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This study was to investigate the effect and possible mechanism of circadian rhythm change on the development of nonalcoholic fatty liver disease (NAFLD) in mice. A total of 80 male SPF-grade 4-week C57BL/6J mice were randomly divided into normal diet normal light/dark cycle (ND-LD) and high-fat diet all dark (HFD-DD) groups. Weight measurements were taken weekly, and after 24 weeks of intervention, 24 mice from both groups were randomly selected and analyzed. Additionally, the remaining mice in the HFD-DD group were divided into two groups: one group continued the high-fat all-dark treatment (HFD-DD-DD), and the other group was restored to normal light/dark cycle treatment (HFD-DD-LD). Mice were euthanized after a total of 48 weeks of intervention. Measurements were taken for each mouse including liver function serum indicators, liver tissue pathological sections, rhythm-related proteins, and determination of the gut microbiota community. The HFD induced NAFLD in mice, exhibiting symptoms such as obesity, lipid and glucose metabolism disorders, elevated liver enzymes, and decreased gut microbiota diversity. The composition of the gut microbiota was significantly different from that of the normal diet group, with a significant increase in the ratio of Firmicutes to Bacteroides. Restoration of normal light/dark cycles exacerbated the disorder of lipid metabolism, liver steatosis, and the expression of BMAL1 in mice and significantly reduced the diversity of gut microbiota. Circadian rhythm changes aggravate the development of NAFLD induced by a high-fat diet by affecting glucose metabolism, liver steatosis, and gut microbiota diversity. Restoration of normal circadian rhythm did not improve NAFLD. Our findings open up new avenues for the prevention, diagnosis, and treatment of NAFLD. • High-fat diet and circadian changes reduce gut microbiome richness and diversity. • HFD-DD (24th week) BMAL1 is higher than HFD-LD, indicating circadian influence. • HFD groups show elevated body weights, liver ratios, and abnormal liver structure. • HFD-DD-LD shows reduced gut microbiome richness compared to HFD-DD-DD. • Rhythm restoration didn't improve metabolism or steatosis in HFD-fed mice. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research. TGR5 can serve as an effective target for the treatment of obesity by regulating thermogenesis, metabolism, inflammation and appetite. [Display omitted] [ABSTRACT FROM AUTHOR]

Cognitive dysfunction is one of the common central nervous systems (CNS) complications of diabetes mellitus, which seriously affects the quality of life of patients and results in a huge economic burden. The glymphatic system dysfunction mediated by aquaporin-4 (AQP4) loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment (DCI). However, the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear. Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators. Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus, and skeletal muscle, liver and adipose tissue are the key target insulin resistance organs. In this review, the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed. We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet, which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI. Furthermore, the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized, which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients. AQP4-targeted miRNAs can be transmitted through exosomes in peripheral insulin resistance tissues to mediate the communication between central and peripheral cells thereby destroying the main histological and biomolecular basis of the glymphatic system and ultimately inducing cognitive dysfunction. [Display omitted] [ABSTRACT FROM AUTHOR]

Existing research has suggested that depression results in disorders of glucose metabolism in the organism which causing insufficient energy supply. However, the overall changes in glucose metabolism that arise from depression have not been clarified. In this study, the depression-like behavior in chronically unpredictable mild stressed rats was investigated, and the fate of glucose was tracked through isotope tracing and mass spectrometry, with a focus on metabolite changes in cecal contents. As indicated by the results, the isotopic results of cecal contents can indicate the metabolic end of the organism. Moreover, the TCA cycle activity was notably reduced, and the gluconeogenesis pathway was abnormally up-regulated in the CUMS-induced rats. The organism expedited other glucose metabolism pathways to make up for the insufficiency of energy. As a result, the activity of the inefficient glycolysis pathway was increased. Existing research has only investigated the metabolism of 13C-glucose, and lipids and proteins have been rarely explored. The chronic unpredictable mild stress can inhibit the entry of pyruvate into mitochondria in SD rats, such that the activity of TCA is reduced, and insufficient energy supply is caused. The organism is capable of expediting other glucose metabolism rate pathways to make up for the insufficiency of energy, whereas it still cannot compensate for the loss of energy. As a result, CUMS-induced rats exhibited high-rate and low-efficiency glucose metabolism. [Display omitted] • Stable isotope tracer metabolomics revealed the glucose metabolism disorder caused by depression in CUMS-induced rats. • Blocked TCA cycle leads to an increase in the activity of inefficient glucose metabolic pathways. • The overall glucose metabolism caused by depression is characterized by high rate and low efficiency. • Improving the overall glucose metabolism caused by depression is a potential method to treat depression. [ABSTRACT FROM AUTHOR]

Physical exercise can improve glucose metabolism; however, the best type, volume, intensity, and frequency aren't knowledge. High-Intensity Interval Training (HIIT), an emergent exercise type implicated as a short time-efficient exercise to improve metabolic health, needs more investigation regarding the traditional Moderate-Intensity Continuous Training (MICT). To identify the effects of MICT and HIIT on glycemic control of older people with glucose metabolism impairments. Our research question was based on the PICO model and the systematic review of the literature according to the guidelines of the preferred report items for systematic reviews and PRISMA meta-analyses. An extensive search was conducted in the Web of Science, PubMed, and Scielo databases. Only English language papers were included. The keywords used were "HIIT and metabolism of the elderly", "HIIT and glucose metabolism of the elderly", and "MICT and metabolism of the elderly", which were crossed with the Boolean operators "AND" and "OR" or both according to the guidelines of the PRISMA. Seventy papers were retrieved in the initial search. After applying all inclusions and exclusion parameters, 63 articles were excluded. In the end, six papers were classified as eligible for this study. All data categorically demonstrates that both HIIT and MICT can improve glucose metabolism with a larger effect size towards the HIIT model after the meta-analysis, pointing to HIIT as the most effective strategy. Both modalities can improve glucose metabolism in the elderly with a clear advantage for HIIT over MICT. • The MICT can improve the glucose metabolism in diabetic elderly. • The HIIT can improve the glucose metabolism in diabetic elderly. • The HIIT have an advantage over MICT on glucose metabolism in diabetic elderly. [ABSTRACT FROM AUTHOR]

[Display omitted] • DHA improves systemic glucose metabolism disorders. • DHA prevents hippocampal neuroinflammation. • DHA attenuates hippocampal oxidative stress. • DHA inhibits hippocampal amyloid formation and Tau phosphorylation. • DHA ameliorates hippocampal insulin resistance. • DHA improves cognitive function. Diminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function. This study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD). Eight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested. DHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aβ burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein. DHA improves cognitive function by enhancing hippocampal insulin sensitivity. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent liver disease that is closely related to obesity and metabolic disorders. 5-methoxyflavone (5-MF) is a flavonoid with DNA polymerase-β inhibitory properties. In this study, we explored the effects of 5-MF on NAFLD and its potential mechanisms using oleic acid/palmitic acid-treated HepG2 cells and high-fat diet-fed C57BL/6J mice. Our results showed that 5-MF not only alleviated fat deposition and hepatic steatosis, but also improved oxidative damage. In addition, 5-MF has the effect of alleviating disorders of glucose metabolism and enhancing energy expenditure in HFD-induced obese mice. Mechanistically, reverse screening methods and molecular docking analysis were used in combination, and revealed that cytochrome P450 1A1 (CYP1A1) is the target for 5-MF. Further experiments showed that 5-MF ameliorated triglycerides deposition by inhibiting the enzyme activity and protein expression of CYP1A1. In conclusion, 5-MF provides a novel strategy for the prevention and treatment of high-fat-induced NAFLD. [Display omitted] • 5-Methoxyflavone reduces total triglycerides in hepatocytes by interacting with cytochrome P450 1A1. • 5-Methoxyflavone alleviates high-fat diet-induced fat deposition and hepatic steatosis in mice. • 5-Methoxyflavone can improve glucose metabolism disorders and increase energy expenditure. • 5-Methoxyflavone alleviates high-fat diet-induced oxidative stress. [ABSTRACT FROM AUTHOR]

Obesity is a global epidemic, it can induce glucose and lipid metabolism disorder and non-alcoholic fatty liver disease (NAFLD). This study explored a new way to control weight and improve fatty liver, namely, living in hypoxia environment and supplement with lactoferrin (Lf). Sixty male C57BL/6J mice were divided into six groups, namely, control, hypoxia, high-fat diet, hypoxia + high-fat diet, hypoxia + high-fat diet + low dose Lf intervention, and hypoxia + high-fat diet + high-dose Lf intervention. Mice in the hypoxia treatment groups were treated with approximately 11.5 % oxygen for 6 h every day for 8 weeks. Results showed that interventions combining Lf and hypoxia treatments showed better effect against obesity and NAFLD than hypoxia treatment alone. The interventions controlled weight gain in mice, improved glucolipid metabolism in mice. The combination intervention reduced cholesterol absorption by reducing the level of hydrophobic bile acids, and elevating the level of hydrophilic bile acids. Gut microbiota analysis revealed that the combination intervention considerably elevated short chain fatty acids (SCFAs)-producing bacteria level, and reduced the Desulfovibrionaceae_unclassified level. Thus, Lf combined with hypoxia intervention effectively prevents obesity and NAFLD by restoring gut microbiota composition and bile acid profile. [ABSTRACT FROM AUTHOR]

Objective: The high levels of oxidative stress and apoptosis of pancreatic islet cells after severe burns lead to the dysfunction of islets and glucose metabolism disorders. Silent information regulator of transcription 1 (SIRT1) can decrease oxidative stress and apoptosis of islets in diabetes mellitus. This study aimed to investigate the role of SIRT1 on pancreatic islets and whether nicotinamide mononucleotide (NMN) can impact the function of pancreatic islets after severe burns.Methods: A 30% total body surface area full-thickness burn model was established using male C57BL/6 mice, and mice were randomized into sham group, burn group, burn + NMN group and burn + NMN + EX-527 group. The concentration of nicotinamide adenine dinucleotide (NAD), the expression of SIRT1, apoptosis induction, mitochondrial function and related signalling pathways of pancreatic islets at 24 h after severe burns were tested.Results: Severe burns led to decreased NAD level and SIRT1 expression of pancreatic islets, increased apoptosis rate, and mitochondrial dysfunction of pancreatic islets. NAD repletion by NMN and upregulation of SIRT1 expression reduced the phosphorylation and acetylation levels of NF-κB p65 and burn-induced apoptosis. Meanwhile, the mitochondrial function of islets was rescued by NMN treatment through the SIRT1/UCP2 axis and SIRT1/PGC1-α axis. In addition, the fasting blood glucose decreased and glucose-stimulated insulin secretion was improved with NMN treatment after severe burns. This protective effect of NMN could be abolished by EX-527, the inhibitor of SIRT1.Conclusion: NMN can increase the concentration of NAD+ of pancreatic islets and regulate SIRT1 and its downstream targets, thereby reducing apoptosis, maintaining mitochondrial function and improving pancreatic islet function after severe burn injury. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a significant public health problem. Diabetic kidney disease (DKD) is the most common complication of DM, and its incidence has been increasing with the increasing prevalence of DM. Given the association between DKD and mortality in patients with DM, DKD is a significant burden on public health resources. Despite its significance in DM progression, the pathogenesis of DKD remains unclear. Aberrant glucose uptake by cells is an important pathophysiological mechanism underlying DKD renal injury. Glucose is transported across the bilayer cell membrane by a glucose transporter (GLUT) located on the cell membrane. Multiple GLUT proteins have been identified in the kidney, and GLUT1 is one of the most abundantly expressed isoforms. GLUT1 is a crucial regulator of intracellular glucose metabolism and plays a key pathological role in the phenotypic changes in DKD mesangial cells. In an attempt to understand the pathogenesis of DKD better, we here present a review of studies on the role of GLUT1 in the development and progression of DKD. [Display omitted] [ABSTRACT FROM AUTHOR]

There is a growing body of evidence suggesting that the composition of intestinal flora plays a significant role in regulating lipid metabolism. 2′, 3′, 5′-tri- O -acetyl- N 6-(3-hydroxyphenyl) adenosine (IMM H007) is a new candidate compound for regulating blood cholesterol and other lipids. In this study, we conducted metagenomic and metabolomic analyses on samples from high-fat diet-fed (HFD) hamsters treated with IMM H007. Our findings revealed that IMM-H007 reversed the imbalance of gut microbiota caused by a high-fat diet. Additionally, it activated adiponectin receptor and pantothenate and CoA biosynthesis pathway-related genes, which are known to regulate lipid and glucose metabolism. Furthermore, IMM-H007 promotes cholesterol metabolism by reducing the abundance of genes and species associated with 7α-dehydroxylation and bile salt hydrolase (BSH). Metabolomics and pharmacological studies have shown that IMM-H007 effectively improved glucose and lipid metabolism disorders caused by HFD, reduced the aggregation of secondary bile acids (SBAs), significantly increased the content of hyodeoxycholic acid (HDCA), and also activated the expression of VDR in the small intestine. As a result, there was a reduction in the leakage of diamine oxidase (DAO) into the bloodstream in hamsters, accompanied by an upregulation of ZO-1 expression in the small intestine. The results suggested that IMM-H007 regulated glucose and lipid metabolism, promoted cholesterol metabolism through activating the expression of VDR, inhibiting inflammatory and improving the permeability of the intestinal barrier. Thus, our study provides new understanding of how IMM-H007 interacts with intestinal function, microbiota, and relevant targets, shedding light on its mechanism of action. [Display omitted] • IMM-H007 elicited the expression of intestinal VDR, and decreases the genes linked to 7α-dehydroxylase and bile hydrolase. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice. [Display omitted] [ABSTRACT FROM AUTHOR]

As the most widely employed artificial nanomaterials, silver nanoparticles (AgNPs) have been implicated in oxidative stress-induced liver injury. Despite these observations, the precise mechanisms underpinning AgNPs-induced hepatotoxicity have yet to be fully elucidated. This study embarked on an intersectional analysis of the GEO dataset (GSE139560), which encompassed murine liver tissues subjected to AgNPs, alongside datasets related to ferroptosis. Through this approach, three pivotal ferroptosis-associated genes (Arrdc3 , Txnip , and Egfr) were identified. Further integration with disease model analysis from GSE111407 and GSE183158 unveiled a significant association between AgNPs exposure and alterations in glucose metabolism and insulin signaling pathways, intricately linked with the identified key ferroptosis genes. This correlation fostered the hypothesis that ferroptosis significantly contributed to the hepatotoxicity triggered by AgNPs. Subsequent Gene Set Enrichment Analysis (GSEA) pointed to the activation of ferroptosis-associated pathways, specifically MAPK and PPAR, under AgNPs exposure. Examination of the miRNA-mRNA interaction network revealed co-regulated upstream miRNAs targeting these pivotal genes, establishing a nexus to ferroptosis and heightened liver susceptibility. Experimental validation employing an adult zebrafish model exposed to AgNPs from 90 to 120 dpf demonstrated elevated levels of Fe2+ and MDA in the zebrafish livers, along with conspicuous mitochondrial morphological alterations, thereby reinforcing the notion that AgNPs precipitate liver dysfunction predominantly through the induction of ferroptosis. These insights collectively underscore the role of ferroptosis in mediating the adverse effects of AgNPs on liver glucose metabolism and insulin sensitivity, culminating in liver dysfunction. Overall, these results enhance the understanding of nanomaterial-induced hepatotoxicity and inform strategies to mitigate such health risks. [Display omitted] • Arrdc3 , Txnip and Egfr were the key genes of ferroptosis under AgNPs exposure. • Ferroptosis is linked to glucose metabolism diseases and SAP from AgNPs exposure. • Ferroptosis is the mechanism of liver inflammation under AgNPs exposure in zebrafish. [ABSTRACT FROM AUTHOR]

• Nitrite exposure induce mitochondrial oxidative damage and ER stress. • Nitrite exposure disturbed glucose metabolism by modulating HIF1α-related glycogenesis and glycolysis. • Nitrite exposure perturbed lipid homeostasis via SREBP-regulated lipogenesis and PPARα-mediated lipolysis. • Fish adapted to nitrite exposure by shifting from aerobic to anaerobic glucose metabolism and prioritizing lipids for energy. Nitrite, a highly toxic environmental contaminant, induces various physiological toxicities in aquatic animals. Herein, we investigate the in vivo effects of nitrite exposure at concentrations of 0, 0.2, 2, and 20 mg/L on glucose and lipid metabolism in zebrafish. Our results showed that exposure to nitrite induced mitochondrial oxidative stress in zebrafish liver and ZFL cells, which were evidenced by increased levels of malondialdehyde (MDA) and reactive oxygen species (ROS) as well as decreased mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP). Changes in these oxidative stress markers were accompanied by alterations in the expression levels of genes involved in HIF-1α pathway (hif1α and phd), which subsequently led to the upregulation of glycolysis and gluconeogenesis-related genes (gk, pklr, pdk1, pepck, g6pca, ppp1r3cb, pgm1, gys1 and gys2), resulting in disrupted glucose metabolism. Moreover, nitrite exposure activated ERs (Endoplasmic Reticulum stress) responses through upregulating of genes (atf6, ern1 and xbp1s), leading to increased expression of lipolysis genes (pparα, cpt1aa and atgl) and decreased expression of lipid synthesis genes (srebf1, srebf2, fasn, acaca, scd, hmgcra and hmgcs1). These results were also in consistent with the observed changes in glycogen, lactate and decreased total triglyceride (TG) and total cholesterol (TC) in the liver of zebrafish. Our in vitro results showed that co-treatment with Mito-TEMPO and nitrite attenuated nitrite-induced oxidative stress and improved mitochondrial function, which were indicated by the restorations of ROS, MMP, ATP production, and glucose-related gene expression recovered. Co-treatment of TUDCA and nitrite prevented nitrite-induced ERs response and which was proved by the levels of TG and TC ameliorated as well as the expression levels of lipid metabolism-related genes. In conclusion, our study suggested that nitrite exposure disrupted hepatic glucose and lipid metabolism through mitochondrial dysfunction and ERs responses. These findings contribute to the understanding of the potential hepatotoxicity for aquatic animals in the presence of ambient nitrite. [ABSTRACT FROM AUTHOR]

The incidence of cerebral infarction triggered by abnormal glucose tolerance has increased; however, the relationship between glucose concentration in the brain and the detailed mechanism of post ischemic cell death remains unclear. Nicotinamide phosphoribosyltransferase (NAMPT), an adipocytokine, is the rate-limiting enzyme for NAD+ synthesis in the salvage pathway. Although NAMPT activation prevents neuronal injury, the relationship between NAMPT activity, glucose metabolism disorders, and cerebral ischemia-induced neuronal cell death is unknown. In this study, we determined changes in NAMPT on cerebral ischemic injuries with diabetes using a db/db mouse model of type 2 diabetes and then identified the underlying mechanisms using Neuro2a cells. The expression of inflammatory cytokine mRNAs was increased in db/db and db/+ middle cerebral artery occlusion and reperfusion (MCAO/R) mice. Although NeuN-positive cells were decreased after MCAO/R, the number of NAMPT and NeuN double-positive cells in NeuN-positive neuronal cells increased in db/db MCAO/R mice. Next, the role of NAMPT in Neuro2a cells under conditions of high glucose (HGC) and oxygen–glucose deprivation (OGD), which mimics diabetes-complicated cerebral infarction, was examined. Treatment with P7C3-A20, a NAMPT activator, suppressed the decrease in cell viability caused by HGC/OGD; however, there were no significant differences in the levels of cleaved caspase-3 and Bax proteins. Moreover, increased FoxO3a and LC3-II levels after HGC/OGD were inhibited by P7C3-A20 treatment. Our findings indicate that NAMPT activation is associated with neuronal survival under ischemic conditions with abnormal glucose tolerance through the regulation of FoxO3a/LC3. [Display omitted] • The number of NAMPT and NeuN double-positive cells was increased after stroke with diabetes. • NAMPT protein in Neuro2A cells increased only after HGC/OGD. • P7C3-A20 suppressed a decrease in cell viability induced by HGC/OGD. • LC3II and FoxO3a proteins increased after HGC/OGD, which was suppressed by P7C3-A20. [ABSTRACT FROM AUTHOR]

With the increasing prevalence of metabolic disorders, hyperglycemia has become a common risk factor that endangers people's lives and the need for new drug solutions is burgeoning. Trans-2, 4-dimethoxystilbene (TDMS), a synthetic stilbene, has been found as a novel hypoglycemic small molecule from glucose consumption test. Normal C57BL/6 J mice, mouse models of type 1 diabetes mellitus and diet-induced obesity subjected to TDMS gavage were found with lower glycemic levels and better glycemic control. TDMS significantly improved the symptoms of polydipsia and wasting in type 1 diabetic mice, and could rise their body temperature at the same time. It was found that TDMS could promote the expression of key genes of glucose metabolism in HepG2, as do in TDMS-treated liver, while it could improve the intestinal flora and relieve intestinal metabolic dysbiosis in hyperglycemic models, which in turn affected its function in the liver, forming the gut-liver axis. We further fished PPARγ by virtual screening that could be promoted by TDMS both in-vitro and in-vivo, which was regulated by upstream signaling of AMPKα phosphorylation. As a novel hypoglycemic small molecule, TDMS was proven to be promising with its glycemic improvements and amelioration of diabetes symptoms. It promoted glucose absorption and utilization by the liver and improved the intestinal flora of diabetic mice. Therefore, TDMS is expected to become a new hypoglycemic drug that acts through gut-liver axis via AMPKα-PPARγ signaling pathway in improving glycemic metabolism, bringing new hope to patients with diabetes and glucose metabolism disorders. [Display omitted] • Trans-2, 4-dimethoxystilbene (TDMS) is identified as a novel hypoglycemic small molecule. • PPARγ is the hypoglycemic target of TDMS with AMPKα-PPARγ pathway being activated in the liver. • Trans-2, 4-dimethoxystilbene improved intestinal flora and acted through the gut-liver axis. [ABSTRACT FROM AUTHOR]

Diabetes leading to brain glucose metabolism disorders and cerebrovascular complications. Fucoidan is a kind of sulfated polysaccharides which found in brown algae, has multiply bioactivities and considered to be a promising therapeutic agent. Despite the increasing amount of evidence suggesting the diabetes protective role of fucoidans, the effect of fucoidan on brain abnormalities in type 2 diabetes mellitus patients remains unclear. In this study a low molecular weight fucoidan (LMWF) was obtained from Saccharina japonica and its effect on the cerebrovascular damage in db / db mice was investigated. Results were shown after LMWF treatment, the degree of cerebrovascular damage, the number of apoptotic neuronal cells and the inflammation were all decreased in db / db mice. Moreover, LMWF could up-regulates CD34 and VEGFA expression in db / db mice brain, and the subintestinal vessel angiogenesis in zebrafish was also promoted by LMWF. Moreover, the lumen formation of HUVEC endothelial cells was rescued by LMWF which was destroyed in high glucose treated endothelial cells. Further study found, LMWF alleviates vascular injury by up-regulating the expression level of phosphorylated PI3K and phosphorylated AKT. Our study indicates that LMWF has the potential to develop a cerebrovascular protection agent for type 2 diabetes patients. • LMWF could reduce cerebrovascular damage in db / db mice. • LMWF could promote brain angiogenesis by up-regulating PI3K/AKT/VEGF signal pathway. • LMWF could protect type 2 diabetes mice brain from damage by reducing inflammation and neuron cell apoptosis. [ABSTRACT FROM AUTHOR]

Hovenia dulcis is a traditional medicinal and edible plant and has a major geographical presence in China. In this study, a polysaccharide purified from H. dulcis (HDPs-2A) was found to ameliorate type 1 diabetes mellitus (T1DM) in streptozotocin-induced diabetic rat. HDPs-2A treatment resulted in significantly lower fasting blood glucose levels, but higher body weight, plasma insulin, and liver glycogen levels. Moreover, HDPs-2A improved dyslipidemia, pancreatic oxidative stress, and reduced serum pro-inflammatory factors. In addition, HDPs-2A up-regulated PDX-1, activated and up-regulated IRS2 expression, and regulated apoptosis and regeneration of islet β cells to recover islet β-cell function injury in TIDM rats. HDPs-2A also up-regulated the expression of pancreatic GK and GLUT2 to improve insulin secretion ability of islet β-cells, ultimately improving the glucose metabolism disorder of T1DM rats. Moreover, HDPs-2A significantly up-regulated the expression of GK and down-regulated the expression of G6Pase in liver to improve liver glycogen synthesis, inhibit liver gluconiogenesis, and improve liver glucose metabolism disorder of T1DM rats. In summary, the hypoglycemic mechanisms of HDPs-2A may include regulating the regeneration and apoptosis of islet β-cells and activating liver glycometabolism-related signaling pathways in T1DM rats. • HDPs-2A significantly reduced fasting blood glucose in T1DM rats. • HDPs-2A can reduce symptoms of diabetes by regulating the apoptosis and regeneration of islet β-cells. • HDPs-2A can reduce symptoms of diabetes by regulating glucose metabolic pathway. [ABSTRACT FROM AUTHOR]

As one of the most serious microvascular complications of diabetes mellitus (DM), diabetic retinopathy (DR) can cause visual impairment and even blindness. With the rapid increase in the prevalence of DM, the incidence of DR is also rising year by year. Preventing and effectively treating DR has become a major focus in the medical field. Traditional Chinese medicine (TCM) has a wealth of experience in treating DR and has achieved significant results with various herbs and TCM prescriptions. Traditional Chinese Medicine (TCM) provides a comprehensive therapeutic strategy for diabetic retinopathy (DR), encompassing anti-inflammatory and antioxidant actions, anti-neovascularization, neuroprotection, regulation of glucose metabolism, and inhibition of apoptosis. This review provides an overview of the current status of TCM treatment for DR in recent years, including experimental studies and clinical researches, to explore the clinical efficacy and the underlying modern mechanisms of herbs and TCM prescriptions. Besides, we also discussed the challenges TCM faces in treating DR, such as drug-drug interactions among TCM components and the lack of high-quality evidence-based medicine practice, which pose significant obstacles to TCM's application in DR. [Display omitted] • Traditional Chinese medicine (TCM) has potential therapeutic effects in the treatment of diabetic retinopathy (DR). • This review aims to provide a guidance for clinical application of TCM strategies in DR. [ABSTRACT FROM AUTHOR]

Mailuo Shutong Pill (MLST), a traditional Chinese medicine (TCM), has been widely used for clearing heat and detoxifying, eliminating stasis and dredging meridians, dispelling dampness and diminishing swelling. Earlier study found that MLST could improve cerebral ischemic-reperfusion injury, however, the potential mechanism has not been well evaluated. In this study, a well established and widely used mice model of middle cerebral artery occlusion/reperfusion (MCAO/R) was preformed to evaluate the protective function of MLST on cerebral ischemic-reperfusion injury and further discuss the potential pharmacological mechanisms. Chemical profiling of MLST was analyzed based on Ultra-high-performance liquid chromatography electrospray ionization orbitrap tandem mass spectrometry. ICR mice were challenged by MCAO/R surgery. The protective effect of MLST on MCAO/R injury was evaluated by neurological deficit score, cerebral infarct rate, brain water content, H&E and nissl staining. The blood-brain barrier (BBB) integrity was detected by Evans blue staining. The potential pharmacological mechanism of MLST in treating MCAO/R injury was further elucidated by the methods of proteomics, central carbon targeted metabolomics, as well as Western blot. Immunohistochemistry was used to detect the microglia infiltration, enzyme linked immunosorbent assay (ELISA) kit was explored to evaluate the content of IL-1β, TNF-α and IL-6 in brain tissue, and Western blot was used to detect proteins expression in brain tissue. A total of 76 chemical compounds have been determined in MLST. MLST effectively protected mice from MCAO/R injury, which was confirmed by lower neurological deficit score, cerebral infarct rate, brain water content and nissl body loss, and improved brain pathology. Meanwhile, MLST upregulated the expression of ZO-1, Occludin and Claudin 5 by downregulating the ratio of TIMP1/MMP9 to suppress the entrance of Evans blue to brain tissue, indicating that MLST maintained the integrity of BBB. Further studies indicated that MLST inhibited the inflammatory level of brain tissue by inhibiting microglia infiltration and downregulating NLRP3 inflammasome signaling pathway. The results of proteomics, Western blot, and central carbon targeted metabolomics confirmed that MLST regulated Glycolysis/Gluconogenesis, Pyruvate metabolism and TCA cycle in brain tissue of mice with MCAO/R. MLST inhibits neuroinflammation by regulating glucose metabolism disorders to interfere with immune metabolism reprogramming and inhibit the NLRP3 inflammasome signaling pathway, and finally improve cerebral ischemia-reperfusion injury. This study confirms that MLST is a potential drug for treating Cerebral ischemic stroke. [Display omitted] • Mailuo Shutong Pill (MLST) alleviates cerebral ischemia-reperfusion injury (I/R). • MLST induces regression of I/R by inhibiting neuroinflammation. • MLST regulates the glucose metabolism disorders in mice with MCAO/R. [ABSTRACT FROM AUTHOR]

Quercetin and its glycosides (QG), vitally natural flavonoid, have been popular for health benefits. However, the absorption and metabolism affect their bioavailability, and the metabolic transformation alters their biological activities. This review systematically summarizes the bioavailability and pathways for the absorption and metabolism of quercetin/QG in vivo and in vitro, the biological activities and mechanism of quercetin/QG and their metabolites in treating glucolipid metabolism are discussed. After oral administration, quercetin/QG are mainly absorbed by the intestine, undergo phase II metabolism in the small intestine and liver to form conjugates and are metabolized into small phenolic acids by intestinal microbiota. Quercetin/QG and their metabolites exert beneficial effects on regulating glucolipid metabolism disorders, including improving insulin resistance, inhibiting lipogenesis, enhancing thermogenesis, modulating intestinal microbiota, relieving oxidative stress, and attenuating inflammation. This review enhances understanding of the mechanism of quercetin/QG regulate glucolipid metabolism and provides scientific support for the development of functional foods. Systematically summarized the bioavailability, absorption and metabolism of quercetin and its glycosides, and their effects and mechanism of regulating glucolipid metabolism disorders. [Display omitted] • Factors affected the bioavailability of quercetin and its important glycosides (QG) were reported. • Elucidated the absorption, metabolism, and excretion pathway of quercetin/QG. • Quercetin/QG and their metabolites played a crucial role in attenuating glucose and lipid metabolism disorders. [ABSTRACT FROM AUTHOR]

Paramylon is a polysaccharide primarily composed of β-1,3-glucan, characterized by its high crystallinity and insolubility in water. Enhancing its water solubility through structural modifications presents an effective strategy to unlock its biological activity. In this study, carboxymethylation was employed to produce carboxymethylated paramylon (CEP) with varying carboxyl concentrations. The successful introduction of carboxyl groups led to a notable improvement in water solubility. In vivo experiments demonstrated that CEP reduced fasting blood glucose levels by 24.42 %, improved oral glucose tolerance, and enhanced insulin sensitivity in diabetic mice. Additionally, CEP regulated lipid homeostasis and ameliorated liver damage. Through modulation of the adenosine monophosphate-activated protein kinase/phosphoinositide 3-kinase/protein kinase B pathway and the glucose-6-phosphatase/phosphoenolpyruvate carboxykinase pathway, CEP effectively regulated hepatic glucose absorption and production. Furthermore, CEP mitigated diabetes-induced lipid metabolism disorders. These findings suggest that CEP holds significant promise in ameliorating glucose metabolism disorder, indicating its potential as a novel hypoglycemic functional food. [Display omitted] • Carboxymethylated paramylon (CEP) was synthesized to enhance its water solubility. • CEP lower fasting blood glucose and triglyceride in T2DM mice. • CEP's hypoglycemic efficacy correlates with carboxymethylation degree. [ABSTRACT FROM AUTHOR]

Inhibition of carbohydrate digestive enzymes is a key focus across diverse fields, given the prominence of α-glucosidase inhibitors as preferred oral hypoglycaemic drugs for diabetes treatment. β-conglycinin is the most abundant functional protein in soy; however, it is unclear whether the peptides produced after its gastrointestinal digestion exhibit α-glucosidase inhibitory properties. Therefore, we examined the α-glucosidase inhibitory potential of soy peptides. Specifically, β-conglycinin was subjected to simulated gastrointestinal digestion by enzymatically cleaving it into 95 peptides with gastric, pancreatic and chymotrypsin enzymes. Eight soybean peptides were selected based on their predicted activity; absorption, distribution, metabolism, excretion and toxicity score; and molecular docking analysis. The results indicated that hydrogen bonding and electrostatic interactions play important roles in inhibiting α-glucosidase, with the tripeptide SGR exhibiting the greatest inhibitory effect (IC 50 = 10.57 μg/mL). In vitro studies revealed that SGR markedly improved glucose metabolism disorders in insulin-resistant HepG2 cells without affecting cell viability. Animal experiments revealed that SGR significantly improved blood glucose and decreased maltase activity in type 2 diabetic zebrafish larvae, but it did not result in the death of zebrafish larvae. Transcriptomic analysis revealed that SGR exerts its anti-diabetic and hypoglycaemic effects by attenuating the expression of several genes, including Slc2a1 , Hsp70 , Cpt2 , Serpinf1 , Sfrp2 and Ggt1a. These results suggest that SGR is a potential food-borne bioactive peptide for managing diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel hypoglycemic peptide, AADTDYRFS (AS-9), was identified in ripened pu-erh tea. • The hypoglycemic mechanism was analyzed through molecular docking, dynamic simulation, and cell experiments. • Hydrogen bonding and hydrophobic interactions drive the binding of AS-9 to α-glucosidase. • AS-9 increases glucose consumption in insulin-resistant HepG2 cells. • The hypoglycemic mechanism of AS-9 involves the activation of the IRS-1/PI3K/Akt signaling pathways. Ripened pu-erh tea is known to have beneficial hypoglycemic properties. However, it remains unclear whether the bioactive peptides produced during fermentation are also related to hypoglycemic potential. This study aimed to identify hypoglycemic peptides in ripened pu-erh tea and to elucidate their bioactive mechanisms using physicochemical property prediction, molecular docking, molecular dynamics simulations, and cell experiments. Thirteen peptides were identified by liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS). Among them, AADTDYRFS (AS-9) and AGDGTPYVR (AR-9) exhibited high α-glucosidase inhibitory activity, with half-maximal inhibitory concentration (IC 50) values of 0.820 and 3.942 mg/mL, respectively. Molecular docking and dynamics simulations revealed that hydrogen bonding, hydrophobic interactions, and van der Waals forces assist peptides AS-9 and AR-9 in forming stable and tight complexes with α-glucosidase. An insulin-resistance (IR)-HepG2 cell model was established. AS-9 was non-toxic to IR-HepG2 cells and significantly increased the glucose consumption capacity, hexokinase, and pyruvate kinase activities of IR-HepG2 cells (p < 0.05). AS-9 alleviated glucose metabolism disorders and ameliorated IR by activating the IRS-1/PI3K/Akt signaling pathway and increasing the expression levels of MDM2 , IRS-1 , Akt , PI3K , GLUT4 , and GSK3β genes. In addition, no hemolysis of mice red blood cells red blood cells occurred at concentrations below 1 mg/mL. This work first explored hypoglycemic peptides in ripened pu-erh tea, providing novel insights for enhancing its functional value. [ABSTRACT FROM AUTHOR]

Diameter, plaque score, and resistance index (RI) in the common carotid artery (CCA) are indicators of arterial remodeling, atherosclerosis, and vascular resistance, respectively. This study investigated the longitudinal association between adipose tissue insulin resistance or serum free fatty acid (FFA) levels and the CCA parameters. This retrospective cohort analysis included 1089 participants (mean age 57.6 years; 40.0 % women) with data on health checkups from January 1982 to March 2003 and carotid artery ultrasonography from January 2015 to June 2019. Baseline serum FFA and immunoreactive insulin levels were assessed before and 30, 60, and 120 min after glucose ingestion. Adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and FFA levels. An RI value >0.75 was defined as high RI. A significant association was found between Adipo-IR and RI; however, Adipo-IR showed no association with CCA diameter or plaque score. The incidence of high RI increased with Adipo-IR quartile (Q) groups (47.3 % in Q1, 52.8 % in Q2, 53.3 % in Q3, 62.4 % in Q4; Cochrane–Armitage test for trend, p < 0.001). In multivariate analysis, Adipo-IR levels (Q4 vs. Q1 odds ratio: 1.67, 95 % confidence interval: 1.12–2.51) were positively associated with high RI incidence. Moreover, a significant association was found between RI and serum FFA levels after glucose intake, but not fasting FFA levels. Future vascular resistance was predicted by insulin resistance in the adipose tissue. After glucose intake, serum FFA levels may significantly impact vascular resistance development. [Display omitted] • Adipo-IR is a valid indicator of insulin resistance in the adipose tissue. • Resistance index (RI) in the carotid artery reflects vascular resistance. • Adipo-IR predicted future increased RI. • Serum FFA levels after glucose intake were associated with increased RI. [ABSTRACT FROM AUTHOR]

The increasing side effects of traditional medications used to treat type II diabetes have made research into the development of safer and more effective natural medications necessary. ACT001, a derivative of parthenolide, has been shown to have good anti-inflammatory and antitumor effects; however, its role in diabetes is unclear. The short-chain fatty acid propionate is a common food preservative that has been found to cause disturbances in glucose metabolism in mice and humans. This study aimed to investigate whether sodium propionate could aggravate insulin resistance in obese mice and cause diabetes and to study the alleviative effects and potential mechanisms of action of ACT001 on insulin resistance in diabetic mice. Type II diabetic mice were adminietered sodium propionate combined with a high-fat diet (HFD + propionate) by gavage daily for four weeks. Biochemical analysis showed that ACT001 significantly affected blood glucose concentration in diabetic mice, mainly by downregulating the expression of phosphoenolpyruvate carboxykinase 2 and glucose-6-phosphatase. Meanwhile, the level of fatty acid-binding protein 4 in the liver was significantly decreased. ACT001 has a protective effect on the liver and adipose tissue of mice. In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs. [Display omitted] • Sodium propionate aggravates glucose metabolism disorder in obese mice and eventually causes diabetes. • ACT001 improves glucose tolerance and reduces insulin resistance in T2DM mice. • ACT001 inhibits the expression of liver gluconeogenesis genes and reduces fasting blood glucose concentration in T2DM mice. • ACT001 affects the expression of clock genes and enhances the motor activity of T2DM mice. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. Retinoid-interferon-induced mortality 19 (GRIM19) is a functional component of mitochondrial complex I that plays a role in cellular energy metabolism. However, the role of GRIM19 in the pathogenesis of PCOS is still unclear. To investigate the role of GRIM19 in the pathogenesis of PCOS. We first measured the expression of GRIM19 in human granulosa cells (hGCs) from patients with and without PCOS (n = 16 per group), and then established a PCOS mouse model with WT and Grim19 +/− mice for in vivo experiments. Glucose uptake-related genes RAC1 and GLUT4 and energy metabolism levels in KGN cells were examined in vitro by knocking down GRIM19 in the cell lines. Additionally, ovulation-related genes such as p- ERK1/2, HAS2, and PTX3 were also studied to determine their expression levels. GRIM19 expression was reduced in hGCs of PCOS patients, which was negatively correlated with BMI and serum testosterone level. Grim19 +/− mice with PCOS exhibited a markedly anovulatory phenotype and disturbed glycolipid metabolism. In vitro experiments, GRIM19 deficiency inhibited the RAC1/GLUT4 pathway, reducing insulin-stimulated glucose uptake in KGN cells. Moreover, GRIM19 deficiency induced mitochondrial dysfunction, defective glucose metabolism, and apoptosis. In addition, GRIM19 deficiency suppressed the expression of ovulation-related genes in KGN cells, which was regulated by dihydrotestosterone mediated androgen receptor. GRIM19 deficiency may mediate ovulation and glucose metabolism disorders in PCOS patients. Our results suggest that GRIM19 may be a new target for diagnosis and treatment. • Metabolism disorders, hyperandrogenism, and anovulation are characteristics of PCOS. • Grim19 +/− mice with PCOS exhibit significant anovulatory and metabolism disorders. • GRIM19 deficiency induces impaired glucose uptake in granulosa cells via RAC1/GLUT4. • GRIM19 depletion inhibits the expression of ovulation-related genes by ERK signaling. • Dihydrotestosterone can decrease the expression of GRIM19 via the androgen receptor. [ABSTRACT FROM AUTHOR]

Brain atrophy is related to vascular risk factors and can increase cognitive dysfunction risk. This community-based, cross-sectional study investigated whether glucose metabolic disorders due to body fatness are linked to regional changes in brain structure and a decline in neuropsychological function in cognitively healthy older adults. From 2016 to 2019, 429 participants underwent measurements for cortical thickness and subcortical volume using 3 T magnetic resonance imaging and for cognitive function using the neuropsychological screening battery. The effects of body fatness mediated by impaired glucose metabolism on neuroimaging markers and cognitive function was investigated using partial least square structural equation modeling. Total grey matter volume (β = −0.020; bias-corrected (BC) 95% confidence interval (CI) = -0.047 to −0.006), frontal (β = −0.029; BC 95% CI = −0.063 to −0.005) and temporal (β = −0.022; BC 95% CI = −0.051 to −0.004) lobe cortical thickness, and hippocampal volume (β = −0.029; BC 95% CI = −0.058 to −0.008) were indirectly related to body fatness. Further, frontal/temporal lobe thinning was associated with recognition memory (β = −0.005; BC 95% CI = −0.012 to −0.001/β = −0.005; BC 95% CI = −0.013 to −0.001) and delayed recall for visual information (β = −0.005; BC 95% CI = −0.013 to −0.001/β = −0.005; BC 95% CI = −0.013 to −0.001). Additionally, the smaller the hippocampal volume, the lower the score in recognition memory (β = −0.005; BC 95% CI = −0.012 to −0.001), delayed recall for visual information (β = −0.005; BC 95% CI = −0.012 to −0.001), and verbal learning (β = −0.008; BC 95% CI = −0.017 to −0.002). Our findings indicate that impaired glucose metabolism caused by excess body fatness affects memory decline as well as regional grey matter atrophy in elderly individuals with no neurological disease. • Partial least squares path modeling was tested among the cognitively intact elderly. • Body fatness is associated with brain atrophy via impaired glucose metabolism (IGM). • Body fatness relates to memory functions via IGM & observed regional atrophy. [ABSTRACT FROM AUTHOR]

Relationship between physical activity and fasting glucose in people with abnormal glucose metabolism is not well-known. This study was to investigate dose–response association between physical activity (PAT) and fasting glucose from two independent surveys among Chinese adults with abnormal glucose metabolism. 9419 adults with abnormal glucose metabolism from two independent surveys among Chinese adults were analyzed. Demographics, level of fasting glucose and PAT (in Met Score) were measured. Dose-response relationship between fasting glucose and PAT was assessed by natural cubic spline model. Certain threshold point was identified, and linear regression models were then used within each threshold interval to assess the liner relationship functions. Models were adjusted for confounding factors and were stratified in subgroup analyses by the main population characteristics including survey site, gender and age-group. Overall the relationship between PAT and fasting glucose was not in a linear association (Linearity test: p < 0.0001). Level of fasting glucose was not associated with amount of PAT until a threshold point (square-rooted Met Score 66.6 (original Met score: 4436 MET-minutes per week), 95% confidence intervals (65.2–69.3 (4,251−4,802 MET-minutes per week)). After this threshold, an inverse association was observed: each increase of every standard deviation of square-rooted Met Score 29.8 (888 MET-minutes per week) was associated with a 0.25 mmol/L decrease in fasting glucose, with adjustment for confounding factors. The patterns of relationship were tested to be consistent in subgroup analyses by survey site, gender and age group. Our study indicated that among adults with abnormal glucose metabolism the level of fasting glucose was only inversely associated with square-rooted Met Score beyond a certain square-rooted Met Score amount. [ABSTRACT FROM AUTHOR]

Diabetes during pregnancy is associated with an increased risk of foetal and neonatal complications and long-term complications in the offspring. Brain-derived neurotrophic factor (BDNF), a neurotrophin that has a crucial role in neurogenesis modulation and neural pathway maturation during neurodevelopment, may have a role in protecting neurons against injury and diseases by modulating glucose metabolism. The aim of this study was to investigate the possible relationship between the serum BDNF levels of infants of mothers with gestational diabetes (IMGD) and neurodevelopmental outcomes of the children after birth. A total of 24 candidates, including 8 IMGD and 16 healthy infants, were recruited for the study. Medical records were reviewed. Serum BDNF levels of the study participants were collected at birth and at 6 and 12 months of age. Developmental outcomes of each candidate were assessed using the Bayley Scales of Infant Development III (BSID III) at 6 and 12 months of corrected age. Compared to non-IMGD, IMGD had greater mean body weight (p = 0.04) and height (p < 0.01) at age 12 months. The language composite score was significantly lower in IMGD at 12 months of age (p = 0.038). The BDNF content was significantly higher in the non-IMGD than in the IMGD group at 12 months of age (p = 0.013). In this study, we demonstrated that infants of mothers with gestational diabetes do worse in language development and have lower BDNF levels at 12 months of age. There may be a close correlation between language outcomes and serum BDNF levels at 12 months of age. A follow-up study on future developmental status is warranted. [ABSTRACT FROM AUTHOR]

• We report the prevalence of abnormal glucose and lipid metabolism in pediatric SMA. • Insulin resistance, hyperglycemia, dyslipidemia, and fatty liver may occur in SMA. • Overweight/obese non-ambulatory SMA patients are particularly at risk. • Young underweight children with SMA might develop fasting hypoglycemia. We aimed to estimate the prevalence of glucose and lipid metabolism disorders in children and adolescents with spinal muscular atrophy (SMA) types 2 and 3. A cross-sectional study was conducted. Medical history, anthropometric measurements, pubertal status, blood chemistry (glucose and insulin levels, lipid profile, aminotransferases, and hemoglobin A1c [HbA1c]), and liver ultrasound were obtained in all patients. Oral glucose tolerance test was performed in those with body mass index (BMI) >25th percentile or glucose or HbA1c levels in the prediabetic range. A total of 37 patients with SMA (22 type 2, 15 type 3) with a median age of 8.5 years (range 2–18.9 years) were included. Eleven patients (29.7%) met the criteria for prediabetes, but none had overt type 2 diabetes. Dyslipidemia was detected in 11 patients (29.7%), and 4 (10.8%) had hepatic steatosis on ultrasound. Sixteen patients (43.2%) had at least one abnormal finding (prediabetes, dyslipidemia, or hepatic steatosis); all but one were non-ambulatory and 12 (75%) had BMI ≥85th percentile. One young child developed fasting hypoglycemia. Our results suggest that non-ambulatory overweight/obese SMA patients are particularly prone to abnormalities in glucose and lipid metabolism. Young underweight patients might develop fasting hypoglycemia. [ABSTRACT FROM AUTHOR]

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α , thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure. [Display omitted] • Intrauterine arsenic exposure causes disorders of glucose tolerance and insulin resistance in adult offspring. • Intrauterine arsenic exposure causes DNA hydroxymethylation reprogramming of HNF4α by reducing the TET2 levels in livers. • Arsenic reduces the stability of TET2 by binding to it. • Supplementation of AA during gestation alleviates arsenic-induced disorders of glucose metabolism in adult offspring. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy (NE) is a diagnosis that is usually unexpected. Though there are many risk factors for the condition and multiple theories as to its genesis, the majority of cases cannot be predicted prior to the occurrence of the clinical syndrome. Indeed, it is common for a pregnant person to have multiple risk factors and a completely healthy child. Conversely, people with seemingly no risk factors may go on to have a profoundly affected child. In this synopsis we review risk factors, potential mechanisms for encephalopathy, the complicated issue of choosing which morbidity to take on and how the maternal level of care may influence outcomes. The reader should be able to better understand the limitations of current testing and the profound levels of maternal intervention that have been undertaken to prevent or mitigate the rare, but devastating occurrence of NE. Further, we suggest candidate future approaches to prevent the occurrence, and decrease the severity of NE. Any future improvements in the NE syndrome cannot be achieved via obstetric intervention and management alone or conversely, by improvements in treatments offered post-birth. Multidisciplinary approaches that encompass prepregnancy health, pregnancy care, intrapartum management and postpartum care will be necessary. [ABSTRACT FROM AUTHOR]

Phthalic acid esters (PAEs) are environmental endocrine disruptors thought to interfere with glucose metabolism in humans. Most of the related research has focused on population epidemiological studies, with the underlying mechanisms remaining unresolved. Using an in vivo animal model, we examined the effects of oral administration of two commonly used PAEs [di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP)] on glucose homeostasis and insulin secretion. DEHP (750 mg/kg, 1/40 LD 50), DBP (500 mg/kg, 1/40 LD 50), and DEHP (750 mg/kg) + DBP (500 mg/kg) exert an influence on glucose metabolism and elicit a reduction in insulin sensitivity in rats. Furthermore, these substances induce detrimental effects on the structure and functionality of pancreatic β-cells. DEHP and/or DBP triggered an increase in plasma malondialdehyde (MDA) and reduction in superoxide dismutase (SOD) activity; a reduction in the phosphorylation of phosphatidyl inositol 3 kinase (PI3K) and phospho-protein kinase B (p-Akt473) proteins; an increase in the relative expression of Bax, Caspase-8, cleaved-Caspase-9, and cleaved-Caspase-3; and a reduction in the relative expression of Bcl-2-related Bax in pancreatic tissue and of gastrocnemius glucose transporter 4 (GLUT4) in the gastrocnemius muscle. Based on these findings, these PAEs can disrupt glucose metabolism, possibly via oxidative damage of the PI3K/Akt/GLUT4 pathway; this damage induces pancreatic β-cell apoptosis, affects pancreatic β-cell function, and affects glucose metabolism and insulin resistance in rats. To the best of our knowledge, this study was the first to show that the combined effect of the two PAEs affects glucose metabolism and insulin resistance in rats that is significantly higher than the effects of each PAE. Thus, safety standards and studies do not consider this effect as a significant oversight when blending PAEs. We assert that this must be addressed and corrected for establishing more impactful and safer standards. [Display omitted] • Typical phthalic acid esters (PAEs) can cause glucose metabolism disorders in rats. • PI3K/Akt/GLUT4 is involved in the disorders of rats exposed to typical PAEs. • A combination of typical PAEs caused more pronounced effects than single PAEs. • Typical PAEs are risk factor to induce type-2 diabetes. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease is one of the complications of diabetes mellitus, which can eventually progress to end-stage kidney disease. The increasing prevalence of diabetic kidney disease has brought huge economic burden to society and seriously jeopardized public health. Ferroptosis is an iron-dependent, non-apoptosis-regulated form of cell death. The regulation of ferroptosis involves different molecular mechanisms and multiple cellular metabolic pathways. In recent years, ferroptosis has been proved to be closely related to the occurrence and development of diabetic kidney disease, and can interact with pathological changes such as fibrosis, inflammation, oxidative stress, and disorders of glucose and lipid metabolism, destroying the structure, form and function of the inherent cells of the kidney, and promoting the progression of the disease. Traditional Chinese medicine has a long history of treating diabetic kidney disease with remarkable curative effect. Current scholars have shown that the oral administration of traditional Chinese medicine and the external treatment of Chinese medicine can regulate GPX4, Nrf2, ACSL4, PTGS2, TFR1 and other key signaling molecules, curb ferroptosis, and prevent the progressive deterioration of diabetic kidney disease. In this paper, the mechanism of ferroptosis and diabetic kidney disease and the prevention and treatment of traditional Chinese medicine are analyzed and summarized, in order to provide new ideas and new plans for the treatment of diabetic kidney disease. • Diabetes kidney disease can develop to end-stage kidney disease. • Ferroptosis may play a role as a facilitator in diabetic kidney disease. • Traditional Chinese medicine is an important means to treat diabetes kidney disease. • Traditional Chinese medicine intervenes in the process of ferroptosis in various ways. [ABSTRACT FROM AUTHOR]

Maternal high-fat diet (HFD) is related to an increased risk of glucose metabolism disorders throughout the whole life of offspring. The pancreas is a glucose homeostasis regulator. Accumulating evidence has revealed that maternal HFD affects offspring pancreas structure and function. However, the potential mechanism remains unclear. In this study, the mouse dam was fed with HFD or control diet (CD) during prepregnancy, pregnancy and lactation. The pancreatic insulin secretion function and islet genome methylome of offspring were analyzed. Pancreatic islet specific gene methylation was detected by using MeDIP qPCR. The results showed that body weight, blood glucose after oral glucose loads, fasting serum insulin, and HOMA-IR index values were significantly higher in male 12-week-old offspring from HFD dams than in the offspring from CD dams. Maternal HFD induced insulin secretion defects in male offspring. Compared with that in maternal CD group, methylation of the Abcc8 and Kcnj11 genes was increased in maternal HFD group in male offspring pancreatic islets. Furthermore, the expression levels of Abcc8 and Kcnj11 were downregulated by intrauterine exposure to a maternal HFD. In summary, maternal HFD results in a long-term functional disorder of the pancreas that is involved in insulin secretion-related gene DNA hypermethylation. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic and endocrine disorder characterised by hyperglycaemia. Type 2 diabetes mellitus accounts for >90% of people with diabetes. Disorders of blood glucose metabolism and a series of adverse reactions triggered by hyperglycaemia-such as oxidative stress and inflammation-are conducive to the occurrence of diabetic macrovascular complications, which pose severe challenges to the quality of life and life expectancy of people with diabetes. In recent years, epigenetics has attracted more and more researchers' attention as they explore the causes and treatment of diabetes. Epigenetics refers to the regulation of gene expression without changes in gene content. Research focusses on DNA methylation, histone post-translational modification and non-coding RNA. A series of studies have shown that epigenetic regulation accelerates the development of atherosclerosis by interfering with the physiological activities of macrophages, endothelial cells and smooth muscle cells, such as inflammation, lipid deposition and apoptosis. Therefore, it is particularly important to explore new epigenetic discoveries to reduce the severity and harmfulness of diabetes. This study reviewed recent advances in epigenetics in the pathogenesis of diabetes mellitus and its macrovascular complications. [ABSTRACT FROM AUTHOR]

TGR5, a G protein-coupled bile acid receptor, is expressed in various tissues and regulates several physiological processes. In the skeletal muscle, TGR5 activation is known to induce muscle hypertrophy; however, the effects on glucose and lipid metabolism are not well understood, despite the fact that the skeletal muscle plays a major role in energy metabolism. Here, we demonstrate that skeletal muscle-specific TGR5 transgenic (Tg) mice exhibit increased glucose utilization, without altering the expression of major genes related to glucose and lipid metabolism. Metabolite profiling analysis by capillary electrophoresis time-of-flight mass spectrometry showed that glycolytic flux was activated in the skeletal muscle of Tg mice, leading to an increase in glucose utilization. Upon long-term, high-fat diet challenge, blood glucose clearance was improved in Tg mice without an accompanying increase in insulin sensitivity in skeletal muscle and a reduction of body weight. Moreover, Tg mice showed improved age-associated glucose intolerance. These results strongly suggest that TGR5 ameliorated glucose metabolism disorder that is caused by diet-induced obesity and aging by enhancing the glucose metabolic capacity of the skeletal muscle. Our study demonstrates that TGR5 activation in the skeletal muscle is effective in improving glucose metabolism and may be beneficial in developing a novel strategy for the prevention or treatment of hyperglycemia. [ABSTRACT FROM AUTHOR]

Programmed cell death factor 4 (PDCD4) is originally described as a tumor suppressor gene that exerts antineoplastic effects by promoting apoptosis and inhibiting tumor cell proliferation, invasion, and metastasis. Several investigations have probed the aberrant expression of PDCD4 with the progression of metabolic diseases, such as polycystic ovary syndrome (PCOS), obesity, diabetes, and atherosclerosis. It has been ascertained that PDCD4 causes glucose and lipid metabolism disorders, insulin resistance, oxidative stress, chronic inflammatory response, and gut flora disorders to regulate the progression of metabolic diseases. This review aims to summarize the latest researches to uncover the structure, expression regulation, and biological functions of PDCD4 and to elucidate the regulatory mechanism of the development of tumors and metabolic diseases. This review has emphasized the understanding of the PDCD4 role and to provide new ideas for the research, diagnosis, and treatment of tumors and metabolic diseases. Image 1 • PDCD4 inhibits the progression of tumors by influencing apoptosis, cell proliferation, invasion and metastasis. • PDCD4 is involved in glucolipid metabolism, insulin resistance, inflammatory response and intestinal flora disorders. • The abnormal expression of PDCD4 aggravates metabolic diseases, such as PCOS, obesity, diabetes and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background Obese children are vulnerable to vitamin D deficiency and impaired cardiovascular health; vitamin D replenishment might improve their cardiovascular health. Objectives The aims were to determine, in vitamin D–deficient overweight and obese children, whether supplementation with vitamin D3 1000 or 2000 IU/d is more effective than 600 IU/d in improving arterial endothelial function, arterial stiffness, central and systemic blood pressure (BP), insulin sensitivity (1/fasting insulin concentration), fasting glucose concentration, and lipid profile and to explore whether downregulation of adipocytokines and markers of systemic inflammation underlies vitamin D effects. Methods We conducted a randomized, double-masked, controlled clinical trial in 225 10- to 18-y-old eligible children. Change in endothelial function at 6 mo was the primary outcome. Results Dose–response increases in serum 25-hydroxyvitamin D concentrations were significant and tolerated without developing hypercalcemia. Changes at 3 and 6 mo in endothelial function, arterial stiffness, systemic-systolic BP, lipids, and inflammatory markers did not differ between children receiving 1000 or 2000 IU vitamin D and children receiving 600 IU. Some secondary outcomes differed between groups. Compared with the 600-IU group, central-systolic, central-diastolic, and systemic-diastolic BP was lower at 6 mo in the 1000-IU group [−2.66 (95% CI: −5.27, −0.046), −3.57 (−5.97, −1.17), and −3.28 (−5.55, −1.00) mm Hg, respectively]; insulin sensitivity increased at 3 and 6 mo and fasting glucose concentration declined at 6 mo (−2.67; 95% CI: −4.88, −0.46 mg/dL) in the 2000-IU group. Conclusions Correction of vitamin D deficiency in overweight and obese children by vitamin D3 supplementation with 1000 or 2000 IU/d versus 600 IU/d did not affect measures of arterial endothelial function or stiffness, systemic inflammation, or lipid profile, but resulted in reductions in BP and fasting glucose concentration and in improvements in insulin sensitivity. Optimization of children's vitamin D status may improve their cardiovascular health. This trial was registered at clinicaltrials.gov as NCT01797302. [ABSTRACT FROM AUTHOR]

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review. [ABSTRACT FROM AUTHOR]

Background and Aims: Data on the prospective relationship of alcohol consumption at more moderate levels with systolic and diastolic function are scarce. We aimed to examine the prospective association of alcohol consumption with echocardiographic measures of cardiac structure and function, in individuals with and without type 2 diabetes (T2DM).Methods and Results: We included 778 participants from the Hoorn Study (aged 68.4 ± 7.2 years, 49% women), a population-based prospective cohort study, oversampled for people with impaired glucose metabolism or T2DM. Self-reported alcohol consumption was collected at baseline with a validated food-frequency questionnaire and categorized into: none (0/week), light (>0-≤30 g/week), light-to-moderate (>30-≤70 g/week), moderate (>70-≤140 g/week), and heavy drinkers (>140 g/week). Echocardiography was performed at baseline (N = 778) and after 8 years follow-up (N = 404). Multiple linear regression was used to study the association between alcohol consumption and echocardiographic measures (left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and left ventricular mass index (LVMI)), adjusted for confounders. Moderate and heavy alcohol consumption were associated with a decreased LVEF of -3.91% (CI: -7.13;-0.69) for moderate and -4.77% (-8.18;-1.36) for heavy drinkers compared to light drinkers. No associations were found between alcohol consumption, LVMI and LAVI. Modified Poisson regression showed a trend that higher alcohol consumption amounts were associated with a higher risk of incident systolic dysfunction (LVEF≤50%) (P-for-trend 0.058).Conclusion: The findings provide longitudinal evidence that moderate and heavy alcohol consumption are associated with decreased LVEF and trend towards a higher risk of incident LV systolic dysfunction, compared to light drinkers. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is one of the most common infectious pathogen and associated with significant morbidity and mortality. Although processing the IAV hemagglutinin (HA) envelope glycoprotein precursor is a pre-requisite for viral membrane fusion activity, viral entry and transmission, HA-processing protease is not encoded in the IAV genome and thus the cellular trypsin-type serine HA-processing proteases determine viral infectious tropism and viral pathogenicity. The initial process of IAV infection of the airway is followed by marked upregulation of ectopic trypsin in various organs and endothelial cells through the induction of various proinflammatory cytokines, and this process has been termed the "influenza virus−cytokine−trypsin" cycle. In the advanced stage of IAV infection, the cytokine storm induces disorders of glucose and lipid metabolism and the "metabolic disorders−cytokine" cycle is then linked with the "influenza virus−cytokine−trypsin" cycle, to advance the pathogenic process into energy crisis and multiple organ failure. Application of protease inhibitors and treatment of metabolic disorders that break these cycles and their interconnection is therefore a promising therapeutic approach against influenza. This review discusses IAV pathogenicity on trypsin type serine HA-processing proteases, cytokines, metabolites and therapeutic options. • Cellular influenza hemagglutinin-processing proteases determine infectious tropism. • Limited secretory and membrane-bound trypsin-like proteases participate viral entry. • Upregulated trypsin after influenza virus infection enhances viral pathogenicity. • Influenza virus–cytokine–trypsin cycle interconnects with metabolic disorder. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic disease caused by disorders of insulin secretion and utilization. Long-term hyperglycemia, insulin resistance, and disorders of glucose and lipid metabolism cause vascular endothelial cell damage. Endothelial dysfunction is a key feature of diabetic vascular complications such as diabetic nephropathy, retinopathy, neuropathy, and atherosclerosis. Importantly, cell death is thought to be a key factor contributing to vascular endothelial injury. Morphologically, cell death can be divided into three forms: type I apoptosis, type II autophagy, and type III necrosis. According to the difference in function, cell death can be divided into accidental cell death (ACD) and regulated cell death (RCD). RCD is a controlled process involving numerous proteins and precise signaling cascades. Multiple subroutines covered by RCD may be involved in diabetic endothelial dysfunction, including apoptosis, autophagy, necroptosis, pyroptosis, entosis, ferroptosis, ferroautophagy, parthanatos, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, cuproptosis, and PANoptosis. This article briefly reviews the mechanism and significance of cell death associated with diabetic endothelial dysfunction, which will help deepen the understanding of diabetic endothelial cell death and provide new therapeutic ideas. [ABSTRACT FROM AUTHOR]

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aβ and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aβ plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD. [Display omitted] • Semaglutide (Wegovy, Ozempic, Rybelsus) is an effective diabetes drug. • Semaglutide improved cognition in the 3xtg mouse model of AD. • The drug increases glucose utilization as shown in 18FDG-PET-CT. • The effect is dependent on the SIRT1/GLUT4 signaling pathway. [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age, with ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology (PCOM) as the clinical features. Androgen excess, insulin resistance, obesity, adipose tissue dysfunction, ovulatory dysfunction, and gut microbiota dysbiosis are the main pathological features and pathogenesis of PCOS and are related to systemic chronic low-grade inflammation and chronic ovarian tissue inflammation in PCOS. With the advances in immune-endocrine interaction studies, research on the role of immune cells in the occurrence and development of PCOS is gradually increasing. As the core of innate immunity, macrophages play an indispensable role in systemic inflammatory response. Meanwhile, they are involved in maintaining the stability and function of the ovary as the most abundant immune cells in ovarian tissue. Studies in humans and mice have found that the polarization of macrophages into M1 type plays multiple roles in the pathogenesis of PCOS. This review describes the distribution characteristics of macrophage subpopulations in patients and animal models with PCOS, discusses the role of macrophage-related metabolic inflammation in PCOS, and summarizes the relationship between macrophages and PCOS-related pathological features and its possible mechanisms, to further understand the pathogenesis of PCOS and reveal the role of macrophages in it. In addition, research on immune-endocrine interactions can also provide direction for finding new therapeutic targets for PCOS. [Display omitted] • In PCOS, macrophages polarize to the pro-inflammatory M1 type, building a bridge between the pathogenesis of PCOS. • Hyperandrogenism, Insulin resistance, obesity, and glucose and lipid metabolism disorder cause the M1 macrophage levels to increase. • Macrophage pyroptosis induced by microbiota dysbiosis is associated with the pathogenesis of PCOS. • Macrophages in the ovary participate in the regulation of the process of folliculogenesis, ovulation, and luteolysis. • In PCOS, the increased level of M1-type macrophages in the ovary affects follicle maturation. [ABSTRACT FROM AUTHOR]

PCOS is the most common endocrine disorder, affecting 4-21% of women of reproductive age. Rotterdam criteria; oligomenorrhea or amenorrhea after other symptoms were excluded; clinical or biochemical hyperandrogenism, at least two of the criteria of polycystic appearance of the ovary (increased stromal volume and >enlarged ovaries, which are 2 to 8 mm with a diameter of 10 follicles and are located along the periphery of the ovary, forming a pearl necklace) are present on ultrasound can be used in the diagnosis of the disease. In this disease, reproductive system disorders such as hyperandrogenism, anovulation and infertility as well as metabolic, systemic disorders such as hyperinsulinemia, abnormal lipid, glucose levels, obesity are also encountered. The aim of this study is to evaluate the glycemic status of patients diagnosed with PCOS and to detect early glucose metabolism disorders. 43 patients who applied to the gynecology outpatient clinic of Kocaeli City Hospital with the complaint of menstrual irregularity were included in the study.These 43 patients included at least two of the Rotterdam criteria and were diagnosed with PCOS.In the laboratory parameters of these patients, fasting blood glucose, 1st and 2 nd hour values of 75 gram oral glucose test(75 gr OGTT) and hemoglobin A1c values were measured. According to the family history of the patients, 16 (37.2%) were present and 27 (62.8%) were absent. According to the smoking status, 11 (25.6%) of the patients are present and 32 (74.4%) are absent. According to the impaired fasting glucose status(IFG), 40 (93.0%) of the patients were absent and 3 (7.0%) were present. According to the impaired glucose tolerance status(IGT), the patients are distributed as 39 (90.7%) absent and 4 (9.3%) present. According to impaired fasting glucose and impaired glucose tolerance, the patients are distributed as 42 (97.7%) absent and 1 (2.3%) present. According to the diabetes risk, 40 (93.0%) patients are distributed as absent and 3 (7.0%) as present(table 1) 3%of the patients had impaired fasting glucose,4% had impaired glucose tolerance and 3% had a high risk of diabetes mellitus.These results were determined independently of the patients' body mass index and family history. There may be glucose metabolism disorder in the PCOS patient group,regardless of BMI or family history. This can be detected by looking at fasting blood glucose,75 gr OGTT and HbA1c,which are easily accessible and inexpensive tests in the early period. [ABSTRACT FROM AUTHOR]

Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases. [Display omitted] • Paternal Cd impairs glucose metabolism in adult female offspring. • Paternal Cd enhances hepatic phospholipids in adult female offspring. • Paternal Cd reduces phospholipid transport-related mRNAs in offspring livers. • Paternal Cd persistently elevated six phospholipids in fetal and adult female livers. [ABSTRACT FROM AUTHOR]

Haloxyfop-P-methyl is used extensively in agricultural production, and its metabolites in soil have potentially toxic effects on aquatic ecosystems. In this study, we explored the toxicity of haloxyfop-P-methyl on Chiromantes dehaani. The results of the 21-day toxicity test showed that haloxyfop-P-methyl decreased the weight gain (WG), specific growth rate (SGR) and hepatosomatic index (HSI). In glucose metabolism, haloxyfop-P-methyl reduced pyruvate, lactate, lactate dehydrogenase and succinate dehydrogenase, but enhanced glucose-6-phosphate dehydrogenase and hexokinase. Furthermore, expression of glucose metabolism-related genes was upregulated. We cloned the full-length CdG6PDH gene, which contains a 1587 bp ORF that encoded a 528 amino acid polypeptide. In antioxidant system, haloxyfop-P-methyl increased glutathione, thioredoxin reductase and thioredoxin peroxidase activities and activated the Nrf2/ARE pathway through upregulation of ERK , JNK , PKC and Nrf2. In immunity, low concentrations haloxyfop-P-methyl, or short-term exposure, upregulated the expression of immune-related genes and enhanced immune-related enzymes activity, while high concentrations or long-term exposure inhibited immune function. In summary, haloxyfop-P-methyl inhibited the growth performance, disrupted glucose metabolism, activated the antioxidant system, and led to immunotoxicity. The results deepen our understanding of the toxicity mechanism of haloxyfop-P-methyl and provide basic biological data for the comprehensive assessment of the risk of haloxyfop-P-methyl to the environment and humans. [Display omitted] • Haloxyfop-P-methyl inhibited growth performance and disrupted glucose metabolism. • G6PDH was analyzed and played a positive role against haloxyfop-P-methyl exposure. • Oxidative stress induced by haloxyfop-P-methyl exposure suppressed immune function. • Haloxyfop-P-methyl activated the Nrf2/ARE pathway to regulated antioxidant defense. • The PPP was stimulated and anaerobic glycolysis was inhibited by haloxyfop-P-methyl. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes mellitus and a major cause of blindness in young adults. Multiple potential factors influence DR; however, the exact mechanisms are poorly understood. Advanced treatments for DR, including laser therapy, vitrectomy, and intraocular drug injections, slow the disease's progression but fail to cure or reverse visual impairment. Therefore, additional effective methods to prevent and treat DR are required. The biological clock plays a crucial role in maintaining balance in the circadian rhythm of the body. Poor lifestyle habits, such as irregular routines and high-fat diets, may disrupt central and limbic circadian rhythms. Disrupted circadian rhythms can result in altered glucose metabolism and obesity. Misaligned central and peripheral clocks lead to a disorder of the rhythm of glucose metabolism, and chronically high sugar levels lead to the development of DR. We observed a disturbance in clock function in patients with diabetes, and a misaligned clock could accelerate the development of DR. In the current study, we examine the relationship between circadian rhythm disorders, diabetes, and DR. We conclude that: 1) abnormal function of the central clock and peripheral clock leads to abnormal glucose metabolism, further causing DR and 2) diabetes causes abnormal circadian rhythms, further exacerbating DR. Thus, our study presents new insights into the prevention and treatment of DR. • Diabetic retinopathy is a multifactorial blinding disease. • circadian rhythm disturbances are closely related to DR. • Some drugs can both correct circadian rhythm disturbances and treat DR. [ABSTRACT FROM AUTHOR]