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AIM: To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. MATERIALS AND METHODS: A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability. RESULTS: The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P = .215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P = .014) in the sitagliptin group, with a statistically significant difference (P = .009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). CONCLUSIONS: The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.
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Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Humanos , Hemoglobinas Glicadas , Automonitorização da Glicemia , Glicemia , Resultado do Tratamento , Hipoglicemiantes/uso terapêutico , Fosfato de Sitagliptina/efeitos adversos , Metformina/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores de Proteases/uso terapêutico , Quimioterapia Combinada , Método Duplo-CegoRESUMO
AIMS: To evaluate the efficacy and safety of a novel sodium-glucose cotransporter 2 inhibitor, enavogliflozin 0.3 mg monotherapy, in Korean people with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 23 hospitals. Individuals with haemoglobin A1c (HbA1c) of 7.0%-10.0% after at least 8 weeks of diet and exercise modification were randomized to receive enavogliflozin 0.3 mg (n = 83) or placebo (n = 84) for 24 weeks. The primary outcome was a change in HbA1c at week 24 from baseline. Secondary outcomes included the proportion of participants achieving HbA1c <7.0%, change in fasting glucose, body weight and lipid levels. Adverse events were investigated throughout the study. RESULTS: At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was -0.99% (95% confidence interval -1.24%, -0.74%). The proportions of patients achieving HbA1c <7.0% (71% vs. 24%) at week 24 was significantly higher in the enavogliflozin group (p < .0001). Placebo-adjusted mean changes in fasting plasma glucose (-40.1 mg/dl) and body weight (-2.5 kg) at week 24 were statistically significant (p < .0001). In addition, a significant decrease in blood pressure, low-density lipoprotein cholesterol, triglyceride, and homeostasis model assessment of insulin resistance were observed, along with a significant increase in high-density lipoprotein cholesterol. No significant increase in treatment-related adverse events was observed for enavogliflozin. CONCLUSIONS: Monotherapy with enavogliflozin 0.3 mg improved glycaemic control in people with T2DM. Enavogliflozin therapy also exerted beneficial effects on body weight, blood pressure and lipid profile.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Glicemia , Peso Corporal , Colesterol , Método Duplo-Cego , Hemoglobinas Glicadas , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Lipídeos , República da Coreia/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Resultado do TratamentoRESUMO
AIMS: The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium-glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Patients with glycated haemoglobin (HbA1c) of 7.0-10.0%, entered a 2-week placebo run-in period, and were randomized to receive once-daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12. RESULTS: Overall, 194 patients were included in the full analysis set [placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49)]. Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (-0.79%, -0.89%, -0.92% and -0.08%, respectively; p < .001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were -30.5, -31.1, -35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c <7.0% at week 12 was significantly higher in the three enavogliflozin groups than in the placebo group (42.9%, 44.0%, 61.2% and 17.4%, respectively). A higher proportion of patients showed HbA1c reduction by >0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups. CONCLUSIONS: Once-daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well-tolerated treatment for Korean patients with type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Hipoglicemiantes/efeitos adversos , Hemoglobinas Glicadas , Resultado do Tratamento , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Quimioterapia Combinada , Método Duplo-Cego , República da Coreia/epidemiologia , GlicemiaRESUMO
We assessed the risk factors for major amputation of diabetic foot ulcers (DFUs) in patients with diabetic kidney disease (DKD) stages 3b-5. For DFU assessment, in addition to DFU location and presence of infection, ischemia, and neuropathy, vascular calcification was assessed using the medial arterial calcification (MAC) score. Of 210 patients, 26 (12.4%) underwent major amputations. Only the location and extension of DFU, represented by Texas grade differed between the minor and major amputation groups. However, after adjusting for covariates, ulcer location of mid- or hindfoot (vs. forefoot, odds ratio [OR] = 3.27), Texas grades 2 or 3 (vs. grade 0, OR = 5.78), and severe MAC (vs. no MAC, OR = 4.46) was an independent risk factor for major amputation (all P < 0.05). The current use of antiplatelets was a possible protective factor for major amputations (OR = 0.37, P = 0.055). In conclusion, DFU with severe MAC is associated with major amputation in patients with DKD.
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Diabetes Mellitus , Pé Diabético , Nefropatias Diabéticas , Humanos , Pé Diabético/complicações , Pé Diabético/cirurgia , Nefropatias Diabéticas/complicações , Fatores de Risco , Amputação Cirúrgica , Estudos RetrospectivosRESUMO
BACKGROUND: The endocrine disruption of perfluorinated compounds is an emerging issue. We aimed to examine the association of serum perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) levels with incident diabetes and fasting serum glucose concentration. METHODS: This prospective cohort study was based on an urban-based cohort subpopulation from the Korean Genome and Epidemiology Study. Serum samples (600 µL) were received from 100 participants in the normoglycemic baseline survey (2004-2013), and concentrations of PFOA and PFOS were measured using mass spectrometry. The incidence of diabetes was tracked in the follow-up survey (2012-2016). RESULTS: The mean age was 56.4 years (men, 59%). The median serum PFOA and PFOS concentrations were 4.29 ng/mL and 9.44 ng/mL, respectively. PFOA and PFOS concentrations differed according to age, sex, and residential area. After 60 months, 23 patients had diabetes. Log-transformed PFOA (lnPFOA) and log-transformed PFOS (lnPFOS) were significantly higher in those who transitioned to diabetes than in those who did not (both p < 0.05). After multivariate adjustment, lnPFOA (coefficient = 6.98, 95% CI -0.04-14, p = 0.054) and lnPFOS (coefficient = 7.06, 95% CI -0.96-15.08, p = 0.088) predicted increased fasting glucose without statistical significance. In addition, lnPFOA, but not lnPFOS, significantly predicted incident diabetes (HR = 3.98, 95% CI 1.42-11.1, p < 0.01). CONCLUSION: Exposure to PFOA and PFOS may have a potential dysglycemic effect. In particular, exposure to PFOA increased the risk of diabetes. Further research with larger sample size is warranted.
Assuntos
Ácidos Alcanossulfônicos , Diabetes Mellitus , Fluorocarbonos , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Glucose , Jejum , Estudos Prospectivos , Caprilatos , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/epidemiologia , Estudos de CoortesRESUMO
Metabolic stress impairs pancreatic ß-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and ß-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in ß-cells. The vulnerability of ß-cells to oxidative damage caused by iron accumulation has been linked to contributory ß-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic ß-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by ß-cell failure.
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Ferroptose , Células Secretoras de Insulina , Células Secretoras de Insulina/metabolismo , Transdução de Sinais , Estresse Oxidativo , Ferro/metabolismoRESUMO
BACKGROUND: This study was performed to determine the effectiveness of the Smart Care service on glucose control based on telemedicine and telemonitoring compared with conventional treatment in patients with type 2 diabetes. MATERIALS AND METHODS: This 24-week prospective multi-center randomized controlled trial involved 338 adult patients with type 2 diabetes at four university hospitals in South Korea. The patients were randomly assigned to a control group (group A, n = 113), a telemonitoring group (group B, n = 113), or a telemedicine group (group C, n = 112). Patients in the telemonitoring group visited the outpatient clinic regularly, accompanied by an additional telemonitoring service that included remote glucose monitoring with automated patient decision support by text. Remote glucose monitoring was identical in the telemedicine group, but assessment by outpatient visits was replaced by video conferencing with an endocrinologist. RESULTS: The adjusted net reductions in HbA1c concentration after 24 weeks were similar in the conventional, telemonitoring, and telemedicine groups (-0.66% ± 1.03% vs. -0.66% ± 1.09% vs. -0.81% ± 1.05%; p > 0.05 for each pairwise comparison). Fasting glucose concentrations were lower in the telemonitoring and telemedicine groups than in the conventional group. Rates of hypoglycemia were lower in the telemedicine group than in the other two groups, and compliance with medication was better in the telemonitoring and telemedicine than in the conventional group. No serious adverse events were associated with telemedicine. CONCLUSIONS: Telehealthcare was as effective as conventional care at improving glycemia in patients with type 2 diabetes without serious adverse effects.
Assuntos
Automonitorização da Glicemia/métodos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas/análise , Telemedicina/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Diverse mechanisms are involved in the pathogenesis of ß-cell failure in type 2 diabetes. Of them, the accumulation of ceramide, a bioactive lipid metabolite, is suggested to play a major role in inflammatory and stress responses that induce diabetes. However, the downstream inflammatory target of ceramide has not been defined. Using rat islets and the INS-1 ß-cell line, we hypothesized that activation of the redox sensitive protein TXNIP is involved in ceramide-induced ß-cell dysfunction. Incubation of INS-1 cells and primary islets with C2-ceramide (N-acetyl-sphingosine) downregulated insulin and PDX-1 expression and increased ß-cell apoptosis. Ceramide treatment induced a time dependent increase in TXNIP gene expression accompanied by activation of nuclear factor (NF)-κB and reduced mitochondrial thioredoxin (TRX) activity. Pretreatment with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked ceramide-induced up-regulation of TXNIP expression and activity of NF-κB. Blockade of NF-κB nuclear translocation by the peptide SN50 prevented ceramide-mediated TXNIP induction. Furthermore, SSO also attenuated ceramide-induced early loss of insulin signaling and apoptosis. Collectively, our results unveil a novel role of CD36 in early molecular events leading to NF-κB activation and TXNIP expression. These data suggest that CD36 dependent NF-κB-TXNIP signaling contributes to the ceramide-induced pathogenesis of pancreatic ß-cell dysfunction and failure.
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Glycation of apolipoproteins is a major feature of the production of dysfunctional high-density lipoprotein (HDL), which is associated with the incidence of several metabolic diseases such as coronary artery disease and diabetes. In this report, fructated apoA-I (fA-I) induced by fructose treatment showed a covalently multimerized band without cross-linking, and lysine residues were irreversibly modified to prevent crosslinking. Using pancreatic ß-cells, insulin secretion was impaired by fA-I in the lipid-free and reconstituted HDL (rHDL) states, by up to 35%, and 40%, respectively, under hyperglycemic conditions (25 mmol/L glucose). Treatment of human umbilical vein endothelial cells (HUVECs) with fA-I and HDL from elderly patients caused a 1.8-fold and 1.5-fold increased cellular senescence, respectively, along with increased lysosomal enlargement. In the lipid-free and rHDL states, fA-I increased embryo death by 1.5-fold and 2.5-fold, respectively, along with the production of oxidized species. Furthermore, rHDL containing fA-I (fA-I-rHDL) showed a higher isoelectric point (pI, approximately 8.5), whereas rHDL containing nA-I (nA-I-rHDL) showed a narrow band range with lower pI (around 8.0) as well as a much smaller particle size than that of nA-I-rHDL. In conclusion, fructose-mediated apoA-I fructation resulted in the severe loss of several beneficial functions of apoA-I and HDL, including anti-senescence and insulin secretion activities, accompanied with increased susceptibility to protein degradation and structural modification.
Assuntos
Apolipoproteína A-I/farmacologia , Senescência Celular/fisiologia , Embrião não Mamífero/patologia , Frutose/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Insulina/metabolismo , Lipoproteínas HDL/metabolismo , Adulto , Idoso , Animais , Apolipoproteína A-I/química , Aterosclerose/induzido quimicamente , Aterosclerose/fisiopatologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Frutose/química , Glicosilação , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Adulto Jovem , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: This study compared carotid ultrasound (CUS) and traditional risk calculations in determining cardiovascular disease (CVD) risk in patients with type 2 diabetes mellitus (DM) and investigated whether awareness of CVD affects patient and/or physician behavior. METHODS: In this prospective, observational, multicenter study, 797 participants with type 2 diabetes were assessed using CUS, the United Kingdom Prospective Diabetes Study Risk Engine (UKPDSRE) calculator, and the Framingham Risk Score (FRS) algorithm. Health-related behaviors and physician treatments were compared at baseline and at 6 months after assessment. RESULTS: According to CUS, 43.5 % of the participants were at high risk (compared to 10.6 % and 4.3 % using the UKPDSRE and FRS approaches, respectively). Interestingly, 31.5 % of the patients with low risk scores according to the UKPDSRE calculator and 35.8 % of the patients with low risk scores according to the FRS algorithm were found to be at high risk according to CUS. The proportion of patients who achieved target LDL-C levels significantly increased after CUS. Moreover, increased awareness of atherosclerosis through CUS findings significantly altered physician treatment patterns and patient health-related behaviors. CONCLUSIONS: Carotid atherosclerosis was detected in more than 30 % of all participants with low or intermediate risk stratification scores. Improved awareness of atherosclerosis through CUS findings had a positive impact on both patient and physician behavior, resulting in improved CV risk management.
Assuntos
Aterosclerose/diagnóstico , Comportamento , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Pacientes/psicologia , Médicos/psicologia , Adulto , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/epidemiologia , Doenças das Artérias Carótidas/etiologia , Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco/métodos , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologiaRESUMO
Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 µM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic ß-cells through a decrease in fatty acid influx via inhibition of CD36.
Assuntos
Anticolesterolemiantes/farmacologia , Antígenos CD36/metabolismo , Ezetimiba/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Antígenos CD36/antagonistas & inibidores , Antígenos CD36/genética , Células Cultivadas , Citometria de Fluxo , Glucose/toxicidade , Insulina/genética , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Ácido Palmítico/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
The ß-cell relies predominantly on glucose utilization to generate adenosine triphosphate, which is crucial for both cell viability and insulin secretion. The ß-cell has evolved remarkable metabolic flexibility to productively respond to shifts in environmental conditions and changes in glucose availability. Although these adaptive responses are important for maintaining optimal cellular function, there is emerging evidence that the resulting changes in cellular metabolites can impact the epigenome, causing transient and lasting alterations in gene expression. This review explores the intricate interplay between metabolism and the epigenome, providing valuable insights into the molecular mechanisms leading to ß-cell dysfunction in diabetes. Understanding these mechanisms will be critical for developing targeted therapeutic strategies to preserve and enhance ß-cell function, offering potential avenues for interventions to improve glycemic control in individuals with diabetes.
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Glucose , Células Secretoras de Insulina , Humanos , Células Secretoras de Insulina/metabolismo , Glucose/metabolismo , Animais , Epigenômica , Epigênese Genética , Epigenoma , Diabetes Mellitus/metabolismo , Diabetes Mellitus/genéticaRESUMO
AIM: To explore the effect of mixed exposure to per- and polyfluoroalkyl substances (PFAS) on metabolic syndrome (MetS). METHODS: This cross-sectional study used data from the Korean National Environmental Health Survey Cycle 4 (2018-2020). The serum concentrations of five PFAS (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], perfluorohexanesulfonic acid, perfluorononanoic acid [PFNA], and perfluorodecanoic acid [PFDeA]) were measured, and the relative potency factor approach was employed for the mixture of PFAS (Cmix) assessment. MetS was diagnosed if the patient satisfied three of five criteria: central obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure (BP), and elevated glycated hemoglobin (HbA1c). Age, sex, smoking, drinking, and exercise status were considered as covariates. The risk of MetS for single and mixed exposure to PFAS was analyzed using binomial regression and Bayesian kernel machine regression (BKMR). RESULTS: A total of 2984 (male:female = 1:1.3; age range, 19-80 years) adults were enrolled. The prevalence of MetS was 45.6%. Each PFAS and Cmix levels were higher in participants with MetS than in those without MetS. Cmix increased the risk of elevated BP and HbA1c, and eventually MetS (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.11-3.60 per log10Cmix; OR = 1.57, 95% CI 1.07-2.31 in the highest quartile of Cmix [Q4] vs. the lowest [Q1]). Sex-specific analyses revealed that the impact of Cmix was valid in females but not in males (Cmix Q4 vs. Q1: OR = 1.01, 95% CI 0.57-1.8 in males; OR = 2.30, 95% CI 1.38-3.84 in females). In the BKMR analysis, mixed exposure to PFAS dose-dependently increased the risk of MetS, particularly in females. Among single exposures, PFNA contributed significantly to the cumulative effect. CONCLUSION: Mixed exposure to PFAS was associated with a higher risk of MetS in females. Further studies on potential health concerns associated with PFAS mixtures are warranted.
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Ácidos Alcanossulfônicos , Exposição Ambiental , Poluentes Ambientais , Fluorocarbonos , Síndrome Metabólica , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/induzido quimicamente , Fluorocarbonos/sangue , República da Coreia/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Poluentes Ambientais/sangue , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Ácidos Alcanossulfônicos/sangue , Inquéritos Epidemiológicos , Idoso , Estudos Transversais , Caprilatos/sangue , Adulto JovemRESUMO
Progression of ß-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in ß-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in ß-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves ß-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves ß-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved ß-cell function and survival under high-glucose conditions via the glutathione redox balance.
Assuntos
Sulfeto de Hidrogênio , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Sulfeto de Hidrogênio/farmacologia , Antioxidantes/farmacologia , Aldeído Desidrogenase/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Glutationa/metabolismo , Glucose/metabolismoRESUMO
AIMS: The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of ß-cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase-2 (ALDH2). MATERIALS AND METHODS: In order to investigate this hypothesis, doxorubicin was administered to INS-1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot. Mitochondrial ROS, membrane potential, and lipid ROS were determined by commercial fluorescent probes. The cell viability was measured by CCK-assay. RESULTS: Exposure of INS-1 cells to doxorubicin decreased active insulin signaling resulting in elevated ALDH2 degradation, compared with control cells by the induction of acid sphingomyelinase mediated ceramide induction. Further, ceramide induction potentiated doxorubicin induced mitochondrial dysfunction. Treatment with the ALDH2 agonist, ALDA1, blocked doxorubicin-induced acid sphingomyelinase activation which significantly blocked ceramide induction and mitochondrial dysfunction mediated cell death. Treatment with the ALDH2 agonist, ALDA1, stimulated casein kinase-2 (CK2) mediated insulin signaling activation. CK2 silencing neutralized the function of ALDH2 in the doxorubicin treated INS-1 cells. CONCLUSIONS: Mitochondrial ALDH2 activation could inhibit the progression of doxorubicin induced pancreatic ß-cell dysfunction by inhibiting the acid sphingomyelinase induction of ceramide, by regulating the activation of CK2 signaling. Our research lays the foundation of ALDH2 activation as a therapeutic target for the precise treatment of chemotherapy drug induced ß-cell dysfunction.
Assuntos
Aldeído-Desidrogenase Mitocondrial , Apoptose , Caseína Quinase II , Sobrevivência Celular , Doxorrubicina , Células Secretoras de Insulina , Mitocôndrias , Transdução de Sinais , Doxorrubicina/farmacologia , Ratos , Animais , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Apoptose/efeitos dos fármacos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Caseína Quinase II/metabolismo , Caseína Quinase II/antagonistas & inibidores , Linhagem Celular Tumoral , Ceramidas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Antibióticos Antineoplásicos/farmacologiaRESUMO
BACKGRUOUND: This study examines integrating physical and mental healthcare for disadvantaged persons with type 2 diabetes mellitus and mild-to-moderate depression in the community, using a mobile application within a public-private-academic partnership. METHODS: The Korean Diabetes Association has developed a mobile application combining behavioral activation for psychological well-being and diabetes self-management, with conventional medical therapy. Participants were randomly assigned to receive the application with usual care or only usual care. Primary outcomes measured changes in psychological status and diabetes selfmanagement through questionnaires at week 12 from the baseline. Secondary outcomes assessed glycemic and lipid control, with psychological assessments at week 16. RESULTS: Thirty-nine of 73 participants completed the study (20 and 19 in the intervention and control groups, respectively) and were included in the analysis. At week 12, the intervention group showed significant reductions in depression severity and perceived stress compared to the control group. Additionally, they reported increased perceived social support and demonstrated improved diabetes self-care behavior. These positive effects persisted through week 16, with the added benefit of reduced anxiety. While fasting glucose levels in the intervention group tended to improve, no other significant differences were observed in laboratory assessments between the groups. CONCLUSION: This study provides compelling evidence for the potential efficacy of a mobile application that integrates physical and mental health components to address depressive symptoms and enhance diabetes self-management in disadvantaged individuals with type 2 diabetes mellitus and depression. Further research involving larger and more diverse populations is warranted to validate these findings and solidify their implications.
Assuntos
Depressão , Diabetes Mellitus Tipo 2 , Saúde Mental , Aplicativos Móveis , Populações Vulneráveis , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/psicologia , Feminino , Masculino , Pessoa de Meia-Idade , Depressão/terapia , Adulto , Autocuidado/métodos , Idoso , Apoio Social , República da Coreia , Ansiedade/terapia , Autogestão/métodos , Estresse Psicológico/terapia , Glicemia/análiseRESUMO
The rising prevalence of type 2 diabetes (T2D) is posing major challenges for the healthcare systems of many countries, particularly in the Asia-Pacific Region, in which T2D can present at younger ages and lower body mass index when compared with Western nations. There is an important role for insulin therapy in the management of T2D in these nations, but available evidence suggests that insulin is under-utilized and often delayed, to the detriment of patient prognosis. The authors of this article gathered as an advisory panel (representative of some of the larger Asia-Pacific nations) to identify their local barriers to insulin use in T2D, and to discuss ways in which to address these barriers, with their outputs summarized herein. Many of the key barriers identified are well-documented issues of global significance, including a lack of healthcare resources or of an integrated structure, insufficient patient education, and patient misconceptions about insulin therapy. Barriers identified as more innate to Asian countries included local inabilities of patients to afford or gain access to insulin therapy, a tendency for some patients to be more influenced by social media and local traditions than by the medical profession, and a willingness to switch care providers and seek alternative therapies. Strategies to address some of these barriers are provided, with hypothetical illustrative case histories.
RESUMO
Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.
RESUMO
Cells from a human chondrocyte cell line were studied in 1% oxygen and/or a lower glucose concentration (5.5 mM), compared to the routine culture conditions of normoxia and high glucose. HIF-1α, IL-1ß, IL-6, IL-8, COX-2, TNFα, LIF, MMP-3, MMP-13, and reactive oxygen species (ROS) were evaluated, respectively. Effects of hypoxia inducing expression of HIF-1α were statistically significant at 72 h (p<0.05). Increased production of ROS by hypoxia was also observed with passage of time (p<0.05). The effects of hypoxia on HIF-1α and IL-1ß were potentiated by 5.5 mM glucose, especially after 48 h (p<0.05). IL-8 production was significantly induced in 1% O(2), with 5.5 mM glucose (p<0.01). IL-8 mRNA expression and production in response to IL-1ß were potentiated by hypoxia/ischemia (p<0.05, p<0.01, respectively). Up-regulation of IL-1ß, ROS, and IL-8 by hypoxia/ischemia in human chondrocytes may occur in correlation with HIF-1α. IL-8 response to IL-1ß may be potentiated synergically by hypoxia/ischemia, as an effector of hypoxia/ischemia. The results may suggest aggressive biology of the ordinary cartilage hypoxia/ischemia in the context of arthro-degeneration.
Assuntos
Cartilagem Articular/irrigação sanguínea , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Hipóxia/metabolismo , Interleucina-1beta/biossíntese , Interleucina-8/biossíntese , Isquemia/metabolismo , Cartilagem Articular/patologia , Linhagem Celular , Condrócitos/patologia , Glucose/metabolismo , Humanos , Hipóxia/patologia , Isquemia/patologia , Espécies Reativas de Oxigênio/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Evidence consistently shows that diabetes is a risk factor for increased prevalence of gingivitis and periodontitis. But there is a controversy about the relationship between diabetes related factors and periodontal health. The aim of the present study is to explore the relationship between diabetes related factors such as glycosylated hemoglobin, fasting blood glucose, duration of diabetes and compliance to diabetes self management and periodontal health status. METHODS: Periodontal health of 125 participants with type-2 diabetes mellitus was measured by the number of missing teeth, community periodontal index (CPI), Russell's periodontal index and papillary bleeding index. Information on sociodemographic factors, oral hygiene behavior, duration and compliance to self management of diabetes, levels of glycosylated hemoglobin(HbA1c) and fasting blood glucose(FBG) were collected by interview and hospital medical records. Statistically, independent t-test, an analysis of variance (ANOVA), chi-squared test and multiple regression analyses were used to assess the association between diabetes-related factors and periodontal health. RESULTS: Periodontal parameters including the number of missing teeth and papillary bleeding index were significantly influenced by duration of diabetes, FBG and compliance to self management of diabetes. CPI was significantly influenced by duration of diabetes, FBG and HbA1C. And Russell's periodontal index was significantly influenced by duration of diabetes, FBG, HbA1C and compliance to self management of diabetes. Results of multiple linear regression analysis showed that the duration of diabetes showed significant positive correlation with all of the periodontal health parameters, except for missing teeth. HbA1c was correlated with Russell's periodontal and papillary bleeding index. FBG and compliance to self management of diabetes were correlated with missing teeth and papillary bleeding index respectively. CONCLUSIONS: Diabetes-related factors such as duration of diabetes, FBG, HbA1c and compliance to self management of diabetes were significantly correlated with periodontal health among individuals with type-2 diabetes.