Regulation Of Glucose Metabolism Research Articles

Metformin-induced changes of the gut microbiota in patients with type 2 diabetes mellitus: results from a prospective cohort study.

The influence of the microbiota on hypoglycemic agents is becoming more apparent. The effects of metformin, a primary anti-diabetes drug, on gut microbiota are still not fully understood. This prospective cohort study aims to investigate the longitudinal effects of metformin on the gut microbiota of 25 treatment-naïve diabetes patients, each receiving a daily dose of 1500 mg. Microbiota compositions were analyzed at baseline, and at 1, 3, and 6 months of medication using 16S rRNA gene sequencing. Prior to the 3-month period of metformin treatment, significant improvements were noted in body mass index (BMI) and glycemic-related parameters, such as fasting blood glucose (FPG) and hemoglobin A1c (HbA1c), alongside homeostasis model assessment indices of insulin resistance (HOMA-IR). At the 3-month mark of medication, a significant reduction in the α-diversity of the gut microbiota was noted, while β-diversity exhibited no marked variances throughout the treatment duration. The Firmicutes to Bacteroidetes ratio. markedly decreased. Metformin treatment consistently increased Escherichia-Shigella and decreased Romboutsia, while Pseudomonas decreased at 3 months. Fuzzy c-means clustering identified three longitudinal trajectory clusters for microbial fluctuations: (i) genera temporarily changing, (ii) genera continuing to decrease (Bacteroides), and (iii) genera continuing to increase(Lachnospiraceae ND3007 group, [Eubacterium] xylanophilum group, Romboutsia, Faecalibacterium and Ruminococcaceae UCG-014). The correlation matrix revealed associations between specific fecal taxa and metformin-related clinical parameters HbA1c, FPG, Uric Acid (UA), high-density lipoproteincholesterol (HDL-C), alanine aminotransferase (ALT), hypersensitive C-reactive protein (hs-CRP), triglyceride (TG) (P < 0.05). Metacyc database showed that metformin significantly altered 17 functional pathways. Amino acid metabolism pathways such as isoleucine biosynthesis predominated in the post-treatment group. Metformin's role in glucose metabolism regulation may primarily involve specific alterations in certain gut microbial species rather than an overall increase in microbial species diversity. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by metformin.

Regulation of macrophage polarization and glucose metabolism by the ERK/MAPK-HK1 signaling pathway in paraquat-induced acute lung injury.

Acute lung injury is the leading cause of paraquat (PQ) poisoning-related mortality. The mechanism by which macrophages are involved in PQ-induced acute lung injury remains unclear. In recent years, the role of metabolic reprogramming in macrophage functional transformation has received significant attention. The current study aimed to identify the role of altered macrophage glucose metabolism and molecular mechanisms in PQ poisoning-induced acute lung injury. We established a model of acute lung injury in PQ-intoxicated mice via the intraperitoneal injection of PQ. PQ exposure induces macrophage M1 polarization and promotes the release of inflammatory factors, which causes the development of acute lung injury in mice. In vitro analysis revealed that PQ altered glucose metabolism, which could be reversed by siRNA transfection to silence the expression of HK1, a key enzyme in glucose metabolism. RNA sequencing revealed that the ERK/MAPK pathway was the crucial molecular mechanism of PQ pathogenesis. Further, U0126, an ERK inhibitor, could inhibit PQ-induced HK1 activation and macrophage M1 polarization. These findings provide novel insights into the previously unrecognized mechanism of ERK/MAPK-HK1 activation in PQ poisoning.

SIRT1/AMPK-mediated pathway: Ferulic acid from sugar beet pulp mitigating obesity-induced diabetes-linked complications and improving metabolic health.

Obesity-induced type 2 diabetes (T2D) increases the risk of metabolic syndrome due to the high calorie intake. The role of sugar beet pulp (SBP) in T2D and the mechanism of its action remain unclear, though it is abundant in phenolics and has antioxidant activity. In this study, we isolated and purified ferulic acid from SBP, referred to as SBP-E, and studied the underlying molecular mechanisms in the regulation of glucose and lipid metabolism developing high glucose/high fat diet-induced diabetic models in vitro and in vivo. SBP-E showed no cytotoxicity and reduced the oxidative stress by increasing glutathione (GSH) in human liver (HepG2) and rat skeletal muscle (L6) cells. It also decreased body weight gain, food intake, fasting blood glucose levels (FBGL), glucose intolerance, hepatic steatosis, and lipid accumulation. Additionally, SBP-E decreased the oxidative stress and improved the antioxidant enzyme levels in high-fat diet (HFD)-induced T2D mice. Further, SBP-E reduced plasma and liver advanced glycation end products (AGEs), malondialdehyde (MDA), and pro-inflammatory cytokines, and increased anti-inflammatory cytokines in HFD-fed mice. Importantly, SBP-E significantly elevated AMPK, glucose transporter, SIRT1 activity, and Nrf2 expression and decreased ACC expression and SREBP1 levels in diabetic models. Collectively, our study results suggest that SBP-E treatment can improve obesity-induced T2D by regulating glucose and lipid metabolism via SIRT1/AMPK signalling and the AMPK/SREBP1/ACC1 pathway.

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity.

One of the triazole tautomers, 1,2,4-triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti-inflammatory, anti-cancer, anti-bacterial, anti-tuberculosis, and anti-diabetic effects. The review highlights anti-inflammatory effect of 1,2,4-triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in-silico data that illuminate the triazolescapacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4-triazole derivatives, with a focus on their potential efficacy against multi-drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti-diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness.Based oninformation provided, it can be concluded that 1,2,4-triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and medical community as a whole.Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

BackgroundAir exposure is an inevitable source of stress that leads to significant mortality in Coilia nasus. Our previous research demonstrated that adding 10‰ NaCl to aquatic water could enhance survival rates, albeit the molecular mechanisms involved in air exposure and salinity mitigation remained unclear. Conversely, salinity mitigation resulted in decreased plasma glucose levels and improved antioxidative activity. To shed light on this phenomenon, we characterized the transcriptomic changes in the C. nasus brain upon air exposure and salinity mitigation by integrated miRNA-mRNA analysis.ResultsThe plasma glucose level was elevated during air exposure, whereas it decreased during salinity mitigation. Antioxidant activity was suppressed during air exposure, but was enhanced during salinity mitigation. A total of 629 differentially expressed miRNAs (DEMs) and 791 differentially expressed genes (DEGs) were detected during air exposure, while 429 DEMs and 1016 DEGs were identified during salinity mitigation. GO analysis revealed that the target genes of DEMs and DEGs were enriched in biological process and cellular component during air exposure and salinity mitigation. KEGG analysis revealed that the target genes of DEMs and DEGs were enriched in metabolism. Integrated analysis showed that 24 and 36 predicted miRNA-mRNA regulatory pairs participating in regulating glucose metabolism, Ca2+ transport, inflammation, and oxidative stress. Interestingly, most of these miRNAs were novel miRNAs.ConclusionIn this study, substantial miRNA-mRNA regulation pairs were predicted via integrated analysis of small RNA sequencing and RNA-Seq. Based on predicted miRNA-mRNA regulation and potential function of DEGs, miRNA-mRNA regulatory network involved in glucose metabolism and Ca2+ transport, inflammation, and oxidative stress in C. nasus brain during air exposure and salinity mitigation. They regulated the increased/decreased plasma glucose and inhibited/promoted antioxidant activity during air exposure and salinity mitigation. Our findings would propose novel insights to the mechanisms underlying fish responses to air exposure and salinity mitigation.

Sex-specific associations between circadian-related genes and depression in UK Biobank participants highlight links to glucose metabolism, inflammation and neuroplasticity pathways

Depressive disorders have increased in global prevalence, making improved management of these disorders a public health priority. Prior research has linked circadian clock genes to depression, either through direct interactions with mood-related pathways in the brain or by modulating the phase of circadian rhythms. Using machine learning and statistical techniques, we explored associations between 157,347 SNP variants from 51 circadian-related genes and depression scores from the Patient Health Questionnaire 9 (PHQ-9) in 99,939 UK Biobank participants. Our results highlight multiple pathways linking the circadian system to mood, including metabolic, monoamine, immune, and stress-related pathways. Notably, genes regulating glucose metabolism and inflammation (GSK3B, LEP, RORA, and NOCT) were prominent factors in females, in addition to DELEC1 and USP46, two genes of unknown function. In contrast, FBXL3 and DRD4 emerged as significant risk factors for male depression. We also found epistatic interactions involving RORA, NFIL3, and ZBTB20 as either risk or protective factors for depression, underscoring the importance of transcription factors (ZBTB20, NFIL3) and hormone receptors (RORA) in depression etiology. Understanding the complex, sex-specific links between circadian genes and mood disorders will facilitate the development of therapeutic interventions and enhance the efficacy of multi-target treatments for depression.

Effects of the stress hyperglycemia ratio on long-term mortality in patients with triple-vessel disease and acute coronary syndrome

AimsRisk assessment for triple-vessel disease (TVD) remain challenging. Stress hyperglycemia represents the regulation of glucose metabolism in response to stress, and stress hyperglycemia ratio (SHR) is recently found to reflect true acute hyperglycemic status. This study aimed to evaluate the prognostic value of SHR and its role in risk stratification in TVD patients with acute coronary syndrome (ACS).MethodsA total of 3812 TVD patients with ACS with available baseline SHR measurement were enrolled from two independent centers. The endpoint was cardiovascular mortality. Cox regression was used to evaluate the association between SHR and cardiovascular mortality. The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) II (SSII) was used as the reference model in the model improvement analysis.ResultsDuring a median follow-up of 5.1 years, 219 (5.8%) TVD patients with ACS suffered cardiovascular mortality. TVD patients with ACS with high SHR had an increased risk of cardiovascular mortality after robust adjustment for confounding (high vs. median SHR: adjusted hazard ratio 1.809, 95% confidence interval 1.160–2.822, P = 0.009), which was fitted as a J-shaped pattern. The prognostic value of the SHR was found exclusively among patients with diabetes instead of those without diabetes. Moreover, addition of SHR improved the reclassification abilities of the SSII model for predicting cardiovascular mortality in TVD patients with ACS.ConclusionsThe high level of SHR is associated with the long-term risk of cardiovascular mortality in TVD patients with ACS, and is confirmed to have incremental prediction value beyond standard SSII. Assessment of SHR may help to improve the risk stratification strategy in TVD patients who are under acute stress.

Involvement of lncRNAs in the regulation of aerobic glycolysis in hepatocellular carcinoma: Main functions, regulatory mechanisms and potential therapeutic implications (Review).

Even under aerobic conditions, tumor cells can reprogram their metabolism to preferentially metabolize glucose into lactic acid. This abnormal metabolic pattern, known as the 'Warburg' effect or aerobic glycolysis, promotes cancer progression. Long non‑coding RNAs (lncRNAs) are RNAs that are >200 nucleotides in length and do not have protein‑coding capabilities. However, these RNAs play a key role in tumor development. There is increasing evidence to indicate that lncRNAs regulate glucose metabolism in tumor cells by affecting metabolic enzymes and some signaling pathways, thereby regulating the occurrence and progression of hepatocellular carcinoma (HCC). Therefore, it is crucial to understand which lncRNAs play a regulatory role in HCC glycolysis and to determine the related molecular mechanisms. The present review summarized and discussed the functions of lncRNAs, focusing on the regulatory mechanisms of lncRNAs in the process of glycolysis in HCC. In addition, the present review suggests the importance of lncRNAs as future therapeutic targets for antitumor cell metabolism.

MOTS-c is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of AMPK/PGC-1α -mediated mitochondrial biogenesis.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. MOTS-c, a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an AMPK inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

Mechano-sensor Piezo1 inhibits glucagon production in pancreatic α-cells

ObjectiveGlucagon is a critical hormone regulating glucose metabolism. It stimulates the liver to release glucose under low blood sugar conditions, thereby maintaining blood glucose stability. Excessive glucagon secretion and hyperglycemia is observed in individuals with diabetes. Precise modulation of glucagon is significant to maintain glucose homeostasis. Piezo1 is a mechanosensitive ion channel capable of converting extracellular mechanical forces into intracellular signals, thus regulating hormonal synthesis and secretion. This study aims to investigate the role of Piezo1 in regulating glucagon production in α cells. MethodsThe effects of Piezo1 on glucagon production were examined in normal- or high-fat diet fed α cell-specific Piezo1 knockout mice (Gcg-Piezo1−/−), and the murine pancreatic α cell line αTC1–6. Expression of Proglucagon was investigated by real-time PCR and western blotting. Plasma glucagon and insulin were detected by enzyme immunoassay. ResultsUnder both normal- and high-fat diet conditions, Gcg-Piezo1−/− mice exhibited increased pancreatic α cell proportion, hyperglucagonemia, impaired glucose tolerance, and activated pancreatic mTORC1 signaling. Activation of Piezo1 by its agonist Yoda1 or overexpression of Piezo1 led to decreased glucagon synthesis and suppressed mTOR signaling pathway in αTC1–6 cells. Additionally, the levels of glucagon in the medium were also reduced. Conversely, knockdown of Piezo1 produced opposite effects. ConclusionOur study uncovers the regulatory role of the Piezo1 ion channel in α cells. Piezo1 influences glucagon production by affecting mTOR signaling pathway.

Unsaturated Fatty Acid Synthesis Is Associated with Worse Survival and Is Differentially Regulated by MYCN and Tumor Suppressor microRNAs in Neuroblastoma.

MYCN amplification (MNA) and disruption of tumor suppressor microRNA (TSmiR) function are key drivers of poor outcomes in neuroblastoma (NB). While MYCN and TSmiRs regulate glucose metabolism, their role in de novo fatty acid synthesis (FAS) and unsaturated FAS (UFAS) remains poorly understood. Here, we show that FAS and UFAS (U/FAS) genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk (HR) NB and that their expression is associated with lower overall survival. RNA-Seq analysis of human NB cell lines revealed parallel U/FAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to target these genes extensively. We further observed that both MYC and MYCN upregulated U/FAS pathway genes while suppressing TSmiR host gene expression, suggesting a possible U/FAS regulatory network between MYCN and TSmiRs in NB. NB cells are high in de novo synthesized omega 9 (ω9) unsaturated fatty acids and low in both ω6 and ω3, suggesting a means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model in which MYCN and TSmiRs regulate U/FAS and play an important role in NB pathology, with implications for other MYC family-driven cancers.

Trilobatin regulates glucose metabolism by ameliorating oxidative stress and insulin resistance in vivo and in vitro.

Trilobatin, a glycosylated dihydrochalcone, has been reported to have anti-diabetic properties. However, the underlying mechanism remains unexplained. In this investigation, the regulation of trilobatin on glucose metabolism of insulin resistance (IR)-HepG2 cells and streptozocin (STZ)-induced mice and its mechanism were evaluated. Different doses of trilobatin (5, 10 and 20 μM) increased glucose consumption, glycogen content, hexokinase (HK), and pyruvate kinase (PK) activity in IR-HepG2 cells. Among them, the HK and PK activity in IR-HepG2 cells treated with 20 μM trilobatin were 1.84 and 2.05 times than those of the IR-group. The overeating, body and tissue weight, insulin levels, liver damage, and lipid accumulation of STZ-induced mice were improved after feeding with different doses of trilobatin (10, 50, and 100mg/kg/d) for 4 weeks. Compared with STZ-induced mice, fasting blood glucose decreased by 61.11% and fasting insulin (FINS) increased by 48.6% after feeding trilobatin (100mg/kg/d). Meanwhile, data from quantitative real-time polymerase chain reaction (qRT-PCR) revealed trilobatin ameliorated glycogen synthesis via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway in IR-HepG2 cells and in STZ-induced mice. Furthermore, in vitro and in vivo experiments showed that trilobatin ameliorated oxidative stress by regulating the mRNA expression of nuclear erythroid-2 related factor 2 (Nrf2)/kelch-like ECH associated protein-1 (Keap-1) pathway as well as heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1). Our research reveals a novel pharmacological activity of trilobatin: regulating glucose metabolism through PI3K/Akt/GSK-3β and Nrf2/Keap-1 signaling pathways, improving insulin resistance and reducing oxidative stress. Trilobatin can be used as a reliable drug resource for the treatment of glucose metabolism disorders.

1,3,4-Oxadiazole Scaffold in Antidiabetic Drug Discovery: An Overview.

Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. With the increasing number of cases of diabetes and drug-resistant diabetes, there is an urgent need to develop new potent molecules capable of combating this cruel disease. Medicinal chemistry concerns the discovery, development, identification, and interpretation of the mode of action of biologically active compounds at the molecular level. Oxadiazole-based derivatives have come up as a potential option for antidiabetic drug research. Oxadiazole is a five-membered heterocyclic organic compound containing two nitrogen atoms and one oxygen atom in its ring. Oxadiazole hybrids have shown the ability to improve glucose tolerance, enhance insulin sensitivity, and reduce fasting blood glucose levels. The mechanisms underlying the antidiabetic effects of oxadiazole involve the modulation of molecular targets such as peroxisome proliferator-activated receptor gamma (PPARγ), α-glucosidase, α-amylase and GSK-3β which regulate glucose metabolism and insulin secretion. The present review article describes the chemical structure and properties of oxadiazoles and highlights the antidiabetic activity through action on different targets. The SAR for the oxadiazole hybrids has been discussed in this article, which will pave the way for the design and development of new 1,3,4-oxadiazole derivatives as promising antidiabetic agents in the future. We expect that this article will provide comprehensive knowledge and current innovation on oxadiazole derivatives with antidiabetic potential and will fulfil the needs of the scientific community in designing and developing efficacious antidiabetic agents.

MIF/NR3C2 Axis Regulates Glucose Metabolism Reprogramming in Pancreatic Cancer through MAPK-ERK and AP-1 Pathways.

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2), and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2, LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2, and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of MAPK-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 (AP-1) to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.

Eicosapentaenoic acid-mediated activation of PGAM2 regulates skeletal muscle growth and development via the PI3K/AKT pathway

Eicosapentaenoic acid regulates glucose uptake in skeletal muscle and significantly affects whole-body energy metabolism. However, the underlying molecular mechanism remains unclear. Here we report that eicosapentaenoic acid activates phosphoglycerate mutase 2, which mediates the conversion of 2-phosphoglycerate into 3-phosphoglycerate. This enzyme plays a pivotal role in glycerol degradation, thereby facilitating the proliferation and differentiation of satellite cells in skeletal muscle. Interestingly, phosphoglycerate mutase 2 inhibits mitochondrial metabolism, promoting the formation of fast-type muscle fibers. Treatment with eicosapentaenoic acid and phosphoglycerate mutase 2 knockdown induced opposite transcriptomic changes, most of which were enriched in the PI3K-AKT signaling pathway. Phosphoglycerate mutase 2 activated the PI3K-AKT signaling pathway, which inhibited the phosphorylation of FOXO1, and, in turn, inhibited mitochondrial function and promoted the formation of fast-type muscle fibers. Our results suggest that eicosapentaenoic acid promotes skeletal muscle growth and regulates glucose metabolism by targeting phosphoglycerate mutase 2 and activating the PI3K/AKT signaling pathway.

Regulatory Effect of Osteocytes on Extramedullary and Bone Marrow Adipose Tissue Development and Function.

This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of nuclear receptors peroxisome proliferator-activated receptor gamma (PPARG) and alpha (PPARA) in this support. PPARG and PPARA proteins, key regulators of glucose and fatty acid metabolism, are highly expressed in osteocytes. They play significant roles in the regulation of osteocyte secretome and osteocyte bioenergetics; both activities contributing to the levels of systemic energy metabolism in part through an effect on metabolic function of extramedullary and bone marrow adipocytes. The PPARs-controlled osteocyte endocrine/paracrine activities, including sclerostin expression, directly regulate adipocyte function, while the PPARs-controlled osteocyte fuel utilization and oxidative phosphorylation contribute to the skeletal demands for glucose and fatty acids, whose availability is under the control of adipocytes. Bone is an inherent element of systemic energy metabolism with PPAR nuclear receptors regulating osteocyte-adipocyte metabolic axes.

Associations of adupocutokine and metaboliv hormone level in young people aged 25-44 years with type 2 diabetes mellitus and abdominal obesity

BACKGROUND: Diabetes mellitus and obesity are two closely related diseases that are a global public health problem. Obesity is characterized by an increase in the volume of adipose tissue and a change in the production and function of adipocytokines, which leads to a violation of the regulation of insulin sensitivity and glucose metabolism, contributing to the development of insulin resistance and diabetic pathology.AIM: The aim of this study was to evaluate the concentrations of individual adipocytokines and metabolic hormones in patients with DM2 and without diabetes, depending on the presence/absence of abdominal obesity (AO).MATERIALS AND METHODS: A single-center observational cross-sectional study was conducted. A population subsample of men and women aged 25–44 years was examined. Socio-demographic data were collected, anthropometric measurements were performed. The levels of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 (GLP-1), glucagon, were determined in blood serum by multiplex analysis using a set of reagents Human Metabolic Hormone V3 (USA) and Human Adipokine Panel 1 (USA) on a Luminex MAGPIX flow fluorimeter (USA). interleukin 6, insulin, leptin, monocytic chemotactic factor 1 (MCP-1), pancreatic polypeptide (PP), peptide YY (PYY), tumor necrosis factor alpha (TNF-α), adiponectin, adipsin, lipocalin-2, plasminogen activator inhibitor-1 (PAI-1) and resistin.RESULTS: The study included 105 people. The main group consisted of 35 people with diabetes mellitus, 11 of them without AO and 24 with AO, the control group consisted of 70 people without diabetes mellitus (35 people with AO and 35 without AO), comparable in gender and age with the main group. In individuals with abdominal obesity, regardless of the presence of type 2 diabetes mellitus, the levels of C-peptide, GLP-1, insulin, leptin and TNF-alpha are higher than in individuals without abdominal obesity. The chance of having diabetes mellitus and AO is associated with an increase in leptin levels (OR=1.367, 95% CI: 1.050–1.779, p=0.020).CONCLUSION: The results of our study show that the indicators of the adipocytokine profile differ significantly in individuals with the presence/absence of abdominal obesity. According to our data, leptin makes the greatest contribution to the development of SD2 against the background of AO. Further research is needed to identify causal relationships and determine whether treatment that regulates adipocytokine levels can help in personalized approaches to the prevention and treatment of type 2 diabetes mellitus.

The 26RFa (QRFP)/GPR103 neuropeptidergic system: A key regulator of energy and glucose metabolism.

Obesity and type 2 diabetes are strongly associated pathologies, currently considered as a worldwide epidemic problem. Understanding the mechanisms that drive the development of these diseases would enable to develop new therapeutic strategies for their prevention and treatment. Particularly, the role of the brain in the energy and glucose homeostasis has been studied for two decades. In specific, the hypothalamus contains well-identified neural networks regulating appetite and potentially also glucose homeostasis. A new concept has thus emerged, suggesting that obesity and diabetes could be due to a dysfunction of the same, still poorly understood, neural networks. The neuropeptide 26RFa (also termed QRFP) belongs to the family of RFamide regulatory peptides and has been identified as the endogenous ligand of the human G protein-coupled receptor GPR103 (QRFPR). The primary structure of 26RFa is strongly conserved during vertebrate evolution, suggesting its crucial roles in the control of vital functions. Indeed, the 26RFa/GPR103 peptidergic system is reported to be involved in the control of various neuroendocrine functions, notably the control of energy metabolism in which it plays an important role, both centrally and peripherally, since 26RFa regulates feeding behavior, thermogenesis and lipogenesis. Moreover, 26RFa is reported to control glucose homeostasis both peripherally, where it acts as an incretin, and centrally, where the 26RFa/GPR103 system relays insulin signaling in the brain to control glucose metabolism. This review gives a comprehensive overview of the role of the 26RFa/GPR103 system as a key player in the control of energy and glucose metabolism. In pathophysiological context, this neuropeptidergic system represents a prime therapeutic target whose mechanisms are highly relevant to decipher.

Bergenin alleviates proliferative arterial diseases by modulating glucose metabolism in vascular smooth muscle cells

BackgroundVascular smooth muscle cell (VSMC) proliferation and phenotypic switching are key mechanisms in the development of proliferative arterial diseases. Notably, reprogramming of the glucose metabolism pattern in VSMCs plays an important role in this process. PurposeThe aim of this study is to investigate the therapeutic potential and the mechanism underlying the effect of bergenin, an active compound found in Bergenia, in proliferative arterial diseases. MethodsThe effect of bergenin on proliferative arterial disease was evaluated using platelet-derived growth factor (PDGF)-stimulated VSMCs and a mouse model of carotid artery ligation. VSMC proliferation and phenotypic switching were evaluated in vitro using cell counting kit-8, 5-ethynyl-2-deoxyuridine incorporation, scratch, and transwell assays. Carotid artery neointimal hyperplasia was evaluated in vivo using hematoxylin and eosin staining and immunofluorescence. The expression of proliferation and VSMC contractile phenotype markers was evaluated using PCR and western blotting. ResultsBergenin treatment inhibited PDGF-induced VSMC proliferation and phenotypic switching and reduced neointimal hyperplasia in the carotid artery ligation model. Additionally, bergenin partially reversed the PDGF-induced Warburg-like glucose metabolism pattern in VSMCs. RNA-sequencing data revealed that bergenin treatment significantly upregulated Ndufs2, an essential subunit of mitochondrial complex I. Ndufs2 knockdown attenuated the inhibitory effect of bergenin on PDGF-induced VSMC proliferation and phenotypic switching, and suppressed neointimal hyperplasia in vivo. Conversely, Ndufs2 overexpression enhanced the protective effect of bergenin. Moreover, Ndufs2 knockdown abrogated the effects of bergenin on the regulation of glucose metabolism in VSMCs. ConclusionThese findings suggest that bergenin is effective in alleviating proliferative arterial diseases. The reversal of the Warburg-like glucose metabolism pattern in VSMCs during proliferation and phenotypic switching may underlie this therapeutic mechanism.

Abstract LB295: Unsaturated fatty acid synthesis is associated with poor prognosis and is differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma

Abstract Dysregulated metabolism is a hallmark of cancer. While the role of glucose metabolism in cancer has been extensively studied, relatively little has been done to understand the role of poly-unsaturated fatty acids in cancer biology. To gain insight into their contribution to cancer progression we determined the expression patterns and outcome associations of both saturated and unsaturated fatty acid synthesis (UFAS) genes in pediatric neuroblastoma (NB), and fatty acid levels in NB cell lines derived from high-risk tumors. MYCN amplification and disruption of tumor suppressor miRNAs (TSmiR) function are central drivers of poor outcomes in NB. MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in UFAS remains poorly understood. Using complementary analysis of publicly available genomic datasets and cultured NB cell measurements we examined the potential regulation of UFAS genes through MYCN and MYC activity and posttranscriptional regulation by TSmiRs. Here we show that de novo and UFAS pathway genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. Additionally, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, using mass spectrometry analysis we found NB cells to be high in de novo synthesized omega 9 (ω9) unsaturated fatty acids and low in both ω6 and ω3. This finding provides a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC-driven cancers. Citation Format: Dennis A. Sheeter, Secilia Garza, Hui Gyu Park, Lorraine-Rana Benhamou, Nikki R. Badi, Erika C. Espinosa, Kumar Kothapalli, J. Thomas Brenna, John T. Powers. Unsaturated fatty acid synthesis is associated with poor prognosis and is differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB295.