Liver Glucose Research Articles

Sequence variants associated with BMI affect disease risk through BMI itself.

Mendelian Randomization studies indicate that BMI contributes to various diseases, but it's unclear if this is entirely mediated by BMI itself. This study examines whether disease risk from BMI-associated sequence variants is mediated through BMI or other mechanisms, using data from Iceland and the UK Biobank. The associations of BMI genetic risk score with diseases like fatty liver disease, knee replacement, and glucose intolerance were fully attenuated when conditioned on BMI, and largely for type 2 diabetes, heart failure, myocardial infarction, atrial fibrillation, and hip replacement. Similar attenuation was observed for chronic kidney disease and stroke, though results varied. Findings were consistent across sexes, except for myocardial infarction. Residual effects may result from temporal BMI changes, pleiotropy, measurement error, non-linear relationships, non-collapsibility, or confounding. The attenuation extent of BMI genetic risk score on disease associations suggests the potential impact of reducing BMI on disease risk.

Avenanthramides Ameliorate Insulin Resistance by Modulating Gluconeogenesis and Glycogen Synthesis in HepG2 Cells.

Diabetes mellitus (DM) is a multifaceted metabolic condition, mainly defined by elevated blood glucose levels. A feature of type 2 DM includes insulin resistance (IR), which involves impairments within the insulin signaling pathways. Avenanthramides (AVNs) are phenolic alkaloids found in Avena sativa L. The major AVNs are AVN A, AVN B, and AVN C. They have been reported to offer benefits in preventing inflammation, cancer, and cardiovascular diseases. However, the effects of AVNs on the liver glucose metabolism pathways remain unknown. This study examined the effects and underlying mechanisms through which AVNs alleviate IR induced by free fatty acid (FFA) in HepG2 cells. The results indicated that FFA treatment significantly decreased glucose consumption by 34.54% compared to the control. However, treatments with AVN A, B, and C at 100 μM increased glucose uptake by 57.93%, 58.28%, and 53.10%, respectively, compared to FFA treatment alone. This effect occurs through the increased expression of glucose transporter 4. Furthermore, AVNs significantly enhanced the glycogen content. AVNs induced increased phosphorylation of insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (Akt). AVNs treatment decreased the levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in HepG2 cells. This effect was attributed to AMP-activated protein kinase activation and inhibition of forkhead box protein O1. Collectively, these results suggest that AVNs regulate glucose metabolism by activating the IRS-1/PI3K/Akt pathway, which is related to glycogen synthesis, and by inhibiting key molecules that promote gluconeogenesis.

Metabolic Effects of Loquat Juice (Eriobotrya japonica Lindl Mkarkeb Variety) on Lipid Homeostasis, Liver Steatosis, and Oxidative Stress in Hyperlipidemic Mice Fed a High-Fat–High-Fructose Diet

Background: Loquat fruit is consumed for its flavorful taste and a rich array of health-promoting compounds like phenolics, flavonoids, and carotenoids. This study aimed at the biochemical characterization of fresh juice from the Moroccan Mkarkeb variety of loquat and evaluating its effects on lipid homeostasis and liver steatosis in hyperlipidemic mice. Methods: The biochemical characterization followed AOAC methods. In vivo study involved hyperlipidemic mice fed a high-fat, high-fructose diet for 6 weeks and treated with loquat juice at 3.5 and 7 mL kg−1 or fenofibrate at 4 mg·kg−1. The concentrations of lipids in plasma, liver, adipose tissue, feces, and bile and blood glucose levels were quantified. Liver steatosis was visually examined and confirmed histologically, and liver injury markers (AST, ALT, ALP, LDH, and TB) were measured. Liver oxidative stress was assessed by measuring MDA content and antioxidative enzyme activities. Results: Our findings indicate that fresh loquat juice is poor in fat and protein and contains moderate sugars with a low energy value (40.82 ± 0.25 kcal/100 g). It is also rich in minerals, vitamin C, phenolic acids, flavonoids, and carotenoids. The juice effectively restored lipid metabolism by enhancing reverse cholesterol transport and lowering LDL-cholesterol, triglycerides, and the atherogenic index. The studied juice decreases blood glucose and prevents weight gain and lipid accumulation in the liver and adipose tissue. The juice prevents lipotoxicity-induced liver injury, corrects toxicity markers, and improves the liver’s morphological and histological structures. It also reduces oxidative stress by lowering MDA and activating SOD and catalase. Conclusions: The juice holds high nutritional and medicinal value, potentially preventing lipid disorders and cardiovascular issues.

Duration of morning hyperinsulinemia determines hepatic glucose uptake and glycogen storage later in the day.

The second-meal phenomenon refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4 h of morning hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during an afternoon hyperinsulinemic-hyperglycemic (HIHG) clamp. Our current aim was to determine if the duration or pattern of morning hyperinsulinemia is important for the afternoon response to a HIHG clamp. To determine this, the same total amount of insulin was administered either over 2 h in the first (Ins2h-A) or second (Ins2h-B) half of the morning or over the entire 4 h (Ins4h) of the morning. In the 4-h afternoon period, all three groups had 4x-basal insulin, 2x-basal glycemia, and portal glucose infusion to expose the liver to the primary postprandial regulators of hepatic glucose metabolism. During the afternoon clamp, there was a marked increase in HGU and hepatic glycogen synthesis in the Ins4h group compared with the Ins2h-A and Ins2h-B groups, despite matched hepatic glucose loads and total insulin infusion rates. Thus, the longer duration (Ins4h) of lower hyperinsulinemia in the morning seems to be the key to much greater liver glucose uptake during the afternoon clamp.NEW & NOTEWORTHY Morning insulin exposure primes the liver for increased hepatic glucose uptake and glycogen storage during a subsequent hyperinsulinemic-hyperglycemic clamp. This study addressed whether the pattern and/or duration of insulin delivery in the morning influences insulin's ensuing priming effect. We found that despite receiving equal total doses of insulin in the morning, a prolonged, lower rate of morning insulin delivery improved afternoon liver glucose metabolism more effectively than a shorter, higher rate of delivery.

Essential role of germ cell glycerol-3-phosphate phosphatase for sperm health, oxidative stress control and male fertility in mice.

Obesity, diabetes and high-calorie diets are associated with defective sperm function and lowered male fertility. Mature spermatozoa primarily use fructose and glucose, and glucose and glycerol metabolism are important for sperm function. We recently discovered a novel mammalian enzyme, glycerol-3-phosphate (Gro3P) phosphatase (G3PP), and showed that it operates the glycerol shunt by hydrolyzing Gro3P to glycerol, and regulates glucose, lipid and energy metabolism in pancreatic β-cells and liver. We now observed that G3PP expression is the highest in the testis and spermatozoa, and investigated its role in male fertility. We examined G3PP expression during spermatogenesis in mouse and assessed male fertility and spermatozoon function in conditional germ cell specific G3PP-KO (cG3PP-KO) mice and tamoxifen-inducible conditional germ cell G3PP-KO (icG3PP-KO) mice. We also determined the structural and metabolic parameters and oxidative stress in the spermatozoa from icG3PP-KO and control mice. G3PP expression in mouse spermatocytes and spermatids markedly increases during spermatogenesis. Male cG3PP-KO mice, in which germ cell G3PP is deleted from embryonic stage, are infertile due to dysfunctional sperm with reduced motility and capacitation, and elevated spontaneous acrosomal reaction and oxidative stress. However, in icG3PP-KO male mice do not have altered fertility, due to the presence of ∼10% normal spermatozoa. icG3PP-KO spermatozoa display significantly reduced functionality and morphological and ultrastructural alterations. The icG3PP-KO spermatozoa show reduced glycerol production, elevated levels of Gro3P and reactive oxygen species (ROS), and oxidative stress that is associated with increased mitochondrial membrane potential. Germ cell G3PP deletion leads to the generation of spermatozoa that are functionally and structurally abnormal, likely due to the build-up of Gro3P that increases mitochondrial membrane potential, ROS, and oxidative stress and alters spermatozoa function. Overall, the results indicate that G3PP and the glycerol shunt are essential for normal spermatozoa function and male fertility.

Hesperetin-copper (II) complex improves liver glucose metabolism by regulating the IRS-1/PI3K/AKT signaling pathway in T2DM mice

The metal complexes of flavonoids have attracted widespread attention because of their distinct structural and functional characteristics. Hesperetin-Cu(II) complex [Hsp-Cu(II)] showed good hypoglycemic potential, but its hypoglycemic effect and mechanism in vivo are still vague. This study aimed to investigate the hypoglycemic effects of Hsp-Cu(II) on type 2 diabetic (T2DM) mice and its underlying mechanism. The results showed that Hsp-Cu(II) (50 mg/kg) effectively improved hyperglycemia and dyslipidemia, increased the fast insulin level and HOMA-IR to alleviate the insulin resistance in the T2DM mice. Compared with the Diseased group, treatment of Hsp-Cu(II) at 50 mg/kg reduced the activities of α-amylase, phosphoenolpyruvate carboxy kinase (PEPCK) and glucose 6-phosphatase (G6Pase) by 31.7%, 45.5% and 35.1%, respectively; elevated the level of glutathione and activities of superoxide dismutase and catalase by 27.2%, 71.7% and 36.7%, respectively, and decreased the malondialdehyde content by 23.6% to improve the liver antioxidant abilities; reduced the activities of alanine aminotransferase and aspartate aminotransferase by 15.6% and 28.1%, as well as the levels of inflammatory factors to relieve liver damage. In addition, Hsp-Cu(II) activated the insulin receptor substrate-1/phosphoinositide-3-kinase/protein kinase B (IRS-1/PI3K/AKT) signaling pathway to up-regulate the protein expression levels of phospho-glycogen synthase kinase-3β (p-GSK-3β) and phospho-fork head box transcription factor O1 (p-FoxO1) and down-regulate the mRNA expression of PEPCK and G6Pase. Therefore, Hsp-Cu(II) may regulate hepatic glucose metabolism through IRS-1/PI3K/AKT‒GSK3β pathways to increase the hepatic glycogen content and IRS-1/PI3K/AKT‒FoxO1‒PEPCK/G6Pase pathways to inhibit gluconeogenesis, maintain hepatic glucose homeostasis, thus exerting the hypoglycemia effect in T2DM. These discoveries may provide a scientific basis for developing Hsp-Cu(II) as a food function factor to alleviate T2DM.

Cardiac corin and atrial natriuretic peptide regulate liver glycogen metabolism and glucose homeostasis

BackgroundCardiovascular function and metabolic homeostasis are closely linked, but the underlying mechanisms are not fully understood. Corin is a protease that activates atrial natriuretic peptide (ANP), an essential hormone for normal blood pressure and cardiac function. The goal of this study is to investigate a potential corin and ANP function in regulating liver glycogen metabolism and glucose homeostasis.MethodsLiver glycogen and blood glucose levels were analyzed in Corin or Nppa (encoding ANP) knockout (KO) mice. ANP signaling was examined in livers from Corin and Nppa KO mice and in cultured human and mouse hepatocytes by western blotting.ResultsWe found that Corin and Nppa KO mice had reduced liver glycogen contents and increased blood glucose levels. By analyzing conditional KO mice lacking either cardiac or renal Corin, we showed that cardiac corin and ANP act in an endocrine manner to enhance cGMP-protein kinase G (PKG)-AKT-GSK3 signaling in hepatocytes. In cultured hepatocytes, ANP treatment stimulated PKG signaling, glucose uptake, and glycogen production, which could be blocked by small molecule PKG and AKT inhibitors.ConclusionsOur results indicate that corin and ANP are important regulators in liver glycogen metabolism and glucose homeostasis, suggesting that defects in the corin and ANP pathway may contribute to both cardiovascular and metabolic diseases.

Repurposing expired metformin to fluorescent carbon quantum dots for ratiometric and color tonality visual detection of tetracycline with greenness evaluation

Repurposing expired drugs is highly significant as it prevents the accumulation of pharmaceutical wastes, optimizes resource usage, and reduces environmental harm. Metformin, used for type II diabetes, lowers blood sugar via decreasing liver glucose production and increasing muscle insulin sensitivity. However, the growing number of expired tablets annually necessitates a strategic approach for repurposing or reusing these tablets. Herein, we develop a simple hydrothermal approach for converting expired metformin to valuable fluorescent carbon quantum dots (m-CQDs) with sizes smaller than 10 nm. The m-CQDs displayed a blue emission at 420 nm when excited at 350 nm. Interestingly, when tetracycline (TC) was added, the blue emission diminished, and a greenish-yellow emission emerged at 530 nm. This emission tunning was the resulting of combination of inner filter effect and aggregation induced emission. Leveraging this dynamic emission tunning, we developed both ratiometric-based fluorescence and color tonality-based visual detection methods for detecting TC in pharmaceuticals and wastewater. More importantly, three assessment tools, ComplexMoGAPI, AGREE, and BAGI were used to evaluate the environmental sustainability of the proposed analytical method. The evaluation confirmed the sustainability of the method and the alignment with the greenness guidelines for analytical methods.

Estimation of liver standardized uptake value in F18-FDG PET/CT scanning: impact of different malignancies, blood glucose level, body weight normalization, and imaging systems.

The aim of this work was to investigate homogeneity and stability of liver SUV in terms of different malignancies considering different body normalization schemes and blood glucose concentrations as well as PET/CT imaging systems. The study included 207 patients with four different types of cancers namely breast, lymphoma, lung, and bone-metastasis. Data acquisition was performed with GE Discovery IQ, Biograph mCT, uMI 550, and Ingenuity TF64 after a single intravenous injection of 194 ± 67.5 MBq of 18F-FDG. In body weight normalization, SUVmax and SUVmean in bone-mets as well as SUVmean in lung patients were not statistically different among scanners especially for data corrected for glucose levels (p = 0.062, 0.121, and 0.150, respectively). In SUVlbm derived from lung patients, there was no significant differences in Philips in comparison to GE and Siemens (both, p > 0.05) for data corrected and not corrected for glucose levels. In SUVbsa, the only non-significant difference revealed among scanners was in the measurements of SUVmean obtained from lung and bone-mets (p = 0.107 and 0.114) both corrected for glucose levels. In SUVbmi, SUVmean of lung and bone-mets as well as SUVmax of bone-mets showed a non-significant differences among the four different scanning systems (p = 0.303, 0.091, and 0.222, respectively) for data corrected for glucose levels. Liver glucose correction needs further investigations in individual tumors but could be potentially affected by whether measurements are made on SUVmean versus SUVmax, body weight normalization, as well as the imaging system. As such, selection of normalization to body weight method should be carefully selected before clinical adoption and clinically adopted and body surface area would provide the highest correlation. As such, normalization of body weight should be carefully made before clinical adoption. SUVmean proves to be useful and stable metric when liver is corrected for blood glucose levels.

The effect of anti‐imbalance on glycolipid metabolic homeostasis via the liver–gut axis intervened by 3′‐sialyllactose in obese mice

AbstractSialic acid could ameliorate disorders associated with glycolipid metabolism. 3′‐Sialyllactose (3′‐SL), a type of oligosaccharide, contains sialic acid. We examined the effects of 3′‐SL on glycolipid metabolism in obese mice with high fat diet and explore the underlying mechanisms. A total of 160 male C57BL/6J mice were fed with high‐fat diet for 8 weeks to construct obese mice model. Sixty successfully constructed obese mice were randomly divided three 3′‐SL dosage‐dependent groups, one free sialic acid N‐acetylneuraminic acid (Neu5Ac) group, and one blank control group. Each group of obese mice (n = 12) was continuously supplemented by 3′‐SL or Neu5Ac for 10 weeks. Ten‐week 3′‐SL supplementation and Neu5Ac supplementation both yielded remarkedly lower body weight, reduced fat content, increased energy expenditure and active daily exercises with improved glycolipid biomarkers, and attenuated proinflammation. 3′‐SL increased the colonic abundances of Akkermansia, Lactobacillus, and Solibacillus and reduced those of Enterobacter and Enterococcus. Changes were also observed in colonic and liver transcript and metabolites, which were mainly enriched in glycolipid metabolism, ameliorated immune function, and mitigated inflammatory signals, autophagy, bile acid metabolism, and insulin resistance. Akkermansia and Solibacillus were significantly associated with changes in colonic metabolites and transcriptome genes. The liver bile component and glucose metabolites were significantly correlated with transcriptional gene expression in the aforementioned differential pathways. Therefore, 3′‐SL can enhance the gut microbiota, regulate intestinal immunity and bile acid metabolism, reduce liver oxidative stress and autophagy processes, alleviate chronic inflammation levels, and improve islet function and lower blood sugar levels by acting through the gut–liver axis.

The effect of aqueous extracts and isolation proteinous compound from clove buds on serumglucose, triglyceride , glutathione and malnodialdehyde levels in alloxan induced diabetic mice

This study was included preparing acold aqueous extract of clove buds The study also comprised the isolation and studying the proteinous compound,which was seperated using gel filtration technique and determined approximately molecular weight of this isolated compound(6799) dalton . The aim of the study demonstrate effects of the crude aqueous, non proteinous extract, proteinous precipitate and proteinous compound on serum glucose, total cholesterol, triglyceride and high density lipoprotein-cholesterol levels, also glutathione and malondialdehyde levels in liver and kidney tissues in diabetic mice-induced alloxan.Extracts were administerated interaperitioneally. The results were indicated that the crude aqueous, non proteinous extract, proteinous precipitate and proteinous compound which were caused asignificant decrease in serum glucose, total cholesterol, triglyceride levels and malondialdehyde level in liver and kidney tissues, while aproteinous precipitate don’t show asignificant decrease in serum cholesterol level but all extracts don’t show asignificant changes in serum high density lipoprotein-cholesterol level in alloxan induced diabetic mice, on other wise all extracts showed asignificant increase in glutathione level in liver and kidney tissues except non proteinous extract and proteinous precipitate which were caused asignificant increase in glutathione level in liver tissue only.

8359 Increased hepatic SGK1 activity promotes metabolic dysfunction-associated fatty liver disease in a sex-dependent manner

Abstract Disclosure: A. Vastola-Mascolo: None. G. Hernández: None. D. Alvarez de la Rosa: None. The serum and glucocorticoid-induced kinase 1 (SGK1) is a Ser/Thr kinase with key roles in fluid and electrolyte homeostasis, blood pressure regulation and energy metabolism. Its expression is controlled by steroid hormones such as glucocorticoids, mineralocorticoids and estrogen, in addition to other stimuli such as glucose. SGK1 activation mainly depends on the PI3 kinase pathway, implicating it in insulin signaling. Previous work from our laboratory demonstrated that a systemic increase in SGK1 activity exacerbates diet-induced development of metabolic syndrome in mouse, characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. In addition, a high-fat diet rapidly led to the development of hepatic steatosis. We now test the hypothesis that at least part of the effects of increased systemic SGK1 activity promoting the development of metabolic syndrome are due to alterations in liver glucose or lipid handling. To that end we developed a mouse strain with hepatocyte-specific transgenic SKG1 expression and challenged it with high-fat or high-fat/high-sucrose diets. Our results show sex differences in the development of obesity, with a marked increase in body weight in female, but not male transgenic animals. Glucose homeostasis was normal in both sexes. Increased obesity in females correlated with increased lipid accumulation in the liver. However, liver fibrosis, inflammation and dyslipidemia were more marked in male animals, further suggesting an interaction between SGK1 and sex steroid hormone signaling. Our results demonstrate a key role of SGK1 in liver lipid metabolism and suggest a crosstalk between this signaling pathway and sex hormones, which determine a more negative outcome in male animals. Presentation: 6/1/2024

Development and validation of a web-based nomogram for acute kidney injury in acute non-variceal upper gastrointestinal bleeding patients.

Acute kidney injury (AKI) is a common and serious complication in patients with acute non-variceal upper gastrointestinal bleeding (NVUGIB). Early prediction and intervention are crucial for improving patient outcomes. Data for patients presenting with acute NVUGIB in this retrospective study were sourced from the MIMC-IV database. Patients were randomly allocated into training and validation cohorts for further analysis. Independent predictors for AKI were identified using least absolute shrinkage and selection operator regression and multivariable logistic regression analyses in the training cohort. Based on the logistic regression results, a nomogram was developed to predict early AKI onset in acute NVUGIB patients, and implemented as a web-based calculator for clinical application. The nomogram's performance was evaluated through discrimination, using the C-index, calibration curves, and decision curve analysis (DCA) to assess its clinical value. The study involved 1082 acute NVUGIB patients, with 406 developing AKI. A multivariable logistic regression identified five key AKI predictors: CKD, use of human albumin, chronic liver disease, glucose, and blood urea nitrogen. The nomogram was constructed based on independent predictors. The nomogram exhibited robust accuracy, evidenced by a C-index of 0.73 in the training cohort and 0.72 in the validation cohort. Calibration curves demonstrated satisfactory concordance between predicted and observed AKI occurrences. DCA revealed that the nomogram offered considerable clinical benefit within a threshold probability range of 7% to 54%. Our nomogram is a valuable tool for predicting AKI risk in patients with acute NVUGIB, offering potential for early intervention and improved clinical outcomes.

Plasma C24:0 ceramide impairs adipose tissue remodeling and promotes liver steatosis and glucose imbalance in offspring of rats

Fetal programming by exposure to high-energy diets increases the susceptibility to type 2 diabetes mellitus (T2DM2) in the offspring. Glucose imbalance during fetal programming might be associated to still unknown selective lipid species and their characterization might be beneficial for T2DM diagnosis and treatment. We aim to characterize the effect of the lipid specie, C24:0 ceramide, on glucose imbalance and metabolic impairment in cellular and murine models. A lipidomic analysis identified accumulation of C24:0 ceramide in plasma of offspring rats exposed to high-energy diets during fetal programing, as well as in obese-T2DM subjects. In vitro experiments in 3T3L-1, hMSC and HUH7 cells and in in vivo models of Wistar rats and C57BL/6 mice demonstrated that C24:0 ceramide disrupted glucose balance, and differentiation and lipid accumulation in adipocytes, whereas promoted liver steatosis. Mechanistically, C24:0 ceramide impaired mitochondrial fatty acid oxidation in adipocytes and hepatic cells, tentatively by favoring reactive oxygen species accumulation and calcium overload in the mitochondria; and also, activates endoplasmic reticulum (ER) stress in hepatocytes. We propose that C24:0 ceramide accumulation in the offspring followed a prenatal diet exposure, impair lipid allocation into adipocytes and enhances liver steatosis associated to mitochondrial dysfunction and ER stress, leading to glucose imbalance.

Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis

AimsTo compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). MethodsA database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. ResultsTwenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] −51.47; 95 % confidence interval [CI]: −68.25 to −34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD −47.08; 95 % CI: −58.83 to −35.34; SUCRA 75.5), GLP-1R agonists (MD −37.36; 95 % CI: −69.52 to −5.21; SUCRA 52.3) and THR-β agonists (MD −33.20; 95 % CI: −43.90 to −22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD −9.65; 95 % CI: −19.28 to −0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD −5.79; 95 % CI: −9.50 to −2.09; SUCRA 58.2), and GLP-1RAs (MD −5.58; 95 % CI: −15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. ConclusionThese results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Estimating the Biological Variables of Thyroid Patients and Their Impact on Diabetics in Kirkuk

Background: Investigating the impact of sugar on biochemical variables in patients with thyroid dysfunction in Kirkuk, including some previously unmeasured biological variables. Materials and Techniques: From November to May, this study occurred in Kirkuk. Blood samples were collected from 120 patients aged 20 to 80 years, including 40 diabetics, 40 with both hyperthyroidism and diabetes, and 40 with both hypothyroidism and diabetes, as well as 40 healthy individuals aged 20 to 40 without chronic diseases. Levels of TSH, T4, T3, HbA1c, GPT, GOT, ALP, and HBs were measured in the serum using Beckman Coulter Access2, Spectrophotometer, and Boditech Med INC I-Chroma AFP-25 devices. Results: The study found that TSH levels were significantly elevated in patients with diabetes and hypothyroidism (P≤0.01), while T4 and T3 levels were significantly decreased (P≥0.01). HbA1c levels showed a significant increase (P≤0.01) in all groups: diabetes with hypothyroidism, diabetes with hyperthyroidism, and diabetes alone. Enzyme levels (GOT, GPT, ALP, HBs) were also significantly elevated (P≤0.01) in these groups. Conclusion: In conclusion, TSH regulation is vital, with high levels indicating hypothyroidism related to obesity and diabetes. Elevated HbA1c shows poor glucose control, and hyperthyroidism with diabetes worsens liver function and glucose metabolism, stressing the need for integrated management.

A weekly 4-methylpyrazole treatment attenuates the development of non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in male mice: Role of JNK.

4-methylpyrazole (4MP, fomepizole) is a competitive inhibitor of alcohol dehydrogenase (ADH) preventing the metabolism of ethylene glycol and methanol, respectively, into their toxic metabolites. 4MP seems also to possess a potential in the treatment of intoxication from other substance, for example, acetaminophen, and to modulate JNK-dependent signalling. Here, we determined if a treatment with 4MP once weekly affects the development of diet-induced non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in C57BL/6 mice. Male C57BL/6 mice (6-8 weeks old, n = 7-8/group) were pair-fed either a liquid control diet (C) or a liquid sucrose-, fat- and cholesterol-rich diet (SFC) for 8 weeks while being concomitantly treated with 4MP (50 mg/kg bw i.p.) or vehicle once a week. Liver damage, inflammatory markers and glucose tolerance were assessed. Moreover, in endotoxin-challenged J774A.1 cells pretreated with 4MP, pro-inflammatory markers were assessed. The concomitant treatment of SFC-fed mice with 4MP attenuated the increase in JNK phosphorylation and pro-inflammatory markers like IFNγ, IL-6 and 3-nitrotyrosine protein adducts in liver tissue found in vehicle-treated SFC-fed mice, while not affecting impairments of glucose tolerance or the increase in portal endotoxin levels. Moreover, a pretreatment of endotoxin-stimulated J774A.1 cells with 4MP significantly attenuated the increases in JNK phosphorylation and pro-inflammatory mediators like IL-6 and Mcp1. Taken together, our results suggest that a treatment with 4MP once weekly attenuates the activation of JNK and dampens the development of non-obese MASLD in mice.

A systematic review of the anti-inflammatory and anti-fibrotic potential of human umbilical cord mesenchymal stem cells-derived exosomes in experimental models of liver regeneration.

Chronic liver injuries and their complications are leading causes of death, especially in developing countries (Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023). The available and effective treatment plans are limited, implicating the need for innovative treatment approaches (Tsuchiya et al. in Inflamm Regener, 2019;Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023;Younossi et al. in Clin Gastroenterol Hepatol 21:1978-1991, 2023;). This paper aims to summarize the effects and mechanisms of hUC-MSC-exo on liver injuries and its complications; it also suggests future directions for future research. The outcomes of interest are the morphology and histology of the liver, pathology score, liver function enzyme, glucose and lipid metabolism, and the effect hUC-MSC-exo had on gene regulation regarding liver diseases. A comprehensive review of nineteen studies was conducted to assess the effectiveness of the implementation of the hUC-MSC-Exo, instilling confidence in the validity of the findings. Regarding the morphology and histology of the liver and pathology score, hUC-MSC-exo treatment resulted in improved liver morphology post-treatment, as indicated by the reduction in pathology scores. However, these observed improvements in the liver surface are not directly attributed to the hUC-MSC-Exo itself but to the overall healing processes stimulated by the treatment. In physiological outcomes, hUC-MSC-exo also improves glucose and lipid metabolism, especially in diet-induced liver injury and its complications. In gene regulation, one interesting gene in this intervention is the fat mass and obesity-associated (FTO), in which hUC-MSC-exo combined with miRNAs can suppress FTO. HUC-MSC-Exo can improve by utilizing several possible pathways, targeting pinpoints in the pathogenesis of liver disease or glucose and lipid metabolism. This study presents hUC-MSC-exo better in all outcomes of interest compared to the control or sham group. Further specification of indications of the hUC-MSC-exo method may be beneficial and essential to be analyzed in future reviews to better understand the effectiveness of each hUC-MSC-exo dose, duration, and medium.

Positron emission tomography combined with serum biomarkers detects fibrotic MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is a rising global disease signaling the urgent need for non-invasive tests (NITs). Recent work demonstrated that dynamic 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) imaging can identify MASH by measuring liver glucose transport rate, K1, and liver CT attenuation. By combining dynamic PET/CT with the serum-based fibrosis-4 (FIB-4) test, we were able to better distinguish clinical MASH from fibrotic subtypes, enabling determination of the core tenets of MASH: steatosis, inflammation, and fibrosis. Future studies using FDG-PET technology can further enable concomitant prediction of MASH severity and extrahepatic comorbidities such as cardiovascular disease.

Mitigation of methylglyoxal-induced hepatotoxicity by Boerhavia diffusa L. aerial extract: Insights from cellular and animal models

BackgroundBoerhavia diffusa (Punarnava), is a perennial herb with a long-standing reputation for its antioxidative and anti-inflammatory properties, dating back to ancient times. Methylglyoxal is an advanced glycation end-product, known to be toxic in liver cell line as well as in mice model. Our objective is to illustrate the protective action of punarnava aerial extracts in methylglyoxal-induced hepatotoxicity in cell line and mice model. MethodsPunarnava aerial parts were collected and different solvent extracts were prepared in methanol, dichloromethane and hexane by maceration followed by their LCMS/MS characterization, determination of total phenolic, total flavonoid contents and antioxidant activity by DPPH reagent. Cell viability of the extracts and methylglyoxal was assessed using different cell lines. In vitro protective effect of punarnava methanolic extract (PME) against methylglyoxal was evaluated by cell migration assay, NO and ROS production assays and Oil Red O staining in HepG2 cell line. BALB/c mice were pretreated with Punarnava methanolic extract (200 mg/kg and 400 mg/kg) for seven days followed by 290 mg/kg methylglyoxal administration for 6 hrs to induce hepatotoxicity. Serum glucose, AST, ALT, ALP and GSH level were checked and liver histopathological damages were identified. ResultsAmong the three Punarnava extracts, PME possessed maximum antioxidant, total phenolic and flavonoid content as well as least cytotoxic to liver cell line. Methylglyoxal showed maximum toxicity in HepG2 cells with IC50 (50 % inhibitory concentration) 3 µM. PME confers protection against methylglyoxal-induced cytotoxicity by decreasing ROS, promoting cell migration and preventing loss of cell viability. No significant change was observed in NO production and Oil Red O staining. PME-treated mice showed decrease in liver ALP levels and glucose with intact cellular morphology compared to hepatocyte steatosis and nuclear degeneration in methylglyoxal-treated group. DiscussionsIndigenous herb Punarnava is effective in protecting liver cells from damage induced by the glycolytic byproduct, methylglyoxal.