Liver Glucose Research Articles

Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic β-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High-Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation.

Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational metabolic dysfunction caused by maternal obesity. The benefits of maternal exercise on offspring health may arise from multiple factors and have recently been shown to involve DNA demethylation of critical hepatic genes leading to enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet the effects of maternal obesity and exercise on histone methylation in offspring are not known. Here, we find that maternal high-fat diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose metabolism in C57BL/6 mice through a mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of histone H3 lysine 4 (H3K4) methyltransferase leading to decreased H3K4me3 at the promoters of glucose metabolic genes. Remarkably, the entire signal was restored if the HFD-fed dams had exercised during pregnancy. WDR82 overexpression in hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels. Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression, and glucose metabolism. Maternal exercise regulates a multicomponent epigenetic system in the fetal liver resulting in the transmission of the benefits of exercise to offspring.

Urinalysis, but Not Blood Biochemistry, Detects the Early Renal Impairment in Patients with COVID-19.

Background: Coronavirus 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has created a tremendous economic and medical burden. The prevalence and prognostic value of SARS-CoV-2-induced kidney impairment remain controversial. The current study aimed to provide additional evidence on the incidence of acute kidney injury (AKI) in COVID-19 patients and propose the use of urinalysis as a tool for screening kidney impairment. Methods: 178 patients with confirmed COVID-19 were enrolled in this retrospective cohort study. The laboratory examinations included routine blood tests, blood biochemical analyses (liver function, renal function, lipids, and glucose), blood coagulation index, lymphocyte subset and cytokine analysis, urine routine test, C-reactive protein, erythrocyte sedimentation, and serum ferritin. Results: No patient exhibited a rise in serum creatinine or Cystatin C and occurrence of AKI, and only 2.8% of patients were recorded with an elevated level of blood urea nitrogen among all cases. On the contrary, 54.2% of patients who underwent routine urine testing presented with an abnormal urinalysis as featured by proteinuria, hematuria, and leucocyturia. Conclusions: Kidney impairment is prevalent among COVID-19 patients, with an abnormal urinalysis as a clinical manifestation, implying that a routine urine test is a stronger indication of prospective kidney complication than a blood biochemistry test.

No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: A randomized placebo-controlled cross-over study.

Patients with glycogen storage disease type V (GSDV), also known as McArdle disease, have blocked glycogen breakdown due to myophosphorylase deficiency, leading to exercise intolerance, muscle pain, and risk of muscle damage. Blood‐derived ketone bodies (KBs) constitute an alternative energy source that could fuel the muscle independent of glycogenolysis. However, except for long‐time fasting or ketogenic dieting, KBs are present in low quantities. This led us to explore the effects of a drink containing exogenously produced KBs in the form of D‐β‐hydroxybutyrate esters (KE) on exercise capacity and metabolism in patients with GSDV. Eight GSDV patients and four healthy controls (HC) were included in this placebo‐controlled, cross‐over study where subjects were randomized to receive a KE drink with 395 mgKE/kg or placebo drink on two separate days 25 min before a submaximal cycle exercise test. The primary outcome was exercise capacity as indicated by heart rate response (HR) to exercise. Secondary outcomes included perceived exertion (PE) and measures of KB, carbohydrate, and fat metabolism during exercise. In GSDV, the KE drink vs. placebo increased plasma KBs and KB oxidation (p ≤ 0.0001) but did not improve exercise capacity as judged from HR (p = 0.120) and PE (p = 0.109). In addition, the KE drink lowered plasma glucose, free fatty acids, and lowered lipolytic rate and glucose rate of appearance compared with placebo. Similar results were found in the HC group. The present study indicates that an increase in KB oxidation by oral KE supplementation does not improve exercise capacity in GSDV possibly because of KB‐induced inhibition of lipolysis and liver glucose output. Thus, oral KE supplementation alone cannot be recommended as a treatment option for patients with GSDV.

Beneficial Activities of Alisma orientale Extract in a Western Diet-Induced Murine Non-Alcoholic Steatohepatitis and Related Fibrosis Model via Regulation of the Hepatic Adiponectin and Farnesoid X Receptor Pathways.

The hepatic adiponectin and farnesoid X receptor (FXR) signaling pathways play multiple roles in modulating lipid and glucose metabolism, reducing hepatic inflammation and fibrosis, and altering various metabolic targets for the management of non-alcoholic fatty liver disease (NAFLD). Alisma orientale (AO, Ze xie in Chinese and Taeksa in Korean) is an herbal plant whose tubers are enriched with triterpenoids, which have been reported to exhibit various bioactive properties associated with NAFLD. Here, the present study provides a preclinical evaluation of the biological functions and related signaling pathways of AO extract for the treatment of NAFLD in a Western diet (WD)-induced mouse model. The findings showed that AO extract significantly reversed serum markers (liver function, lipid profile, and glucose) and improved histological features in the liver sections of mice fed WD for 52 weeks. In addition, it also reduced hepatic expression of fibrogenic markers in liver tissue and decreased the extent of collagen-positive areas, as well as inhibited F4/80 macrophage aggregation and inflammatory cytokine secretion. The activation of adiponectin and FXR expression in hepatic tissue may be a major mechanistic signaling cascade supporting the promising role of AO in NAFLD pharmacotherapy. Collectively, our results demonstrated that AO extract improves non-alcoholic steatohepatitis (NASH) resolution, particularly with respect to NASH-related fibrosis, along with the regulation of liver enzymes, postprandial hyperglycemia, hyperlipidemia, and weight loss, probably through the modulation of the hepatic adiponectin and FXR pathways.

Cardiovascular risk, fatty liver disease, glucose and insulin curve among prediabetes phenotypes in Peruvian population

AimsTo describe the cardiovascular risks, fatty liver disease, and glucose and insulin curve among prediabetes phenotypes (PPh) in Peruvian population. MethodsA study was carried out using a secondary database of a series of patients with identified risk factors for diabetes mellitus type 2 in one clinic in Lima, Peru. Patients were divided according with the OGTT in impaired glucose 2h or IGT(Pph1), impaired fasting glucose or IFG(Pph3) or both(Pph2). Results259 patients were identified for analysis, 149 of whom had normal OGTT, 94 had prediabetes (36.3%), and 16 diabetes (6.2%). We found that 37(39.4%), 37(39.4%) and 20(21.2%) presented Pph1, Pph-2 and Pph-3 respectively. Most of the cardiovascular risks and hepatic function comparison showed no difference in our study sample groups. However, we found that Pph2 showed significantly higher abnormalities in HDL-c, triglycerides, hepatic steatosis, and HOMA-IR compared with normal OGTT group (p < 0.05). Interestingly, this difference was not seen with the other phenotypes. Also, hepatic steatosis was higher in Pph2 compared to Pph3 (p < 0.05). HOMA-IR was high in Phenotype 2 compared with Phenotype 1. Regarding hepatic steatosis, this was high in all prediabetes phenotypes, however we found this to be of statistical significance in Pph2 compared to Pph3 (p < 0.01). ConclusionsIn general, prediabetes phenotypes show a similar association with cardiovascular risk factors and hepatic steatosis, however, Pph2 show more differences in specific comparisons. We believe that this study is a starting point for further investigation to understand prediabetes in Peruvian population and be able to improve disease risk stratification.

Schizophyllum commune-derived \u03b2-glucan improves intestinal health demonstrating protective effects against constipation and common metabolic disorders

It has been proven that β-glucan produced by Schizophyllum commune has beneficial effects on obesity, obesity-associated constipation, and colitis conditions; however, the protective effect of the compound on host at basal state is yet to be investigated. C57BL/6 J mice were fed with a normal diet (ND), normal diet supplemented with 3 g/kg (BG_low), and 5 g/kg (BG_high) of β-glucan (BG) for 12 weeks. Body weight, food and water intake and fecal status were monitored weekly. Intestine was stained by Periodic acid–Schiff (PAS) and Alcian Blue to evaluate the mucin layer thickness and goblet cell population. Morphological changes in internal organs and intestinal motility were also assessed, while serum biomarkers for liver injury and glucose level were analyzed. On the other hand, fecal microbiota and associated metabolic activities were also investigated. β-glucan bulked feces, decreased fecal moisture, and proliferated goblet cells resulted in a thickened lubricating mucin layer; however, the intestinal transit rate did not increase. The abundance of beneficial bacteria was increased while the harmful strains was decreased in a dose-dependent manner by the effect of β-glucan. Specific short chain fatty acid (SCFA)-producing strains, such as Roseburia, Ruminococcus, and Bifidobacteria, were selectively increased by β-glucan. In addition, consumption of β-glucan lowered level of obesity-associated biomarkers. Schizophyllum commune β-glucan showed an insignificant change in transit rate in healthy conditions when compared with obesity, despite similar effects on increasing mucus production and bulked feces. Nonetheless, the outcomes proposed protective effects against obesity, diabetes, inflammatory bowel diseases (IBD), and constipation, in which the modification of the gut microbiota by β-glucan is the largest contributor.

Multi-omics-based label-free metabolic flux inference reveals obesity-associated dysregulatory mechanisms in liver glucose metabolism

SummaryGlucose homeostasis is maintained by modulation of metabolic flux. Enzymes and metabolites regulate the involved metabolic pathways. Dysregulation of glucose homeostasis is a pathological event in obesity. Analyzing metabolic pathways and the mechanisms contributing to obesity-associated dysregulation in vivo is challenging. Here, we introduce OMELET: Omics-Based Metabolic Flux Estimation without Labeling for Extended Trans-omic Analysis. OMELET uses metabolomic, proteomic, and transcriptomic data to identify relative changes in metabolic flux, and to calculate contributions of metabolites, enzymes, and transcripts to the changes in metabolic flux. By evaluating the livers of fasting ob/ob mice, we found that increased metabolic flux through gluconeogenesis resulted primarily from increased transcripts, whereas that through the pyruvate cycle resulted from both increased transcripts and changes in substrates of metabolic enzymes. With OMELET, we identified mechanisms underlying the obesity-associated dysregulation of metabolic flux in the liver.

Dietary Vitamin C Intake Is Associated With Improved Liver Function and Glucose Metabolism in Chinese Adults.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases worldwide. Dietary vitamin C intake might play an important role in reducing the risk of NAFLD. This study assesses the relationship between dietary vitamin C intake and diagnostic biomarkers of NAFLD.MethodsThe data from the 2009 China Health and Nutrition Survey (CHNS), nine provinces across four diverse regions (Northeast, East Coast, Central, and West) were included in the study. The dietary vitamin C intake of participants was calculated based on 3-day 24-h diet questionnaires at the individual level. The associations of dietary vitamin C intake and the biochemical indicators of liver function and glucose/lipid metabolism were determined.ResultsA total of 8,307 participants were included in the final analysis. The mean dietary vitamin C intake for the overall, male and female subjects was 79.8 ± 58.6, 81.6 ± 55.3, and 78.2 ± 61.2 mg/day, respectively. The prevalence of inadequate dietary vitamin C intake for the overall, male and female subjects was 24.4, 26.5, and 22.6%, respectively. Intake of vitamin C was associated with both lower concentrations of plasma ferritin and hemoglobin A1c (HbA1c). Higher dietary vitamin C intake was associated with higher albumin, even further adjusted for body mass index (BMI), residence, and smoking status. No improvement in lipid metabolism was found.ConclusionThis study demonstrated that higher dietary vitamin C intake is a benefit for improving glucose metabolism and liver function in which reducing ferritin, a biomarker of iron accumulation, may be involved.

Intestinal microbiomics and liver metabolomics insights into the preventive effects of chromium (III)-enriched yeast on hyperlipidemia and hyperglycemia induced by high-fat and high-fructose diet

In recent years, organic chromium (III) supplements have received increasing attentions for their low toxicity, high bioavailability and wide range of health-promoting benefits. This study aimed to investigate the preventive effects of chromium (III)-enriched yeast (YCr) on high-fat and high-fructose diet (HFHFD)-induced hyperlipidemia and hyperglycemia in mice, and further clarify its mechanism of action from the perspective of intestinal microbiomics and liver metabolomics. The results indicated that oral administration of YCr remarkably inhibited the aberrant elevations of body weight, blood glucose and lipid levels, hepatic cholesterol (TC) and triglyceride (TG) levels caused by HFHFD. Liver histological examination showed that oral YCr intervention inhibited HFHFD induced liver lipid accumulation. Besides, 16S rDNA amplicon sequencing showed that YCr intervention was beneficial to ameliorating intestinal microbiota dysbiosis by altering the proportion of some intestinal microbial phylotypes. Correlation-based network analysis indicated that the key intestinal microbial phylotypes intervened by YCr were closely related to some biochemical parameters associated with glucose and lipid metabolism. Liver metabolomics analysis revealed that dietary YCr intervention significantly regulated the levels of some biomarkers involved in purine metabolism, glycerophospholipid metabolism, citrate cycle, pyrimidine metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and so on. Moreover, dietary YCr intervention regulated the mRNA levels of key genes associated with glucose, cholesterol, fatty acids and bile acids metabolism in liver. These findings suggest that dietary YCr intervention has beneficial effects on glucose and lipid metabolism by regulating intestinal microbiota and liver metabolic pathway, and thus can be served as a functional component to prevent hyperlipidemia and hyperglycemia.

Rodent models in placental research. Implications for fetal origins of adult disease.

Rodent models in rats, mice, and guinea pigs have been extremely helpful to gain insight into pregnancy physiology and pathologies-related. Moreover, they have allowed understanding the mechanism that links an adverse intrauterine environment with the origin of adult disease. In this regard, the effects of diverse maternal conditions, such as undernutrition, obesity, hypoxia, and hyperandrogenism on placental function and its long-term consequences for the offspring, have been widely analyzed through rodents models involving dietary manipulations, modifications in environmental oxygen, surgical and pharmacological procedures that reduce uteroplacental blood flow and administrations of exogenous testosterone and dihydrotestosterone (DHT) mimicking maternal androgen excess. Both in human and in rodent models, these interventions induce modifications of placental morphology, transport of glucose, amino acid, and fatty acids, steroid synthesis, and signaling pathways control placental function. These changes are associated with the increase of pro-inflammatory and oxidative stress markers. For its part, offspring exhibit alterations in organs involved in metabolic control such as the hypothalamus, adipose tissue, liver, skeletal muscle, and pancreas altering the intake and preferences for certain foods, the metabolism of glucose and lipid, and hormonal function leading to fat accumulation, insulin resistance, fatty liver, dyslipidemia, and elevated glucose levels. Therefore, the present review discusses the evidence emerging from rodent models that relate maternal nutrition, hypoxia, and androgen exposure to the maternal mechanisms that lead to fetal programming and their metabolic consequences in postnatal life.

Efeitos da suplementação com açaí (Euterpe Oleracea Mart.) associada ao exercício físico em animais e humanos: revisão de escopo

ABSTRACT Objective This scoping review aimed to map evidence on açai supplementation combined with exercise in animal and/or human experimental studies. Methods The search considered six electronic databases and screening of relevant references. The selection process and data extraction were performed by two independent authors. The study characteristics, and AS (e.g., form, intervention time, amount ingested) and exercise (e.g., types, intensity, and duration) strategies were summarized, as well as their reported results. Results From an initial total of 342 studies identified; 11 (5 with animal and 6 with human models) were eligible. In animals, açai supplementation and exercise led to benefits in exercise tolerance and improvements in several hemodynamic parameters, as well as significant improvements in liver markers and glucose metabolism. In humans, açai supplementation indicated positive results in increasing exhaustion time to 90% of VO2max and increasing intensity at the anaerobic threshold. Conclusion We conclude that future research involving animals and humans should examine açai supplementation and exercise with (a) obesity models to test the effect of adiponectin on body composition with analysis of histological and histochemical parameters; (b) eccentric injury protocols with the incorporation of muscle quality variables to assess recovery; (c) chronic açai supplementation and strength training; (d) comparison of different forms of açai supplementation in exercise protocols.

Distinctive effects of different types of advanced glycation end-products (AGEs) on liver glucose metabolism.

Increasing evidence has shown that AGEs can impair insulin sensitivity and affect glucose homeostasis. Owing to the heterogeneity of AGEs, it is still unclear which one has the strongest potential to disrupt glucose metabolism. Our study explored the effects of different types of AGEs on hepatic glucose metabolism. Three typical AGEs representing different formation pathways, namely AGEs from a glucose and lysine reaction mixture, methylglyoxal-modified BSA (MGO-BSA) and carboxymethyl lysine (CML), were chosen to treat HepG2 cells. The results indicate that only CML and MGO-BSA could disturb glucose metabolism, and MGO-BSA was the most active in promoting insulin resistance, as manifested by the inactivation of insulin receptor substrate-1 and decreased phosphorylation of AKT. Moreover, mice fed with an MGO-BSA-enriched diet showed increased blood glucose as well as impaired glucose tolerance. The present study revealed the distinctive effects of various AGEs on glucose metabolism and suggested that AGEs with high molecular weight might exert a higher pathogenic effect than small AGEs.

Off-target lipid metabolism disruption by the mouse constitutive androstane receptor ligand TCPOBOP in humanized mice

The constitutive androstane receptor (CAR) controls xenobiotic clearance, regulates liver glucose, lipid metabolism, and energy homeostasis. These functions have been mainly discovered using the prototypical mouse-specific CAR ligand TCPOBOP in wild-type or CAR null mice. However, TCPOBOP is reported to result in some off-target metabolic effects in CAR null mice.In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyses in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the model, human CAR retains its constitutive activity in metabolism regulation; however, it is not activated by TCPOBOB.Notably, we observed that TCPOBOP affected lipid homeostasis by elevating serum and liver triglyceride levels and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and decrease of its metabolites in humanized CAR mice. RNA-seq analysis has shown divergent gene expression levels in wild-type and humanized CAR mice. Gene expression regulation in humanized mice is mainly involved in lipid metabolic processes and in the PPAR, leptin, thyroid, and circadian clock pathways. In contrast, CAR activation by TCPOBOP in wild-type mice reduced liver and plasma triglyceride levels and induced a typical transcriptomic proliferative response in the liver.In summary, we identified TCPOBOP as a disruptor of lipid metabolism in humanized CAR mice. The divergent effects of TCPOBOP in humanized mice in comparison with the prototypical CAR-mediated response in WT mice warrant the use of appropriate model ligands and humanized animal models during the testing of endocrine disruption and the characterization of adverse outcome pathways.

More simple more worse: Simple carbohydrate diets cause alterations in glucose and lipid metabolism in Nile tilapia (Oreochromis niloticus)

Dietary carbohydrates are widely used in aquafeeds as cheap energy source and improve quality of feeds. However, comprehensive assessment of the effects of dietary carbohydrate complexity on fish metabolism and liver health is currently lacking. This study investigated the effect of replacing 50% of starch by using sucrose, fructose and glucose. Four isonitrogenic (400 g/kg protein) and isolipidic (60 g/kg fat) feeds containing starch (polysaccharide), sucrose (disaccharide) and fructose and glucose (monosaccharides) were fed to three replicates of 4.5 ± 0.30 g Nile tilapia (Oreochromis niloticus) for eight weeks. Afterwards, growth performance, feed utilization efficiency, glucose and lipid metabolism and liver health were evaluated. The results showed that the Nile tilapia fed on monosaccharide diets had significantly lower growth and feed utilization efficiency than those fed on disaccharide and polysaccharide diets. The Nile tilapia fed on monosaccharide diets reduced significantly lipid deposition, hepatosomatic index (HSI), serum alanine transaminase (ALT) and aspartate aminotransferase (AST) and expression of lipid metabolism genes than those fed on polysaccharide diet. The Nile tilapia fed on disaccharide diet increased significantly the serum insulin, muscle glycogen, and muscle glycogen synthase (gs) gene expression compared with those fed on polysaccharide diet. Interestingly, the Nile tilapia fed on monosaccharide diets reduced significantly the glycogen content while they increased insulin, glucose and the expression of liver gluconeogenesis genes such as glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxykinase (pepck) than those fed on polysaccharide diet. Contrary, the Nile tilapia fed on disaccharide diet downregulated liver glucose catabolism and lowered serum triglyceride (TG) levels than those fed on polysaccharide but enhanced muscle peroxisome proliferator activated receptor alpha (pparα) and carnitine palmitoyltransferase 1a (cpt1a) gene expression, liver gluconeogenesis and pentose phosphate pathways. These results indicate that Nile tilapia utilizes better dietary polysaccharides and disaccharides than monosaccharides. Feeding Nile tilapia on monosaccharide diets caused insulin resistance and glucose metabolism disorders manifested by hyperinsulinism and hyperglycemia, respectively. The carbohydrate complexity affects the nutritional metabolism and liver health of fish.

Effect of mulberry galacto-oligosaccharide isolated from mulberry on glucose metabolism and gut microbiota in a type 2 diabetic mice

• Mulberry galacto-oligosaccharide (MGO) could reduce blood sugar fluctuations in type 2 diabetic mice. • MGO alleviates the oxidative stress. • MGO up-regulates PI3K/Akt pathways in type 2 diabetic mice. • MGO displayed a positive effect in the liver glucose metabolism pathways. • MGO was able to change the fecal microbiota in type 2 diabetic mice. Mulberry possesses many biological characteristics, such as reduce blood sugar and antioxidant properties, but whether mulberry galacto-oligosaccharide (MGO) can impact the characteristics of the gut microbiota is not yet clear. The objective of this work was to investigate the protective effects of MGO in type 2 diabetic (T2D) mice. The analysis of typical diabetic symptoms and serum status showed that oral MGO alleviated hyperglycemia, insulin resistance and oxidative stress in diabetic mice. These changes were caused by up-regulating the expression of key proteins in the PI3K/Akt pathway, involved in the control of liver glycolysis and gluconeogenesis, and liver glucose metabolism having a positive hypoglycemic effect. Additionally, the gut microbiota indicated that MGO treatment could positively modulate the microbiome composition to decrease the blood glucose in diabetic mice by promoting the growth of Prevotellaceae and Lactobacillus, whereas decreasing the abundance of Lachnospiraceae .

Comparison of biochemical and safety parameters of regular kratom (Mitragyna speciosa Korth.) users at two different time periods

ABSTRACT Introduction Kratom is a medicinal plant native to Southeast Asia. This present study was primarily undertaken to investigate changes in the vital signs, hematological, and biochemical parameters of regular kratom users. Method Five male regular kratom users were recruited for this longitudinal study. Subjects volunteered to undergo two sessions of blood tests and vital signs assessments after a 3-month interval (baseline: T1; after 3 months: T2). Result There were no significant alterations found in the hematological and biochemical of kratom users, except for a decrease in white cell count after a 3-month interval. In general, the kidney, liver function tests, thyroid, and glucose parameters were not significantly affected. Calcium, total protein, and globulin levels were significantly increased at T2 compared to T1, but all these parameters were within the normal reference range. There were alterations in the lipid profile, where total cholesterol and LDL cholesterol parameters were elevated at both T1 and T2, while significant increase in HDL cholesterol, and decrease in triglycerides levels were observed at T2 compared to T1. Conclusion Our results indicated that continuous consumption of kratom decoction at a daily mitragynine dose of 76.3–114.8 mg did not appear to alter the safety hematological and biochemical parameters of kratom users.

Maternal High-Fat Feeding Affects the Liver and Thymus Metabolic Axis in the Offspring and Some Effects Are Attenuated by Maternal Diet Normalization in a Minipig Model.

Maternal high-fat diet (HFD) affects metabolic and immune development. We aimed to characterize the effects of maternal HFD, and the subsequent diet-normalization of the mothers during a second pregnancy, on the liver and thymus metabolism in their offspring, in minipigs. Offspring born to high-fat (HFD) and normal diet (ND) fed mothers were studied at week 1 and months 1, 6, 12 of life. Liver and thymus glucose uptake (GU) was measured with positron emission tomography during hyperinsulinemic-isoglycemia. Histological analyses were performed to quantify liver steatosis, inflammation, and hepatic hematopoietic niches (HHN), and thymocyte size and density in a subset. The protocol was repeated after maternal-diet-normalization in the HFD group. At one week, HFDoff were characterized by hyperglycemia, hyperinsulinemia, severe insulin resistance (IR), and high liver and thymus GU, associating with thymocyte size and density, with elevated weight-gain, liver IR, and steatosis in the first 6 months of life. Maternal diet normalization reversed thymus and liver hypermetabolism, and increased HHN at one week. It also normalized systemic insulin-sensitivity and liver fat content at all ages. Instead, weight-gain excess, hyperglycemia, and hepatic IR were still observed at 1 month, i.e., end-lactation. We conclude that intra-uterine HFD exposure leads to time-changing metabolic and immune-correlated abnormalities. Maternal diet-normalization reversed most of the effects in the offspring.

Caffeine and EGCG Alleviate High-Trans Fatty Acid and High-Carbohydrate Diet-Induced NASH in Mice: Commonality and Specificity.

Caffeine and epigallocatechin-3-gallate (EGCG), which respectively, are the main functional extracts from coffee and green tea, and present protective effects against non-alcoholic fatty liver diseases (NAFLD). These two beverages and their functional extracts are highly recommended as potential treatments for obesity and NAFLD in clinics; however, their pharmacodynamic effects and pharmacological mechanisms in non-alcoholic steatohepatitis (NASH) remain unclear. Therefore, the aim of this study was to explore the commonality and specificity of the pharmacodynamic effects and pharmacological mechanisms of caffeine and EGCG on NASH mice, which were fed with a high-trans fatty acid/high-carbohydrate (HFHC) diet. C57BL/6J mice were fed a normal diet (control group) or an HFHC diet (HFHC group) for 24 weeks. HFHC group mice were additionally treated with caffeine (75 mg/kg) or EGCG (100 mg/kg) for 6 weeks, using obeticholic acid (OCA,10 mg/kg) as a positive control group. The pharmacological effects of the drugs, including effects on glucose and lipid metabolism and liver inflammation and fibrosis, were evaluated. Gene expression in liver tissue samples from the different groups were assessed. Both caffeine and EGCG significantly reduced the liver manifestations of NASH induced by HFHC. The pathological aspects of liver lipid deposition, inflammation, and liver fibrosis in both groups were strongly ameliorated. Of note, most indexes were strongly reversed in the caffeine group, although AST activity, fasting blood glucose, and the HOMA-IR index were improved in the ECGC group. There were 714 differentially expressed genes between the caffeine and HFHC groups and 268 differentially expressed genes between the EGCG and HFHC groups. Twenty and 17 NASH-related KEGG signaling pathways were enriched by caffeine and EGCG. This study confirmed that 75 mg/kg caffeine and 100 mg/kg EGCG could significantly improve liver lipid deposition, glucose metabolism, inflammation, and fibrosis in a mouse model of NASH induced by HFHC. The bioinformatics platform we built for caffeine and EGCG in NASH disease found that the two drugs may greatly overlap in improving the mechanism related to NASH inflammation. However, caffeine may have better potential in regulating glucose metabolism and EGCG may have better potential in regulating lipid metabolism.

Paternal Zn-deficiency abolishes metabolic effects in offspring induced by diet type.

Accumulating evidence implicates that offspring are susceptible to paternal alterations in numerous fetal disorders, such as growth and metabolic defects. However, less study has been conducted to define the relationship between paternal zinc deficiency (ZnD) and energy metabolism of offspring. In the present study, we used a paternal ZnD exposure (Zn at 0.3 μg/g) model to test energy metabolism of male and female offspring with the intervention of diet type (high-fat diet and low-fat diet). Our results demonstrated that paternal ZnD decreased body weight (BW) gain per week (P < 0.01) and ME intake per week (P < 0.05) at 11 weeks in male offspring with high-fat diet intervention but not in female offspring. Further, anabolism and catabolism of hepatic energy products also exhibited alterations. ZnD attenuated liver glucose but increased lipids content accompanied with elevated adiponectin and reduction in leptin level in serum, which exhibited lipid metabolic disturbance and smaller ratio of liver weight to BW in male but not female offspring. The qRT-PCR and liver energy metabolites analysis revealed that paternal ZnD mainly induced reduction in glucose tolerance and lowered glucose uptaking ability in male offspring and thereby alleviated glycolysis and the tricarboxylic acid cycle (TCA) cycle, which displayed a male gender-dependency. Therefore, we propose that paternal ZnD abolishes metabolic effects in male offspring induced by diet type intervention. Our findings reveal a novel link between paternal Zn-D and offspring energy metabolism.