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Type 2 diabetes mellitus (T2DM) is a risk factor for male infertility, but the underlying molecular mechanisms remain unclear. Advanced glycation end products (AGEs) are pathogenic molecules for diabetic vascular complications. Here, we investigated the effects of the DNA aptamer raised against AGEs (AGE-Apt) on testicular and sperm abnormalities in a T2DM mouse model. KK-Ay (DM) and wild-type (non-DM) 4- and 7-week-old male mice were sacrificed to collect the testes and spermatozoa for immunofluorescence, RT-PCR, and histological analyses. DM and non-DM 7-week-old mice were subcutaneously infused with the AGE-Apt or control-aptamer for 6 weeks and were then sacrificed. Plasma glucose, testicular AGEs, and Rage gene expression in 4-week-old DM mice and plasma glucose, testicular AGEs, oxidative stress, and pro-inflammatory gene expressions in 7-week-old DM mice were higher than those in age-matched non-DM mice, the latter of which was associated with seminiferous tubular dilation. AGE-Apt did not affect glycemic parameters, but it inhibited seminiferous tubular dilation, reduced the number of testicular macrophages and apoptotic cells, and restored the decrease in sperm concentration, motility, and viability of 13-week-old DM mice. Our findings suggest that AGEs-Apt may improve sperm abnormality by suppressing AGE-RAGE-induced oxidative stress and inflammation in the testes of DM mice.
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Aptámeros de Nucleótidos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Productos Finales de Glicación Avanzada , Inflamación , Estrés Oxidativo , Receptor para Productos Finales de Glicación Avanzada , Motilidad Espermática , Testículo , Animales , Masculino , Estrés Oxidativo/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Ratones , Aptámeros de Nucleótidos/farmacología , Testículo/metabolismo , Testículo/efectos de los fármacos , Testículo/patología , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus Experimental/metabolismo , Motilidad Espermática/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Inflamación/metabolismo , Inflamación/patología , Espermatozoides/metabolismo , Espermatozoides/efectos de los fármacos , Recuento de EspermatozoidesRESUMEN
SMTP-44D has been reported to have anti-oxidative and anti-inflammatory reactions, including reduced expression of receptor for advanced glycation end products (RAGE) in experimental diabetic neuropathy. Although activation of RAGE with its ligands, and advanced glycation end products (AGEs), play a crucial role in atherosclerotic cardiovascular disease, a leading cause of death in diabetic patients, it remains unclear whether SMTP-44D could inhibit experimental atherosclerosis by suppressing the AGEs-RAGE axis. In this study, we investigated the effects of SMTP-44D on atherosclerotic plaque formation and expression of AGEs in apolipoprotein-E null (Apoe-/-) mice. We further studied here whether and how SMTP-44D inhibited foam cell formation of macrophages isolated from Apoe-/- mice ex vivo. Although administration of SMTP-44D to Apoe-/- mice did not affect clinical or biochemical parameters, it significantly decreased the surface area of atherosclerotic lesions and reduced the atheromatous plaque size, macrophage infiltration, and AGEs accumulation in the aortic roots. SMTP-44D bound to immobilized RAGE and subsequently attenuated the interaction of AGEs with RAGE in vitro. Furthermore, foam cell formation evaluated by Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and gene expression of RAGE, cyclin-dependent kinase 5 (Cdk5) and CD36 in macrophages isolated from SMTP-44D-treated Apoe-/- mice were significantly decreased compared with those from saline-treated mice. Gene expression levels of RAGE and Cdk5 were highly correlated with each other, the latter of which was also positively associated with that of CD36. The present study suggests that SMTP-44D may inhibit atherosclerotic plaque formation in Apoe-/- mice partly by blocking the AGEs-RAGE-induced ox-LDL uptake into macrophages via the suppression of Cdk5-CD36 pathway.
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Aterosclerosis , Placa Aterosclerótica , Animales , Ratones , Placa Aterosclerótica/genética , Placa Aterosclerótica/complicaciones , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Aterosclerosis/metabolismo , Lipoproteínas LDL , Productos Finales de Glicación Avanzada/metabolismo , Apolipoproteínas E/metabolismo , Apolipoproteínas , Ratones NoqueadosRESUMEN
To evaluate the clinical efficacy of a new enzyme-linked immunosorbent assay (ELISA) system for simultaneously detecting three islet cell autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) (3 Screen ICA ELISA) in Japanese patients with acute-onset type 1 diabetes (T1D). In addition, clinical factors affecting the 3 Screen ICA ELISA index were investigated. We compared the positivity values of 3 Screen ICA ELISA with that of each autoantibody alone in 97 patients with acute-onset T1D (mean age 48.7 years, 49% male) and 100 non-diabetic subjects (mean age 47.0 years, 50% male). Serum thyroid stimulating hormone receptor antibody, thyroid peroxidase antibody (TPOAb) and thyroglobulin autoantibody levels were also evaluated. The cut-off value of the 3 Screen ICA ELISA was determined based on the 97th percentile of 100 non-diabetic controls (threshold for positivity, ≥14 index). The mean age of disease onset and duration of diabetes were 34.2 years and 14.5 years, respectively. Among all T1D patients, the positivity of 3 Screen ICA ELISA was 71.1%, while that of GADA, IA-2A, and ZnT8A were 59.8%, 25.8%, and 25.8%, respectively. The median 3 Screen ICA index was 121.9 (8.7-468.2) and was associated with titers of each autoantibody, most so with GADA, and was significantly higher in TPOAb-positive patients than in TPOAb-negative patients. Our findings suggests that the 3 Screen ICA ELISA may be a time-saving diagnostic tool for evaluating islet autoantibodies in acute-onset T1D patients.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Japón , Autoanticuerpos , Glutamato Descarboxilasa , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced CD36 gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and Cdk5 and CD36 gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). Cdk5 and CD36 gene expression levels were correlated with each other. An antioxidant, N-acetyl-l-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and CD36 gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not Cdk5 gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5-CD36 pathway via RAGE-mediated oxidative stress.
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Antígenos CD36/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Estrés Oxidativo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Animales , Aptámeros de Nucleótidos , Antígenos CD36/genética , Quinasa 5 Dependiente de la Ciclina/genética , Humanos , Modelos Biológicos , Células U937RESUMEN
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to play a protective role against atherosclerosis in both animal models and patients with type 2 diabetes (T2D). However, since T2D is associated with dyslipidemia, hypertension and insulin resistance, part of which are ameliorated by DPP-4 inhibitors, it remains unclear whether DPP-4 inhibitors could have anti-atherosclerotic properties directly by attenuating the harmful effects of hyperglycemia. Therefore, we examined whether a DPP-4 inhibitor, teneligliptin, could suppress oxidized low-density lipoprotein (ox-LDL) uptake, foam cell formation, CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression of macrophages isolated from streptozotocin-induced type 1 diabetes (T1D) mice and T1D patients as well as advanced glycation end product (AGE)-exposed mouse peritoneal macrophages and THP-1 cells. Foam cell formation, CD36 and ACAT-1 gene expression of macrophages derived from T1D mice or patients increased compared with those from non-diabetic controls, all of which were inhibited by 10 nmol/L teneligliptin. AGEs mimicked the effects of T1D; teneligliptin attenuated all the deleterious effects of AGEs in mouse macrophages and THP-1 cells. Our present findings suggest that teneligliptin may inhibit foam cell formation of macrophages in T1D via suppression of CD36 and ACAT-1 gene expression partly by attenuating the harmful effects of AGEs.
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Antígenos CD36/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Células Espumosas/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Esterol O-Aciltransferasa/metabolismo , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Espumosas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Pirazoles/farmacología , Células THP-1/efectos de los fármacos , Células THP-1/metabolismo , Tiazolidinas/farmacologíaRESUMEN
BACKGROUND: Excess fat deposition could induce phenotypic changes of perivascular adipose tissue (PVAT remodeling), which may promote the progression of atherosclerosis via modulation of adipocytokine secretion. However, it remains unclear whether and how suppression of PVAT remodeling could attenuate vascular injury. In this study, we examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, luseogliflozin on PVAT remodeling and neointima formation after wire injury in mice. METHODS: Wilt-type mice fed with low-fat diet (LFD) or high-fat diet (HFD) received oral administration of luseogliflozin (18 mg/kg/day) or vehicle. Mice underwent bilateral femoral artery wire injury followed by unilateral removal of surrounding PVAT. After 25 days, injured femoral arteries and surrounding PVAT were analyzed. RESULTS: In LFD-fed lean mice, neither luseogliflozin treatment or PVAT removal attenuated the intima-to-media (I/M) ratio of injured arteries. However, in HFD-fed mice, luseogliflozin or PVAT removal reduced the I/M ratio, whereas their combination showed no additive reduction. In PVAT surrounding injured femoral arteries of HFD-fed mice, luseogliflozin treatment decreased the adipocyte sizes. Furthermore, luseogliflozin reduced accumulation of macrophages expressing platelet-derived growth factor-B (PDGF-B) and increased adiponectin gene expression. Gene expression levels of Pdgf-b in PVAT were correlated with the I/M ratio. CONCLUSIONS: Our present study suggests that luseogliflozin could attenuate neointimal hyperplasia after wire injury in HFD-fed mice partly via suppression of macrophage PDGF-B expression in PVAT. Inhibition of PVAT remodeling by luseogliflozin may be a novel therapeutic target for vascular remodeling after angioplasty.
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Tejido Adiposo/efectos de los fármacos , Adiposidad/efectos de los fármacos , Dieta Alta en Grasa , Arteria Femoral/efectos de los fármacos , Neointima , Obesidad/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Sorbitol/análogos & derivados , Remodelación Vascular/efectos de los fármacos , Lesiones del Sistema Vascular/tratamiento farmacológico , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Animales , Modelos Animales de Enfermedad , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Arteria Femoral/fisiopatología , Linfocinas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/fisiopatología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Sorbitol/farmacología , Lesiones del Sistema Vascular/complicaciones , Lesiones del Sistema Vascular/metabolismo , Lesiones del Sistema Vascular/fisiopatologíaRESUMEN
Following publication of the original article [1], the authors identified a number of errors. In Result (P.3), Table 1 (P.4), Table 5 (P.9) and Supplementary Table 1, the correct unit for adiponectin was µg/mL. In Table 1 (P.4), the correct value for the post treatment body weight in dapagliflozin was 76.2±14.8. In Table 6 (P.10), the correct value for the pre treatment sd LDL/LDL-C in decreased LDL-C group was 0.38±0.10.
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BACKGROUND: The sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been reported to increase both low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol (C). This study aimed to determine how SGLT-2 inhibitors affect LDL and HDL-C subspecies. METHODS: This single center, open-label, randomized, prospective study included 80 patients with type 2 diabetes taking prescribed oral hypoglycemic agents. Patients were allocated to receive dapagliflozin (n = 40) or sitagliptin (n = 40) as add-on treatment. Fasting blood samples were collected before and 12 weeks after this intervention. Small dense (sd) LDL-C, large buoyant (lb) LDL-C, HDL2-C, and HDL3-C levels were determined using our established homogeneous assays. Statistical comparison of blood parameters before and after treatment was performed using the paired t test. RESULTS: Dapagliflozin and sitagliptin comparably decreased HbA1c (0.75 and 0.63%, respectively). Dapagliflozin significantly decreased body weight, systolic blood pressure, plasma triglycerides and liver transaminases, and increased adiponectin; sitagliptin did not alter these measurements. LDL-C and apolipoprotein (apo) B were not significantly changed by dapagliflozin, whereas HDL-C and apo AI were increased. Dapagliflozin did not alter concentrations of LDL-C, but sd LDL-C decreased by 20% and lb LDL-C increased by 18%. Marked elevation in lb LDL-C (53%) was observed in individuals (n = 20) whose LDL-C was elevated by dapagliflozin. However, sd LDL-C remained suppressed (20%). Dapagliflozin increased HDL2-C by 18% without affecting HDL3-C. Sitagliptin did not alter plasma lipids or lipoprotein subspecies. CONCLUSIONS: A SGLT-2 inhibitor, dapagliflozin suppresses potent atherogenic sd LDL-C and increased HDL2-C, a favorable cardiometabolic marker. Although LDL-C levels are elevated by treatment with dapagliflozin, this was due to increased concentrations of the less atherogenic lb LDL-C. However, these findings were not observed after treatment with dipeptidyl peptidase-4 inhibitor, sitagliptin. Trial registration UMIN Clinical Trials Registry (UMIN000020984).
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Compuestos de Bencidrilo/administración & dosificación , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Glucósidos/administración & dosificación , Lipoproteínas HDL2/sangre , Fosfato de Sitagliptina/administración & dosificación , Proteínas de Transporte de Sodio-Glucosa/antagonistas & inhibidores , Adulto , LDL-Colesterol/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Lipoproteínas HDL2/agonistas , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
INTRODUCTION: Recent trials have shown that glucagon-like peptide-1 receptor agonists considerably reduce atherosclerotic cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). Oxidative stress, a surrogate marker of cardiovascular risk, is associated with glucose variability. However, to the best of our knowledge, no studies have compared the effects of injectable semaglutide and dulaglutide therapies on oxidative stress and glucose variability assessed via continuous glucose monitoring (CGM). This study aimed to analyze and compare the effects of semaglutide and dulaglutide therapies on oxidative stress and glucose variability as assessed through CGM. METHODS: This is an open-label, multicenter, randomized, prospective, parallel-group comparison study. Overall, 37 patients with T2DM treated with dulaglutide for at least 12 weeks were randomized into two groups: one receiving continuous dulaglutide therapy (n = 19) and one receiving injectable semaglutide therapy (n = 18) groups. The coprimary endpoints were changes in the results of the diacron-reactive oxygen metabolites test, an oxidative stress marker, and CGM-evaluated glucose variability after 24 weeks. The secondary endpoint was changes in the Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores. RESULTS: Switching to semaglutide therapy was better than continuous dulaglutide therapy in reducing oxidative stress, glucose variability, and glycated hemoglobin levels. Conversely, continuous dulaglutide therapy was better than semaglutide therapy in terms of DTSQ scores for "Convenience" and "Recommend." CONCLUSION: Injectable semaglutide therapy may be more effective than dulaglutide therapy in ameliorating oxidative stress and regulating glucose metabolism, including glucose variability, in patients with T2DM, while dulaglutide therapy may be more effective in terms of treatment satisfaction. CLINICAL TRIAL REGISTRATION: UMIN-CRT ID: UMIN000042670 (registered 7 December 2020).
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BACKGROUND: The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG). METHODS: The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high-resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a lower 1,5-AG group (n = 36) and a higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups. RESULTS: The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT. CONCLUSION: Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease.
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Glucemia/análisis , Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/etiología , Hiperglucemia/complicaciones , Periodo Posprandial , Rigidez Vascular , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Grosor Intima-Media Carotídeo , Desoxiglucosa/sangre , Femenino , Humanos , Hiperglucemia/sangre , Hiperglucemia/fisiopatología , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Análisis de la Onda del Pulso , Factores de RiesgoRESUMEN
AIMS/INTRODUCTION: This study aimed to compare the positivity rates of glutamic acid decarboxylase autoantibodies (GADA) and ElisaRSR™ 3 Screen ICA™ (3 Screen ICA), a newly developed assay for the simultaneous measurement of GADA, insulinoma-associated antigen-2 autoantibodies (IA-2A), and zinc transporter 8 autoantibodies (ZnT8A), in recently obtained sera from patients who had been previously diagnosed with slowly progressive type 1 diabetes (SPIDDM). MATERIALS AND METHODS: We enrolled 53 patients with SPIDDM who were positive for GADA at the diagnosis and 98 non-diabetic individuals, and investigated the diagnostic accuracy of the 3 Screen ICA (cutoff index ≥30 units) compared with that of GADA. In addition, we compared the clinical characteristics of patients with SPIDDM who were negative or positive on 3 Screen ICA. RESULTS: The positivity rates of 3 Screen ICA, GADA, IA-2A, and ZnT8A were 88.7, 86.8, 24.5, and 13.2%, respectively. The respective sensitivity, specificity, and positive and negative predictive values for SPIDDM were 88.7, 100, 100, and 94.2% by 3 Screen ICA and 86.8, 100, 100.0, and 93.3% by GADA. There were no significant differences in age at onset, duration of diabetes, body mass index, glycated hemoglobin and C-peptide levels, and the prevalence of autoimmune thyroiditis between patients with SPIDDM who were positive or negative on 3 Screen ICA. However, the prevalence of insulin users was significantly higher in those who were positive than in those who were negative on 3 Screen ICA. CONCLUSIONS: Similar to GADA, 3 Screen ICA may be a useful diagnostic tool for detecting patients with SPIDDM.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Diabetes Autoinmune Latente del Adulto , Humanos , Glutamato Descarboxilasa , Autoanticuerpos , InsulinaRESUMEN
AIMS/INTRODUCTION: Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C levels, pemafibrate and statins can reduce sdLDL-C levels. However, it remains unclear whether adding pemafibrate or increasing statin doses would more effectively reduce sdLDL-C levels in patients receiving statin therapy. MATERIALS AND METHODS: A total of 97 patients with type 2 diabetes and hypertriglyceridemia who were treated with statins were randomly assigned to the pemafibrate 0.2 mg/day addition or statin dose doubled, and followed for 12 weeks. sdLDL-C was measured by our established homogenous assay. RESULTS: The percentage and absolute reductions of sdLDL-C levels were significantly greater in the pemafibrate add-on group than the statin doubling group (-32.8 vs -8.1%; -16 vs -3 mg/dL, respectively). Triglyceride levels were reduced only in the pemafibrate add-on group (-44%), and LDL-C levels were reduced only in the statin doubling group (-8%), whereas levels of non-high-density lipoprotein-C and apolipoprotein B were similarly decreased (7-9%) in both groups. The absolute reductions of sdLDL-C levels were closely associated with decreased triglyceride, LDL-C, non-high-density lipoprotein-C and apolipoprotein B. In the subgroup analysis, the effect of pemafibrate add-on on sdLDL-C reductions was observed irrespective of baseline lipid parameters or statin type. No serious adverse effects were observed in both groups. CONCLUSIONS: In patients with type 2 diabetes and hypertriglyceridemia, the addition of pemafibrate to a statin is superior to doubling a statin in reducing sdLDL-C without increasing adverse effects.
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Diabetes Mellitus Tipo 2 , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipertrigliceridemia , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , LDL-Colesterol , Estudios Prospectivos , Hipertrigliceridemia/tratamiento farmacológico , Triglicéridos , Lipoproteínas , Apolipoproteínas/uso terapéuticoRESUMEN
We have developed DNA aptamers that can inhibit the toxic effects of advanced glycation end products (AGE-Apts). We herein evaluated the effects of AGE-Apts on muscle mass and strength in senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old male SAMP8 mice received subcutaneous infusion of control DNA aptamers (CTR-Apts) or AGE-Apts. Mice in an age-matched senescence-accelerated mouse resistant strain 1 (SAMR1) group were treated with CTR-Apts as controls. The soleus muscles were collected after the 8-week intervention for weight measurement and histological, RT-PCR, and immunofluorescence analyses. Grip strength was measured before and after the 8-week intervention. AGE-Apt treatment inhibited the progressive decrease in the grip strength of SAMP8 mice. SAMP8 mice had lower soleus muscle weight and fiber size than SAMR1 mice, which was partly restored by AGE-Apt treatment. Furthermore, AGE-Apt-treated SAMP8 mice had a lower interstitial fibrosis area of the soleus muscle than CTR-Apt-treated SAMP8 mice. The soleus muscle levels of AGEs, oxidative stress, receptor for AGEs, and muscle ring-finger protein-1 were increased in the CTR-Apt-treated mice, all of which, except for AGEs, were inhibited by AGE-Apt treatment. Our present findings suggest that the subcutaneous delivery of AGE-Apts may be a novel therapeutic strategy for aging-related decrease in skeletal muscle mass and strength.
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BACKGROUND: Urinary N-acetyl-ß-D-glucosaminidase (NAG) excretion is increased in patients with impaired glucose tolerance (IGT). This study investigated when during the oral glucose tolerance test (OGTT) the plasma glucose, urine glucose, and insulin levels correlate most strongly with urinary N-acetyl-ß-d-glucosaminidase (NAG) levels in prediabetic subjects. METHODS: The OGTT was administered to 80 subjects who had not yet received a diagnosis of diabetes mellitus (DM) and in whom HbA1c levels were ≤6.8% and fasting plasma glucose levels were <7.0 mmol/l. Forty-two subjects had normal glucose tolerance (NGT), 31 had impaired glucose tolerance (IGT), and 7 had DM according to World Health Organization criteria. Serum levels of cystatin C, the estimated glomerular filtration rate, the urinary albumin-to-creatinine (Cr) ratio, urinary and serum ß2-microglobulin, and urinary NAG were measured as markers of renal function. RESULTS: NAG levels were significantly higher in subjects with DM and in subjects with IGT than in subjects with NGT. No significant associations were observed between glycemic status and other markers of renal function. Multiple linear regression analysis showed that the NAG level was positively correlated with plasma glucose levels at 120 min of the OGTT and was associated with the glycemic status of prediabetic patients. CONCLUSION: These results suggest that postprandial hyperglycemia is an independent factor that causes renal tubular damage in prediabetes patients.
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Acetilglucosaminidasa/orina , Glucemia/metabolismo , Estado Prediabético/sangre , Estado Prediabético/orina , Adolescente , Adulto , Anciano , Cistatina C/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: Sodium-glucose cotransporter-2 (SGLT2) inhibitors exhibit cardioprotective properties in patients with diabetes. However, SGLT2 is not expressed in the heart, and the underlying molecular mechanisms are not fully understood. We investigated whether the SGLT2 inhibitor luseogliflozin exerts beneficial effects on high glucose-exposed cardiomyocytes via the suppression of sodium-hydrogen exchanger-1 (NHE-1) activity. METHODS: Mouse cardiomyocytes were incubated under normal or high glucose conditions with vehicle, luseogliflozin, or the NHE-1 inhibitor cariporide. NHE-1 activity and gene expression were evaluated by the SNARF assay and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis, respectively. Six-week-old male db/db mice were treated with vehicle or luseogliflozin for 6 weeks, and the hearts were collected for histological, RT-PCR, and western blot analyses. RESULTS: High glucose increased NHE-1 activity and transforming growth factor (Tgf)-ß2 mRNA levels in cardiomyocytes, both of which were inhibited by luseogliflozin or cariporide, whereas their combination showed no additive suppression of Tgf-ß2 mRNA levels. Luseogliflozin attenuated cardiac hypertrophy and fibrosis in db/db mice in association with decreased mRNA and protein levels of TGF-ß2. CONCLUSIONS: Luseogliflozin may suppress cardiac hypertrophy in diabetes by reducing Tgf-ß2 expression in cardiomyocytes via the suppression of NHE-1 activity.
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Diabetes Mellitus , Miocitos Cardíacos , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Animales , Cardiomegalia/patología , Diabetes Mellitus/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Humanos , Masculino , Ratones , Miocitos Cardíacos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/farmacología , Sorbitol/análogos & derivados , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta2/farmacologíaRESUMEN
AIMS/HYPOTHESIS: Although IGF-1 is known to promote organ growth, including exocrine pancreas, the association between plasma IGF-1 levels and pancreatic size remains unclear in diabetic patients. METHODS: This cross-sectional study was designed to investigate the correlations among pancreatic volume (PV) based on computed tomography, IGF-1 levels, age- and sex-adjusted IGF-1 levels (IGF-1 Z-score), and C-peptide levels in patients with type 1 diabetes (T1D) (n = 51) and type 2 diabetes (T2D) (n = 104) in a Japanese population. RESULTS: PV was significantly correlated with body weight (BW) in both types of diabetes. PV adjusted for BW (PV/BW), IGF-1 Z-score and C-peptide levels were significantly lower in patients with T1D than T2D. There was a significant positive correlation between C-peptide levels and PV/BW in both subtypes of diabetes. IGF-1 Z-scores were significantly correlated with PV/BW in patients with T1D (r = 0.37, P = 0.007), but not T2D. Although IGF-1 Z-scores were not correlated with age, age of disease onset, disease duration, HbA1c, or C-peptide levels in both types of diabetes, a multivariable liner regression analysis revealed that IGF-1 Z-score and C-peptide levels were independent correlates of PV/BW in T1D patients, while C-peptide levels were a sole correlate in T2D. CONCLUSIONS/INTERPRETATION: Decreased IGF-1 levels might be one causal factor for smaller pancreas in patients with T1D.
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Biomarcadores/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Factor I del Crecimiento Similar a la Insulina/análisis , Páncreas/patología , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Páncreas/metabolismo , PronósticoRESUMEN
BACKGROUND: Methimazole (MMI) is used to treat hyperthyroidism in Graves' disease. It is rare to encounter patients in whom hyperthyroidism cannot be controlled using high doses of MMI.Case presentation: A 21-year-old woman was referred to our hospital because of MMI-resistant Graves' disease. Although her MMI dose had been increased to 120 mg/day, her serum thyroid hormone concentration was too high to be measured. Additional therapy with lithium carbonate, and then with dexamethasone and inorganic iodine, was initiated. After 14 days, the patient's serum thyroid hormone concentration normalized, while she was taking 150 mg/day MMI, 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, and total thyroidectomy was then performed. The patient was discharged 8 days after the thyroidectomy and experienced no major complications. CONCLUSIONS: We have presented a rare case of Graves' disease that was resistant to high-dose MMI. Combination therapy of MMI with lithium carbonate, dexamethasone and inorganic iodine may represent a therapeutic option for the preoperative preparation of patients with MMI-resistant Graves' disease.
Asunto(s)
Enfermedad de Graves , Metimazol , Adulto , Antitiroideos/uso terapéutico , Femenino , Enfermedad de Graves/tratamiento farmacológico , Humanos , Metimazol/uso terapéutico , Hormonas Tiroideas , Tiroxina , Adulto JovenRESUMEN
Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr-/-) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala2]GIP(1-42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused subcutaneously with [D-Ala2]GIP(1-42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr-/- mice infused with [D-Ala2]GIP(1-42). When macrophages were isolated from Gipr+/+ and Gipr-/- mice, and then exposed to [D-Ala2]GIP(1-42), similar results were obtained. [D-Ala2]GIP(1-42) attenuated ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala2]GIP(1-42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the effects of [D-Ala2]GIP(1-42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor.
RESUMEN
Diabetic cardiomyopathy is associated with an increased risk for heart failure and death in patients with diabetes. We investigated here whether and how GIP attenuated cardiac hypertrophy and fibrosis in diabetic mice with obesity. Diabetic db/db mice at 7 weeks old were infused with vehicle or GIP (50 nmol/kg/day) for 6 weeks, and hearts were collected for histological and RT-PCR analyzes. Cardiomyocytes isolated from neonatal mice were incubated with or without 300 nM [D-Ala2]-GIP, 30 mM glucose, or 100 µg/mL advanced glycation end products (AGEs) for RT-PCR and lucigenin assays. Compared with non-diabetic mice, diabetic mice exhibited larger left ventricle wall thickness and cardiomyocyte sizes and more fibrotic areas in association with up-regulation of myosin heavy chain ß (ß-Mhc) and transforming growth factor-beta2 (Tgf-ß2) mRNA levels, all of which were inhibited by GIP infusion. High glucose increased NADPH oxidase-driven superoxide generation and up-regulated ß-Mhc, Tgf-ß2, and receptor for AGEs mRNA levels in cardiomyocytes, and augmented the AGE-induced ß-Mhc gene expression. [D-Ala2]-GIP attenuated all of the deleterious effects of high glucose and/or AGEs on cardiomyocytes. Our present findings suggest that GIP could inhibit cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-ß2.