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BMJ Open Diabetes Research & Care Jun 2021Saliva collection is a non-invasive test and is convenient. 1,5-anhydroglucitol (1,5-AG) is a new indicator reflecting short-term blood glucose levels. This study aimed...
INTRODUCTION
Saliva collection is a non-invasive test and is convenient. 1,5-anhydroglucitol (1,5-AG) is a new indicator reflecting short-term blood glucose levels. This study aimed to explore the relationship between saliva 1,5-AG and insulin secretion function and insulin sensitivity.
RESEARCH DESIGN AND METHODS
Adult patients with type 2 diabetes who were hospitalized were enrolled. Based on blood glucose and C-peptide, homeostasis model assessment 2 for β cell secretion function, C-peptidogenic index (CGI), △2-hour C-peptide (2hCP)/△2-hour postprandial glucose (2hPG), ratio of 0-30 min area under the curve for C-peptide and area under the curve for glucose (AUC/AUC), and AUC/AUC were calculated to evaluate insulin secretion function, while indicators such as homeostasis model assessment 2 for insulin resistance were used to assess insulin sensitivity.
RESULTS
We included 284 subjects (178 men and 106 women) with type 2 diabetes aged 20-70 years. The saliva 1,5-AG level was 0.133 (0.089-0.204) µg/mL. Spearman's correlation analysis revealed a significantly negative correlation between saliva 1,5-AG and 0, 30, and 120 min blood glucose, glycated hemoglobin A, and glycated albumin (all p<0.05), and a significantly positive association between saliva 1,5-AG and CGI (=0.171, p=0.004) and AUC /AUC (=0.174, p=0.003). The above correlations still existed after adjusting for age, sex, body mass index, and diabetes duration. In multiple linear regression, saliva 1,5-AG was an independent factor of CGI (standardized =0.135, p=0.015) and AUC /AUC (standardized =0.110, p=0.020).
CONCLUSIONS
Saliva 1,5-AG was related to CGI and AUC/AUC in patients with type 2 diabetes.
TRIAL REGISTRATION NUMBER
ChiCTR-SOC-17011356.
Topics: Adult; China; Deoxyglucose; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Saliva
PubMed: 34167955
DOI: 10.1136/bmjdrc-2021-002199 -
Gene Expression Feb 2017Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Sorafenib is the only first-line systemic drug for advanced HCC, but it...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Sorafenib is the only first-line systemic drug for advanced HCC, but it has very limited survival benefits because patients treated with sorafenib either suffer from side effects or show disease progression after initial response. Thus, there is an urgent need to develop novel strategies for first-line and second-line therapies. The association between sorafenib resistance and glycolysis prompted us to screen several drugs with known antiglycolytic activity to identify those that will sensitize cells to sorafenib. We demonstrate that the combination of glycolytic inhibitor 2-deoxyglucose (2DG) and sorafenib drastically inhibits viability of sorafenib-sensitive and -resistant cells. However, the combination of other antiglycolytic drugs like lonidamine, gossypol, 3-bromopyruvate, and imatinib with sorafenib does not show synergistic effect. Cell cycle analysis revealed that the combination of 2DG and sorafenib induced cell cycle arrest at G0/G1. Mechanistic investigation suggests that the cell cycle arrest is due to depletion of cellular ATP that activates AMP-activated protein kinase (AMPK), which, in turn, inhibits mammalian target of rapamycin (mTOR) to induce cell cycle arrest. This study provides strong evidence for the therapeutic potential of the combination of sorafenib and 2DG for HCC.
Topics: AMP-Activated Protein Kinases; Adenosine Triphosphate; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Deoxyglucose; Drug Synergism; G1 Phase; Humans; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Resting Phase, Cell Cycle; Sorafenib
PubMed: 27938509
DOI: 10.3727/105221616X693855 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Aug 2022Epilepsy is a syndrome of central nervous system dysfunction caused by many reasons, which is mainly characterized by abnormal discharge of neurons in the brain....
OBJECTIVES
Epilepsy is a syndrome of central nervous system dysfunction caused by many reasons, which is mainly characterized by abnormal discharge of neurons in the brain. Therefore, finding new targets for epilepsy therapy has always been the focus and hotspot in neurological research field. Studies have found that 2-deoxy--glucose (2-DG) exerts anti-epileptic effect by up-regulation of K channel subunit mRNA and protein. By using the database of TargetScan and miRBase to perform complementary pairing analysis on the sequences of miRNA and related target genes, it predicted that miR-194 might be the upstream signaling molecule of K channel. This study aims to explore the mechanism by which 2-DG exerts its anti-epileptic effect by regulating K channel subunits and via miR-194.
METHODS
A magnesium-free epilepsy model was established and randomly divided into a control group, an epilepsy group (EP group), an EP+2-DG group, and miR-194 groups (including EP+miR-194 mimic, EP+miR-194 mimic+2-DG, EP+miR-194 mimic control, EP+miR-194 inhibitor, EP+miR-194 inhibitor+2-DG, and EP+miR-194 inhibitor control groups). The 2-DG was used to intervene miR-194 mimics, patch-clamp method was used to detect the spontaneous recurrent epileptiform discharges, real-time PCR was used to detect neuronal , and expressions, and the protein levels of Kir6.1 and Kir6.2were detected by Western blotting.
RESULTS
Compared with the control group, there was no significant difference in the amplitude of spontaneous discharge potential in the EP group (>0.05), but the frequency of spontaneous discharge was increased (<0.05). Compared with the EP group, the frequency of spontaneous discharge was decreased (<0.05). Compared with the EP+miR-194 mimic control group, the mRNA and protein expressions of and in the EP+miR-194 mimic group were down-regulated (all <0.05). Compared with the EP+miR-194 inhibitor control group, the mRNA and protein expressions of and in the EP+miR-194 inhibitor group were up-regulated (all <0.05). After pretreatment with miR-194 mimics, the mRNA and protein expression levels of K channel subunits and were decreased (all <0.05). Compared with the EP+2-DG group, the mRNA and protein expression levels of and in the EP+miR-194 mimic+2-DG group were down-regulated (all <0.05) and the mRNA and protein expression levels of and in the EP+miR-194 inhibitor+2-DG group were up-regulated (all <0.05).
CONCLUSIONS
The 2-DG might play an anti-epilepsy effect by up-regulating K channel subunits Kir6.1 and Kir6.2via miR-194.
Topics: Adenosine Triphosphate; Anticonvulsants; Deoxyglucose; Epilepsy; Glucose; Humans; MicroRNAs; Potassium Channels, Inwardly Rectifying; RNA, Messenger; Signal Transduction
PubMed: 36097778
DOI: 10.11817/j.issn.1672-7347.2022.220111 -
Neuro-oncology Feb 2017Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However,...
BACKGROUND
Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS).
METHODS
Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model.
RESULTS
GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS.
CONCLUSION
The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.
Topics: Animals; Antimetabolites; Apoptosis; Brain Neoplasms; Cell Proliferation; Deoxyglucose; Drug Synergism; Drug Therapy, Combination; Energy Metabolism; Glioblastoma; Glycolysis; Humans; Hypoglycemic Agents; Metformin; Mice; Mice, Nude; Oxidative Phosphorylation; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 27571886
DOI: 10.1093/neuonc/now174 -
Osteoarthritis and Cartilage Feb 2017Aging is an important osteoarthritis (OA) risk factor and compromised stress defense responses may mediate this risk. The Sestrins (Sesn) promote cell survival under...
OBJECTIVES
Aging is an important osteoarthritis (OA) risk factor and compromised stress defense responses may mediate this risk. The Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. This study examined Sesn expression in normal and OA cartilage and functions of Sesn in chondrocytes.
METHODS
Sesn expression in human and mouse normal and OA cartilage was analyzed by quantitative polymerase chain reaction (PCR) and immunohistochemistry. Sesn function was investigated by using small interfering RNA (siRNA) mediated Sesn knockdown and overexpression with analysis of cell survival, gene expression, autophagy, and AMPK and mTOR activation.
RESULTS
Sesn mRNA levels were significantly reduced in human OA cartilage and immunohistochemistry of human and mouse OA cartilage also showed a corresponding reduction in protein levels. In cultured human chondrocytes Sesn1, 2 and 3 were expressed and increased by tunicamycin, an endoplasmic reticulum (ER) stress response inducer and 2-deoxyglucose (2DG), a metabolic stress inducer. Sesn1 and 2 were increased by tBHP, an oxidative stress inducer. Sesn knockdown by siRNA reduced chondrocyte viability under basal culture conditions and in the presence of 2DG. Sesn overexpression enhanced LC3-II formation and autophagic flux, and this was related to changes in mTOR but not AMPK activation.
CONCLUSION
These findings are the first to show that Sesn expression is suppressed in OA affected cartilage. Sesn support chondrocyte survival under stress conditions and promote autophagy activation through modulating mTOR activity. Suppression of Sesn in OA cartilage contributes to deficiency in an important cellular homeostasis mechanism.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Animals; Cartilage, Articular; Chondrocytes; Deoxyglucose; Female; Gene Knockdown Techniques; Heat-Shock Proteins; Humans; Male; Mice; Middle Aged; Nuclear Proteins; Osteoarthritis; Oxidative Stress; RNA, Small Interfering; Tunicamycin; Young Adult
PubMed: 27693501
DOI: 10.1016/j.joca.2016.09.017 -
Biochimica Et Biophysica Acta. General... Sep 2023Glycolytic inhibitor 2-deoxy-d-glucose (2-DG) binds to hexokinase in a non-competitive manner and phosphoglucose isomerase in a competitive manner, blocking the initial...
Multitranscript analysis reveals an effect of 2-deoxy-d-glucose on gene expression linked to unfolded protein response and integrated stress response in primary human monocytes and monocyte-derived macrophages.
BACKGROUND
Glycolytic inhibitor 2-deoxy-d-glucose (2-DG) binds to hexokinase in a non-competitive manner and phosphoglucose isomerase in a competitive manner, blocking the initial steps of the glycolytic pathway. Although 2-DG stimulates endoplasmic reticulum (ER) stress, activating the unfolded protein response to restore protein homeostasis, it is unclear which ER stress-related genes are modulated in response to 2-DG treatment in human primary cells. Here, we aimed to determine whether the treatment of monocytes and monocyte-derived macrophages (MDMs) with 2-DG leads to a transcriptional profile specific to ER stress.
METHODS
We performed bioinformatics analysis to identify differentially expressed genes (DEGs) in previously reported RNA-seq datasets of 2-DG treated cells. RT-qPCR was performed to verify the sequencing data on cultured MDMs.
RESULTS
A total of 95 common DEGs were found by transcriptional analysis of monocytes and MDMs treated with 2-DG. Among these, 74 were up-regulated and 21 were down-regulated. Multitranscript analysis showed that DEGs are linked to integrated stress response (GRP78/BiP, PERK, ATF4, CHOP, GADD34, IRE1α, XBP1, SESN2, ASNS, PHGDH), hexosamine biosynthetic pathway (GFAT1, GNA1, PGM3, UAP1), and mannose metabolism (GMPPA and GMPPB).
CONCLUSIONS
Results reveal that 2-DG triggers a gene expression program that might be involved in restoring protein homeostasis in primary cells.
GENERAL SIGNIFICANCE
2-DG is known to inhibit glycolysis and induce ER stress; however, its effect on gene expression in primary cells is not well understood. This work shows that 2-DG is a stress inducer shifting the metabolic state of monocytes and macrophages.
Topics: Humans; Glucose; Monocytes; Endoribonucleases; Protein Serine-Threonine Kinases; Unfolded Protein Response; Macrophages; Endoplasmic Reticulum Chaperone BiP; Deoxyglucose; Gene Expression; Sestrins
PubMed: 37290716
DOI: 10.1016/j.bbagen.2023.130397 -
Pharmacology Research & Perspectives Oct 2020The β -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic...
The β -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at β-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [ H]-2-deoxyglucose uptake, cellular glycolysis, and O consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at β -adrenoceptors as they were largely absent in adipocytes derived from β -adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the β -adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the β -adrenoceptor.
Topics: Acetanilides; Adenosine Monophosphate; Adipocytes, Beige; Adipocytes, Brown; Adrenergic beta-3 Receptor Agonists; Animals; CHO Cells; Cells, Cultured; Cricetulus; Deoxyglucose; Gene Knockout Techniques; Glycolysis; Male; Mice; Oxygen; Thiazoles; Uncoupling Protein 1
PubMed: 32813332
DOI: 10.1002/prp2.643 -
Journal of Nuclear Medicine : Official... Mar 2023Ultrasensitive, high-resolution, extended-field-of-view total-body (TB) PET using the first-of-its-kind 194-cm axial-field-of-view uEXPLORER may facilitate the...
Ultrasensitive, high-resolution, extended-field-of-view total-body (TB) PET using the first-of-its-kind 194-cm axial-field-of-view uEXPLORER may facilitate the interrogation of biologic hallmarks of hitherto difficult-to-evaluate low-signal vessel wall pathology in cardiovascular disease. Healthy volunteers were imaged serially for up to 12 h after a standard dose of F-FDG ( = 15) or for up to 3 h after injection of a very low dose (about 5% of a standard dose; = 15). A cohort undergoing standard F-FDG PET ( = 15) on a conventional scanner with a 22-cm axial field of view served as a comparison group. Arterial wall signal, crosstalk with hematopoietic and lymphoid organs, and image quality were analyzed using standardized techniques. TB PET depicted the large vessel walls with excellent quality. The arterial wall could be imaged with high contrast up to 12 h after tracer injection. Ultralow-dose TB F-FDG images yielded a vessel wall signal and target-to-background ratio comparable to those of conventional-dose, short-axial-field-of-view PET. Crosstalk between vessel wall and lymphoid organs was identified with better accuracy in both TB PET cohorts than in conventional PET. TB PET enables detailed assessment of in vivo vessel wall biology and its crosstalk with other organs over an extended time window after tracer injection or at an ultralow tracer dose. These initial observations support the feasibility of serial imaging in low-risk populations and will stimulate future mechanistic studies or therapy monitoring in atherosclerosis and other vessel wall pathologies.
Topics: Humans; Fluorodeoxyglucose F18; Atherosclerosis; Arteries; Risk Factors; Biology
PubMed: 36175139
DOI: 10.2967/jnumed.122.264550 -
JCI Insight Apr 2019Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function...
Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro application of 2-DG decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3 to 5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated the loss of parvalbumin-expressing inhibitory interneurons. In summary, 2-DG may have therapeutic potential to restore network function following TBI.
Topics: Animals; Antimetabolites; Brain Contusion; Brain Injuries, Traumatic; Cerebral Cortex; Cortical Excitability; Deoxyglucose; Diet, Ketogenic; Disease Models, Animal; Epilepsy, Post-Traumatic; GABAergic Neurons; Glycolysis; In Vitro Techniques; Interneurons; Mice; Neural Inhibition; Parvalbumins
PubMed: 31038473
DOI: 10.1172/jci.insight.126506 -
The American Journal of Clinical... Jan 2022Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of...
BACKGROUND
Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.
OBJECTIVES
To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.
METHODS
In 2566 individuals of the population-based Maastricht Study (age: 60 ± 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in > 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.
RESULTS
Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β: 0.08; 95% CI: 0.02, 0.13) and SAF (β: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (β: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.
CONCLUSIONS
Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).
Topics: Aged; Chromatography, Liquid; Cross-Sectional Studies; Deoxyglucose; Diabetes Mellitus, Type 2; Diet; Diet Surveys; Dietary Exposure; Fasting; Female; Glycation End Products, Advanced; Glyoxal; Humans; Linear Models; Male; Mass Spectrometry; Middle Aged; Netherlands; Optical Imaging; Pyruvaldehyde; Skin
PubMed: 34625788
DOI: 10.1093/ajcn/nqab329