BACKGROUND Tacrolimus(FK506)is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival.However,it is linked to hyperglycemia and insulin resistance,contribut...BACKGROUND Tacrolimus(FK506)is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival.However,it is linked to hyperglycemia and insulin resistance,contributing to new-onset diabetes after transplantation and negatively affecting islet function.AIM To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes.METHODS HL7702 cells were treated with different concentrations of tacrolimus(0.1 mg/L,1 mg/L,5 mg/L)for 24 hours.The proteins involved in insulin signaling were detected by Western blotting.RESULTS Compared with the control group,phosphorylation of insulin receptor substrate(IRS)1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L.Phosphorylation of IRS1 at Ser 1101 was also increased,although not significantly.However,phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly.The levels of phosphorylated glycogen synthase kinase 3αSer 21 and Ser 9 were increased.Surprisingly,phosphorylation of glycogen synthase at Ser 641 was increased.There was no significant change in the activity of glycogen phosphorylase.CONCLUSION Tacrolimus has no direct effect on hepatic glucose metabolism,but inhibits IRS1-mediated insulin signaling.This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.展开更多
Background: Diabetes mellitus (DM) is a disease characterized by hyperglycemia due to (a) insulin-insufficiency (type I DM), or (b) impaired glucose cell-entry (insulin resistance) due to the downregulation of insulin...Background: Diabetes mellitus (DM) is a disease characterized by hyperglycemia due to (a) insulin-insufficiency (type I DM), or (b) impaired glucose cell-entry (insulin resistance) due to the downregulation of insulin cell receptors (type II DM). Type I DM usually presents with florid manifestations contrary to a slowly-progressive type II. Patients and methods: Over the past 10 years, we encountered 9 obese patients with controlled insulin-requiring type II DM for years, at a dose of 62 ± 5 units/day, who developed sudden and severe insulin resistance (IR) that required 210 ± 25 units daily. All patients had very high levels of anti-Glutamic Acid Decarboxylase (GAD) antibodies. Despite a lack of previous testing for anti-GAD antibodies, they were treated, with Cyclosporin A (Cy), as an autoimmune disorder superimposed on their type II MD. Initially all patients were treated with 100 mg, of Cy, twice daily aiming at an initial trough level of 100 - 150 ng/ml. Three months later, the dose was reduced to 50 mg twice daily for a total of 2 years. Results: Amelioration of IR was achieved by 1 month with a reduction of daily insulin requirement to 123 ± 16 units that further decreased to 76 ± 11 by the end of the 3rd month. Such improvement persisted for 2 years and >1 year after Cy discontinuation. Moreover, a decline in insulin requirements was associated with a parallel decrease in anti-GAD antibody levels and an increase in C-peptide insulin without kidney disease. Conclusion: Anti-GAD antibodies can induce acute IR in type II DM, and this phenomenon can be treated safely and effectively with Cy.展开更多
Premixed insulin combines two types of insulin in a single injection.This combination streamlines dosing for patients with type 1 or type 2 diabetes,thereby enhancing convenience.However,patients receiving premixed in...Premixed insulin combines two types of insulin in a single injection.This combination streamlines dosing for patients with type 1 or type 2 diabetes,thereby enhancing convenience.However,patients receiving premixed insulin commonly have less satisfactory blood glucose control.The fixed ratio of insulin in these formulations frequently fails to account for the nuanced demands of individualized glucose-lowering therapy.Moreover,local absorption of mixed insulin and potential systemic autoimmune responses may further compromise glycaemic control.The co-formulation of insulin degludec and insulin aspart introduces a new combination of the two insulin types within a single injection,offering a promising solution for mitigating the limitations inherent in premixed insulin.展开更多
Insulin resistance(IR)is widely recognized as a key contributor to metabolic disorders,and various surrogate indices have been developed to estimate IR in clinical and research settings.The hyperinsulinemic-euglycemic...Insulin resistance(IR)is widely recognized as a key contributor to metabolic disorders,and various surrogate indices have been developed to estimate IR in clinical and research settings.The hyperinsulinemic-euglycemic clamp is considered the gold standard method for assessing insulin resistance due to its precision;however,its complexity limits its widespread clinical application.Consequently,surrogate indices derived from fasting and post-load glucose and insulin levels have been developed to estimate IR,facilitating early detection and risk stratification in metabolic disorders.This mini-review discusses the clinical utility,strengths,and limitations of key IR indices,including the homeostasis model assessment of IR,quantitative insulin sensitivity check index,Matsuda index,and triglyceride-glucose index.Overall,the evidence presented to date suggests that these indices provide valuable estimates of IR in various popula-tions.Yet,their applicability varies depending on ethnic background,disease status,and clinical setting.Integrating these indices into routine clinical practice and research could improve metabolic risk assessment and guide preventive interventions.Further investigations are necessary to refine their accuracy and determine optimal cut-off values for various populations.展开更多
BACKGROUND Cardiovascular disease represents a major complication in patients with type 2 diabetes mellitus(T2DM),with insulin resistance(IR)recognized as a key underlying pathophysiological mechanism.The metabolic sc...BACKGROUND Cardiovascular disease represents a major complication in patients with type 2 diabetes mellitus(T2DM),with insulin resistance(IR)recognized as a key underlying pathophysiological mechanism.The metabolic score for IR(METS-IR),a simple,non-invasive,and insulin-independent surrogate marker of IR,has been validated for risk stratification and prognostic assessment in conditions such as hypertension,ischemic cardiomyopathy,and T2DM.Monitoring fluctuations in METS-IR levels among individuals with T2DM may facilitate early identification of elevated cardiovascular risk and inform timely therapeutic adjustments.AIM To investigate the association between METS-IR and cardiovascular risk in patients with T2DM and to evaluate its potential utility as a predictive biomarker.METHODS This study represents a secondary analysis of a multicenter randomized controlled trial,ultimately including 10191 patients with T2DM aged 40 years to 79 years,with a follow-up duration of approximately 10 years.Baseline METS-IR was calculated using triglycerides,body mass index,high-density lipoprotein cholesterol and fasting plasma glucose.The predictive value of METS-IR for major adverse cardiovascular events(MACEs),all-cause mortality,congestive heart failure,and major coronary heart disease events,was assessed using Cox proportional hazards models,restricted cubic spline analysis,and stratified subgroup analyses.Multivariable adjustments were performed to account for potential confounding factors.RESULTS The incidence of MACEs increased steadily across higher METS-IR quartiles.After adjusting for multiple confounding factors,hazard ratios comparing the highest to the lowest METS-IR quartile were 1.25[95%confidence interval(CI):1.08-1.45]for MACEs,1.55(95%CI:1.23-1.96)for cardiovascular death,1.39(95%CI:1.21-1.59)for allcause mortality,2.22(95%CI:1.74-2.82)for congestive heart failure,and 1.35(95%CI:1.17-1.56)for major coronary heart disease.Restricted cubic spline analysis supported a positive,dose-dependent relationship between rising METS-IR levels and cardiovascular risk.Moreover,adding METS-IR to conventional risk prediction models enhanced their performance,as evidenced by improvements in the C-statistic,net reclassification improvement,and integrated discrimination improvement.Subgroup analyses indicated possible interactions between METS-IR,hemoglobin A1c levels,and aspirin therapy.CONCLUSION METS-IR shows a strong correlation with cardiovascular risk in individuals with T2DM.Tracking METS-IR levels could enhance risk assessment and the prediction of cardiovascular events.展开更多
Objective:To evaluate the therapeutic potential of coumarin-loaded chitosan nanoparticles(CNNPs)in managing high-fructose diet-induced diabetes and associated complications.Methods:CNNPs were synthesized using an ioni...Objective:To evaluate the therapeutic potential of coumarin-loaded chitosan nanoparticles(CNNPs)in managing high-fructose diet-induced diabetes and associated complications.Methods:CNNPs were synthesized using an ionic gelation method with chitosan coating and characterized.Rats with a high-fructose diet-induced diabetes were treated with coumarin and CNNPs(30,70,and 100 mg/kg)for 6-12 weeks.Metabolic,inflammatory,oxidative stress,organ function,and cardiovascular parameters were assessed,and qRT-PCR studies were carried out for measuring the mRNA expression of glucose transporter-4(GLUT-4),sirtuin-1(SIRT1),pyrin domain containing-3(NLRP3),sterol regulatory element binding protein 1c(SREBP-1c),forkhead box O3(FOXO3),and endothelial nitric oxide synthase(eNOS)genes.Results:Nanoparticle characterization revealed a Z-average size of 510.8 nm with a+14 mV zeta potential.CNNP treatment was more effective than coumarin,normalizing glycemic markers(glycosylated hemoglobin,serum insulin,and fasting blood glucose),and lipid profiles(total cholesterol,low-density lipoprotein cholesterol,triglycerides,and high-density lipoprotein cholesterol).Significant improvements were also seen in adipokines(adiponectin,chemerin,and leptin),inflammatory cytokines(interleukin-6 and tumor necrosis factor-α),and oxidative stress markers(catalase,superoxide dismutase and malonaldehyde).In addition,both treatments significantly upregulated the gene expression of SIRT1,GLUT-4,and eNOS,and downregulated FOXO3,SREBP-1c,and NLRP3.Histopathological studies confirmed that CNNPs ameliorated diabetes-induced structural abnormalities in major organs.Conclusions:CNNPs demonstrate improved bioavailability and therapeutic efficacy,offering a promising strategy for managing high-fructose diet-induced metabolic dysfunction and its complications.展开更多
[Objectives]To evaluate the impact of nasal insulin administration on postoperative delirium(POD)through meta-analysis.[Methods]The Cochrane Library,PubMed,Embase,Web of Science,China National Knowledge Infrastructure...[Objectives]To evaluate the impact of nasal insulin administration on postoperative delirium(POD)through meta-analysis.[Methods]The Cochrane Library,PubMed,Embase,Web of Science,China National Knowledge Infrastructure(CNKI),Wanfang Database,and China Science and Technology Journal Database(CSTJ)were systematically searched for relevant literature published prior to February 27,2025.Literature screening and data extraction were conducted by two independent researchers in accordance with predetermined inclusion and exclusion criteria.The primary observation indicator was the incidence of POD across various treatment populations.The risk ratio for the primary outcome was calculated using the Mantel-Haenszel method.The secondary outcomes included the adverse effects associated with insulin treatment,which encompassed the glycemic variability indices,the incidence of nasal irritation symptoms following administration,hypoglycemic reactions,and insulin allergic reactions.The study protocol was registered on PROSPERO(CRD420250607492)before data extraction.[Results]A total of five randomized controlled trials involving 357 patients were included in the analysis.In the adult population undergoing surgical procedures,the administration of insulin via nasal delivery was found to significantly reduce the incidence of POD[RR=0.35,95%CI(0.23-0.53),P<0.001].The results of the subgroup analysis indicated that there were notable differences in the effectiveness of various doses of insulin administered nasally in preventing POD.Specifically,both the 20 U dose group[RR=0.45,95%CI:(0.29,0.70),P<0.001]and the 30 U dose group[RR=0.01,95%CI:(0.03,0.42),P<0.001]showed a significantly lower incidence of POD compared to the control group,with statistically significant conclusions.Conversely,the 40 U dose group[RR=0.47,95%CI:(0.17,1.34),P=0.16]yielded no statistically significant difference.Furthermore,the efficacy in preventing POD was found to be greater in the 30 U dose group compared to the 20 U dose group.Additionally,two cases of hypoglycemic reactions and increased nasal irritation symptom scores were reported in the 40 U dose group across the entire study population(P<0.05),suggesting potential adverse risks associated with this dosage.[Conclusions]The nasal administration of insulin significantly decreases the incidence of POD at a specific dosage,with optimal efficacy and high safety observed at a dosage of 30 U.展开更多
Objective This study aimed to explore the interplay between the life-course body mass index(BMI)trajectories and insulin resistance(IR)on incident diabetes.Methods This longitudinal cohort included 2,336 participants ...Objective This study aimed to explore the interplay between the life-course body mass index(BMI)trajectories and insulin resistance(IR)on incident diabetes.Methods This longitudinal cohort included 2,336 participants who had BMI repeatedly measured 3–8times between 1989 and 2009,as well as glucose and insulin measured in 2009.BMI trajectories were identified using a latent class growth mixed model.The interplay between BMI trajectories and IR on diabetes was explored using the four-way effect decomposition method.Logistic regression and mediation models were used to estimate the interaction and mediation effects,respectively.Results Three distinct BMI trajectory groups were identified:low-stable(n=1,625),mediumincreasing(n=613),and high-increasing(n=98).Both interaction and mediation effects of BMI trajectories and IR on incident diabetes were significant(P<0.05).The proportion of incident diabetes was higher in the IR-obesity than in the insulin-sensitivity(IS)obesity group(18.9%vs.5.8%,P<0.001).After adjusting for covariates,the odds ratios(95%confidence intervals)of the IR,IS-obesity,and IRobesity groups vs.the normal group were 3.22(2.05,5.16),2.05(1.00,3.97),and 7.98(5.19,12.62),respectively.IR mediated 10.7%of the total effect of BMI trajectories on incident diabetes(P<0.001).Conclusion We found strong interactions and weak mediation effects of IR on the relationship between life-course BMI trajectories and incident diabetes.IS-obesity is associated with a lower risk of incident diabetes than IR-obesity.展开更多
Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central com...Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.展开更多
The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evi...The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.展开更多
The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways,with insulin resistance and mitochondrial dysfunction emerging as critical contributors ...The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways,with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline.Insulin resistance impairs neuronal metabolism and synaptic function,fostering neurodegeneration as observed in Alzheimer’s disease and Down syndrome.Indeed,Down syndrome,characterized by the triplication of the APP gene,represents a valuable genetic model for studying early-onset Alzheimer’s disease and accelerated aging.Building on the link between metabolic dysfunctions and neurodegeneration,innovative strategies addressed brain insulin resistance as a key driver of cognitive decline.Intranasal insulin has shown promise in improving cognition in early Alzheimer’s disease and type 2 diabetes,supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration.However,insulin-based therapies risk desensitizing insulin signaling,potentially worsening the disease.Incretins,particularly glucagon-like peptide 1 receptor agonists,offer neuroprotective benefits by enhancing insulin sensitivity,metabolism,and synaptic plasticity while reducing oxidative distress and neuroinflammation.This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance,mitochondrial dynamics(including their roles in energy metabolism),and oxidative distress regulation,as these are pivotal in both Alzheimer’s disease and Down syndrome.By addressing these interconnected mechanisms,innovative treatments may emerge for both metabolic and neurodegenerative disorders.展开更多
Tel Ad办公空间坐落于以色列卡法萨巴一栋翻新建筑内。因自然采光条件有限,设计团队引入中央人工照明中庭,重塑空间流线,并通过材料运用,明确空间界定与功能分区。该中庭既是空间锚点,亦是氛围焦点。鉴于建筑进深较大,难以持续获取自然...Tel Ad办公空间坐落于以色列卡法萨巴一栋翻新建筑内。因自然采光条件有限,设计团队引入中央人工照明中庭,重塑空间流线,并通过材料运用,明确空间界定与功能分区。该中庭既是空间锚点,亦是氛围焦点。鉴于建筑进深较大,难以持续获取自然光线,中庭采用全光谱农业照明系统,以确保绿植全年茂盛生长。同时,空间流线也经重新设计,形成环绕绿色核心的环形路径,既确保了与绿植的持续视觉联系,又使各工作区域间的流线直观且流畅。除满足空间功能需求外,中庭在提升员工福祉与工作效率方面亦扮演关键角色:研究显示,相较于传统无窗办公环境,接触绿植及动态照明等自然元素,可有效降低压力、增强专注力并缓解视疲劳。室内统一采用水磨石地面、不锈钢装饰及天然木饰面,实现了整体空间的连贯性。展开更多
The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurode...The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function.展开更多
Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other...Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis,make deciphering the molecular mechanisms that underlie AD,even more important.Large datasets of single-cell RNA sequencing,single-nucleus RNA-sequencing(snRNA-seq),and spatial transcriptomics(ST)have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD.However,with unique technology,software,and larger databases emerging;a lack of integration of these data can contribute to ineffective use of valuable knowledge.Importantly,there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions,such as sex-specific,region-specific,and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease(ssREAD)database(Wang et al.,2024)was introduced to meet the scientific community’s growing demand for comprehensive,integrated,and accessible data analysis.展开更多
Aim To evaluate the inhibitory effect of chitosan-cysteine conjugate onenzymatic degradation and hypogly-cemic enhancement effect of insulin. Methods Chitosan-cysteineconjugate was synthesized. The protective effect o...Aim To evaluate the inhibitory effect of chitosan-cysteine conjugate onenzymatic degradation and hypogly-cemic enhancement effect of insulin. Methods Chitosan-cysteineconjugate was synthesized. The protective effect of the conjugate against degradation of insulin byα-chymotrypsin and trypsin was evaluated in vitro. Insulin enteric- microspheres were prepared byusing O_1 /Q_2 emulsion solvent evaporation method. The hypoglycemic enhancement effect of theconjugate was studied by oral administration of insulin solution or enteric-microspheres to rats.Results The thiol group content of the synthesized conjugate was about 200 μmol·g^(-1) polymer,which showed a strong protective effect on insulin from enzymatic degradation in vitro. Almost allthe insulin incubated in a-chymotrypsin solution or trypsin solution without chitosan-cysteineconjugate was degraded entirely within 1 h and 5 h respectively, whereas above 75% of insulinremained in the same content of the enzymatic solution containing 4 mg·mL^(-1) conjugate. The drugloading of insulin enteric-microspheres was about 7% . In vivo experiment, chitosan-cysteineconjugate (85 μg·kg^(-1)) prolonged the hypoglycemic time of insulin solution orenteric-microspheres when administered simultaneously with the absorption enhancer SNAC. ConclusionChitosan-cysteine conjugate has a marked inhibitory effect on the enzymatic degradation of insulinin vitro, and it displays a significant hypoglycemic enhancement effect on insulin oral formulationin vivo.展开更多
文摘BACKGROUND Tacrolimus(FK506)is a key calcineurin inhibitor used to prevent organ transplant rejection and is effective in improving graft survival.However,it is linked to hyperglycemia and insulin resistance,contributing to new-onset diabetes after transplantation and negatively affecting islet function.AIM To study the effects of tacrolimus on the insulin signaling pathway of hepatocytes.METHODS HL7702 cells were treated with different concentrations of tacrolimus(0.1 mg/L,1 mg/L,5 mg/L)for 24 hours.The proteins involved in insulin signaling were detected by Western blotting.RESULTS Compared with the control group,phosphorylation of insulin receptor substrate(IRS)1 at Ser 307 and Ser 323 were increased significantly when the tacrolimus concentration reached 1 and 5 mg/L.Phosphorylation of IRS1 at Ser 1101 was also increased,although not significantly.However,phosphorylation of Ribosomal protein S6 kinase beta-1 at Thr 389 was decreased significantly.The levels of phosphorylated glycogen synthase kinase 3αSer 21 and Ser 9 were increased.Surprisingly,phosphorylation of glycogen synthase at Ser 641 was increased.There was no significant change in the activity of glycogen phosphorylase.CONCLUSION Tacrolimus has no direct effect on hepatic glucose metabolism,but inhibits IRS1-mediated insulin signaling.This may be one of the underlying mechanisms by which tacrolimus induces insulin resistance.
文摘Background: Diabetes mellitus (DM) is a disease characterized by hyperglycemia due to (a) insulin-insufficiency (type I DM), or (b) impaired glucose cell-entry (insulin resistance) due to the downregulation of insulin cell receptors (type II DM). Type I DM usually presents with florid manifestations contrary to a slowly-progressive type II. Patients and methods: Over the past 10 years, we encountered 9 obese patients with controlled insulin-requiring type II DM for years, at a dose of 62 ± 5 units/day, who developed sudden and severe insulin resistance (IR) that required 210 ± 25 units daily. All patients had very high levels of anti-Glutamic Acid Decarboxylase (GAD) antibodies. Despite a lack of previous testing for anti-GAD antibodies, they were treated, with Cyclosporin A (Cy), as an autoimmune disorder superimposed on their type II MD. Initially all patients were treated with 100 mg, of Cy, twice daily aiming at an initial trough level of 100 - 150 ng/ml. Three months later, the dose was reduced to 50 mg twice daily for a total of 2 years. Results: Amelioration of IR was achieved by 1 month with a reduction of daily insulin requirement to 123 ± 16 units that further decreased to 76 ± 11 by the end of the 3rd month. Such improvement persisted for 2 years and >1 year after Cy discontinuation. Moreover, a decline in insulin requirements was associated with a parallel decrease in anti-GAD antibody levels and an increase in C-peptide insulin without kidney disease. Conclusion: Anti-GAD antibodies can induce acute IR in type II DM, and this phenomenon can be treated safely and effectively with Cy.
文摘Premixed insulin combines two types of insulin in a single injection.This combination streamlines dosing for patients with type 1 or type 2 diabetes,thereby enhancing convenience.However,patients receiving premixed insulin commonly have less satisfactory blood glucose control.The fixed ratio of insulin in these formulations frequently fails to account for the nuanced demands of individualized glucose-lowering therapy.Moreover,local absorption of mixed insulin and potential systemic autoimmune responses may further compromise glycaemic control.The co-formulation of insulin degludec and insulin aspart introduces a new combination of the two insulin types within a single injection,offering a promising solution for mitigating the limitations inherent in premixed insulin.
文摘Insulin resistance(IR)is widely recognized as a key contributor to metabolic disorders,and various surrogate indices have been developed to estimate IR in clinical and research settings.The hyperinsulinemic-euglycemic clamp is considered the gold standard method for assessing insulin resistance due to its precision;however,its complexity limits its widespread clinical application.Consequently,surrogate indices derived from fasting and post-load glucose and insulin levels have been developed to estimate IR,facilitating early detection and risk stratification in metabolic disorders.This mini-review discusses the clinical utility,strengths,and limitations of key IR indices,including the homeostasis model assessment of IR,quantitative insulin sensitivity check index,Matsuda index,and triglyceride-glucose index.Overall,the evidence presented to date suggests that these indices provide valuable estimates of IR in various popula-tions.Yet,their applicability varies depending on ethnic background,disease status,and clinical setting.Integrating these indices into routine clinical practice and research could improve metabolic risk assessment and guide preventive interventions.Further investigations are necessary to refine their accuracy and determine optimal cut-off values for various populations.
基金Supported by the Key Research and Development Plan of Hunan Province,No.2022SK2013Central South University,No.2024ZZTS0931.
文摘BACKGROUND Cardiovascular disease represents a major complication in patients with type 2 diabetes mellitus(T2DM),with insulin resistance(IR)recognized as a key underlying pathophysiological mechanism.The metabolic score for IR(METS-IR),a simple,non-invasive,and insulin-independent surrogate marker of IR,has been validated for risk stratification and prognostic assessment in conditions such as hypertension,ischemic cardiomyopathy,and T2DM.Monitoring fluctuations in METS-IR levels among individuals with T2DM may facilitate early identification of elevated cardiovascular risk and inform timely therapeutic adjustments.AIM To investigate the association between METS-IR and cardiovascular risk in patients with T2DM and to evaluate its potential utility as a predictive biomarker.METHODS This study represents a secondary analysis of a multicenter randomized controlled trial,ultimately including 10191 patients with T2DM aged 40 years to 79 years,with a follow-up duration of approximately 10 years.Baseline METS-IR was calculated using triglycerides,body mass index,high-density lipoprotein cholesterol and fasting plasma glucose.The predictive value of METS-IR for major adverse cardiovascular events(MACEs),all-cause mortality,congestive heart failure,and major coronary heart disease events,was assessed using Cox proportional hazards models,restricted cubic spline analysis,and stratified subgroup analyses.Multivariable adjustments were performed to account for potential confounding factors.RESULTS The incidence of MACEs increased steadily across higher METS-IR quartiles.After adjusting for multiple confounding factors,hazard ratios comparing the highest to the lowest METS-IR quartile were 1.25[95%confidence interval(CI):1.08-1.45]for MACEs,1.55(95%CI:1.23-1.96)for cardiovascular death,1.39(95%CI:1.21-1.59)for allcause mortality,2.22(95%CI:1.74-2.82)for congestive heart failure,and 1.35(95%CI:1.17-1.56)for major coronary heart disease.Restricted cubic spline analysis supported a positive,dose-dependent relationship between rising METS-IR levels and cardiovascular risk.Moreover,adding METS-IR to conventional risk prediction models enhanced their performance,as evidenced by improvements in the C-statistic,net reclassification improvement,and integrated discrimination improvement.Subgroup analyses indicated possible interactions between METS-IR,hemoglobin A1c levels,and aspirin therapy.CONCLUSION METS-IR shows a strong correlation with cardiovascular risk in individuals with T2DM.Tracking METS-IR levels could enhance risk assessment and the prediction of cardiovascular events.
基金This article is funded by HEC,520-163233-2AV6-09,Anam Iqbal.
文摘Objective:To evaluate the therapeutic potential of coumarin-loaded chitosan nanoparticles(CNNPs)in managing high-fructose diet-induced diabetes and associated complications.Methods:CNNPs were synthesized using an ionic gelation method with chitosan coating and characterized.Rats with a high-fructose diet-induced diabetes were treated with coumarin and CNNPs(30,70,and 100 mg/kg)for 6-12 weeks.Metabolic,inflammatory,oxidative stress,organ function,and cardiovascular parameters were assessed,and qRT-PCR studies were carried out for measuring the mRNA expression of glucose transporter-4(GLUT-4),sirtuin-1(SIRT1),pyrin domain containing-3(NLRP3),sterol regulatory element binding protein 1c(SREBP-1c),forkhead box O3(FOXO3),and endothelial nitric oxide synthase(eNOS)genes.Results:Nanoparticle characterization revealed a Z-average size of 510.8 nm with a+14 mV zeta potential.CNNP treatment was more effective than coumarin,normalizing glycemic markers(glycosylated hemoglobin,serum insulin,and fasting blood glucose),and lipid profiles(total cholesterol,low-density lipoprotein cholesterol,triglycerides,and high-density lipoprotein cholesterol).Significant improvements were also seen in adipokines(adiponectin,chemerin,and leptin),inflammatory cytokines(interleukin-6 and tumor necrosis factor-α),and oxidative stress markers(catalase,superoxide dismutase and malonaldehyde).In addition,both treatments significantly upregulated the gene expression of SIRT1,GLUT-4,and eNOS,and downregulated FOXO3,SREBP-1c,and NLRP3.Histopathological studies confirmed that CNNPs ameliorated diabetes-induced structural abnormalities in major organs.Conclusions:CNNPs demonstrate improved bioavailability and therapeutic efficacy,offering a promising strategy for managing high-fructose diet-induced metabolic dysfunction and its complications.
文摘[Objectives]To evaluate the impact of nasal insulin administration on postoperative delirium(POD)through meta-analysis.[Methods]The Cochrane Library,PubMed,Embase,Web of Science,China National Knowledge Infrastructure(CNKI),Wanfang Database,and China Science and Technology Journal Database(CSTJ)were systematically searched for relevant literature published prior to February 27,2025.Literature screening and data extraction were conducted by two independent researchers in accordance with predetermined inclusion and exclusion criteria.The primary observation indicator was the incidence of POD across various treatment populations.The risk ratio for the primary outcome was calculated using the Mantel-Haenszel method.The secondary outcomes included the adverse effects associated with insulin treatment,which encompassed the glycemic variability indices,the incidence of nasal irritation symptoms following administration,hypoglycemic reactions,and insulin allergic reactions.The study protocol was registered on PROSPERO(CRD420250607492)before data extraction.[Results]A total of five randomized controlled trials involving 357 patients were included in the analysis.In the adult population undergoing surgical procedures,the administration of insulin via nasal delivery was found to significantly reduce the incidence of POD[RR=0.35,95%CI(0.23-0.53),P<0.001].The results of the subgroup analysis indicated that there were notable differences in the effectiveness of various doses of insulin administered nasally in preventing POD.Specifically,both the 20 U dose group[RR=0.45,95%CI:(0.29,0.70),P<0.001]and the 30 U dose group[RR=0.01,95%CI:(0.03,0.42),P<0.001]showed a significantly lower incidence of POD compared to the control group,with statistically significant conclusions.Conversely,the 40 U dose group[RR=0.47,95%CI:(0.17,1.34),P=0.16]yielded no statistically significant difference.Furthermore,the efficacy in preventing POD was found to be greater in the 30 U dose group compared to the 20 U dose group.Additionally,two cases of hypoglycemic reactions and increased nasal irritation symptom scores were reported in the 40 U dose group across the entire study population(P<0.05),suggesting potential adverse risks associated with this dosage.[Conclusions]The nasal administration of insulin significantly decreases the incidence of POD at a specific dosage,with optimal efficacy and high safety observed at a dosage of 30 U.
基金supported by Grant 82222064 from the National Natural Science Foundation of Chinathe Shandong University Distinguished Young Scholars。
文摘Objective This study aimed to explore the interplay between the life-course body mass index(BMI)trajectories and insulin resistance(IR)on incident diabetes.Methods This longitudinal cohort included 2,336 participants who had BMI repeatedly measured 3–8times between 1989 and 2009,as well as glucose and insulin measured in 2009.BMI trajectories were identified using a latent class growth mixed model.The interplay between BMI trajectories and IR on diabetes was explored using the four-way effect decomposition method.Logistic regression and mediation models were used to estimate the interaction and mediation effects,respectively.Results Three distinct BMI trajectory groups were identified:low-stable(n=1,625),mediumincreasing(n=613),and high-increasing(n=98).Both interaction and mediation effects of BMI trajectories and IR on incident diabetes were significant(P<0.05).The proportion of incident diabetes was higher in the IR-obesity than in the insulin-sensitivity(IS)obesity group(18.9%vs.5.8%,P<0.001).After adjusting for covariates,the odds ratios(95%confidence intervals)of the IR,IS-obesity,and IRobesity groups vs.the normal group were 3.22(2.05,5.16),2.05(1.00,3.97),and 7.98(5.19,12.62),respectively.IR mediated 10.7%of the total effect of BMI trajectories on incident diabetes(P<0.001).Conclusion We found strong interactions and weak mediation effects of IR on the relationship between life-course BMI trajectories and incident diabetes.IS-obesity is associated with a lower risk of incident diabetes than IR-obesity.
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC)+6 种基金STI2030-Major Projects(2021ZD0202700,to HY)the National Natural Science Foundation of China(32241004,to HY)the Natural Science Foundation of Zhejiang Province of China(LR24C090001,to HY)Key R&D Program of Zhejiang Province(2024SSYS0017,to HY)CAMS Innovation Fund for Medical Sciences(2019-12M-5-057,to HY)Fundamental Research Funds for the Central Universities(226-2022-00193,to HY)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT310-01,to HY)。
文摘Type 2 diabetes mellitus has central complications:Diabetes,a metabolic disorder primarily characterized by hyperglycemia due to insufficient insulin secretion,or impaired insulin signaling,has significant central complications.Type 2 diabetes mellitus(T2DM),the most prevalent type of diabetes,affects more than 38 million individuals in the United States(approximately 1 in 10)and is defined by chronic hyperglycemia and insulin resistance,which refers to a reduced cellular response to insulin.
基金supported by grants from NIH T32(DK007260,to WC)the Steno North American Fellowship awarded by the Novo Nordisk Foundation(NNF23OC0087108,to WC).
文摘The shared links between Alzheimer’s disease and type 2 diabetes mellitus:Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two prevalent conditions that come with substantial daily struggles.Emerging evidence highlights that these diseases share similar pathophysiological features,including insulin resistance and chronic inflammation,which contribute to their rapid progression(Chen et al.,2022).Insulin resistance,a hallmark of T2DM,has been suggested to exacerbate neurodegeneration in AD.Similarly,chronic low-grade inflammation in T2DM parallels with neuroinflammation,which is observed in AD,suggesting overlapping pathophysiological mechanisms in T2DM and AD.
基金supported by Fondi Ateneo grants funded by Sapienza University (#RM120172A3160B53) to EBfunds from Jerome-Lejeune Foundation (#1887-2019b) to EBthe European Union–Next Generation EU (Project ECS 0000024Rome Technopole,–CUP B83C22002820006, NRPMission 4 Component 2 Investment 1.5 to LRR)
文摘The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways,with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline.Insulin resistance impairs neuronal metabolism and synaptic function,fostering neurodegeneration as observed in Alzheimer’s disease and Down syndrome.Indeed,Down syndrome,characterized by the triplication of the APP gene,represents a valuable genetic model for studying early-onset Alzheimer’s disease and accelerated aging.Building on the link between metabolic dysfunctions and neurodegeneration,innovative strategies addressed brain insulin resistance as a key driver of cognitive decline.Intranasal insulin has shown promise in improving cognition in early Alzheimer’s disease and type 2 diabetes,supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration.However,insulin-based therapies risk desensitizing insulin signaling,potentially worsening the disease.Incretins,particularly glucagon-like peptide 1 receptor agonists,offer neuroprotective benefits by enhancing insulin sensitivity,metabolism,and synaptic plasticity while reducing oxidative distress and neuroinflammation.This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance,mitochondrial dynamics(including their roles in energy metabolism),and oxidative distress regulation,as these are pivotal in both Alzheimer’s disease and Down syndrome.By addressing these interconnected mechanisms,innovative treatments may emerge for both metabolic and neurodegenerative disorders.
文摘The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function.
文摘Alzheimer’s disease(AD)is the most common form of dementia.In addition to the lack of effective treatments,there are limitations in diagnostic capabilities.The complexity of AD itself,together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis,make deciphering the molecular mechanisms that underlie AD,even more important.Large datasets of single-cell RNA sequencing,single-nucleus RNA-sequencing(snRNA-seq),and spatial transcriptomics(ST)have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD.However,with unique technology,software,and larger databases emerging;a lack of integration of these data can contribute to ineffective use of valuable knowledge.Importantly,there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions,such as sex-specific,region-specific,and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease(ssREAD)database(Wang et al.,2024)was introduced to meet the scientific community’s growing demand for comprehensive,integrated,and accessible data analysis.
文摘Aim To evaluate the inhibitory effect of chitosan-cysteine conjugate onenzymatic degradation and hypogly-cemic enhancement effect of insulin. Methods Chitosan-cysteineconjugate was synthesized. The protective effect of the conjugate against degradation of insulin byα-chymotrypsin and trypsin was evaluated in vitro. Insulin enteric- microspheres were prepared byusing O_1 /Q_2 emulsion solvent evaporation method. The hypoglycemic enhancement effect of theconjugate was studied by oral administration of insulin solution or enteric-microspheres to rats.Results The thiol group content of the synthesized conjugate was about 200 μmol·g^(-1) polymer,which showed a strong protective effect on insulin from enzymatic degradation in vitro. Almost allthe insulin incubated in a-chymotrypsin solution or trypsin solution without chitosan-cysteineconjugate was degraded entirely within 1 h and 5 h respectively, whereas above 75% of insulinremained in the same content of the enzymatic solution containing 4 mg·mL^(-1) conjugate. The drugloading of insulin enteric-microspheres was about 7% . In vivo experiment, chitosan-cysteineconjugate (85 μg·kg^(-1)) prolonged the hypoglycemic time of insulin solution orenteric-microspheres when administered simultaneously with the absorption enhancer SNAC. ConclusionChitosan-cysteine conjugate has a marked inhibitory effect on the enzymatic degradation of insulinin vitro, and it displays a significant hypoglycemic enhancement effect on insulin oral formulationin vivo.
