Hepatic Glycogen Research Articles

Altered gut microbiota and microbial metabolism in children with hepatic glycogen storage disease: a case-control study.

Accumulating evidence has demonstrated that gut microbiota dysbiosis correlated with altered metabolism are implicated in liver metabolic diseases. However, data on pediatric hepatic glycogen storage disease (GSD) are limited. Here, we aimed to investigate the features of the gut microbiota and metabolites in hepatic GSD children from China. Totals of 22 hepatic GSD patients and 16 age- and gender-matched healthy children were enrolled from the Shanghai Children's Hospital, China. Pediatric GSD patients were confirmed as having hepatic GSD via genetic diagnosis and/or liver biopsy pathology. The control group comprised children without any history of chronic diseases or clinically relevant GSD or symptoms of any other metabolic diseases. The baseline characteristics of the two groups were gender- and age-matched matched using chi-squared test and the Mann-Whitney U test, respectively. The gut microbiota, bile acids (BAs), and short chain fatty acids (SCFAs) were determined from the feces using 16S ribosomal RNA (rRNA) gene sequencing, ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and gas chromatography-mass spectrometry (GC-MS), respectively. The alpha diversity of fecal microbiome was significantly lower in hepatic GSD patients [observed species richness (Sobs): P=0.011; abundance-based coverage estimator (ACE): P=0.011; Chao: P=0.011; Shannon: P<0.001], and their microbial community was more distanced from that of the control [principal coordinate analysis (PCoA) on genus level, unweighted UniFrac: P=0.011]. Relative abundances of phyla Firmicutes (P=0.030) and Bacteroidetes (P=0.029), families Lachnospiraceae (P=0.012), Ruminococcaceae (P=0.008), and Peptostreptococcaceare (P=0.031), genera Blautia (P=0.017), Eubacterium_hallii_group (P=0.032), and Faecalibacterium (P=0.017) were decreased, whereas phyla Actinobacteria (P=0.033), Proteobacteria (P=0.049), families Bifidobacteriaceae (P=0.030), Lactobacillaceae (P=0.034), and Veillonellaceae (P=0.033), genera Lactobacillus (P=0.011), Enterobater (P=0.034), and Veillonella (P=0.014) were increased in hepatic GSD. Altered microbial metabolisms were characterized by increased abundances of primary BAs (P=0.009) and decreased concentrations of SCFAs in hepatic GSD children. Furthermore, the altered bacterial genera were correlated with the changes of both fecal BAs and SCFAs. The hepatic GSD patients in this study presented with gut microbiota dysbiosis which correlated with altered BAs metabolism and fecal SCFAs changes. Further studies are needed to investigate the driver of these changes mediated by either the genetic defect, disease status, or diet therapy.

Hypoglycemic mechanisms of Polygonatum sibiricum polysaccharide in db/db mice via regulation of glycolysis/gluconeogenesis pathway and alteration of gut microbiota

Polygonatum rhizoma polysaccharide (PP) is a main ingredient of Polygonatumrhizoma, which is both food and traditional herbal medicine. In this study, we aimed to investigate the hypoglycemic effect of PP and the underlying mechanisms in db/db mice. Our finding showed that PP significantly ameliorates diabetic symptoms by reducing glucose levels in blood and urine and increasing insulin and leptin abundance in the serum. Histopathological examination revealed that PP improved the pathological state and increased hepatic glycogen storage in liver. Additionally, RT-qPCR results indicated that PP significantly down-regulated the expression of phosphoenolpyruvate carboxykinase 1. Furthermore, 16s rRNA sequencing results demonstrated that PP intervention resulted in an increase in beneficial bacteria genus and a reduction in harmful genus. Redundancy analysis revealed the correlation between intestinal flora and clinical factors. Taken together, these results suggest that PP has a significant hypoglycemic effect on type 2 diabetes (T2D) through up-regulating serum insulin and leptin, as well as hepatic glycogen storage, and down-regulating hepatic phosphoenolpyruvate carboxykinase 1 expression, as well as modulating gut microbiota composition. In conclusion, this study investigated the mechanisms of PP in the treatment of diabetes in db/db mice. To the best of our knowledge, this is the first study to explore the positive and negative correlations between gut microbiota and clinical factors, such as oxidative stress injury in liver and glucose related indicators in the blood.

Sacha Inchi (Plukenetia volubilis L.) Oil Improves Hepatic Insulin Sensitivity and Glucose Metabolism through Insulin Signaling Pathway in a Rat Model of Type 2 Diabetes.

This study aimed to evaluate the role of sacha inchi oil (SI) in alleviating hepatic insulin resistance and improving glucose metabolism by inhibiting oxidative stress and inflammation in a rat model of type 2 diabetes. This model was established by providing a high-fat diet and streptozotocin to the rats, thereby inducing diabetes. The diabetic rats were treated orally with 0.5, 1, and 2 mL/kg body weight (b.w.) of SI or 30 mg/kg b.w. of pioglitazone daily for 5 weeks. Blood and hepatic tissues were used for insulin sensitivity, carbohydrate metabolism, oxidative stress, and inflammatory status assessment. Treatment with SI attenuated hyperglycemia and insulin resistance indices, and improved hepatic histopathological alterations in the diabetic rats in a dose-dependent manner, which is correlated with the decreased serum levels of the liver enzymes, alanine transaminase and aspartate transaminase. SI significantly diminished the hepatic oxidative status of the diabetic rats by inhibiting malondialdehyde and enhancing the antioxidant superoxide dismutase, catalase, and glutathione peroxidase activities. Moreover, pro-inflammatory cytokine levels, including tumor necrosis factor-α and interleukin-6, in the liver of the diabetic rats were significantly decreased by the SI. Furthermore, SI treatment enhanced the hepatic insulin sensitivity of the diabetic rats, as shown by the increased insulin receptor substrate-1 and p-Akt protein expression, decreased phosphoenolpyruvate carboxykinase-1 and glucose-6-phospatase protein expression, and increased hepatic glycogen content. Overall, these findings suggest that SI exerts a potential hepatic insulin-sensitizing effect and an improvement in glucose metabolism in the type 2 diabetic rats, at least in part through enhancing insulin signaling, antioxidant defense, and inhibiting inflammation.

Isolated hepatomegaly became Her’s – a case report

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders caused by mutations in one of the several enzymes involved in glycogen synthesis or breakdown. GSD VI is caused by mutations of PYGL gene encoding hepatic glycogen phosphorylase on chromosome 14q22.1, which has a major role in glycogen metabolism. We report a case of 2year old girl child presented with complaints of slowly progressive abdominal distention of one year duration. Abdominal examination revealed hepatomegaly (liver span 9cm). Lab investigations revealed mild anemia, hypertriglyceridemia and normal liver function. Liver biopsy showed marked elevation of glycogen content in liver with structurally normal glycogen which was consistent with GSD. Sanger sequencing done to identify the subtype of GSD showed PYGL gene mutation, pathogenic variant of type-VIGSD. In the case of isolated hepatomegaly, a glycogen storage disease must be considered in the differential diagnosis and Sanger sequencing must be done for confirmation and prognostication

Glycophagy mediated glucose-induced changes of hepatic glycogen metabolism via OGT1-AKT1-FOXO1Ser238 pathway

Glycophagy is the autophagy degradation of glycogen. However, the regulatory mechanisms for glycophagy and glucose metabolism remain unexplored. Herein, we demonstrated that high-carbohydrate diet (HCD) and high glucose (HG) incubation induced glycogen accumulation, protein kinase B (AKT)1 expression and AKT1-dependent phosphorylation of forkhead transcription factor O1 (FOXO1) at Ser238 in the liver tissues and hepatocytes. The glucose-induced FOXO1 phosphorylation at Ser238 prevents FOXO1 entry into the nucleus and the recruitment to the GABA(A) receptor-associated protein like 1 (gabarapl1) promoter, reduces the gabarapl1 promoter activity, and inhibits glycophagy and glucose production. The glucose-dependent O-GlcNAcylation of AKT1 by O-GlcNAc transferase (OGT1) enhances the stability of AKT1 protein and promotes its binding with FOXO1. Moreover, the glycosylation of AKT1 is crucial for promoting FOXO1 nuclear translocation and inhibiting glycophagy. Our studies elucidate a novel mechanism for glycophagy inhibition by high carbohydrate and glucose via OGT1-AKT1-FOXO1Ser238 pathway in the liver tissues and hepatocytes, which provides critical insights into potential intervention strategies for glycogen storage disorders in vertebrates, as well as human beings.

The Liver and Glycogen: In Sickness and in Health

The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation.

Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model

Use of dipeptidyl peptidase-4 (DPP4) inhibitor in some clinical trials might have caused heart failure (HF), leading to increased hospitalizations. The aim of the present study was to determine whether linagliptin has any effect on chronic dilated HF, and its underlying mechanisms. Physiologic and pathologic studies were conducted on heart/muscle-specific manganese superoxide dismutase-deficient mice, which exhibited dilated cardiomyopathy, and were randomized to receive a low dose (1 mg/kg, HF-L group) or high dose (10 mg/kg, HF–H group) mixed with food, or normal food (HF group), for 8 weeks. Linagliptin increased mortality and heart/body weight ratio in mice with HF. Cardiac contractility and fibrosis worsened, whereas hepatic glycogen content and individual carbohydrate consumption decreased significantly in the HF–H group, when compared with the HF control group. Therefore, we performed a complementary experiment by supplementing glucose to the mice treated with high-dose linagliptin (HF-HG group). Adequate glucose supplementation reduced heart/body weight ratio and cardiac fibrosis, and improved cardiac contractility, without changing mortality. Following oral administration of 13C glucose, the respiratory 13C decreased in the HF–H and HF-HG groups, when compared with that in the HF group; the fecal 13C increased, suggesting that linagliptin inhibited glucose absorbance in the intestine. In addition, the expression of GLUT2, a glucose transporter was downregulated in the small intestine. Linagliptin treatment exacerbated HF, which increased mortality, cardiac function, and fibrosis. DPP4 inhibitors might boost cardiac cachexia and exacerbate HF, at least in part, through the modification of glucose utilization and absorption.

Hepatic leucine carboxyl methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism

Impaired glucose regulation is one of the most important risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which have become a major public health issue worldwide. Dysregulation of carbohydrate metabolism in liver has been shown to play a critical role in the development of glucose intolerance but the molecular mechanism has not yet been fully understood. In this study, we investigated the role of hepatic LCMT1 in the regulation of glucose homeostasis using a liver-specific LCMT1 knockout mouse model. The hepatocyte-specific deletion of LCMT1 significantly upregulated the hepatic glycogen synthesis and glycogen accumulation in liver. We found that the liver-specific knockout of LCMT1 improved high fat diet-induced glucose intolerance and insulin resistance. Consistently, the high fat diet-induced downregulation of glucokinase (GCK) and other important glycogen synthesis genes were reversed in LCMT1 knockout liver. In addition, the expression of GCK was significantly upregulated in MIHA cells treated with siRNA targeting LCMT1 and improved glycogen synthesis. In this study, we provided evidences to support the role of hepatic LCMT1 in the development of glucose intolerance induced by high fat diet and demonstrated that inhibiting LCMT1 could be a novel therapeutic strategy for the treatment of glucose metabolism disorders.

Evaluation of single and combined effects of mancozeb and metalaxyl on the transcriptional and biochemical response of zebrafish (Danio rerio)

Mancozeb and metalaxyl are fungicidal agents frequently used in combination to control fungi in crops that may affect non-target organisms when entering ecosystems. This study aims to evaluate the environmental effects of Mancozeb (MAN) and Metalaxyl (MET), alone and in combination, on zebrafish (Danio rerio) as an experimental model. The oxidative stress biomarkers and the transcription of genes involved in detoxification in zebrafish (Danio rerio) were assessed after co-exposure to MAN (0, 5.5, and 11 μg L−1) and MET (0, 6.5, and 13 mg L−1) for 21 days. Exposure to MAN and MET induced a significant increase in the expression of genes related to detoxification mechanisms (Ces2, Cyp1a, and Mt2). Although Mt1 gene expression increased in fish exposed to 11 μg L−1 of MAN combined with 13 mg L−1 of MET, Mt1 expression was down-regulated significantly in other experimental groups (p < 0.05). The combined exposure to both fungicides showed synergistic effects in the expression levels that are manifested mainly at the highest concentration. Although a significant (p < 0.05) increase in alkaline phosphatase (ALP) and transaminases (AST and ALT), catalase activities, the total antioxidant capacity, and malondialdehyde (MDA) contents in the hepatocytes of fish exposed to MAN and MET alone and in combination was detected, lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT) activities, and hepatic glycogen content decreased significantly (p < 0.05). Overall, these results emphasize that combined exposure to MET and MAN can synergistically affect the transcription of genes involved in detoxification (except Mt1 and Mt2) and biochemical indicators in zebrafish.

Taraxasterol Inhibits Hepatic Gluconeogenesis and Increases Glycogen Synthesis via the PI3K/Akt Signaling Pathway

Objective: Taraxasterol (TS) is the main active compound of Taraxacum, which plays a significant role in the treatment of diabetes in many classic prescriptions. However, the mechanisms of TS in the treatment of diabetes remain unclear. This study aimed to investigate the underlying mechanism of TS in hepatic gluconeogenesis and glycogen synthesis in HepG2 cells with insulin resistance (IR). Methods: Molecular docking was conducted by using Discovery Studio (DS) to predict the target of TS in the treatment of diabetes. Then we treated HepG2 cells with glucosamine for 18 h. After the cells were treated with TS, the glucose consumption was examined. Oil red O staining was used to detect the lipid accumulation of HepG2 cells, and cellular glucose uptake levels were assessed using fluorescent 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxy-D-glucose. The expression of the related proteins of the PI3K/Akt signaling pathway in the HepG2 cells was evaluated by western blot assay. Results: The molecular docking analysis revealed a good binding pose between the insulin receptor and TS. Furthermore, TS administration significantly enhanced glucose uptake and consumption, and reduced lipid accumulation in HepG2 cells with IR. The results of pharmacological mechanism study showed that TS up-regulated glycogenesis by PI3K/Akt/GSK3-motivated GS activation, and down-regulated gluconeogenesis by PI3K/Akt/FoxO1 expression of PEPCK and G6Pase in HepG2 cells with IR. Conclusions: Molecular docking and in vitro experimental results indicate that TS suppresses hepatic gluconeogenesis and augments glycogen synthesis by the PI3K/Akt signaling pathway, and it may have similar effects as insulin in regulating blood glucose.

Starvation and Refeeding Regulate Glycogen Synthase Gene Expression in Rat Liver at the Posttranscriptional Level

Starvation and refeeding affect glycogen metabolism. The effects of starvation and refeeding on the level of glycogen synthase (GS) gene expression were examined in rat liver. Depletion of hepatic glycogen stores by 72 h of starvation (7% of control) was supercompensated by 24 h of refeeding a standard laboratory diet (247% of control). Upon further refeeding, glycogen concentration gradually returned to control levels after 120 h. After 72 h of starvation, GS activity and immunoreactive protein in the liver were 60–64% lower than in control rats with free access to food. After 72 h of refeeding, GS activity and immunoreactive protein returned to control values. No significant differences in GS mRNA levels were found between fed, starved and refed rats, as determined by Northern blot analysis and PCR quantification, indicating that the long-term regulation of GS gene expression in starvation and refeeding occurs via a posttranscriptional mechanism. The amount of GS mRNA associated with polyribosomes was 90% lower in starved than in fed rats. These data indicate that the efficiency of GS mRNA translation, rather than its abundance, decreases during starvation.

Hypoglycemic Potential of Carica papaya in Liver Is Mediated through IRS-2/PI3K/SREBP-1c/GLUT2 Signaling in High-Fat-Diet-Induced Type-2 Diabetic Male Rats.

Regardless of socioeconomic or demographic background, the prevalence of type 2 diabetes mellitus, which affects more than half a billion people worldwide, has been steadily increasing over time. The health, emotional, sociological, and economic well-being of people would suffer if this number is not successfully handled. The liver is one of the key organs accountable for sustaining metabolic balance. Elevated levels of reactive oxygen species inhibit the recruitment and activation of IRS-1, IRS-2, and PI3K-Akt downstream signaling cascade. These signaling mechanisms reduce hepatic glucose absorption and glycogenesis while increasing hepatic glucose output and glycogenolysis. In our work, an analysis of the molecular mechanism of Carica papaya in mitigating hepatic insulin resistance in vivo and in silico was carried out. The gluconeogenic enzymes, glycolytic enzymes, hepatic glycogen tissue concentration, oxidative stress markers, enzymatic antioxidants, protein expression of IRS-2, PI3K, SREBP-1C, and GLUT-2 were evaluated in the liver tissues of high-fat-diet streptozotocin-induced type 2 diabetic rats using q-RT-PCR as well as immunohistochemistry and histopathology. Upon treatment, C. papaya restored the protein and gene expression in the liver. In the docking analysis, quercetin, kaempferol, caffeic acid, and p-coumaric acid present in the extract were found to have high binding affinities against IRS-2, PI3K, SREBP-1c, and GLUT-2, which may have contributed much to the antidiabetic property of C. papaya. Thus, C. papaya was capable of restoring the altered levels in the hepatic tissues of T2DM rats, reversing hepatic insulin resistance.

Antidiabetic and Antidyslipidemic Effects of Artemisia mesatlantica, an Endemic Plant from Morocco.

The study aimed to assess the antihyperglycemic and antidyslipidemic activities of Artemisia mesatlantica. Artemisia mesatlantica is an endemic plant of Morocco used in traditional medicine as an alternative treatment for diabetes. The study was designed to examine the antihyperglycemic and antidyslipidemicability of aqueous extract of Artemisia mesatlantica (AMAE) in experimental animal models. The effect of the single and repeated oral administration (7 days of treatment) of AMAE (60 mg/kg) on blood glucose and lipid profile were assessed in normal and streptozotocin-induced diabetic rats. Furthermore, to confirm the antidyslipidemic effect of Artemisia mesatlantica, a model of hyperlipidemia induced by tyloxapol (Triton WR-1339) in rats was used. The AMAE (60 mg/kg) was able to significantly reduce glycaemia, improve lipid profile and increase hepatic glycogen content in STZ-induced diabetic rats. In addition, pretreatment of rats for 7 consecutive days with an aqueous extract of Artemisia mesatlantica (600 mg/kg) prior to tyloxapol injection prevented increases in plasma levels of total cholesterol, triglycerides and LDL-c. From these observed results, it can be deduced that Artemisia mesatlantica possesses remarkable antidiabetic and antihyperlipidemic properties.

Physiological Doses of Oral Casein Affect Hepatic Glycogen Metabolism in Normal Food-Deprived Rats

In a previous study, administration of casein hydrolysate to food-deprived rats at a dose of 4 g/kg body wt resulted in an increase in portal plasma glucagon concentration. This was associated with an activation of phosphorylase a and a decrease in hepatic glycogen concentration. The present study was undertaken to determine whether similar results would be obtained with smaller doses. Doses of 1 and 2 g/kg body wt were administered to food-deprived rats. At a dose of 2 g/kg, portal plasma glucagon concentration was significantly elevated. This was associated with a slight increase in phosphorylase a activity (P < 0.05) and a 50% decrease in hepatic glycogen concentration (P < 0.01). At a dose of 1 g casein hydrolysate/kg body wt, changes in portal plasma glucagon concentration, phosphorylase a activity and hepatic glycogen concentration generally were not observed. Hepatic glucose, uridine diphosphoglucose, ATP and glucose-6-phosphate concentrations were unaffected by either dose of casein hydrolysate. The data indicate a dose-response relationship between casein hydrolysate administration and effects on glycogen metabolism in the liver. Protein-induced glycogenolysis is likely to occur when rats ingest a moderate amount of a pure protein meal.

Cinnamaldehyde supplementation acts as an insulin mimetic compound improving glucose metabolism during adolescence, but not during adulthood, in healthy male rats.

Adolescence is a critical period of increased vulnerability to nutritional modifications, and adolescents may respond differently from adults to dietary intake and nutraceuticals. Cinnamaldehyde, a major bioactive compound of cinnamon, improves energy metabolism, as has been shown in studies conducted primarily in adult animals. We hypothesized that cinnamaldehyde treatment may have a higher impact on the glycemic homeostasis of healthy adolescent rats than on healthy adult rats. Male adolescent (30 days) or adult (90 days) Wistar rats received cinnamaldehyde (40 mg/kg) for 28 days by gavage. The oral glucose tolerance test (OGTT), liver glycogen content, serum insulin concentration, serum lipid profile, and hepatic insulin signaling marker expression were evaluated. Cinnamaldehyde-treated adolescent rats showed less weight gain (P = 0.041), improved OGTT (P = 0.004), increased expression of phosphorylated IRS-1 (P = 0.015), and a trend to increase phosphorylated IRS-1 (P = 0.063) in the liver of adolescent rats in the basal state. None of these parameters was modified after treatment with cinnamaldehyde in the adult group. Cumulative food intake, visceral adiposity, liver weight, serum insulin, serum lipid profile, hepatic glycogen content, and liver protein expression of IRβ, phosphorylated IRβ, AKT, phosphorylated AKT, and PTP-1B in the basal state were similar between both age groups. In a healthy metabolic condition, cinnamaldehyde supplementation affects glycemic metabolism in adolescent rats while promoting no changes in adult rats.

Impact of different processing mulberry leaf on growth, metabolism and liver immune function of largemouth bass (Micropterus salmoides)

Mulberry leaf is abundant in bioactive ingredients, and their release could be affected by different treatment technologies. In this study, the mulberry leaf was treated with methods of superfine grinding (MG), wall-broken (MB), and water extraction-methanol precipitation (ME). Three processing mulberry leaves were equally added to the feed of largemouth bass (Micropterus salmoides), respectively, and the growth, liver health and intestinal microorganisms were analyzed. According to statistical analysis, the growth of the three experimental groups was remarkedly better than that of the control group fed with a basic diet. The MB group had a higher specific growth rate (SGR) and weight gain rate (WGR) than the MG and ME groups. Mulberry leaf supplementation could significantly reduced blood glucose and serum total cholesterol (TC), very low-density lipoprotein (VLDL) and triglyceride (TG) levels, improved hepatic glycogen, lipid and TG levels, and these parameter values of the MB group were superior to the other treatments. Additionally, MB treatment could up-regulate the expressions of gpx and cat in the liver compared with the control and boost the activities of antioxidant enzymes (GSH-Px and CAT). Meanwhile, MB supplementation suppressed the expressions of pro-inflammatory cytokines (TNFα and IL-8) and up-regulated anti-inflammatory cytokines (IL-10 and TGF-β) in liver compared to the control group. Accordingly, the hepatic histostructure showed an improvement in the treatment group, and mulberry leaf could also dramatically lower the apoptosis of hepatic cells, particularly in the MB group. Furthermore, MB treatment reduced gut dysbiosis by limiting the development of gram-negative and possibly dangerous bacteria. In sum, this study firstly disclosed that the biological effectiveness of mulberry leaf might be impacted by various processing techniques. Especially MB-treatment effectively ameliorates glucose, lipid metabolism and liver immunology in largemouth bass.

A novel approach to repositioning memantine for metabolic syndrome-induced steatohepatitis: Modulation of hepatic autophagy, inflammation, and fibrosis

AimsThis study investigated the possible hepatoprotective effects of memantine, compared to pioglitazone, in rat steatohepatitis, emphasizing its role in modulating hepatic autophagy. Main methodsMetabolic syndrome (MetS) was provoked in adult male Wistar rats by a high fructose/fat/salt regimen for eight weeks. Then, rats were administered either memantine or pioglitazone daily for 10 weeks (both at 20 mg/kg, orally). An oral glucose tolerance test (OGTT) was done at the end of the study, and serum liver enzymes, lipids, and fasting blood glucose were measured. Also, hepatic contents of inflammatory, oxidative, and autophagy markers were quantified. Additionally, histopathological examinations of general hepatic structure and glycogen content were performed. Key findingsCompared to the MetS rats, memantine normalized fasting serum insulin, Homeostatic Model Assessment (HOMA-IR), serum lipids, and liver enzymes (ALT and AST). Memantine also markedly reduced hepatic inflammatory markers; NF-κB and TNF-α. In addition, hepatic NRF2 and GSH were augmented, while hepatic MDA was reduced by memantine. Interestingly, livers of the memantine group showed elevated Beclin1 and LC3 and reduced p62 contents compared to the MetS group indicating that memantine preserved hepatic autophagy. Histopathological examination revealed that memantine ameliorated hepatic steatosis and inflammation. Pioglitazone also mitigated most of the steatohepatitis-related changes, however, memantine was more effective in most of the studied parameters. SignificanceThe hepatoprotective effect of memantine against steatohepatitis is mediated, at least partly, through conserving hepatic autophagy along with anti-inflammatory, antioxidant, and anti-fibrotic effects.

Garlic (Allium sativum L.) polysaccharide ameliorates type 2 diabetes mellitus (T2DM) via the regulation of hepatic glycogen metabolism

This study intends to explore the antihyperglycemic effect and the possible hypoglycemic mechanism of garlic (Allium sativum L.) polysaccharide (GP) using an animal model. Kunming mice were fed with GP (1.25, 2.5, 5.0 g/kg‧bw) for five weeks after insulin resistance (IR) engendering by a high-oil-high-sugar diet and streptozotocin (STZ). Intragastric administration of GP effectively improved the disease of polyphagia and polydipsia in diabetic mice. The fasting blood glucose (FBG) in the high-dose GP (DGH) group was meaningfully 42% lower than that in the diabetic model (DC) group showing its hypoglycemic effect. GP might manipulate hepatic glycogen metabolism by regulating the content of glucokinase (GK), glycogen synthase (GS), and phosphoenolpyruvate carboxykinase (PEPCK). Results showed that GP with a low relative molecular weight (MW) of 2.0 kDa consisted predominately of a 2,1-β-D-Fruf backbone with 20.7% side chains owning the structure-effect on hypoglycemia indicating it could be a potential supplement for the intervention and management of hyperglycemia.

Effects of Dietary Steroid Saponins on Growth Performance, Serum and Liver Glucose, Lipid Metabolism and Immune Molecules of Hybrid Groupers (♀Epinephelus fuscoguttatus × ♂Epinephelus lanceolatu) Fed High-Lipid Diets.

High-lipid diets are attributed to excessive lipid deposition and metabolic disturbances in fish. The aim of this experiment was to investigate the effects of steroidal saponins on growth performance, immune molecules and metabolism of glucose and lipids in hybrid groupers (initial weight 22.71 ± 0.12 g) fed high-lipid diets. steroidal saponins (0%, 0.1% and 0.2%) were added to the basal diet (crude lipid, 14%) to produce three experimental diets, designated S0, S0.1 and S0.2, respectively. After an 8-week feeding trial, no significant differences were found between the S0 and S0.1 groups in percent weight gain, specific growth rate, feed conversion ratio, protein efficiency ratio and protein deposition rate (p > 0.05). All those in the S0.2 group were significantly decreased (p < 0.05). Compared to the S0 group, fish in the S0.1 group had lower contents of serum triglyceride and low-density lipoprotein cholesterol and higher high-density lipoprotein cholesterol and glucose (p < 0.05). The activities of superoxide dismutase, catalase and glutathione peroxidase were significantly higher, and malondialdehyde contents were significantly lower in the S0.1 group than in the S0 group (p < 0.05). Hepatic triglyceride, total cholesterol and glycogen were significantly lower in the S0.1 group than in the S0 group (p < 0.05). Activities of lipoprotein lipase, total lipase, glucokinase and pyruvate kinase, and gene expression of lipoprotein lipase, triglyceride lipase and glucokinase, were significantly higher in the S0.1 group than in the S0 group. Interleukin-10 mRNA expression in the S0.1 group was significantly higher than that in the S0 group, while the expression of interleukin-6 and tumor necrosis factor-α genes were significantly lower than those in the S0 group. In summary, adding 0.1% steroidal saponins to a high-lipid diet not only promoted lipolysis in fish livers, but also activated glycolysis pathways, thus enhancing the utilization of the dietary energy of the groupers, as well as supporting the fish's nonspecial immune-defense mechanism.

A prolonged fast improves overnight substrate oxidation without modulating hepatic glycogen in adults with and without nonalcoholic fatty liver: A randomized crossover trial

Increasing overnight fasting time seems a promising strategy to improve metabolic health in individuals with nonalcoholic fatty liver (NAFL). Mechanisms underlying the beneficial effects of fasting may be related to larger fluctuations in hepatic glycogen and higher fat oxidation. This study investigated whether prolonging an overnight fast depletes hepatic glycogen stores and improves substrate metabolism in individuals with NAFL and healthy lean individuals. Eleven individuals with NAFL and ten control individuals participated in this randomized crossover trial. After a 9.5-hour or 16-hour fast, hepatic glycogen was measured by using carbon-13 magnetic resonance spectroscopy, and a meal test was performed. Nocturnal substrate oxidation was measured with indirect calorimetry. Extending fasting time led to lower nocturnal carbohydrate oxidation and higher fat oxidation in both groups (intervention × time, p < 0.005 for carbohydrate and fat oxidation). In both arms, the respiratory exchange ratio measured during the night remained higher in the group with NAFL compared with the control group (population p < 0.001). No changes were observed in hepatic glycogen depletion with a prolonged overnight fast in the group with NAFL or the control group. These results suggest that acutely prolonging the overnight fast can improve overnight substrate oxidation and that these alterations are not mediated by changes in hepatic glycogen depletion.