid hormone responsive (THRSP) and lipid metabolism and that ER stress may participate in the synthesis of key regulators of adipogenesis. However, the specific mechanisms remain to be investigated. Methods: In this study, we explored the roles of THRSP in lipid metabolism by interfering with THRSP gene expression in mouse mesenchymal stem cells, comparing the effects on adipogenesis between control and interfered groups, and by combining transcriptomic and proteomic analysis. Results: Our results showed that the number of lipid droplets was significantly reduced after interfering with THRSP, and the expression levels of key regulators of adipogenesis, such as LPL, FABP4, PLIN1, and CIDEC, were significantly downregulated. Both transcriptomic and proteomic results showed that the differential genes (proteins) were enriched in the processes of lipolytic regulation, ER stress, cholesterol metabolism, sphingolipid metabolism, PPAR signaling pathway, and glycerophospholipid metabolism. The ER stress marker gene, ATF6, was the most significantly downregulated transcription factor. In addition, RT-qPCR validation indicated that the expression levels of PPAR signaling pathway gene SCD1; key genes of lipid droplet generation including LIPE, DGAT1, and AGPAT2; and ER stress marker gene ATF6 were significantly downregulated. Conclusions: These suggest that THRSP is involved in regulating ER stress and the PPAR signaling pathway, which is closely related to lipid synthesis and metabolism. Interfering with the expression of THRSP may be helpful in ameliorating the occurrence of diseases related to abnormalities in lipid metabolism.

The incidence of insulin resistance (IR) and hepatic steatosis is increasing, with dietary fiber playing a protective role against these disorders. Ocimum basilicum L., widely used in food, pharmaceutical, and cosmetic industries, but their health-promoting properties remain underexplored. This study evaluated the effects of a fiber-rich fraction of partially defatted basil seeds (BSF) on IR, hepatic steatosis, and polyunsaturated fatty acid and short-chain fatty acid (SCFA) profiles in high-fat diet (HFD)-fed C57BL/6 J male mice. Mice were assigned to four groups and fed either a control diet or HFD, supplemented with BSF or oat flour for 4 weeks. HFD induced IR, hepatic steatosis, proinflammatory state, and a significant decreased in SCFA production. In contrast, supplementation with BSF attenuated IR, steatosis, liver damage, oxidative stress, and inflammation, while increasing n-3 polyunsaturated fatty acids in liver, adipocytes, and erythrocytes, and enhancing SCFA production, suggesting potential therapeutic benefits in managing these conditions.

Diabetes mellitus (DM), a major cause of mortality, is characterized by insulin resistance and β-cell dysfunction. The increasing prevalence of DM is linked to lifestyle changes and there is a need for alternative approaches to conventional oral hypoglycemic agents. Polysaccharides, particularly non-starch polysaccharides (NSPs), have been identified as promising hypoglycemic agents. Cereals, especially wheat, are key sources of dietary polysaccharides, with NSPs derived from wheat beer attracting significant interest. This study aimed to investigate the hypoglycemic and hypolipidemic effects of NSPs extracted from wheat beer in STZ-induced diabetic C57BL/6J male mice. The results showed that NSPs extract positively influenced blood glucose regulation, lipid profiles, and liver and kidney functions, by attenuating liver AST and kidney CRE levels in a dose-dependent manner. The NSPs demonstrated anti-oxidative and anti-inflammatory properties, potentially providing significant benefits in managing diabetes and its complications. Moreover, the study revealed the histoprotective effects of NSPs on the liver and pancreas, reducing lipid deposition, necrosis, and inflammation. These findings highlight the multifaceted advantages of NSPs and suggest their potential as effective agents in diabetes management. This study supports the need for further research into the therapeutic potential of NSPs and their application in developing innovative treatments for diabetes and its associated complications.

Pancreatic fat is associated with obesity and type 2 diabetes mellitus (T2DM); however, the relationship between different types of pancreatic fat and diabetes status remains unclear. Therefore, we aimed to determine the potential of different types of pancreatic fat accumulation as a risk factor for T2DM in overweight or obese patients. In total, 104 overweight or obese patients were recruited from January 2020 to December 2022. The patients were divided into three groups: normal glucose tolerance (NGT), impaired fasting glucose or glucose tolerance (IFG/IGT), and T2DM. mDixon magnetic resonance imaging (MRI) was used to detect pancreatic fat in all three groups of patients. The pancreatic head fat (PHF), body fat (PBF), and tail fat (PTF) in the IFG/IGT group were 21, 20, and 31% more than those in the NGT group, respectively. PHF, PBF, and PTF were positively associated with glucose metabolic dysfunction markers in the NGT group, and inter-lobular fat volume (IFV) was positively associated with these markers in the IFG/IGT group. The areas under the receiver operating characteristic curves for PHF, PBF, and PTF (used to evaluate their diagnostic potential for glucose metabolic dysfunction) were 0.73, 0.73, and 0.78, respectively, while those for total pancreatic volume (TPV), pancreatic parenchymal volume, IFV, and IFV/TPV were 0.67, 0.67, 0.66, and 0.66, respectively. These results indicate that intra-lobular pancreatic fat, including PHF, PTF, and PBF, may be a potential independent risk factor for the development of T2DM. Additionally, IFV exacerbates glucose metabolic dysfunction. Intra-lobular pancreatic fat indices were better than IFV for the diagnosis of glucose metabolic dysfunction.

Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome characterized by the excessive accumulation of fat within liver cells, which can progress to end-stage liver disease in severe cases, posing a threat to life. Pyroptosis is a distinct, pro-inflammatory form of cell death, differing from traditional apoptosis. In recent years, there has been growing research interest in the association between pyroptosis and NAFLD, encompassing the mechanisms and functions of pyroptosis in the progression of NAFLD, as well as potential therapeutic targets. Controlled pyroptosis can activate immune cells, eliciting host immune responses to shield the body from harm. However, undue activation of pyroptosis may worsen inflammatory responses, induce cellular or tissue damage, disrupt immune responses, and potentially impact liver function. This review elucidates the involvement of pyroptosis and key molecular players, including NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome, gasdermin D (GSDMD), and the caspase family, in the pathogenesis and progression of NAFLD. It emphasizes the promising prospects of targeting pyroptosis as a therapeutic approach for NAFLD and offers valuable insights into future directions in the field of NAFLD treatment.

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-β1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 inhibitor. ZDF rats were divided into chow diet, HFD, and HFD + Tenovin-1 groups. Tenovin-1 reduced hepatic damage, inhibited inflammatory cell infiltration, micro/ macro-vesicular steatosis and prevented collagen deposition HFD-fed rats. Tenovin-1 reduced serum biochemical parameters, triglyceride (TG) and malondialdehyde (MDA) levels but increased glutathione, catalase, and superoxide dismutase levels. Tenovin-1 mitigated proinflammatory cytokines IL-6, IL-1β, TNFα and fibrosis biomarkers in HFD rats, TGF-β1-activated LX-2 and FFA treated SCC cells. Additionally, Tenovin-1 suppressed SIRT1/2 expression and inhibited JNK-1 and STAT3 phosphorylation in HFD rats and FFA-treated SCC cells. In conclusion, Tenovin-1 attenuates hepatic fibrosis by stimulating antioxidants and inhibiting inflammatory cytokines under HFD conditions in diabetic rats.

The current obesity pandemic has given rise to associated comorbidities and complications, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). During the last decade, certain glucagon-like peptide 1 receptor agonists (GLP-1RA), originally developed as antihyperglycemic drugs, also demonstrated efficacy for weight loss.

To review shared pathophysiologic features of common metabolic diseases and compare therapeutic strategies to reduce body weight and related complications.

We performed an extensive literature research to describe the effects of lifestyle modification, first-generation anti-obesity drugs, and GLP-1RA on weight loss in humans with obesity, type 2 diabetes and MASLD.

Until recently, treatment of obesity has been limited to lifestyle modification, which offer moderate degree and sustainability of weight loss. The few approved first-generation anti-obesity drugs are either limited to short term use or to certain forms of obesity. Some GLP-1RA significantly decrease caloric intake and body weight. Liraglutide and semaglutide have therefore been approved for treating people with obesity. They also lead to a reduction of hepatic fat content and inflammation in people with biopsy-confirmed MASLD. Possible limitations comprise adverse effects, treatment adherence and persistence.

Certain GLP-1RA are superior to lifestyle modification and first-generation anti-obesity drugs in inducing weight loss. They have therefore markedly changed the portfolio of obesity treatment with additional beneficial effects on steatotic liver disease.

This study investigated the influence of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) levels on the degree of atherosclerosis and major adverse cardiovascular and cerebrovascular events (MACCE) in older adults with non-alcoholic fatty liver disease.

The degree of atherosclerosis severity was assessed by the standard Gensini score quartile method. According to the degree of atherosclerosis, patients were divided into mild (0-24 points; n=84), moderate (25-53 points; n=86), and severe groups (≥54 points; n=84) and then categorized as MACCE (n=30) or non-MACCE (n=224) according to 6-month follow-up data. The patients' age, sex, smoking history, medical history, and early morning fasting venous blood, for measuring biochemical indexes, were collected. Clinical data were compared between groups and the relationship between Gensini scores and PCSK9 was evaluated.

Compared with the mild group, the moderate and severe groups had higher high-sensitivity C-reactive protein(hs-CRP), PCSK9, triglycerides(TG), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)[Lp(a)] levels and lower high-density lipoprotein cholesterol(HDL-C) levels (all P<0.05). Moreover, PCSK9 positively correlated with Gensini scores (r=0.657, P<0.01). The MACCE and non-MACCE groups had significantly different ages, statin use, Gensini scores, PCSK9, and LDL-C (all P<0.05). Multi-factorial Cox risk regression analysis showed the Gensini score (HR=1.018, 95% CI: 1.006~1.029) and PCSK9 (HR=1.147, 95% CI: 1.038~1.287) were independent risk factors for MACCE.

The Gensini score and PCSK9 levels can be used as predictive indicators for the degree of illness and occurrence of MACCE in older NAFLD patients.

Considering the positive association between visceral adiposity index (VAI) and type 2 diabetes mellitus (T2DM), no comprehensive assessment on the summarized and dose-response relationship between VAI and T2DM has yet been reported. Therefore, we performed a meta-analysis, including dose-response analysis, to quantitively elucidate this association.

MEDLINE via PubMed and Embase databases were searched for relevant articles up to December 14, 2021. Random-effects generalized least squares regression models were used to assess the quantitative association between VAI and T2DM risk across studies. Restricted cubic splines were used to model the dose-response association. A total of 9 prospective cohort studies and 5 cross sectional studies were included in our review. Based on the meta-analysis, the pooled RR of T2DM was 2.05 (95% CI 1.74-2.41) for the highest versus reference VAI category. We found that the risk of T2DM was increased by 44% (RR, 1.44; 95% CI, 1.23-1.68) with each 1-unit increment of VAI. While, we found no evidence of a nonlinear dose-response association of VAI and T2DM (Pnon-linearity = 0.428). With the linear cubic spline model, when compared to population with VAI at 0.6, for those with VAI at 2.0, the risk of T2DM was increased by 81% (RR, 1.81; 95% CI 1.55-2.12).

Our meta-analysis provides quantitative data suggesting that VAI is associated with an increased risk of T2DM. Public health strategies focusing on weight loss among obesity, especially the people characterized by the thin-on-the-outside--fat-on-the-inside phenotype could possibly reduce a substantial risk of T2DM.

PROSPERO CRD42022372666.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. Although numerous clinical trials have been conducted over the last few decades, an effective treatment has not been approved yet. Extensive research has accumulated a large amount of data and experience; however, the vast number of clinical trials and new therapeutic targets for NAFLD make it impossible to keep abreast of the relevant information. Therefore, a systematic analysis of the existing trials is necessary.

Here, we reviewed clinical trials on NAFLD registered in the mandated federal database, ClinicalTrials.gov, to generate a detailed overview of the trials related to drugs and therapeutic targets for NAFLD treatment. Following screening for pertinence to therapy, a total of 440 entries were identified that included active trials as well as those that have already been completed, suspended, terminated, or withdrawn.

We summarize and systematically analyze the state, drug development pipeline, and discovery of treatment targets for NAFLD. We consider possible factors that may affect clinical outcomes. Furthermore, we discussed these results to explore the mechanisms responsible for clinical outcomes.

We summarised the landscape of current clinical trials and suggested the directions for future NAFLD therapy to assist internal medicine specialists in treating the whole clinical spectrum of this highly prevalent liver disease.

Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.

Multiple observational studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and chronic liver diseases (CLDs). However, the causality of T2DM on CLDs remained unknown in various ethnic groups.

We obtained instrumental variables for T2DM and conducted a two-sample mendelian randomization (MR) study to examine the causal effect on nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), viral hepatitis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection risk in Europeans and East Asians. The primary analysis utilized the inverse variance weighting (IVW) technique to evaluate the causal relationship between T2DM and CLDs. In addition, we conducted a series of rigorous analyses to bolster the reliability of our MR results.

In Europeans, we found that genetic liability to T2DM has been linked with increased risk of NAFLD (IVW : OR =1.3654, 95% confidence interval [CI], 1.2250-1.5219, p=1.85e-8), viral hepatitis (IVW : OR =1.1173, 95%CI, 1.0271-1.2154, p=0.0098), and a suggestive positive association between T2DM and HCC (IVW : OR=1.2671, 95%CI, 1.0471-1.5333, p=0.0150), HBV (IVW : OR=1.1908, 95% CI, 1.0368-1.3677, p=0.0134). No causal association between T2DM and HCV was discovered. Among East Asians, however, there was a significant inverse association between T2DM and the proxies of NAFLD (ALT: IVW OR=0.9752, 95%CI 0.9597-0.9909, p=0.0021; AST: IVW OR=0.9673, 95%CI, 0.9528-0.9821, p=1.67e-5), and HCV (IVW: OR=0.9289, 95%CI, 0.8852-0.9747, p=0.0027). Notably, no causal association was found between T2DM and HCC, viral hepatitis, or HBV.

Our MR analysis revealed varying causal associations between T2DM and CLDs in East Asians and Europeans. Further research is required to investigate the potential mechanisms in various ethnic groups, which could yield new insights into early screening and prevention strategies for CLDs in T2DM patients.

Insulin resistance is implicated in both the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression from steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma, which is known to be more common in people with type 2 diabetes. This article reviews the role of insulin resistance in the metabolic dysfunction observed in obesity, type 2 diabetes, atherogenic dyslipidemia, and hypertension and how it is a driver of the natural history of NAFLD by promoting glucotoxicity and lipotoxicity. The authors also review the genetic and environmental factors that stimulate steatohepatitis and fibrosis progression and their relationship with cardiovascular disease and summarize guidelines supporting the treatment of NAFLD with diabetes medications that reduce insulin resistance, such as pioglitazone or glucagon-like peptide 1 receptor agonists.

Background: While it has been shown that steatotic liver disease (SLD) is associated with systemic changes in immune response, the impact of SLD on sepsis outcomes has not yet been established. The aim of this study was to investigate the association between SLD and sepsis severity and outcomes. Methods: A prospective observational study included consecutively hospitalized adult patients with community-acquired sepsis during a 16-month period. Results: Of the 378 included patients (49.5% male, median age of 69, IQR 57-78 years), 174 (46%) were diagnosed with SLD. Patients with SLD were older and more frequently fulfilled the criteria for metabolic syndrome. There were no differences in the source and etiology of sepsis between the groups. Patients with SLD exhibited a higher incidence of acute kidney injury (29.3% vs. 17.6%), the need for renal replacement therapy (16.1% vs. 8.8%), and more frequent use of invasive mechanical ventilation (29.3% vs. 18.1%). In-hospital mortality was significantly higher in the SLD group (18.39% vs. 9.8%). The multivariable analysis indicated that SLD was associated with mortality (HR 2.82, 95% CI 1.40-5.71) irrespective of the other elements within metabolic syndrome. Conclusions: SLD might be associated with higher sepsis in-hospital mortality, and more frequent development of acute kidney and respiratory insufficiency requiring more critical care support.

To explore the association between type 2 diabetes mellitus (T2DM) and body composition based on magnetic resonance fat fraction (FF) mapping.

A total of 341 subjects, who underwent abdominal MRI examination with FF mapping were enrolled in this study, including 68 T2DM patients and 273 non-T2DM patients. The FFs and areas of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and abdominal muscle (AM) were measured at the level of the L1-L2 vertebral. The FF of bone marrow adipose tissue (BMAT) was determined by the averaged FF values measured at the level of T12 and L1 vertebral, respectively. The whole hepatic fat fraction (HFF) and pancreatic fat fraction (PFF) were measured based on 3D semi-automatic segmentation on the FF mapping. All data were analyzed by GraphPad Prism and MedCalc.

VAT area, VAT FF, HFF, PFF of T2DM group were higher than those of non-T2DM group after adjusting for age and sex (P < 0.05). However, there was no differences in SAT area, SAT FF, BMAT FF, AM area and AM FF between the two groups (P > 0.05). VAT area and PFF were independent risk factors of T2DM (all P < 0.05). The area under the curve (AUC) of the receiver operating characteristic (ROC) for VAT area and PFF in differentiating between T2DM and non-T2DM were 0.685 and 0.787, respectively, and the AUC of PFF was higher than VAT area (P < 0.05). Additionally, in seemingly healthy individuals, the SAT area, VAT area, and AM area were found to be significantly associated with being overweight and/or obese (BMI ≥ 25) (all P < 0.05).

In this study, it was found that there were significant associations between T2DM and VAT area, VAT FF, HFF and PFF. In addition, VAT area and PFF were the independent risk factors of T2DM. Especially, PFF showed a high diagnostic performance in discrimination between T2DM and non-T2DM. These findings may highlight the crucial role of PFF in the pathophysiology of T2DM, and it might be served as a potential imaging biomarker of the prevention and treatment of T2DM. Additionally, in individuals without diabetes, focusing on SAT area, VAT area and AM area may help identify potential health risks and provide a basis for targeted weight management and prevention measures.

The incidence of non-B and non-C hepatocellular carcinoma (NBNC-HCC) is increasing globally. Metabolically associated fatty liver disease (MAFLD) has been a contributing factor to this rising trend in NBNC-HCC incidence. The monocyte-to-high-density lipoprotein-cholesterol ratio (MHR) is a new prognostic marker that connects systemic inflammation with disorders of lipid metabolism. Therefore, MHR may be a potential prognostic predictor of patients with MAFLD-related HCC (MAFLD-HCC). This study aims to investigate the relationship between the MHR and prognosis of patients with MAFLD-HCC and construct a novel prognostic prediction tool for MAFLD-HCC.

This retrospective study of patients with MAFLD-HCC included training (n = 112) and internal validation (n = 37) cohorts. Univariate and multivariate Cox proportional hazard regression analysis was conducted to identify independent risk factors of survival. A visual nomogram was constructed to assess the performance of the two groups. Furthermore, receiver operating characteristic (ROC) curves and calibration curves were used to verify the prognostic discriminative ability of this nomogram, even in the MHR, ALBI grade, and MHR-ALBI model.

Univariate and multivariate analyses revealed that extrahepatic metastases, Vascular invasion, Barcelona staging B, C, D, elevated ALBI Grade 3, C-reactive protein (CRP), and MHR were independent risk factors for the prognosis of MAFLD-HCC. Moreover, calibration plots showed good discrimination and consistency when the significant factors were entered into the nomogram. Meanwhile, the MHR strongly correlated with the prognosis of cancer under a background of MAFLD-HCC, with a sensitivity of 88.89% and a specificity of 79.61%. Importantly, the performance of the MHR alone (AUC = 86.2) was not only superior to the ALBI grade (AUC = 63.8) but was comparable to the combination of MHR and ALBI (AUC = 88.5).

The novel nomogram demonstrated good value in predicting the overall survival of patients with MAFLD-HCC. The MHR may be a potential predictor of prognosis.

Nonalcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic, and it is the most common cause of liver diseases. The patients with severe insulin-resistant diabetes having high body mass index (BMI), high-grade adipose tissue insulin resistance, and high hepatocellular triacylglycerols (triglycerides; TAG) content develop hepatic fibrosis within a 5-year follow-up. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol (DAG), fatty acyl CoA, or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/nonalcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with an increase in saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in the liver tissue of patients with NASH. Hepatocyte lipoapoptosis is a critical feature of NASH. In the "second hit," reduced glutathione levels due to oxidative stress lead to the overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused at least by two ineffectual cyclical pathways. First is the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and the second is the Kelch like-ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. In clinical practice, on ultrasonographic examination, the elevation of transaminases, γ-glutamyltransferase, and the aspartate transaminase to platelet ratio index indicates NAFLD. Fibrosis-4 index, NAFLD fibrosis score, and cytokeratin18 are used for grading steatosis, staging fibrosis, and discriminating the NASH from simple steatosis, respectively. In addition to ultrasonography, "controlled attenuation parameter," "magnetic resonance imaging proton-density fat fraction," "ultrasound-based elastography," "magnetic resonance elastography," "acoustic radiation force impulse elastography imaging," "two-dimensional shear-wave elastography with supersonic imagine," and "vibration-controlled transient elastography" are recommended as combined tests with serum markers in the clinical evaluation of NAFLD. However, to confirm the diagnosis of NAFLD, a liver biopsy is the gold standard. Insulin resistance-associated hyperinsulinemia directly accelerates fibrogenesis during NAFLD development. Although hepatocyte lipoapoptosis is a key driving force of fibrosis progression, hepatic stellate cells and extracellular matrix cells are major fibrogenic effectors. Thereby, these are pharmacological targets of therapies in developing hepatic fibrosis. Nonpharmacological management of NAFLD mainly consists of two alternatives: lifestyle modification and metabolic surgery. Many pharmacological agents that are thought to be effective in the treatment of NAFLD have been tried, but due to lack of ability to attenuate NAFLD, or adverse effects during the phase trials, the vast majority could not be licensed.

Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications.

Type 2 diabetes mellitus (T2DM) is one of most common metabolic diseases and continues to be a leading cause of death worldwide. Although great efforts have been made to elucidate the pathogenesis of diabetes, the underlying mechanism still remains unclear. Notably, overwhelming evidence has demonstrated that mitochondria are tightly correlated with the development of T2DM, and the defects of mitochondrial function in peripheral insulin-responsive tissues, such as skeletal muscle, liver and adipose tissue, are crucial drivers of T2DM. Furthermore, exercise training is considered as an effective stimulus for improving insulin sensitivity and hence is regarded as the best strategy to prevent and treat T2DM. Although the precise mechanisms by which exercise alleviates T2DM are not fully understood, mitochondria may be critical for the beneficial effects of exercise.

To assess the association of ectopic fat deposition in the liver and pancreas quantified by Dixon magnetic resonance imaging (MRI) with insulin sensitivity and β-cell function in patients with central obesity.

A cross-sectional study of 143 patients with central obesity with normal glucose tolerance (NGT), prediabetes (PreD), and untreated type 2 diabetes mellitus (T2DM) was conducted between December 2019 and March 2022. All participants underwent routine medical history taking, anthropometric measurements, and laboratory tests, including a standard glucose tolerance test to quantify insulin sensitivity and β-cell function. The fat content in the liver and pancreas was measured with MRI using the six-point Dixon technique.

Patients with T2DM and PreD had a higher liver fat fraction (LFF) than those with NGT, while those with T2DM had a higher pancreatic fat fraction (PFF) than those with PreD and NGT. LFF was positively correlated with homeostatic model assessment of insulin resistance (HOMA-IR), while PFF was negatively correlated with homeostatic model assessment of insulin secretion (HOMA-β). Furthermore, using a structured equation model, we found LFF and PFF to be positively associated with glycosylated hemoglobin via HOMA-IR and HOMA-β, respectively.

In patients with central obesity, the effects of LFF and PFF on glucose metabolism. were associated with HOMA-IR and HOMA-β, respectively. Ectopic fat storage in the liver and pancreas quantified by MR Dixon imaging potentially plays a notable role in the onset ofT2DM.

We highlight the potential role of ectopic fat deposition in the liver and pancreas in the development of type 2 diabetes in patients with central obesity, providing valuable insights into the pathogenesis of the disease and potential targets for intervention.

• Ectopic fat deposition in the liver and pancreas is associated with T2DM. • T2DM and prediabetes patients had higher liver and pancreatic fat fractions than normal individuals. • The results provide valuable insights into pathogenesis of T2DM and potential targets for intervention.

Lipid metabolic diseases have substantial morbidity and mortality rates, posing a significant threat to human health. PPARα, a member of the peroxisome proliferator-activated receptors (PPARs), plays a crucial role in lipid metabolism and immune regulation. Recent studies have increasingly recognized the pivotal involvement of PPARα in diverse pathological conditions. This comprehensive review aims to elucidate the multifaceted role of PPARα in metabolic diseases including liver diseases, diabetes-related diseases, age-related diseases, and cancers, shedding light on the underlying molecular mechanisms and some regulatory effects of natural/synthetic ligands of PPARα. By summarizing the latest research findings on PPARα, we aim to provide a foundation for the possible therapeutic exploitation of PPARα in lipid metabolic diseases.

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway is mainly responsible for the activation and release of a cascade of proinflammatory mediators that contribute to the development of hepatic diseases. During alcoholic liver disease development, the NLRP3 inflammasome pathway contributes to the maturation of caspase-1, interleukin (IL)-1β, and IL-18, which induce a robust inflammatory response, leading to fibrosis by inducing profibrogenic hepatic stellate cell (HSC) activation. Substantial evidence demonstrates that nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) via NLRP3 inflammasome activation, ultimately leading to fibrosis and hepatocellular carcinoma (HCC). Activation of the NLRP3 inflammasome in NASH can be attributed to several factors, such as reactive oxygen species (ROS), gut dysbiosis, leaky gut, which allow triggers such as cardiolipin, cholesterol crystals, endoplasmic reticulum stress, and uric acid to reach the liver. Because inflammation triggers HSC activation, the NLRP3 inflammasome pathway performs a central function in fibrogenesis regardless of the etiology. Chronic hepatic activation of the NLRP3 inflammasome can ultimately lead to HCC; however, inflammation also plays a role in decreasing tumor growth. Some data indicate that NLRP3 inflammasome activation plays an important role in autoimmune hepatitis, but the evidence is scarce. Most researchers have reported that NLRP3 inflammasome activation is essential in liver injury induced by a variety of drugs and hepatotropic virus infection; however, few reports indicate that this pathway can play a beneficial role by inducing liver regeneration. Modulation of the NLRP3 inflammasome appears to be a suitable strategy to treat liver diseases.

Duodenal ablation improves glycaemic control and weight loss, so it has been applied using hydrothermal catheters in obese and type 2 diabetes patients, indicating similar mechanisms and therapeutic effects as bariatric surgeries. Endoscopic photodynamic therapy is an innovative procedure that easily accessible to endocrine or gastrointestinal organs, so it is critical for the sprayed photosensitizer (PS) to long-term interact with target tissues for enhancing its effects. Surfactant-like PS was more stable in a wide range of pH and 2.8-fold more retained in the duodenum at 1 h than hydrophilic PS due to its amphiphilic property. Endoscopic duodenal ablation using surfactant-like PS was performed in high fat diet induced rat models, demonstrating body weight loss, enhanced insulin sensitivity, and modulation of incretin hormones. Locoregional ablation of duodenum could affect the profiles of overall intestinal cells secreting meal-stimulated hormones and further the systemic glucose and lipid metabolism, regarding gut-brain axis. Our strategy suggests a potential for a treatment of minimally invasive bariatric and metabolic therapy if accompanied by detailed clinical trials.

Liver fibrosis plays a key role in the progression of non-alcoholic fatty liver disease to cirrhosis. Considering weight change is known to be closely associated with increased risk of liver fibrosis, we aimed to address a gap in evidence regarding the existence of this association in patients with type 2 diabetes (T2D).

We included data on 622 T2D patients and 1618 non-T2D participants from the 2017-2018 cycle of the National Health and Nutrition Examination Survey (NHANES). We assessed liver fibrosis by the median values of liver stiffness measurement (LSM). According to the participants' body mass index (BMI) at age 25 (early adulthood), 10 years prior (middle adulthood), and at the 2017-2018 cycle (late adulthood), we categorised weight change patterns into stable non-obese, weight loss, weight gain, and stable obese. We applied logistic regression to association analysis and used population attributable fraction (PAF) to analyses hypothetical prevention regimens.

The prevalence of liver fibrosis was higher in T2D patients (23.04%) than in non-T2D participants (6.70%), while weight change was associated with a greater risk of fibrosis in the former compared to the latter group. Compared with T2D patients in the stable non-obese group, stable obese individuals from 10 years prior to the 2017-2018 cycle had the highest risk of developing liver fibrosis, corresponding to an adjusted odds ratio (aOR) of 3.13 (95% confidence interval = 1.84-5.48). Absolute weight change patterns showed that the risk of liver fibrosis was highest (aOR = 2.94) when T2D patients gained at least 20 kg of weight from 10 years prior to 2017-2018 cycle.

Obesity in middle and late adulthood is associated with an increased risk of T2D complicated with liver fibrosis.

Hyperactivation of protein tyrosine phosphatase (PTP1B) has been associated with several metabolic malfunctions ranging from insulin resistance, metaflammation, lipotoxicity, and hyperglycaemia. Liver metabolism failure has been proposed as a core element in underlying endocrine disorders through persistent inflammation and highly fibrotic phenotype.

In this study, the outcomes of PTP1B inhibition using trodusquemine (MSI-1436) on key equine metabolic syndrome (EMS)-related alterations including inflammation, fibrosis, and glucose uptake have been analyzed in liver explants collected from EMS-affected horses using various analytical techniques, namely, flow cytometry, RT-qPCR, and Western blot.

PTP1B inhibition using trodusquemine resulted in decreased proinflammatory cytokines (IL-1β, TNF-α, and IL-6) release from liver and PBMC affected by EMS and regulated expression of major proinflammatory microRNAs such as miR-802 and miR-211. Moreover, MSI-1436 enhanced the anti-inflammatory profile of livers by elevating the expression of IL-10 and IL-4 and activating CD4+CD25+Foxp3+ regulatory T cells in treated PBMC. Similarly, the inhibitor attenuated fibrogenic pathways in the liver by downregulating TGF-β/NOX1/4 axis and associated MMP-2/9 overactivation. Interestingly, PTP1B inhibition ameliorated the expression of TIMP-1 and Smad7, both important antifibrotic mediators. Furthermore, application of MSI-1436 was found to augment the abundance of glycosylated Glut-2, which subsequently expanded the glucose absorption in the EMS liver, probably due to an enhanced Glut-2 stability and half-life onto the plasma cell membranes.

Taken together, the presented data suggest that the PTP1B inhibition strategy and the use of its specific inhibitor MSI-1436 represents a promising option for the improvement of liver tissue integrity and homeostasis in the course of EMS and adds more insights for ongoing clinical trials for human MetS management.

Diabetes mellitus is a metabolic disease clinically-characterized as acute and chronic hyperglycemia. It is emerging as one of the common conditions associated with incident liver disease in the US. The mechanism by which diabetes drives liver disease has become an intense topic of discussion and a highly sought-after therapeutic target. Insulin resistance (IR) appears early in the progression of type 2 diabetes (T2D), particularly in obese individuals. One of the co-morbid conditions of obesity-associated diabetes that is on the rise globally is referred to as non-alcoholic fatty liver disease (NAFLD). IR is one of a number of known and suspected mechanism that underlie the progression of NAFLD which concurrently exhibits hepatic inflammation, particularly enriched in cells of the innate arm of the immune system. In this review we focus on the known mechanisms that are suspected to play a role in the cause-effect relationship between hepatic IR and hepatic inflammation and its role in the progression of T2D-associated NAFLD. Uncoupling hepatic IR/hepatic inflammation may break an intra-hepatic vicious cycle, facilitating the attenuation or prevention of NAFLD with a concurrent restoration of physiologic glycemic control. As part of this review, we therefore also assess the potential of a number of existing and emerging therapeutic interventions that can target both conditions simultaneously as treatment options to break this cycle.