Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation

BACKGROUND Synaptotagmins(SYTs)are a family of 17 membrane transporters that function as calcium ion sensors during the release of Ca2+-dependent neurotransmitters and hormones.However,few studies have reported whether members of the SYT family play a role in glucose uptake in diabetic retinopathy(DR)through Ca2+/glucose transporter-1(GLUT1)and the possible regulatory mechanism of SYTs.AIM To elucidate the role of the SYT family in the regulation of glucose transport in retinal pigment epithelial cells and explore its potential as a therapeutic target for the clinical management of DR.METHODS DR was induced by streptozotocin in C57BL/6J mice and by high glucose medium in human retinal pigment epithelial cells(ARPE-19).Bioinformatics analysis,reverse transcriptase-polymerase chain reaction,Western blot,flow cytometry,ELISA,HE staining,and TUNEL staining were used for analysis.RESULTS Six differentially expressed proteins(SYT2,SYT3,SYT4,SYT7,SYT11,and SYT13)were found between the DR and control groups,and SYT4 was highly expressed.Hyperglycemia induces SYT4 overexpression,manipulates Ca2+influx to induce GLUT1 fusion with the plasma membrane,promotes abnormal expression of the glucose transporter GLUT1 and excessive glucose uptake,induces ARPE-19 cell apoptosis,and promotes DR progression.Parkin deficiency inhibits the proteasomal degradation of SYT4 in DR,resulting in SYT4 accumulation and enhanced GLUT1 fusion with the plasma membrane,and these effects were blocked by oe-Parkin treatment.Moreover,dysregulation of the myelin transcription factor 1(Myt1)-induced transcription of SYT4 in DR further activated the SYT4-mediated stimulus-secretion coupling process,and this process was inhibited in the oe-MYT1-treated group.CONCLUSION Our study reveals the key role of SYT4 in regulating glucose transport in retinal pigment epithelial cells during the pathogenesis of DR and the underlying mechanism and suggests potential therapeutic targets for clinical DR.

Effects of suppressing glucose transporter-1 by an antisense oligodeoxynucleotide on the growth of human hepatocellular carcinoma cells

BACKGROUND:The glucose transporter-1(Glut-1),a key ratelimiting factor in the transport and metabolism of glucose in cancer cells,is over-expressed in many human cancer cells and this overexpression is correlated with poor biological behavior. The increased levels of Glut-1 expression in hepatocellular carcinoma(HCC)cells functionally affect tumorigenicity.This study was undertaken to investigate effects of suppressing Glut-1 by an antisense oligodeoxynucleotide(AS-ODN)on the growth of human hepatocellular carcinoma(HepG-2)cells. METHODS:We used AS-ODN targeting against the Glut-1 gene in a HepG-2 cell line.There were four experimental groups: empty pcDNA3.1 vector(mock transfection),pcDNA3.1-anti-Glut(+),pcDNA3.1-Glut(+),and non-transfected HepG-2 cells. The Glut-1 mRNA expression was detected by RT-PCR and the Glut-1 protein expression by Western blotting after cell culture, and the glucose uptake was detected after glucose stimulation in each group. RESULTS:Compared with non-transfected HepG-2 or Glut-1 pcDNA3.1,a down-regulation of Glut-1 mRNA in HepG-2 cells transfected with anti-Glut-1 pcDNA3.1 was noted(P<0.05).Glut-1 protein in HepG-2 cells transfected with Glut-1 AS-ODN was decreased compared with non-transfected HepG-2,Glut-1 pcDNA3.1,or empty vectors. Glucose uptake by the HepG-2 cells transfected with AS-ODN was decreased at 1 hour after glucose stimulation.CONCLUSIONS:The application of Glut-1 AS-ODN can down-regulate the expression of Glut-1 at mRNA and protein,and inhibit glucose uptake partially in HepG-2 cells.The Glut-1 gene maybe a potential therapeutic target for HCC.

Constructing recombinant replication-defective adenoviral vectors that express glucose transporter-1 through in vitro ligation

BACKGROUND： We constructed a homologous recombination bacterial method based on the pAdEasy system, a widely used system, for generating recombinant adenoviral vectors that express glucose transporter- 1 （GLUT 1） in rats, OBJECTIVE： This study was designed to investigate the feasibility of generating recombinant replication-defective adenoviral vectors that express GLUT1 in rats by in vitro ligation based on the Adeno-X^TM system. DESIGN： An in vitro cell-based experiment. SETTING： This study was performed at the Linbaixin Medical Research Center of the Second Hospital Affiliated to Sun Yat-sen University and Central Laboratory for Prevention and Treatment of Tumor, Sun Yat-sen University between January and August 2004. MATERIALS： Male, adult, Sprague Dawley rats were used to extract total RNA from brain tissue. E. coli DH5 a and human embryonic kidney 293 cells （HEK293 cells） used in the present study were cryo-preserved by the Second Hospital Affiliated to Sun Yat-sen University. Rabbit anti-rat GLUT1 polyclonal antibody （Chemicon, U.S.A.） and primers （Shanghai Boya Bioengineering Co., Ltd） were also used. METHODS： E1/E3-deleted replication-defective adenoviral vectors were used. Using in vitro ligation, the target gene was first sub-cloned into a shuttle vector plasmid to obtain the fragment containing target gene expression cassettes by enzyme digestion. Subsequently, the fragment was co-transformed with linearized adenoviral backbone vector into the E. coli strain. The recombinant adenoviral plasmid was transfected into HEK293 cells to assembly recombinant adenoviral vectors with replication capabilities. The procedure was repeated several times for recombinant adenoviral vectors amplification. MAIN OUTCOME MEASURES： Efficiency of recombinant adenoviral vectors to express the target gene was measured by gene and protein expression through polymerase chain reaction and Western Blot assays, respectively. RESULTS： Results demonstrated that recombinant adenoviral vectors successfully expressed GLUT1 protein, with a relative molecular mass of 55000 in HEK293 cells. These results suggest that recombinant adenoviral vectors obtained by homologous bacterial recombination feature high efficiency, rapidness, and simplicity. CONCLUSION： We successfully amplified the rat GLUT1 gene and constructed replication-defective adenoviral vectors expressing GLUT1. The replication-defective adenoviral vectors proved to successfully express the target gene in HEK293 cells.

Value of glucose transport protein 1 expression in detecting lymph node metastasis in patients with colorectal cancer

BACKGROUND There are limited data on the use of glucose transport protein 1(GLUT-1)expre-ssion as a biomarker for predicting lymph node metastasis in patients with colorectal cancer.GLUT-1 and GLUT-3,hexokinase(HK)-II,and hypoxia-induced factor(HIF)-1 expressions may be useful biomarkers for detecting primary tumors and lymph node metastasis when combined with fluorodeoxyglucose(FDG)uptake on positron emission tomography/computed tomography(PET/CT).AIM To evaluate GLUT-1,GLUT-3,HK-II,and HIF-1 expressions as biomarkers for detecting primary tumors and lymph node metastasis with 18F-FDG-PET/CT.METHODS This retrospective study included 169 patients with colorectal cancer who underwent colectomy and preoperative 18F-FDG-PET/CT at Chungbuk National University Hospital between January 2009 and May 2012.Two tissue cores from the central and peripheral areas of the tumors were obtained and were examined by a dedicated pathologist,and the expressions of GLUT-1,GLUT-3,HK-II,and HIF-1 were determined using immunohisto-chemical staining.We analyzed the correlations among their expressions,various clinicopathological factors,and the maximum standardized uptake value(SUVmax)of PET/CT.RESULTS GLUT-1 was found at the center or periphery of the tumors in 109(64.5%)of the 169 patients.GLUT-1 positivity was significantly correlated with the SUVmax of the primary tumor and lymph nodes,regardless of the biopsy site(tumor center,P<0.001 and P=0.012;tumor periphery,P=0.030 and P=0.010,respectively).GLUT-1 positivity and negativity were associated with higher and lower sensitivities of PET/CT,respectively,for the detection of lymph node metastasis,regardless of the biopsy site.GLUT3,HK-II,and HIF-1 expressions were not significantly correlated with the SUVmax of the primary tumor and lymph nodes.CONCLUSION GLUT-1 expression was significantly correlated with the SUVmax of 18F-FDG-PET/CT for primary tumors and lymph nodes.Clinicians should consider GLUT-1 expression in preoperative endoscopic biopsy in interpreting PET/CT findings.

Continuous glucose monitoring metrics in pregnancy with type 1 diabetes mellitus

Managing diabetes during pregnancy is challenging,given the significant risk it poses for both maternal and foetal health outcomes.While traditional methods involve capillary self-monitoring of blood glucose level monitoring and periodic HbA1c tests,the advent of continuous glucose monitoring(CGM)systems has revolutionized the approach.These devices offer a safe and reliable means of tracking glucose levels in real-time,benefiting both women with diabetes during pregnancy and the healthcare providers.Moreover,CGM systems have shown a low rate of side effects and high feasibility when used in pregnancies complicated by diabetes,especially when paired with continuous subcutaneous insulin infusion pump as hybrid closed loop device.Such a combined approach has been demonstrated to improve overall blood sugar control,lessen the occurrence of preeclampsia and neonatal hypoglycaemia,and minimize the duration of neonatal intensive care unit stays.This paper aims to offer a comprehensive evaluation of CGM metrics specifically tailored for pregnancies impacted by type 1 diabetes mellitus.

Regulation of the expression and function of glucose transporter-1 by TGF- β1 and high glucose in mesangial cells

Objective To study the effects of high glucose and transforming growth factor β1 (TGF β1) on the expression and function of glucose transporter 1 (GLUT1) in mouse mesangial cells Methods Cultured mouse mesangial cells were used The expression of GLUT1 mRNA was detected by Northern Blot; glucose uptake and its kinetics were determined with a 2 Deoxy [ 3H] D glucose uptake assay Results Mesangial cells exposed to enriched glucose medium (20?mmol/L) for 72 hours demonstrated a decrease in both GLUT1 mRNA and V max for uptake of the glucose analog, 2 deoxy D glucose (2DOG), as compared to mesangial cells cultured in physiologic glucose concentrations(5 5?mmol/L) In contrast, hypertonic mannitol had no effect on GLUT1 mRNA levels TGF β1 treatment for 10 hours stimulated 2DOG uptake, both in 5 5?mmol/L and 20?mmol/L glucose medium, by approximately 4 28 fold in a dose dependent manner (2?ng/ml maximum) Kinetic analysis of 2DOG uptake revealed an increase in V max and a decrease in K m in the presence of TGF β1 TGF β1 also up regulated the expression of GLUT1 mRNA in mesangial cells The addition of anti TGF β neutralizing antibody (30?μg/ml) in mesangial cells cultured in enriched glucose medium (20?mmol/L) led to a 40% decrease in 2DOG uptake Conclusions The expression of GLUT1 can be suppressed by exposure of mesangial cells to high glucose medium, which may serve as a protective mechanism against possible adverse effects of excessive glucose flux into cells TGF β1 stimulates glucose uptake by enhancing the expression and function of GLUT1 in mesangial cells This effect is independent of the glucose milieu in the cultured medium

Effect of exercise during pregnancy on offspring development through ameliorating high glucose and hypoxia in gestational diabetes mellitus

BACKGROUND Gestational diabetes mellitus(GDM)women require prenatal care to minimize short-and long-term complications.The mechanism by which exercise during pregnancy affects organ development and whether glucose transporter(GLUT)1 plays a role in GDM offspring organ development remains unknown.AIM To determine the effect of exercise during pregnancy on the cardiac,hepatic and renal development of GDM mother’s offspring.METHODS Placenta samples were collected from humans and mice.GDM mouse models were created using streptozotocin along with a GDM with exercise group.The hearts,livers and kidneys of 3-and 8-week-old offspring were collected for body composition analysis and staining.The effects of high glucose levels and hypoxia were investigated using HTR8/SVneo.Transwell and wound-healing assays were performed to assess cell migration.Immunofluorescence accompanied with TUNEL and Ki67 staining was used to explore apoptosis and proliferation.RESULTS Exercise during pregnancy downregulated the GLUT1 and hypoxia inducible factor-1αexpression in placenta from individuals with GDM.Cobalt chloride induced hypoxia and high glucose levels also significantly decreased migration and apoptosis of HTR8/SVneo cells.In addition,exercise reduced inflammatory cell infiltration in the liver and decreased the tubular vacuolar area in the kidneys of offspring.CONCLUSION GDM affects the growth and development of organs in offspring.Exercise during pregnancy can reverse adverse effects of GDM on the development of the heart,liver,and kidney in offspring.

LIN28A attenuates high glucose-induced retinal pigmented epithelium injury through activating SIRT1-dependent autophagy

AIM:To evaluate the effects of LIN28A(human)on high glucose-induced retinal pigmented epithelium(RPE)cell injury and its possible mechanism.METHODS:Diabetic retinopathy model was generated following 48h of exposure to 30 mmol/L high glucose(HG)in ARPE-19 cells.Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blot tested the expression of the corresponding genes and proteins.Cell viability as well as apoptosis was determined through cell counting kit-8(CCK-8)and flow cytometry assays.Immunofluorescence assay was adopted to evaluate autophagy activity.Caspase 3 activity,oxidative stress markers,and cytokines were appraised adopting their commercial kits,respectively.Finally,ARPE-19 cells were preincubated with EX527,a Sirtuin 1(SIRT1)inhibitor,prior to HG stimulation to validate the regulatory mechanism.RESULTS:LIN28A was downregulated in HG-challenged ARPE-19 cells.LIN28A overexpression greatly inhibited HGinduced ARPE-19 cell viability loss,apoptosis,oxidative damage as well as inflammatory response.Meanwhile,the repressed autophagy and SIRT1 in ARPE-19 cells challenged with HG were elevated after LIN28A overexpression.In addition,treatment of EX527 greatly inhibited the activated autophagy following LIN28A overexpression and partly abolished the protective role of LIN28A against HG-elicited apoptosis,oxidative damage as well as inflammation in ARPE-19 cells.CONCLUSION:LIN28A exerts a protective role against HG-elicited RPE oxidative damage,inflammation,as well as apoptosis via regulating SIRT1/autophagy.

Dual-functional marigold-like Zn_(x)Cd_(1-x)S homojunction for selective glucose photoreforming with remarkable H_(2)coproduction

The global commitment to pivoting to sustainable energy and products calls for technology development to utilize solar energy for hydrogen(H_(2))and value-added chemicals production by biomass photoreforming.Herein,a novel dual-functional marigold-like Zn_(x)Cd_(1-x)S homojunction has been the production of lactic acid with high-yield and H_(2)with high-efficiency by selective glucose photoreforming.The optimized Zn_(0.3)Cd_(0.7)S exhibits outstanding H_(2)generation(13.64 mmol h^(-1)g^(-1)),glucose conversion(96.40%),and lactic acid yield(76.80%),over 272.80 and 19.21 times higher than that of bare ZnS(0.05 mmol h^(-1)g^(-1))and CdS(0.71 mmol h^(-1)g^(-1))in H_(2)generation,respectively.The marigold-like morphology provides abundant active sites and sufficient substrates accessibility for the photocatalyst,while the specific role of the homojunction formed by hexagonal wurtzite(WZ)and cubic zinc blende(ZB)in photoreforming biomass has been demonstrated by density functional theory(DFT)calculations.Glucose is converted to lactic acid on the WZ surface of Zn_(0.3)Cd_(0.7)S via the photoactive species·O_(2)^(-),while the H_(2)is evolved from protons(H^(+))in H_(2)O on the ZB surface of Zn_(0.3)Cd_(0.7)S.This work paves a promising road for the production of sustainable energy and products by integrating photocatalysis and biorefine.

Enhanced glucose homeostasis via Clostridium symbiosummediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery

BACKGROUND The small intestine is known to play a crucial role in the development and remission of diabetes mellitus(DM).However,the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood.AIM To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism.METHODS Streptozotocin(STZ)was used to induce DM in Sprague-Dawley(SD)rats at a dose of 60 mg/kg.The rats were then randomly divided into two groups:The mid-small intestine bypass(MSIB)group and the sham group(underwent switch laparotomy).Following a 6-wk recovery period post-surgery,the rats underwent various assessments,including metabolic parameter testing,analysis of liver glycogen levels,measurement of key gluconeogenic enzyme activity,characterization of the gut microbiota composition,evaluation of hormone levels,determination of bile acid concentrations,and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor.RESULTS The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism,along with increased hepatic glycogen content.Furthermore,there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase.Importantly,the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus,Clostridium symbiosum,Ruminococcus gnavus,and Bilophila.Moreover,higher levels of secondary bile acids,such as intestinal lithocholic acid,were observed in this group.Remarkably,the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1(GLP-1)at 6 wk postoperatively,highlighting their potential role in glucose regulation.These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota.CONCLUSION The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats.This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1,resulting in a favorable modulation of glucose homeostasis.

Decreased TRPM7 alleviates high glucose-induced renal tubular epithelial cell injury by inhibiting the HMGB1/TLR4 signaling pathway

Objective:To explore the regulatory mechanism of transient receptor potential melastatin-7(TRPM7)in high glucose-induced renal tubular epithelial cell injury.Methods:The expression of TRPM7 in the serum of diabetic nephropathy patients and high glucose-induced HK-2 cells was detected by RT-qPCR.Then,the TRPM7 interference vector was constructed,and the downstream high mobility group box 1(HMGB1)/Toll-like receptor 4(TLR4)signaling pathway proteins were detected.Next,in addition to interference with TRPM7 expression,overexpression of HMGB1 in high glucose-induced HK-2 cells was performed.Cell activity,apoptosis,oxidative stress levels,and inflammation levels were determined by CCK8,TUNEL,Western blotting,immunofluorescence and related kits.Results:TRPM7 expression was upregulated in the serum of diabetic nephropathy patients and high glucose-induced HK-2 cells.Interference with TRPM7 reduced cell damage,epithelial-mesenchymal transition,oxidative stress,and inflammatory response in high glucose-induced HK-2 cells via inhibiting the HMGB1/TLR4 signaling pathway.However,the effects induced by TRPM7 silencing were abrogated by HMGB1 overexpression.Conclusions:Decreased TRPM7 alleviates high glucose-induced renal tubular epithelial cell injury by inhibiting the HMGB1/TLR4 signaling pathway.Further animal experiments and clinical trials are warranted to verify its effect.

Effects of glucagon-like peptide-1 receptor agonists on glucose excursion and inflammation in overweight or obese type 2 diabetic patients

BACKGROUND Currently,the lack of comparative studies between weekly and daily formulations of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for glucose excursion is worth investigation.AIM To investigate the effects of weekly and daily formulations of GLP-1RA on glucose excursion and inflammation in overweight and obese patients with type 2 diabetes.METHODS Seventy patients with type 2 diabetes mellitus who were treated at our hospital between January 2019 and January 2022 were enrolled in this retrospective analysis.All patients were treated with metformin.We evaluated changes in blood glucose levels and a series of important indicators in patients before and after treatment with either a weekly or daily preparation of GLP-1RA(group A;n=33 and group B;n=37).RESULTS The degree of decrease in the levels of fasting blood glucose,mean blood glucose,mean amplitude of glycemic excursions,total cholesterol,triglycerides,tumor necrosis factor-α,interleukin-6,and high-sensitivity C-reactive protein after treatment in group A was higher than that in group B(P<0.05),whereas the 2-h postprandial blood glucose levels decreased more so in group B than in group A(P<0.001).However,there were no statistically significant differences in the levels of glycated hemoglobin,standard deviation of blood glucose,coefficient of variation,absolute mean of daily differences,percentage of time with 3.9 mmol/L<glucose<10 mmol/L,and high-and low-density lipoproteins between the two groups(P>0.05).The incidence of adverse reactions was significantly lower in group A than in group B(P<0.05).CONCLUSION The effect of the weekly preparation of GLP-1RA in controlling blood glucose levels in the patients,suppressing inflammation,and reducing adverse reactions was significantly higher than that of the daily preparations,which is worthy of clinical promotion.

Effect of rhein on glucose transporter-1 expression and its function in glomerular mesangial cells

Objective To explore the effect of rhein on the regulation of glucose transporter 1 (GLUT1) overexpression and the possible molecular mechanism that rhein antagonize the effect of transforming growth factor β1 (TGF β1) in glomerular mesangial cells Methods Cultured mouse mesangial cells were used The expression of GLUT1 mRNA was detected by Northern blotting; the ability of glucose uptake was determined by 2 deoxy [ 3H] D glucose uptake assay Results Rhein had no effect on glucose uptake in mesangial cells cultured in normal glucose concentration TGF β1 could upregulate the expression of GLUT1 mRNA and glucose uptake in mesangial cells This effect was markedly attenuated by the addition of rhein in a dose dependent manner Conclusions TGF β1 could upregulate the expression of GLUT1 mRNA and glucose uptake in mesangial cells, resulting in excessive glucose consumption and extracellular matrix production in diabetic nephropathy Rhein antagonized the effect of TGF β1 in mesangial cells, so it might be a hopeful remedy for the treatment of patients with diabetic

IDENTIFICATION OF GLUCOSE TRANSPORTER- 1 AND ITS FUNCTIONAL ASSAY IN MOUSE GLOMERULAR MESANGIAL CELLS CULTURED IN VITRO

To evaluate the role of glucose transporter- l (GLUT1) in the glucose uptake of glomerular mesangial cells. Methods. Cultured C57/SJL mouse mesangial cells were used in the study. The expression of GLUT1 mRNA was detected by RT- PCR. The expression of GLUT1 protein was detected by immunofluorescence and flow cytometry. The uptake of glucose and its kinetics were determined by 2- deoxy- [3H]- D- glucose uptake. Results. Both GLUT1 mRNA and protein were found in mouse glomerular mesangial cells. 2- deoxy- D- glucose uptake and kinetics assay showed that this glucose transporter had high affinity for glucose and the glucose uptake specificity was further confirmed by phloretin. Conclusion. Functional GLUT1 did present in mouse mesangial cells cultured in vitro and it might be the predominant transporter mediated the uptake of glucose into mesangial cells.

Glucagon-like-1 receptor agonists and sodium/glucose cotransporter-2 inhibitors combination—are we exploiting their full potential in a real life setting?

BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)and cardiovascular event prevention.In patients with type 2 diabetes,the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising.AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up.METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with(1)GLP-1RA on top of SGLT-2i,(2)SGLT-2i on top of GLP-1RA compared to(3)simultaneous addition of both agents.The primary study endpoint was the proportion of participants with HbA1c<7.0%and/or 5%bodyweight reduction.Secondary outcomes included changes in fasting plasma glucose(FPG),prandial plasma glucose,lowdensity lipoprotein cholesterol,estimated glomerular filtration rate(eGFR),and cardiovascular(CV)incidents assessment over a follow-up period of 12 mo.RESULTS The majority of patients were over 65-years-old,had diabetes duration for more than 10 years.The initial body mass index was 39.41±5.49 kg/m2 and HbA1c 8.32±1.26%.Around half of the patients in all three groups achieved target HbA1c below 7%.A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy.The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group(P=0.021),and 5%weight loss was dominantly achieved in the simultaneous therapy group(P=0.044).A composite outcome(reduction of HbA1c below 7%(53 mmol/mol)with 5%weight loss)was achieved in 32.3%of total patients included in the study.Only 18.2%of patients attained composite outcome defined as HbA1c below 7%(53 mmol/mol)with 5%weight loss and low-density lipoprotein cholesterol<2.5 mmol/L.There were no significant differences between treatment groups.No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period.CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control,although it remains to be determined whether simultaneous or sequential intensification is better.

口服葡萄糖耐量试验1h血糖对糖尿病前期的诊断和鉴别价值

目的:探讨口服葡萄糖耐量试验(OGTT)1 h血糖对糖尿病前期的诊断和鉴别价值。方法:收集2019年6月至2022年6月于北京中医药大学东直门医院门诊及住院行OGTT的受试者1 206例,其中血糖正常412例,糖尿病前期358例,糖尿病436例。比较3组OGTT不同时点血糖与空腹血糖(FPG)、空腹胰岛素(FINS)、稳态模型胰岛素抵抗指数(HOMA-IR)、胰岛β细胞分泌功能指数(HOMA-β)水平;采用ROC曲线分析OGTT 1 h血糖对糖尿病前期的诊断和鉴别价值。结果:3组OGTT各时点血糖均为糖尿病组>糖尿病前期组>血糖正常组(P<0.05)。FPG、HOMA-IR糖尿病组>糖尿病前期组>血糖正常组,FINS、HOMA-β糖尿病组<糖尿病前期组<血糖正常组(P<0.05)。ROC曲线分析结果显示,OGTT 1 h血糖诊断糖尿病前期的AUC(95%CI)为0.758(0.724~0.792),以敏感度最大选取最佳切点值,该值为9.35 mmol/L,此时敏感度为0.701,特异度为0.709;OGTT 1 h血糖对糖尿病和糖尿病前期鉴别的AUC(95%CI)为0.956(0.942~0.969),以敏感度最大选取最佳切点值,该值为12.55 mmol/L,此时敏感度为0.901,特异度为0.908。结论:OGTT 1 h血糖对糖尿病前期具有一定的诊断和鉴别价值。

姜酮通过激活Nrf2/HO-1信号通路减轻OGD/R后氧化应激损伤对HT22细胞凋亡的抑制作用

目的:探讨姜酮对氧糖剥夺/复糖复氧(OGD/R)后小鼠海马神经元HT22细胞的保护作用,阐明其相关作用机制。方法:培养HT22细胞,设置不同OGD/R时间梯度,建立OGD/R细胞损伤模型。HT22细胞分为对照组、OGD/R组、OGD/R+1μmol·L^(-1)姜酮组、OGD/R+10μmol·L^(-1)姜酮、OGD/R+100μmol·L^(-1)姜酮组和OGD/R+0.2%二甲亚枫(DMSO)组,CCK-8法检测各组细胞活性并计算各组细胞存活率,确定姜酮最适药物浓度。细胞分为对照组、OGD/R组、OGD/R+姜酮组和OGD/R+姜酮+核因子E2相关因子2(Nrf2)抑制剂(ML385)组,OGD/R+姜酮组细胞经姜酮给药处理4 h后予以OGD 8 h和复糖复氧8 h处理,OGD/R+姜酮+ML385组细胞在姜酮给药前予以10μmol·L^(-1)ML385预处理6 h,CCK-8法检测各组细胞活性,Western blotting法检测各组细胞中Nrf2、血红素加氧酶1(HO-1)、B细胞淋巴瘤2(Bcl-2)和Bcl-2相关X蛋白(Bax)蛋白表达水平,酶联免疫吸附试验(ELISA)法检测各组细胞培养上清中超氧化物歧化酶(SOD)活性和丙二醛(MDA)水平。结果:与对照组比较,HT22细胞经OGD 8 h和复糖复糖8 h处理后细胞存活率低于50%,以OGD 8 h和复糖复糖8 h建立HT22细胞OGD/R模型。与OGD/R组比较,OGD/R+不同剂量姜酮组细胞存活率均不同程度升高,其中OGD/R+100μmol·L^(-1)姜酮组细胞存活率升高最明显(P<0.01),故选用100μmol·L^(-1)姜酮用于后续实验。与对照组比较,OGD/R组细胞活性明显降低(P<0.01),细胞中Nrf2、HO-1和Bax蛋白表达水平明显升高(P<0.01),Bcl-2蛋白表达水平明显降低(P<0.05),细胞培养上清中SOD活性明显降低(P<0.01),MDA水平明显升高(P<0.01);与OGD/R组比较,OGD/R+姜酮组细胞活性明显升高(P<0.01),细胞中Nrf2、HO-1和Bcl-2蛋白表达水平明显升高(P<0.05或P<0.01),Bax蛋白表达水平明显降低(P<0.05),细胞培养上清中SOD活性明显升高(P<0.01),MDA水平明显降低(P<0.01);与OGD/R+姜酮组比较,OGD/R+姜酮+ML385组细胞活性明显降低(P<0.01),细胞中Nrf2、HO-1和Bcl-2蛋白表达水平明显降低(P<0.01),Bax蛋白表达水平明显升高(P<0.01),细胞培养上清中SOD活性明显降低(P<0.01),MDA水平明显升高(P<0.05)。结论:姜酮可通过激活Nrf2/HO-1信号通路减轻OGD/R后氧化应激损伤对HT22细胞凋亡的抑制作用。

基于持续扫描式葡萄糖监测系统探讨二甲双胍对青春期T1DM患儿的应用价值

目的基于持续扫描式葡萄糖监测系统探讨二甲双胍联合胰岛素注射液治疗青春期1型糖尿病(T1DM)儿童的疗效。方法2018年1月至2023年5月门诊随访的青春期T1DM儿童99例,48例胰岛素联合盐酸二甲双胍片治疗为观察组,51例单用胰岛素治疗为对照组。比较两组儿童各项临床资料、监测指标及安全性。结果在3个月随访时观察组、对照组平均目标范围内时间(TIR)分别为76.6%±9.1%、65.9%±15.0%,中位高血糖时间(TAR)两组分别为7.0%(3.0%~14.3%)、21.0%(12.0%~29.0%),平均低血糖时间(TBR)两组分别为14.5%±7.1%、10.2%±6.8%,在6个月随访时观察组、对照组平均TIR两组分别为76.0%±8.9%、65.5%±14.3%,中位TAR两组分别为8.0%(3.3%~13.8%)、24.0%(15.0%~29.0%),平均TBR两组分别为14.4%±5.9%、10.0%±6.8%,以上变量两组间差异均有统计学意义(P均<0.05)。观察组两次随访中位胰岛素用量低于对照组。48例观察组患儿两次随访时中位胰岛素用量、中位BMI、平均TIR、平均TBR均高于其基线水平,中位TAR水平低于自身基线水平,以上变量差异均有统计学意义(P均<0.05)。观察组4例(8.33%)出现胃肠道症状,无严重低血糖发生。结论二甲双胍联合胰岛素治疗方案,可以有效提高青春期T1DM儿童TIR。TBR水平增加,并不增加严重低血糖风险,安全性良好。二甲双胍联合胰岛素治疗对青春期T1DM儿童是一种可行的选择。

脂联素、瘦素、Pref-1与胰岛素抵抗关系及联合检测预测糖尿病前期病情进展风险的效能

目的探讨脂联素、瘦素、前脂肪细胞因子-1(Pref-1)与胰岛素抵抗的关系及联合检测预测糖尿病前期病情进展风险的效能。方法选取2019年1月至2023年1月郑州大学第一附属医院收治的304例糖尿病前期患者进行前瞻性队列研究。根据1年内是否进展为糖尿病分为糖尿病组(62例)、糖尿病前期组(242例),另选同期正常糖耐量人群60例作为对照组。比较三组受检者的基线资料及血清脂联素、瘦素、Pref-1表达水平,采用Pearson法分析血清脂联素、瘦素、Pref-1水平与胰岛素抵抗(IR)的相关性,采用Logistic回归分析血清脂联素、瘦素、Pref-1水平对糖尿病前期病情进展的影响,采用受试者工作特征曲线(ROC)分析血清脂联素、瘦素、Pref-1单独及联合检测对糖尿病前期病情进展风险的预测效能。结果三组受检者的年龄、体质量指数(BMI)、甘油三酯、空腹血糖、胰岛素抵抗指数(HOMA-IR)比较,糖尿病组高于糖尿病前期组,且糖尿病前期组高于对照组,差异均有统计学意义(P<0.05);糖尿病组患者的脂联素、Pref-1分别为(2.82±0.93)mg/L、(0.30±0.10)μg/L,明显低于糖尿病前期组的(6.76±2.17)mg/L、(0.51±0.16)μg/L,且糖尿病前期组患者的脂联素、Pref-1明显低于对照组的(8.45±2.80)mg/L、(0.84±0.27)μg/L,而糖尿病组患者的瘦素为(12.00±2.98)μg/L,明显高于糖尿病前期组的(8.79±2.87)μg/L,且糖尿病前期组患者的瘦素明显高于对照组的(3.56±1.09)μg/L,差异均有统计学意义(P<0.05);脂联素(r=-0.694)、Pref-1(r=-0.853)与HOMA-IR呈负相关(P<0.05),瘦素(r=0.660)与HOMA-IR呈正相关(P<0.05);Logistic回归分析结果显示,年龄、BMI、甘油三酯、空腹血糖、脂联素、瘦素、Pref-1是糖尿病前期患者病情进展的独立影响因素,将年龄、BMI、甘油三酯、空腹血糖进行校正,以脂联素、瘦素、Pref-1作为自变量,脂联素、瘦素、Pref-1仍是糖尿病前期患者病情进展的独立影响因素(P<0.05);ROC曲线分析结果显示,脂联素预测糖尿病前期病情进展风险的曲线下面积(AUC)为0.730,截断值≤3.51 mg/L,敏感度为79.03%,特异度为59.09%,瘦素预测的AUC为0.760,截断值>10.78μg/L,敏感度为67.74%,特异度为73.55%,Pref-1预测的AUC为0.795,截断值≤0.37μg/L,敏感度为80.65%,特异度为65.70%,且联合检测预测糖尿病前期病情进展的AUC为0.904,敏感度为87.10%,特异度为82.23%(P<0.05)。结论血清脂肪因子脂联素、Pref-1与不同糖耐量受损人群IR呈负相关,瘦素与之呈正相关,且联合检测对糖尿病前期病情进展风险具有一定预测价值,可作为临床早期预测病情进展风险的辅助指标。

肾上腺嗜铬细胞瘤患者组织葡萄糖转运蛋白1和拓扑异构酶ⅡA表达与临床特征及预后的相关性分析

目的探讨葡萄糖转运蛋白1(GLUT1)和拓扑异构酶ⅡA(TOP2A)在肾上腺嗜铬细胞瘤(PPGL)患者组织中的表达与临床特征及预后的相关性。方法选取2014年3月至2020年6月于新疆维吾尔自治区人民医院行手术切除的120例PPGL组织作为实验组。另收集同期行手术切除的100例无功能肾上腺腺瘤的肾上腺组织作为对照组。采用免疫组织化学染色法检测组织中GLUT1和TOP2A表达情况。通过Cox回归分析PPGL患者预后的影响因素。结果实验组中GLUT1的低表达率和TOP2A的高表达率均高于对照组[51.7%(62/120)比14.0%(14/100)、52.5%(63/120)比19.0%(19/100)],差异均有统计学意义(χ^(2)=34.225、31.829,均P<0.001)。GLUT1、TOP2A表达水平与镜下组织浸润和Ki-67有关(均P<0.05)。预后良好组中GLUT1高表达和TOP2A低表达比例均高于预后不良组,差异均有统计学意义(均P<0.001)。单因素分析结果显示,患者镜下组织浸润、Ki-67、GLUT1、TOP2A均是影响预后的因素(均P<0.001)。Cox多因素回归分析显示TOP2A、镜下组织浸润及Ki-67均是导致PPGL患者预后不良的危险因素,GLUT1为保护因素(均P<0.001)。结论GLUT1在PPGL组织中呈低表达,TOP2A呈高表达,与患者预后不良有关。