Dysregulation Of Glucose Metabolism Research Articles

The impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination

Immunization is recommended for people with diabetes mellitus (DM), but little information is available on their seropositivity rates. To determine the impact of glucose tolerance state on seropositivity rate after hepatitis B vaccination, we included 7645 adult participants from the National Health and Nutrition Examination Survey 2005–2016 who reported three doses of hepatitis B vaccine and were seropositive for anti-hepatitis B surface antibody (≥ 12.0 mIU/mL), after exclusion of those positive for anti-hepatitis B core antibody and/or hepatitis B surface antigen. We classified the states of glucose tolerance as normal glucose tolerance (NGT, 61.68%), abnormal glucose tolerance (AGT, 26.02%), or DM (13.30%). We observed a stepwise decline in hepatitis B seropositivity rate from NGT (53.64%) to AGT (45.52%) to DM (28.84%) (P < 0.0001). We confirmed these results after standardization for age and BMI (P < 0.0001 for all subgroup analyses) and in subgroup analyses by gender and racial/ethnic group. Dysregulated glucose metabolism is associated with a decreased seropositivity rate after hepatitis B vaccination. Our observations suggest that regular follow-up screening for anti-hepatitis B surface antibody, with additional booster vaccination as necessary, is especially important in patients with DM. Whether a similar phenomenon exits for other vaccines, especially COVID-19, remains to be investigated.

Triglyceride mediated upregulation of UCP3 in murine heart

Proper mitochondrial function is of great importance to maintain efficient cardiac function. Dysregulated fatty acid oxidation (FAO) or glucose metabolism is an underlying cause of cardiovascular diseases and metabolic syndrome. The mitochondrial uncoupling protein 3 (UCP3) is proposed to have a protective role in heart disease. However, the physiological function of UCP3 is under debate, and its role as an anti-oxidative protein is critically discussed. UCP3 expression was shown to coincide with FAO, which strengthens the hypothesis about UCP3 involvement in metabolism.

Comprehensive Analyses of Glucose Metabolism in Glioma Reveal the Glioma-Promoting Effect of GALM.

Glioma is the most common tumor with the worst prognosis in the central nervous system. Current studies showed that glucose metabolism could affect the malignant progression of tumors. However, the study on the dysregulation of glucose metabolism in glioma is still limited. Herein, we firstly screened 48 differentially expressed glucose metabolism-related genes (DE-GMGs) by comparing glioblastomas to low-grade gliomas. Then a glucose metabolism-related gene (GMG)-based model (PC, lactate dehydrogenase A (LDHA), glucuronidase beta (GUSB), galactosidase beta 1 (GLB1), galactose mutarotase (GALM), or fructose-bisphosphatase 1 (FBP1)) was constructed by a protein–protein interaction (PPI) network and Lasso regression. Thereinto, the high-risk group encountered a worse prognosis than the low-risk group, and the M2 macrophage was positively relevant to the risk score. Various classical tumor-related functions were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Since protein GALM was rarely studied in glioma, we detected high expression of GALM by western blot and immunohistochemistry in glioma tissues. And experiments in vitro showed that GALM could promote the epithelial-to-mesenchymal transition (EMT) process of glioma cells and could be regulated by TNFAIP3 in glioma cells. Overall, our study revealed the critical role of glucose metabolism in the prognosis of patients with glioma. Furthermore, we demonstrated that GALM was significantly related to the malignancy of glioma and could promote glioma cells’ EMT process.

Профиль экспрессии ряда микроРНК в плаценте при своевременных и преждевременных родах

Introduction. Comparative analysis of the expression levels of a number of microRNAs (miRNAs) in placentas obtained during timely and spontaneous preterm birth (PB) will make it possible to identify those miRNAs that are involved in the genesis of spontaneous PB. MiRNAs characterized by aberrant expression in placental tissues may be promising biomarkers in the blood of pregnant women for assessing the risk of spontaneous PB. Aim. Comparative analysis of expression levels of a number of microRNAs in placental tissue in women in timely and premature birth. Materials and Methods. We performed an analysis of the expression level of a number of miRNAs in placental tissue from 30 patients with PB and perinatal losses (group 1), from 30 patients with PB without perinatal losses (group 2), from 30 maternity women with timely delivery (group 3). The expression levels of the following miRNAs were studied: 31, 100, 146, 150, 20a, 204, 221, 223, 1246, 128, let7a, 126, 451, 92a, 23a, 21, 125b, 26a, 29b, 191, and U6. For this, the material was deparaffinated step by step using mineral oil, then the RNA extraction, reverse transcription reaction, and real-time polymerase chain reaction were carried out. Results. It was found that in PB a statistically significant increase in the expression levels of miRNA-125b, miRNA-29b is observed in placental samples, and a decrease in the expression level of miRNA-451 in comparison with timely delivery placentas. In the PB with perinatal losses, a statistically significant decrease in the expression level of miRNA-150 was registered, and in the absence of perinatal losses, an increase in the expression level of miRNA-223 and miRNA-31 compared with placentas in timely delivery was revealed. In addition, in PB with perinatal losses compared to PB without perinatal losses, a statistically significantly lower level of expression of miRNA-221 and miRNA-223 is noted. Conclusion. Aberrant expression levels of miRNA-125b, miRNA-29b, and miRNA-451 in the placentas of patients with PB indicate their involvement in the pathogenesis of the latter, apparently due to dysregulation of angiogenesis, apoptosis, trophoblast invasion and glucose metabolism.

The Metabolism Reprogramming of microRNA Let-7-Mediated Glycolysis Contributes to Autophagy and Tumor Progression.

Cancer is usually a result of abnormal glucose uptake and imbalanced nutrient metabolization. The dysregulation of glucose metabolism, which controls the processes of glycolysis, gives rise to various physiological defects. Autophagy is one of the metabolic-related cellular functions and involves not only energy regeneration but also tumorigenesis. The dysregulation of autophagy impacts on the imbalance of metabolic homeostasis and leads to a variety of disorders. In particular, the microRNA (miRNA) Let-7 has been identified as related to glycolysis procedures such as tissue repair, stem cell-derived cardiomyocytes, and tumoral metastasis. In many cancers, the expression of glycolysis-related enzymes is correlated with Let-7, in which multiple enzymes are related to the regulation of the autophagy process. However, much recent research has not comprehensively investigated how Let-7 participates in glycolytic reprogramming or its links to autophagic regulations, mainly in tumor progression. Through an integrated literature review and omics-related profiling correlation, this review provides the possible linkage of the Let-7 network between glycolysis and autophagy, and its role in tumor progression.

Abstract 10743: Overexpression of GLUT4 Induces Pulmonary Hypertension

Introduction: Pulmonary arterial hypertension (PAH) induces significantly elevated glucose uptake in the patient lungs and right ventricles (RV), which correlates with the severity of the disease. However, the mechanisms responsible for the increased glucose uptake and its contribution to the PAH pathobiology remain unclear. We discovered that Sugen/hypoxia-induced PAH is associated with a marked overexpression of glucose transporter, GLUT4, starting from the early stage of the disease. Hypothesis: We investigated the role of GLUT4 overexpression in triggering PAH and evaluated the downstream mechanisms responsible for the PAH phenotype. Methods: In this study, we used the mouse model overexpressing human GLUT4 (hGLUT4). RV hemodynamics and function were assessed in hGLUT4 mice treated or not with IMPA1 inhibitor (L690,330, i.p., 22 mg/kg BW, daily for 6 weeks). Isolated pulmonary artery smooth muscle cells (PASMC) were used to perform glucose uptake assays and bioenergetics measurements. Results: hGLUT4 mice showed significantly increased RV systolic pressure (RVSP, 28.98±0.72, p&lt;0.001, N=7-9) and RV hypertrophy (0.319±0.006, p&lt;0.0001, N=7-9) compared to WTs and non-transgenic controls. GLUT4 overexpression significantly increased the glucose uptake in PASMC (~30% increase to control, p&lt;0.01) and induced severe mitochondrial dysfunction in unstimulated and insulin-stimulated cells. Previously, we discovered that an increase in glucose uptake elevates the levels of glucose 6-phosphate (G6P) and activates the G6P metabolizing enzyme, myo-inositol monophosphatase 1 (IMPA1). We confirmed the increased expression of IMPA1, a critical activator of the inositol synthesis and inositol-dependent proliferative pathways in hGLUT4 mice. Notably, treatment with the IMPA1 inhibitor completely reversed PAH by reducing RVSP and RV hypertrophy. Conclusions: We conclude that increased GLUT4 expression is sufficient to induce spontaneous PAH through increased glucose uptake, initiation of mitochondrial dysfunction, and upregulation of IMPA1. This discovery introduces a novel potential target, IMPA1, that connects dysregulated glucose metabolism with activation of the proliferative signaling.

Role of Glycation in Type 2 Diabetes Mellitus and Its Prevention through Nymphaea Species.

The dysregulation of glucose metabolism that includes the modification of biomolecules with the help of glycation reaction results in the formation of advanced glycation end products (AGEs). The formation of AGEs may activate receptors for advanced glycation end products which induce intracellular signaling, ultimately enhancing oxidative stress, a well-known contributor to type 2 diabetes mellitus. In addition, AGEs are possible therapeutic targets for the treatment of type 2 diabetes mellitus and its complications. This review article highlights the antioxidant, anti-inflammatory, and antidiabetic properties of the Nymphaea species, and the screening of such aquatic plants for antiglycation activity may provide a safer alternative to the adverse effects related to glucotoxicity. Since oxidation and glycation are relatively similar to each other, therefore, there is a possibility that the Nymphaea species may also have antiglycating properties because of its powerful antioxidant properties. Herbal products and their derivatives are the preeminent resources showing prominent medicinal properties for most of the chronic diseases including type 2 diabetes mellitus. Among these, the Nymphaea species has also shown elevated activity in scavenging free radicals. This species has a load of phytochemical constituents which shows various therapeutic and nutritional value including anti-inflammatory and antioxidant profiles. To the best of our knowledge, this is the first article highlighting the possibility of an antiglycation value of the Nymphaea species by inhibiting AGEs in mediation of type 2 diabetes mellitus. We hope that in the next few years, the clinical and therapeutic potential may be explored and highlight a better perspective on the Nymphaea species in the inhibition of AGEs and its associated diseases such as type 2 diabetes mellitus.

Salidroside Activates the AMP-Activated Protein Kinase Pathway to Suppress Nonalcoholic Steatohepatitis in Mice.

NASH is becoming a leading cause of liver cirrhosis and HCC. Salidroside (p-hydroxyphenethyl-β-D-glucoside; SAL) has various biological and pharmacological activities, including anti-inflammatory, -oxidant, and -cancer activities. However, the therapeutic effect and underlying molecular mechanism of SAL in NASH remain to be further clarified. In this study, we found that SAL alleviated lipid accumulation and inflammatory response in primary hepatocytes after palmitic acid/oleic acid (PO) stimulation. In addition, SAL effectively prevented high-fat/high-cholesterol (HFHC)-diet-induced NASH progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, and fibrosis. Mechanistically, integrated RNA-sequencing and bioinformatic analysis showed that SAL promoted AMPK-signaling pathway activation in vitro and in vivo, and this finding was further verified by determining the phosphorylation levels of AMPK. Furthermore, the protective effects of SAL on lipid accumulation and inflammation in hepatocytes and livers induced by PO or HFHC stimulation were blocked by AMPK interruption. Our studies demonstrate that SAL protects against metabolic-stress-induced NASH progression through activation of AMPK signaling, indicating that SAL could be a potential drug component for NASH therapy.

Lifetime obesity trends are associated with subclinical myocardial injury: The Trøndelag health study.

Obesity is associated with subclinical myocardial injury as quantified by concentrations of cardiac troponin T, but whether lifetime excess weight history is associated with increased concentrations of cardiac troponin I (cTnI) and how indices of abdominal adiposity and glycemic dysregulation affect these associations remain unclear. We analyzed cTnI with a high-sensitivity assay in 9739 participants in the Trøndelag Health (HUNT) Study at study visit 4 (2017-2019). BMI was assessed at study Visit 1 (1984-1986), 2 (1995-1997), 3 (2006-2008), and 4. Median age at visit 4 was 68.7 years and 59% were women. Concentrations of cTnI were detectable in 84.1% of study participants, with a median of 2.5 (1.5-4.5 ng/L). We identified three clusters of BMI trajectories from visit 1 to 4, (1) stable normal weight, (2) stable overweight, and (3) stable obesity. Participants in clusters 2 and 3 were at increased risk of elevated concentrations of cTnI at visit 4 (odds ratio 1.27, 95% CI 1.09-1.47, and odds ratio 1.70, 95% CI 1.33-2.17, p for trend <0.001). Participants in cluster 3 had 22.0 (95% CI 14.1-29.9) higher concentrations of cTnI compared to participants in cluster 1 (p for trend <0.001). Dysregulated glucose metabolism and abdominal obesity did not influence our results. Individuals with stable overweight or obesity are at increased risk of subclinical myocardial injury, independently of glycemic dysregulation and abdominal adiposity. Our data support a direct detrimental effect of long-standing obesity on cardiovascular health.

Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males.

Reduced Serum Levels of Bone Formation Marker P1NP in Psoriasis.

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-α and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation—N-terminal propeptide of type I procollagen (P1NP) or bone resorption—C-terminal telopeptide of type I collagen (CTX-I)—were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring.

Exposure to Perfluoroalkyl Substances and Glucose Homeostasis in Youth.

Background:Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes.Objective:We examined associations between PFAS exposure and glucose metabolism in youth.Methods:Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; ) participated in annual visits for an average of . Generalizability of findings were tested in young adults from the Southern California Children’s Health Study (CHS; ) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography–high-resolution mass spectrometry; high levels were defined as concentrations percentile.Results:In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels () were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had higher 60-min glucose (95% CI: ; ), higher 2-h glucose (95% CI: ; ), and 25% lower function () compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had higher 60-min glucose (95% CI: ; ) and higher 2-h glucose, which did not meet statistical significance (95% CI: ; ). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism.Discussion:Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200

Slow digestion-oriented dietary strategy to sustain the secretion of GLP-1 for improved glucose homeostasis.

Dysregulated glucose metabolism is associated with many chronic diseases such as obesity and type 2 diabetes mellitus (T2DM), and strategies to restore and maintain glucose homeostasis are essential to health. The incretin hormone of glucagon-like peptide-1 (GLP-1) is known to play a critical role in regulating glucose homeostasis and dietary nutrients are the primary stimuli to the release of intestinal GLP-1. However, the GLP-1 producing enteroendocrine L-cells are mainly distributed in the distal region of the gastrointestinal tract where there are almost no nutrients to stimulate the secretion of GLP-1 under normal situations. Thus, a dietary strategy to sustain the release of GLP-1 was proposed, and the slow digestion property and dipeptidyl peptidase IV (DPP-IV) inhibitory activity of food components, approaches to reduce the rate of food digestion, and mechanisms to sustain the release of GLP-1 were reviewed. A slow digestion-oriented dietary approach through encapsulation of nutrients, incorporation of viscous dietary fibers, and enzyme inhibitors of phytochemicals in a designed whole food matrix will be implemented to efficiently reduce the digestion rate of food nutrients, potentiate their distal deposition and a sustained secretion of GLP-1, which will be beneficial to improved glucose homeostasis and health.

Intranasal 15d-PGJ2 ameliorates brain glucose hypometabolism via PPARγ-dependent activation of PGC-1α/GLUT4 signalling in APP/PS1 transgenic mice

Targeting the common molecular mechanism of type 2 diabetes mellitus and Alzheimer's disease (AD), including dysregulation of glucose metabolism, insulin resistance, and neuroinflammation, might be an efficient treatment strategy for AD. Previous studies have shown that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous PPARγ agonist, has anti-inflammatory, insulin sensitizing and anti-diabetic effects. However, whether 15d-PGJ2 has beneficial effects on AD remains to be elucidated. In the present study, we found that intranasal administration of 15d-PGJ2 (300 ng/30 μL/day) for 3 months significantly inhibited Aβ plaques, suppressed neuroinflammation, and attenuated cognitive deficits in APP/PS1 transgenic mice. Interestingly, 15d-PGJ2 treatment could increase brain glucose uptake, as detected by 18F-FDG microPET imaging, and co-localization of GLUT4 and NeuN in the hippocampus of APP/PS1 mice. Furthermore, 15d-PGJ2 markedly increased the expression of PPARγ and PGC-1α, upregulated GLUT4, and decreased the phosphorylation of IRS-1 (Ser616) in the hippocampus of APP/PS1 mice. Importantly, co-administration of a PPARγ antagonist GW9662 abrogated these protective effects of 15d-PGJ2. Collectively, intranasal 15d-PGJ2 conferred protective effects against AD by activating PPARγ-dependent PGC-1α/GLUT4 signalling. The PPARγ agonist 15d-PGJ2 might be a potential therapeutic drug for AD.

Toll-like receptor 3 ablation prevented high-fat diet-induced obesity and metabolic disorder

Inflammation in insulin-sensitive tissues (e.g., liver, visceral adipose tissue [VAT]) plays a major role in obesity and insulin resistance. Recruitment of innate immune cells drives the dysregulation of glucose and lipid metabolism. We aimed to seek the role of Toll like receptor 3 (TLR3), a pattern recognition receptor involved in innate immunity, obesity and the metabolic disorder. TLR3 expression in liver and VAT from diet induced obese mice and in VAT from overweight women was examined. Body weight, glucose homeostasis and insulin sensitivity were evaluated in TLR3 wild-type and knockout (KO) mice on a chow diet (CD) or high-fat diet for 15 weeks. At euthanasia, blood was collected, and plasma biochemical parameters and adipokines were determined with commercial kits. Flow cytometry was used to measure macrophage infiltration and activation in VAT. Standard western blot, immunohistochemistry and quantative PCR were used to assess molecules in pathways about lipid and glucose metabolism, insulin and inflammation in tissues of liver and VAT. Utilizing human and animal samples, we found that expression of TLR3 was upregulated in the liver and VAT in obese mice as well as VAT in overweight women. TLR3-deficiency protected against high-fat diet induced obesity, glucose intolerance, insulin resistance and lipid accumulation. Lipolysis was enhanced in VAT and hepatic lipogenesis was inhibited in TLR3 KO animals. Macrophages infiltration into adipose tissue was attenuated in TLR3 KO mice, accompanied with inhibition of NF-κB-dependent AMPK/Akt signaling pathway. These findings demonstrated that TLR3 ablation prevented obesity and metabolic disorders, thereby providing new mechanistic links between inflammation and obesity and associated metabolic abnormalities in lipid/glucose metabolism.

Uncurtaining the pivotal role of ABC transporters in diabetes mellitus.

The metabolic disorders are the edge points for the initiation of various diseases. These disorders comprised of several diseases including diabetes, obesity, and cardiovascular complications. Worldwide, the prevalence of these disorders is increasing day by day. The world's population is at higher threat of developing metabolic disease, especially diabetes. Therefore, there is an impregnable necessity of searching for a newer therapeutic target to reduce the burden of these disorders. Diabetes mellitus (DM) is marked with the dysregulated insulin secretion and resistance. The lipid and glucose transporters portray a pivotal role in the metabolism and transport of both of these. The excess production of lipid and glucose and decreased clearance of these leads to the emergence of DM. The ATP-binding cassette transporters (ABCT) are important for the metabolism of glucose and lipid. Various studies suggest the key involvement of ABCT in the pathologic process of different diseases. In addition, the involvement of other pathways, including IGF signaling, P13-Akt/PKC/MAPK signaling, and GLP-1 via regulation of ABCT, may help develop new treatment strategies to cope with insulin resistance dysregulated glucose metabolism, key features in DM.

An Artificial-Intelligence-Discovered Functional Ingredient, NRT_N0G5IJ, Derived from Pisum sativum, Decreases HbA1c in a Prediabetic Population.

The prevalence of prediabetes is rapidly increasing, and this can lead to an increased risk for individuals to develop type 2 diabetes and associated diseases. Therefore, it is necessary to develop nutritional strategies to maintain healthy glucose levels and prevent glucose metabolism dysregulation in the general population. Functional ingredients offer great potential for the prevention of various health conditions, including blood glucose regulation, in a cost-effective manner. Using an artificial intelligence (AI) approach, a functional ingredient, NRT_N0G5IJ, was predicted and produced from Pisum sativum (pea) protein by hydrolysis and then validated. Treatment of human skeletal muscle cells with NRT_N0G5IJ significantly increased glucose uptake, indicating efficacy of this ingredient in vitro. When db/db diabetic mice were treated with NRT_N0G5IJ, we observed a significant reduction in glycated haemoglobin (HbA1c) levels and a concomitant benefit on fasting glucose. A pilot double-blinded, placebo controlled human trial in a population of healthy individuals with elevated HbA1c (5.6% to 6.4%) showed that HbA1c percentage was significantly reduced when NRT_N0G5IJ was supplemented in the diet over a 12-week period. Here, we provide evidence of an AI approach to discovery and demonstrate that a functional ingredient identified using this technology could be used as a supplement to maintain healthy glucose regulation.

Proteomics for personalized medicine in type 2 diabetes mellitus

Diabetes mellitus (DM) is a metabolic disease associated with a number of metabolic disturbances including glucose, lipid, and protein metabolism. A multifaceted interplay of genetic, environmental, and socioeconomic factors contributes to increasing prevalence of DM. Robust efforts have been made to build and strengthen the healthcare systems for the diagnosis and management of DM. However, it remains a medical dilemma how to effectively monitor and manage DM. At present, blood glucose is the gold standard biomarker in the diagnosis and management of DM. The values of blood in monitoring the occurrence and progression of DM have not been well explored. To fully understand the biological changes in the blood of DM patients, we recruited 60 participants including 30 healthy adults and 30 patients diagnosed with DM. By performing deep profiling of proteomes in the blood, we identified a total of 42 proteins that are differentially expressed in the blood of diabetic patients compared with healthy controls. Of the differentially expressed proteins, α2-macroglobulin, L-selectin, APOA1 and APOD could serve as a more sensitive combinational biomarker in distinguishing diabetic patients and healthy controls and may predict the progression of DM. Furthermore, through analyses of gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways associated with the differentially expressed proteins, we discovered that the activation of liver X receptors/retinoid X receptors in diabetic patients was a key biological event that triggers the dysregulation of cholesterol, lipid, and glucose metabolism. Collectively, our study provides a rich and open-access data resource to shed lights on personalized strategies for optimal management of DM.

MIG‐6 Is Essential for Promoting Glucose Metabolic Reprogramming and Tumor Growth in Triple‐Negative Breast Cancer

Treatment of triple-negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen-inducible gene-6 (MIG-6) has long been thought of as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncovered that MIG-6 is upregulated in TNBC and that MIG-6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays revealed that MIG-6 drives glucose metabolism reprogramming toward glycolysis. Mechanistically, MIG-6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein expression and the subsequent upregulation of GLUT1 and other HIF1α-regulated glycolytic genes, substantiating the comprehensive regulation of MIG-6 in glucose metabolism. Moreover, our animal studies demonstrated that MIG-6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG-6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC.

MIG-6 is essential for promoting glucose metabolic reprogramming and tumor growth in triple-negative breast cancer.

Treatment of triple‐negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen‐inducible gene‐6 (MIG‐6) has long been thought of as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncover that MIG‐6 is upregulated in TNBC and that MIG‐6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays reveal that MIG‐6 drives glucose metabolism reprogramming toward glycolysis. Mechanistically, MIG‐6 recruits HAUSP deubiquitinase for stabilizing HIF1α protein expression and the subsequent upregulation of GLUT1 and other HIF1α‐regulated glycolytic genes, substantiating the comprehensive regulation of MIG‐6 in glucose metabolism. Moreover, our mouse studies demonstrate that MIG‐6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG‐6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC.