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1.
Biochem Biophys Res Commun ; 649: 32-38, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36739697

RESUMO

The small GTPase Rho and its effector Rho-kinase (ROCK) are activated in the diabetic kidney, and recent studies decade have demonstrated that ROCK signaling is an integral pathway in the progression of diabetic kidney disease. We previously identified the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism in diabetic glomeruli. However, the effect of pharmacological intervention for ROCK1 is not clear. In the present study, we show that the inhibition of ROCK1 by Y-27632 and fasudil restores fatty acid oxidation in the glomeruli. Mechanistically, these compounds optimize fatty acid utilization and redox balance in mesangial cells via AMPK phosphorylation and the subsequent induction of PGC-1α. A further in vivo study showed that the inhibition of ROCK1 suppressed the downregulation of the fatty acid oxidation-related gene expression in glomeruli and mitochondrial fragmentation in the mesangial cells of db/db mice. These observations indicate that ROCK1 could be a promising therapeutic target for diabetic kidney disease through a mechanism that improves glomerular fatty acid metabolism.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Quinases Associadas a rho/metabolismo , Glomérulos Renais/metabolismo , Rim/metabolismo , Transdução de Sinais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Diabetes Mellitus/metabolismo
2.
Biosci Biotechnol Biochem ; 87(10): 1212-1218, 2023 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-37370223

RESUMO

This study aims to confirm the "vegetable-first" effect. In addition, because we aimed dietary fiber in vegetable salad, the effect after the ingestion of vegetable salad extract (vegetable salad from which solids have been removed) before carbohydrates on postprandial serum glucose level was also evaluated. A total of 13 healthy men were given meals after one-night of fasting: rice-vegetable salad, vegetable salad-rice, and vegetable salad extract-rice. Blood samples were taken at 0, 30, 45, 60, 90, and 120 min after the ingestion of the test meal to measure serum glucose levels. Serum glucose levels were significantly lower after 45 and 60 min in the vegetable salad-rice group compared to the rice-vegetable salad group. No significant difference was found between the vegetable salad extract-rice group and the vegetable salad-rice/rice-vegetable salad group. The result suggested that it might be important to ingest vegetables to obtain the "vegetable-first" effect.


Assuntos
Oryza , Saladas , Masculino , Humanos , Verduras , Voluntários Saudáveis , Glucose , Ingestão de Alimentos , Glicemia , Período Pós-Prandial , Estudos Cross-Over , Insulina
3.
Kidney Int ; 102(3): 536-545, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35597365

RESUMO

Dysregulation of fatty acid utilization is increasingly recognized as a significant component of diabetic kidney disease. Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in the diabetic kidney, and studies over the past decade have illuminated ROCK signaling as an essential pathway in diabetic kidney disease. Here, we confirmed the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism using glomerular mesangial cells and ROCK1 knockout mice. Mesangial cells with ROCK1 deletion were protected from mitochondrial dysfunction and redox imbalance driven by transforming growth factor ß, a cytokine upregulated in diabetic glomeruli. We found that high-fat diet-induced obese ROCK1 knockout mice exhibited reduced albuminuria and histological abnormalities along with the recovery of impaired fatty acid utilization and mitochondrial fragmentation. Mechanistically, we found that ROCK1 regulates the induction of critical mediators in fatty acid metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1α, carnitine palmitoyltransferase 1, and widespread program-associated cellular metabolism. Thus, our findings highlight ROCK1 as an important regulator of energy homeostasis in mesangial cells in the overall pathogenesis of diabetic kidney disease.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Quinases Associadas a rho , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Transdução de Sinais , Quinases Associadas a rho/metabolismo
4.
Int J Mol Sci ; 23(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35409362

RESUMO

The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Glucagon , Animais , Arginina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Camundongos , Proteína Quinase C-delta/genética , Proteína Quinase C-delta/metabolismo
5.
Histochem Cell Biol ; 153(2): 111-119, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31734714

RESUMO

Glycolaldehyde (GA) is a highly reactive hydroxyaldehyde and one of the glycolytic metabolites producing advanced glycation endproducts (AGEs), but its toxicity toward neurons and Schwann cells remains unclear. In the present study, we found that GA exhibited more potent toxicity than other AGE precursors (glyceraldehyde, glyoxal, methylglyoxal and 3-deoxyglucosone) against immortalized IFRS1 adult rat Schwann cells and ND7/23 neuroblastoma × neonatal rat dorsal root ganglion (DRG) neuron hybrid cells. GA affected adult rat DRG neurons and ND7/23 cells more severely than GA-derived AGEs, and exhibited concentration- and time-dependent toxicity toward ND7/23 cells (10 < 100 < 250 < 500 µM; 6 h < 24 h). Treatment with 500 µM GA significantly up-regulated the phosphorylation of c-jun N-terminal kinase (JNK) and p-38 mitogen-activated kinase (p-38 MAPK) in ND7/23 cells. Furthermore, GA-induced ND7/23 cell death was significantly inhibited due to co-treatment with 10 µM of the JNK inhibitor SP600125 or the p-38 MAPK inhibitor SB239063. These findings suggest the involvement of JNK and p-38 MAPK-signaling pathways in GA-induced neuronal cell death and that enhanced GA production under diabetic conditions might be involved in the pathogenesis of diabetic neuropathy.


Assuntos
Acetaldeído/análogos & derivados , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Acetaldeído/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Feminino , Ratos , Ratos Wistar , Células Receptoras Sensoriais/metabolismo
6.
Am J Physiol Renal Physiol ; 317(4): F839-F851, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364374

RESUMO

The small GTPase Rho and its effector Rho kinase (ROCK) are involved in the pathogenesis of diabetic kidney disease. Rho kinase has two isoforms: ROCK1 and ROCK2. However, it remains unclear which is mainly involved in the progression of diabetic glomerulosclerosis and the regulation of profibrotic mediators. Glomeruli isolated from type 2 diabetic db/db mice demonstrated increased gene expression of transforming growth factor (TGF)-ß and its downstream profibrotic mediators. Chemical inhibition of ROCK suppressed the expression of profibrotic mediators in both isolated glomeruli and cultured mesangial cells. An investigation of mechanisms underlying this observation revealed activated ROCK functions through the phosphorylation of JNK and Erk and the nuclear translocation of NF-κB via actin dynamics. Knockdown by siRNA against ROCK1 and ROCK2 showed that ROCK2 but not ROCK1 controls this fibrotic machinery. Further in vivo experiments showed that ROCK2 activity in the renal cortex of db/db mice was elevated compared with control db/m mice. Importantly, oral administration of ROCK2 inhibitor attenuated renal ROCK2 activity, albuminuria, and glomerular fibrosis in db/db mice. These observations indicate that ROCK2 is a key player in the development of diabetic renal injury. Glomerular ROCK2 may be a potential therapeutic target for the treatment of diabetic kidney disease.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/biossíntese , Citoesqueleto/metabolismo , Fibrose/genética , Mesângio Glomerular/metabolismo , NF-kappa B/biossíntese , Fator de Crescimento Transformador beta/farmacologia , Quinases Associadas a rho/metabolismo , Actinas/metabolismo , Animais , Nefropatias Diabéticas/metabolismo , Ativação Enzimática , Mesângio Glomerular/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Quinases Associadas a rho/antagonistas & inibidores
7.
Diabetes Obes Metab ; 21(4): 791-800, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30393955

RESUMO

AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.


Assuntos
Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/metabolismo , Análise de Intenção de Tratamento , Japão , Masculino , Pessoa de Meia-Idade , Planejamento de Assistência ao Paciente , Prevenção Primária , Modelos de Riscos Proporcionais
8.
Lipids Health Dis ; 18(1): 102, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010430

RESUMO

BACKGROUND: We previously reported that the consumption of 8 g of protein per day in the form of lactic-fermented egg white (LAFEW) improves visceral fat obesity. In this study, we investigated the minimum effective intake of LAFEW for visceral fat reduction in the Japanese males with mild obesity. METHODS: Twenty-two Japanese adult males with a Body mass index (BMI) ≥24 and a waist circumference ≥ 85 cm were included in this study. The subjects were divided into three groups, that is, control group, LAFEW 6 g group, and LAFEW 8 g group. The LAFEW 6 and 8 g groups consumed 6 and 8 g, respectively, of egg white protein (EWP) in a drink at breakfast for 8 weeks, whereas the control group consumed a drink containing 8 g of milk whey protein. Body weight, body fat percentage, abdominal circumference, and visceral fat (VF) area around the navel were measured at 0 and 8 weeks after initiating the consumption. RESULTS: No changes in body weight or body fat percentage were observed in any of the groups. No significant differences between the pre- and posttreatment measurements were found in the VF area around the navel in the control group and the LAFEW 6 g group. In the LAFEW 8 g group, the VF area had decreased significantly after 8 weeks of consumption, when compared to that before consumption, and the average observed decrease (Δcm2) was 13.2 ± 4.7 cm2. Among the subjects with an initial BMI > 25, the VF area was significantly smaller in the LAFEW 8 group, when compared to the week 0 values and those in the control group. Visceral fat/subcutaneous fat values in the LAFEW 8 group were also significantly smaller than those in the control group or at week 0. CONCLUSION: The results suggested that the minimum effective intake of EWP in the LAFEW to reduce the VF area in the Japanese men is 8 g. TRIAL REGISTRATION: This clinical trial was retrospectively registered with the University hospital Medical Information Network (UMIN) Center, ( UMIN000031681 ; registered on 12/03/2018).


Assuntos
Clara de Ovo/química , Fermentação , Gordura Intra-Abdominal/efeitos dos fármacos , Ácido Láctico/farmacologia , Adulto , Animais , Galinhas , Dieta , Método Duplo-Cego , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Rim/efeitos dos fármacos , Rim/fisiologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/fisiologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tomografia Computadorizada por Raios X
9.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295940

RESUMO

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents.


Assuntos
Nefropatias Diabéticas/etiologia , Suscetibilidade a Doenças , Inflamação/complicações , Animais , Biomarcadores , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/terapia , Humanos , Mediadores da Inflamação/metabolismo , Transdução de Sinais
10.
Int J Mol Sci ; 20(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884801

RESUMO

The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and migration. A pro-inflammatory lipid mediator, lysophosphatidic acid (LPA), is a potent activator of the Rho/ROCK signalling pathway and has been shown to induce the expression of chemokines and cell adhesion molecules (CAMs). In the present study, we aimed to elucidate the precise mechanism by which ROCK regulates LPA-induced expressions and functions of chemokines and CAMs. We observed that ROCK blockade reduced LPA-induced phosphorylation of IκBα and inhibited NF-κB RelA/p65 phosphorylation, leading to attenuation of RelA/p65 nuclear translocation. Furthermore, small interfering RNA-mediated ROCK isoform knockdown experiments revealed that LPA induces the expression of monocyte chemoattractant protein-1 (MCP-1) and E-selectin via ROCK2 in human aortic endothelial cells (HAECs). Importantly, we found that ROCK2 but not ROCK1 controls LPA-induced monocytic migration and monocyte adhesion toward endothelial cells. These findings demonstrate that ROCK2 is a key regulator of endothelial inflammation. We conclude that targeting endothelial ROCK2 is potentially effective in attenuation of atherosclerosis.


Assuntos
Aterosclerose/genética , Células Endoteliais/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Quinases Associadas a rho/genética , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/genética , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Aorta/citologia , Aorta/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Selectina E/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/genética , Monócitos/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética , Quinases Associadas a rho/metabolismo
11.
Histochem Cell Biol ; 149(5): 537-543, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29435762

RESUMO

Co-culture models of neurons and Schwann cells have been utilized for the study of myelination and demyelination in the peripheral nervous system; in most of the previous studies, however, these cells were obtained by primary culture with embryonic or neonatal animals. A spontaneously immortalized Schwann cell line IFRS1 from long-term cultures of adult Fischer rat peripheral nerves has been shown to retain fundamental ability to myelinate neurites in co-cultures with adult rat dorsal root ganglion neurons and nerve growth factor-primed PC12 cells. Our current investigation focuses on the establishment of stable co-culture system with IFRS1 cells and NSC-34 motor neuron-like cells. NSC-34 cells were seeded at a low density (2 × 103/cm2) and maintained for 5-7 days in serum-containing medium supplemented with non-essential amino acids and brain-derived neurotrophic factor (BDNF; 10 ng/mL). Upon observation of neurite outgrowth under a phase-contrast microscope, the NSC-34 cells were exposed to an anti-mitotic agent mitomycin C (1 µg/mL) for 12-16 h, then co-cultured with IFRS1 cells (2 × 104/cm2), and maintained in serum-containing medium supplemented with ascorbic acid (50 µg/mL), BDNF (10 ng/mL), and ciliary neurotrophic factor (10 ng/mL). Double immunofluorescence staining carried out at day 28 of the co-culture showed myelin protein (P0 or PMP22)-immunoreactive IFRS1 cells surrounding the ßIII tubulin-immunoreactive neurites. This co-culture system can be a beneficial tool to study the pathogenesis of motor neuron diseases (e.g., amyotrophic lateral sclerosis, Charcot-Marie-Tooth diseases, and immune-mediated demyelinating neuropathies) and novel therapeutic approaches against them.


Assuntos
Técnicas de Cocultura/métodos , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Bainha de Mielina/metabolismo , Células de Schwann/citologia , Células de Schwann/metabolismo , Animais , Linhagem Celular , Ratos
12.
Cardiovasc Diabetol ; 17(1): 100, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29991356

RESUMO

BACKGROUND: The relationship between long-term glycemic variability (GV) represented by visit-to-visit HbA1c variability and baroreflex sensitivity (BRS) in type 2 diabetes mellitus (T2DM) has not been clarified by previous literature. The present study is the first to examine the relationships between visit-to-visit HbA1c variability and BRS. METHODS: This retrospective study initially analyzed data on 94 patients with T2DM. Visit-to-visit HbA1c variability was evaluated using the intrapersonal coefficient of variation (CV), standard deviation (SD), and adjusted SD of 8 or more serial measurements of HbA1c during a 2-year period. The BRS was analyzed using the sequence method. Short-term GV was assessed by measuring the glucose CV during 24-h continuous glucose monitoring (CGM). The primary objective was to determine if there was a relationship between visit-to-visit HbA1c variability (HbA1c CV) and BRS. Secondary objectives were to examine the relationship between other variables and BRS and the respective and combined effects of long-term GV (HbA1c CV) and short-term GV (CGM CV) on BRS. RESULTS: A total of 57 patients (mean age 67.2 ± 7.7 years, mean HbA1c 7.3 ± 1.0%) who met this study's inclusion criteria were finally analyzed. In the univariate analysis, HbA1c CV (r = - 0.354, p = 0.007), HbA1c SD (r = - 0.384, p = 0.003), and adjusted HbA1c SD (r = - 0.391, p = 0.003) were significantly related to low levels of BRS. Multiple regression analysis showed that HbA1c CV, HbA1c SD, and adjusted HbA1c SD were inversely related to BRS. Furthermore, although the increase in either long-term GV (HbA1c CV) or short-term GV (CGM CV) as determined by 24-h CGM was inversely correlated with BRS, additional reductions in BRS were not shown in participants with both HbA1c CV and CGM CV values above the median. CONCLUSIONS: Visit-to-visit HbA1c variability was inversely related to BRS independently of the mean HbA1c in patients with T2DM. Therefore, visit-to-visit HbA1c variability might be a marker of reduced BRS in T2DM.


Assuntos
Barorreflexo , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/fisiopatologia , Hemoglobinas Glicadas/metabolismo , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
13.
Cardiovasc Diabetol ; 17(1): 73, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29788955

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) greatly increases the risks of cardiovascular disease and heart failure. In particular, left ventricular diastolic dysfunction that develops from the early stages of T2DM is an important factor in the onset and exacerbation of heart failure. The effect of sodium-glucose cotransporter 2 inhibitors on left ventricular diastolic function has not been elucidated. We have performed the first prospective study on the effects of canagliflozin on left ventricular diastolic function in T2DM. METHODS: This study was performed to evaluate the effects of additional treatment with canagliflozin for 3 months on left ventricular diastolic function in patients with T2DM. A total of 38 patients with T2DM were consecutively recruited for this study. Left ventricular diastolic function was assessed by echocardiography. The primary study outcome was a change in the septal E/e' as a parameter of left ventricular diastolic function. RESULTS: A total of 37 patients (25 males and 12 females) were included in the analysis. Mean age of participants was 64.2 ± 8.1 years (mean ± SD), mean duration of diabetes was 13.5 ± 8.1 years, and mean HbA1c was 7.9 ± 0.7%. Of the participants, 86.5% had hypertension, 100% had dyslipidemia, and 32.4% had cardiovascular disease. Canagliflozin significantly improved left ventricular diastolic function (septal E/e' ratio 13.7 ± 3.5-12.1 ± 2.8, p = 0.001). Furthermore, among the various parameters that changed through the administration of canagliflozin, only changes in hemoglobin significantly correlated with changes in the septal E/e' ratio (p = 0.002). In multiple regression analysis, changes in hemoglobin were also revealed to be an independent predictive factor for changes in the septal E/e' ratio. CONCLUSIONS: This study showed for the first time that canagliflozin could improve left ventricular diastolic function within 3 months in patients with T2DM. The benefit was especially apparent in patients with substantially improved hemoglobin values. Trial registration UMIN Clinical Trials Registry UMIN000028141.


Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Diástole , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
14.
Cardiovasc Diabetol ; 17(1): 36, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29514695

RESUMO

BACKGROUND: It is presently unclear whether glycemic variability (GV) is associated with baroreflex sensitivity (BRS), which is an early indicator of cardiovascular autonomic neuropathy. The present study is the first to examine the relationships between BRS and GV measured using continuous glucose monitoring (CGM). METHODS: This was a multicenter, prospective, open-label clinical trial. A total of 102 patients with type 2 diabetes were consecutively recruited for this study. GV was assessed by measuring the standard deviation (SD), glucose coefficient of variation (CV), and the mean amplitude of glycemic excursions (MAGE) during CGM. The BRS was analyzed from electrocardiogram and blood pressure recordings using the sequence method on the first day of hospitalization. RESULTS: A total of 94 patients (mean diabetes duration 9.7 ± 9.6 years, mean HbA1c 61.0 ± 16.8 mmol/mol [7.7 ± 1.5%]) were analyzed. In the univariate analysis, CGM-SD (r = - 0.375, p = 0.000), CGM-CV (r = - 0.386, p = 0.000), and MAGE (r = - 0.395, p = 0.000) were inversely related to BRS. In addition to GV, the level of BRS correlated with the coefficient of variation in the R-R intervals (CVR-R) (r = 0.520, p = 0.000), heart rate (HR) (r = - 0.310, p = 0.002), cardio-ankle vascular index (CAVI) (r = - 0.326, p = 0.001), age (r = - 0.519, p = 0.000), and estimated glomerular filtration rate (eGFR) (r = 0.276, p = 0.007). Multiple regression analysis showed that CGM-CV and MAGE were significantly related to a decrease in BRS. These findings remained after adjusting the BRS for age, sex, hypertension, dyslipidemia, HR, eGFR, CAVI, and CGM-mean glucose. Additionally, BRS was divided according to quartiles of the duration of diabetes (Q1-4). BRS decreased after a 2-year duration of diabetes independently of age and sex. CONCLUSIONS: GV was inversely related to BRS independently of blood glucose levels in type 2 diabetic patients. Measurement of BRS may have the potential to predict CV events in consideration of GV. Trial registration UMIN Clinical Trials Registry UMIN000025964, 28/02/2017.


Assuntos
Barorreflexo , Automonitorização da Glicemia , Glicemia/metabolismo , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Neuropatias Diabéticas/fisiopatologia , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Hospitalização , Humanos , Hipoglicemiantes/uso terapêutico , Japão , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Dados Preliminares , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
15.
Lipids Health Dis ; 16(1): 101, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28558718

RESUMO

BACKGROUND: Lactic-fermented egg white (LE), produced by lactic acid fermentation of egg white, is an easy-to-consume form of egg white. Here we assessed the effect of daily consumption of LE for 8 weeks on serum total cholesterol (TC) levels. METHODS: The study followed a double-blind, parallel-arm design and included 88 adult men with mild hypercholesterolemia (mean ± standard error) serum TC levels, 229 ± 1.6 mg/dL; range, 204-259 mg/dL). The subjects were randomly divided into three groups, which consumed LE containing 4, 6, or 8 g of protein daily for 8 weeks. Blood samples were collected before starting LE consumption (baseline) and at 4 and 8 weeks to measure serum TC and low-density lipoprotein cholesterol (LDL-C) levels. RESULTS: After 8 weeks of consumption, serum TC levels in the 8 g group decreased by 11.0 ± 3.7 mg/dL, a significant decrease compared to baseline (p < 0.05) and a significantly greater decrease than for the 4 g group (3.1 ± 3.4 mg/dL; p < 0.05). Serum LDL-C levels in the 8 g group decreased by 13.7 ± 3.1 mg/dL, again a significant decrease compared with baseline (p < 0.05) and a significantly greater decrease than that for the 4 g group (2.1 ± 2.9 mg/dL; p < 0.05). CONCLUSION: Consumption of LE for 8 weeks at a daily dose of 8 g of proteins reduced serum TC and LDL-C levels in men with mild hypercholesterolemia, suggesting this may be effective in helping to prevent arteriosclerotic diseases. TRIAL REGISTRATION: This clinical trial was retrospectively registered with the Japan Medical Association Center for Clinical Trials, (JMA-IIA00279; registered on 13/03/2017; https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRE02_04/JMACTRE02_04.aspx?kbn=3&seqno=6530 ).


Assuntos
Colesterol/sangue , Clara de Ovo/química , Hipercolesterolemia/dietoterapia , Adulto , LDL-Colesterol/sangue , Método Duplo-Cego , Fermentação , Humanos , Hipercolesterolemia/sangue , Japão , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
16.
Lipids Health Dis ; 16(1): 237, 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29216922

RESUMO

BACKGROUND: It was reported that egg white protein (EWP) reduced body fat in rats. We developed a lactic-fermented egg white (LE) that facilitates the consumption of egg whites by fermenting them with lactobacillus, and were able to study their intake in humans. In this double-blind, placebo-controlled design, we evaluated the effect of LE on visceral fat area (VFA). METHODS: Participants included 37 adult males and females aged ≥40 years (VFA at navel ≥100 cm2). They were divided into two groups: the control group and the LE group. The control and LE groups consumed drinks containing whey and LE, respectively, for 12 weeks (providing 8 g protein/day). VFA was measured at baseline and at week 12 of intake. Abdominal girth was measured at baseline and at weeks 6 and 12. RESULTS: LE intake decreased VFA significantly compared with baseline (-8.89 cm2, p < 0.05), and VFA was significantly lower than that in the control group (+1.71 cm2, p < 0.05). The LE group showed significant improvement in the ratio of visceral to subcutaneous fat area compared with baseline and the control group (p < 0.05). CONCLUSIONS: The results demonstrated that LE reduces VFA and improves the ratio of visceral to subcutaneous fat area. As other measurement items were not influenced, we concluded that LE improves visceral fat obesity. TRIAL REGISTRATION: This clinical trial was retrospectively registered with the University hospital Medical Information Network (UMIN) Center, ( UMIN000026949 ; registered on 11/04/2017; http://www.umin.ac.jp /).


Assuntos
Proteínas Dietéticas do Ovo/administração & dosagem , Gordura Intra-Abdominal/efeitos dos fármacos , Obesidade Abdominal/dietoterapia , Gordura Subcutânea/efeitos dos fármacos , Adulto , Idoso , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Fermentação , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/fisiopatologia
17.
Int J Mol Sci ; 18(8)2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28820432

RESUMO

Podocyte apoptosis is a key process in the onset of diabetic nephropathy. A significant body of evidence shows that the Notch signaling pathway plays a central role in this process. We found that Rho-kinase mediates transforming growth factor ß (TGF-ß)-induced Notch ligand Jag1 expression. Importantly, TGF-ß-mediated podocyte apoptosis was attenuated by Rho-kinase inhibition. Mechanistically, Rho-kinase regulated Jag1 induction via the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) but not Smad pathways. Consistently, the Rho-kinase inhibitor fasudil prevented albuminuria and the urinary excretion of nephrin in db/db mice and reduced the prevalence of podocyte apoptosis and Jag1 expression. Finally, the expression of Jag1 and apoptosis markers such as Bax and cyclin-dependent kinase inhibitor 1A (CDKN1A) was decreased in podocytes derived from db/db mice treated with fasudil. The present study provides evidence that Rho-kinase plays a key role in podocyte apoptosis. Rho-kinase is an attractive therapeutic target for diabetic nephropathy.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Apoptose/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Podócitos/efeitos dos fármacos , Receptores Notch/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Proteína Jagged-1/metabolismo , Masculino , Proteínas de Membrana/urina , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Podócitos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/metabolismo
18.
Int J Mol Sci ; 18(5)2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28524098

RESUMO

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium-glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Humanos , Florizina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Int Heart J ; 58(5): 794-802, 2017 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-28966330

RESUMO

Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCß by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCß but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCß by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCß2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCß signaling, which leads to MR stabilization and its transcriptional activities.


Assuntos
Diabetes Mellitus Experimental , Regulação da Expressão Gênica , Glucose/administração & dosagem , Hipertensão/genética , Proteína Quinase C beta/genética , RNA/genética , Receptores de Mineralocorticoides/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Camundongos , Camundongos Transgênicos , Proteína Quinase C beta/biossíntese , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Mineralocorticoides/biossíntese , Receptores de Mineralocorticoides/genética , Transdução de Sinais/efeitos dos fármacos
20.
Eur J Neurosci ; 44(1): 1723-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27152884

RESUMO

Amiodarone hydrochloride (AMD), an anti-arrhythmic agent, has been shown to cause peripheral neuropathy; however, its pathogenesis remains unknown. We examined the toxic effects of AMD on an immortalized adult rat Schwann cell line, IFRS1, and cocultures of IFRS1 cells and adult rat dorsal root ganglion neurons or nerve growth factor-primed PC12 cells. Treatment with AMD (1, 5, and 10 µm) induced time- and dose-dependent cell death, accumulation of phospholipids and neutral lipids, upregulation of the expression of gangliosides, and oxidative stress (increased nuclear factor E2-related factor in nuclear extracts and reduced GSH/GSSG ratios) in IFRS1 cells. It also induced the upregulation of LC3-II and p62 expression, with phosphorylation of p62, suggesting that deficient autolysosomal degradation is involved in AMD-induced IFRS1 cell death. Furthermore, treatment of the cocultures with AMD induced detachment of IFRS1 cells from neurite networks in a time- and dose-dependent manner. These findings suggest that AMD-induced lysosomal storage accompanied by enhanced oxidative stress and impaired lysosomal degradation in Schwann cells might be a cause of demyelination in the peripheral nervous system.


Assuntos
Doenças Desmielinizantes/metabolismo , Lisossomos/metabolismo , Estresse Oxidativo , Células de Schwann/metabolismo , Amiodarona/toxicidade , Animais , Células Cultivadas , Inibidores Enzimáticos/toxicidade , Feminino , Gânglios Espinais/citologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/metabolismo , Células PC12 , Fosfolipídeos/metabolismo , Ratos , Ratos Wistar , Células de Schwann/efeitos dos fármacos
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