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1.
Medicine (Baltimore) ; 99(11): e19501, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176092

RESUMO

BACKGROUND: Clinical and basic research supports that blood glucose fluctuation is an important predictor of diabetic vascular disease and an etiology of lower extremity atherosclerosis, which is an important pathological basis for lower extremity vascular diseases. Previous Chinese National Natural Science Foundation trials (No. 81503566) have reported that the traditional Chinese medicine Shenqi compound can reduce blood glucose fluctuation and low-grade inflammation, and protect blood vessels; however, there are no high-quality clinical evidences available to support the same. This multicenter randomized controlled trial aims to obtain more clinical evidence to confirm the efficacy and safety of Shenqi compound in type 2 diabetes with lower extremity atherosclerosis. METHODS: A multicenter RCT will be implemented in this study for a 32-week study period (8 weeks for intervention and 24 weeks for follow-up). Participants will be recruited from the Teaching Hospital of Chengdu University of TCM, Mianyang Hospital of TCM, and Shuangliu Hospital of TCM. Sixty participants will be randomly divided into a treatment group (basic treatment combined with traditional Chinese medicine Shenqi Compound) or a control group (basic treatment combined with Chinese medicine placebo) with 30 participants in each group. Patients will be selected considering the following inclusion criteria: age between 35 and 65 years, and a positive diagnosis for type 2 diabetes with lower extremity atherosclerosis and TCM syndromes. Primary outcome indicator is an arterial color Doppler ultrasound. Secondary outcome indicators include: blood glucose fluctuation indicators (MBG, SDBG, LAGE), islet ß-cell function evaluation indicators (Homa-IR, Homa-islet, SG, SCP), inflammation indicators (NLR, CRP, IL-6), blood lipids, and HbA1c. Safety index includes vital signs (T, P, R, BP), blood, urine, stool routine, liver and renal function, electrocardiogram, and adverse event records. The endpoint event is defined as the presence of gangrene in the lower limbs. DISCUSSION: Explore the clinical effect of traditional Chinese medicine "Shenqi Compound" to reduce blood glucose fluctuation and use HOMA-IR, the area under the glucose curve, and the area under the C-peptide curve to evaluate the effect of protecting islet ß cell function. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR-1900027693). Registered on November 23, 2019. http://www.chictr.org.cn.


Assuntos
Aterosclerose/tratamento farmacológico , Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Hipoglicemiantes/uso terapêutico , Extremidade Inferior/irrigação sanguínea , Medicina Tradicional Chinesa , Aterosclerose/sangue , Aterosclerose/fisiopatologia , Glicemia , China , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Fitoterapia , Fluxo Pulsátil , Ensaios Clínicos Controlados Aleatórios como Assunto , Fluxo Sanguíneo Regional , Projetos de Pesquisa
2.
Medicine (Baltimore) ; 99(3): e18713, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011447

RESUMO

BACKGROUND: Lower extremity artery disease (LEAD) is greatly harmful to Type 2 Diabetes Mellitus patients. Traditional Chinese Medicine (TCM) is an alternative therapy to delay the development of macrovascular diseases, but the existing evidence of its efficacy, safety and mechanism of action is insufficient. We report a study protocol of a multi-center, randomized, double-blind, placebo-controlled trial that aims to use well-designed clinical trial to evaluate the efficacy and safety of Chinese herbal medicine (CHM) Shen-Qi Hua-Yu formula, and to explore efficacy mechanism of the TCM granules and the biomarkers of TCM syndrome. METHODS: This is a multi-center, double-blind, randomized, and placebo-controlled study that randomized 120 participants into 2 groups. The treatment group will receive TCM granules and conventional medicine, while the control group will receive placebo in addition to conventional medicine. Two groups will receive 12-week treatment and 48-week follow-up, with a total of 13 visits. Primary efficacy outcomes included ankle brachial index. Secondary efficacy outcomes included fasting plasma glucose, blood lipid, hemorheology indexes, advanced glycation end products, the inner diameter, peak systolic velocity, end diastolic velocity and mean average velocity of the anterior tibial artery, posterior tibial artery and dorsalis pedis artery, and TCM syndrome score. The safety and endpoint outcomes will be evaluated in this trial. The study will explain the biological therapeutic mechanism of Shen-Qi Hua-Yu formula for diabetic LEAD, and try to use Isobaric tags for Relative and Absolute Quantitation (iTRAQ) and Western blot to screen biomarkers of characteristic diagnosis and clinical efficiency evaluation of the TCM syndrome. DISCUSSION: This study is a multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of CHM in patients with diabetic LEAD, and to interpret the therapeutic mechanism of Shen-Qi Hua-Yu formula in treatment of diabetic LEAD through proteomics technology, and to screen biomarkers with characteristics of TCM diagnosis and clinical efficacy evaluation. On the other hand, to our knowledge, this study may be the first trial of CHM formulas to observe cardiovascular outcomes through long-term follow-up for the treatment of diabetic LEAD, which is of great value. TRIAL REGISTRATION: This study is registered on the Chinese Clinical Trial Registry: ChiCTR1900026372.


Assuntos
Angiopatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Adulto , Idoso , Índice Tornozelo-Braço , Biomarcadores , Glicemia , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Humanos , Lipídeos/sangue , Extremidade Inferior , Masculino , Pessoa de Meia-Idade , Qi , Projetos de Pesquisa , Artérias da Tíbia
4.
J Diabetes Res ; 2019: 9696521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565658

RESUMO

Interventional therapies, such as percutaneous transluminal angioplasty and endovascular stent implantation, are used widely for the treatment of diabetic peripheral vascular complications. Reendothelialization is an essential process in vascular injury following interventional therapy, and hyperglycemia in diabetes mellitus (DM) plays an important role in damaging endothelial layer integrity, leading to the retardance of reendothelialization and excessive neointimal formation. Notoginsenoside Fc (Fc), a novel saponin isolated from Panax notoginseng, effectively counteracts platelet aggregation. Nevertheless, the potential effects and molecular mechanisms of Fc on reendothelialization have yet to be explored. In this study, we present novel findings that show the benefit of Fc in accelerating reendothelialization and alleviating excessive neointimal formation following carotid artery injury in diabetic Sprague-Dawley rats in vivo. Simultaneously, the decreased autophagy of the injured carotid artery in diabetic rats was restored by Fc treatment. Our in vitro results also demonstrated that Fc promoted endothelial cell proliferation and migration under high-glucose treatment by increasing autophagy. In summary, this study supported the notion that Fc could accelerate reendothelialization following vascular injury in diabetic rats by promoting autophagy, suggesting that Fc may exert therapeutic benefits for early endothelial injury and restenosis following intervention in diabetes-associated vascular diseases.


Assuntos
Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Ginsenosídeos/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Angiopatias Diabéticas/patologia , Endotélio Vascular/patologia , Ginsenosídeos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
5.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533227

RESUMO

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.


Assuntos
Angiopatias Diabéticas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glicosídeos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/patologia , Modelos Animais de Doenças , Glicosídeos/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , MicroRNAs , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Substâncias Protetoras/química , Espécies Reativas de Oxigênio/metabolismo
6.
J Biomed Sci ; 26(1): 68, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492153

RESUMO

BACKGROUND: Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. OBJECTIVES: In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. METHOD: We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. RESULTS: Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. CONCLUSIONS: Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.


Assuntos
Cilostazol/farmacologia , Angiopatias Diabéticas/tratamento farmacológico , Glucose/efeitos adversos , Músculo Liso Vascular/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/farmacologia , Transdução de Sinais , Animais , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso Vascular/fisiopatologia , NF-kappa B/metabolismo , Ratos , Receptor para Produtos Finais de Glicação Avançada/metabolismo
8.
Diabetes Metab Syndr ; 13(5): 2873-2877, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31425951

RESUMO

AIM: Diabetic patients predispose to vascular diseases such as nephropathy, and retinopathy. Poor adherence to medical treatment and dietary recommendations in uncontrolled diabetes leads to vascular damages. Vitamin D has been extensively studied and found to be protective against diabetes mellitus. YKL-40 and Monocyte chemoattractant protein-1 (MCP-1) are considered to exert crucial role in diabetes and its complications. Therefore, this study was designed to investigate effects of vitamin D supplementation on serum levels of YKL-40 and MCP-1 involved in the development of diabetic complications. METHODS: For 12 weeks, 48 type 2 diabetic patients enrolled in the trial and randomly were divided into two groups (n = 24 per group), receiving one of the following: 100 µg (4000 IU) vitamin D or placebo. Before and after intervention, serumYKL-40, MCP-1, insulin, IL-6, TNF-α, 25- (OH) vitamin D and HbA1c were measured. RESULTS: Our results revealed that serum levels of 25 (OH) vitamin D significantly increased in vitamin D group (p < 0.001). Vitamin D supplementation also significantly reduced serum YKL-40 levels (-22.7 vs. -2.4 ng/ml; (p-value = 0.003)). There was a significant decline in MCP-1 concentration in intervention group at the end of the study (-45.7 vs. -0.9 pg/ml; (p = 0.001)). Furthermore, there was a significant decrease in IL-6, fasting insulin and HOMA-IR in intervention group after 3 months supplementation. CONCLUSIONS: Daily vitamin D supplementation effectively reduced circulatory YKL-40 and MCP-1 levels in patients with type-2 diabetes and vitamin D deficiency. Vitamin D might contribute in reducing diabetic complications via modulating YKL-40 and MCP-1 signaling pathways.


Assuntos
Biomarcadores/sangue , Quimiocina CCL2/sangue , Proteína 1 Semelhante à Quitinase-3/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/sangue , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/administração & dosagem , Adulto , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/fisiopatologia , Vitaminas/administração & dosagem
9.
Transfus Apher Sci ; 58(4): 498-504, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31311752

RESUMO

Diabetic foot ulcer is a major complication of diabetes mellitus with negative effects on the life quality. Management of diabetic foot ulcers is a big challenge with poor and low sufficient outcome management. Therefore, achievement to effective treatments may treat these ulcers. Nowdays, platelet products are used as an effective and safe agent for promotion of healing proposes in regenerative medicine. Serum rich in growth factors (SRGF) is a source of released growth factors from the platelets. In the present study, effect of allogenous SRGF was investigated on the streptozotocin (STZ)-induced diabetic wounds in rats. STZ (50 mg/kh, SC) caused significant increase in blood glucose and weight loss in rats. Full thickness cutaneous wounds (8 mm diameter) were created bilaterally on the dorsal of the diabetic rats. SRGF was injected at the edges of the wounds of one side only on the first day, and the contrary sides were considered as the control group. The percentage of wound contraction was demonstrared on day 3, 7, 11 after surgery. Tissue specimens were collected for microscopic study on days 7 and 14. Results showed a significant higher rate of wound contraction on days 5 and 7 in the treated group. Histopathologic findings displayed acceleration of re-epithelialization, increased angiogenesis and dense collagen fibers with better organization in the treated group. Current study suggests that SRGF was efficient because facilate wound healing and showed rapid re-epithelialization and increased angiogenesis.


Assuntos
Diabetes Mellitus Experimental , Angiopatias Diabéticas , Peptídeos e Proteínas de Sinalização Intercelular , Soro/química , Pele , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Ratos , Pele/metabolismo , Pele/patologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
10.
Oxid Med Cell Longev ; 2019: 3182627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210838

RESUMO

Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. Natural products have shown to be effective in treating skin wounds. Lupeol is known to stimulate angiogenesis, fibroblast proliferation, and expressions of cytokines and growth factors involved in wound healing. The study is performed to evaluate the wound healing activity of lupeol in streptozotocin-induced hyperglycemic rats by macroscopical, histological, immunohistochemical, immunoenzymatic, and molecular methods. Percentage of wound closure and contraction was increased in the lupeol-treated group when compared to the Lanette group. Histopathological observation revealed decreased inflammatory cell infiltration and increased proliferation of fibroblasts, vascularization, and deposition of collagen fibers after lupeol treatment. Immunohistochemical analyses showed decreased intensity of NF-κB and increased intensity of FGF-2, TGF-ß1, and collagen III. ELISA results revealed downregulated IL-6 levels and upregulated IL-10 levels in response to lupeol. The mRNA expression levels of Hif-1α, Sod-2, and Ho-1 were significantly increased in response to lupeol as compared to Lanette whereas Nf-κb and Vegf-A levels were decreased in relation to insulin and lupeol treatment. These findings indicate that lupeol possesses wound healing potential in hyperglycemic conditions and may be useful as a treatment for chronic wounds in diabetic patients.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Ratos , Ratos Wistar
11.
Can J Diabetes ; 43(7): 510-514, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30930073

RESUMO

This overview deals with mechanisms whereby hyperglycemia-induced oxidative stress compromises vascular endothelial function and provides a background for a recently published study illustrating the beneficial impact of endothelial sodium-glucose cotransporter 2 (SGLT2) inhibitors in attenuating hyperglycemia-induced vascular dysfunction in vitro. The data provide new insight that can possibly lead to improved drug therapy for people with type 2 diabetes. The working hypotheses that underpinned the experiments performed are provided, along with the findings of the study. For the causes of hyperglycemia-induced vascular endothelial dysfunction, the findings point to the key roles of: 1) functional endothelial SGLT2; 2) oxidative stress-induced signalling pathways including mammalian sarcoma virus kinase, the EGF receptor-kinase and protein kinase C; and 3) mitochondrial dysfunction triggered by hyperglycemia was mitigated by an SGLT2 inhibitor in the hyperglycemic mouse aorta vascular organ cultures. The overview sums up the approaches implicated by the study that can potentially counteract the detrimental impact of hyperglycemia on vascular function in people with diabetes, including the clinical use of SGLT2 inhibitors for those with type 2 diabetes already being treated, for example, with metformin, along with dietary supplementation with broccoli-derived sulforaphane and tetrahydrobiopterin. The caveats associated with the study for extending the findings from mice to humans are summarized, pointing to the need to validate the work using vascular tissues from humans. Suggestions for future clinical studies are made, including the assessment of the impact of the therapeutic strategies proposed on measurements of blood flow in subjects with diabetes.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Hiperglicemia/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/química , Biomarcadores/análise , Biopterina/análogos & derivados , Biopterina/uso terapêutico , Glicemia/análise , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/metabolismo , Endotélio Vascular/patologia , Humanos , Incidência , Isotiocianatos/uso terapêutico , Prognóstico
12.
Acta Diabetol ; 56(9): 1051-1060, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30993527

RESUMO

AIMS: Patients with type 2 diabetes (T2D) have an increased risk of cardiovascular disease. Recent cardiovascular outcome trials (CVOTs) with liraglutide, semaglutide, and albiglutide have shown significant reduction in major adverse cardiovascular events. Conversely, the CVOT with exenatide long-acting release (ELAR) confirmed cardiovascular safety of the drug, but did not reached superiority versus placebo. Herein, we systematically evaluated the effect of ELAR versus placebo or active comparators on cardiovascular events and mortality in patients with T2D. METHODS: We screened the literature for randomized controlled trials reporting cardiovascular events and deaths in patients receiving ELAR versus those receiving placebo or any other glucose-lowering medications. Event rates were pooled and compared using the random-effects model. RESULT: We retrieved 16 trials comparing the occurrence of cardiovascular events and mortality in patients treated with ELAR versus placebo or active comparators. The pooled rate ratio for cardiovascular events was similar in the two groups (0.99; 95% CI 0.92-1.06). The rate ratio for all-cause mortality was significantly lower in exenatide group than in comparators (0.87; 95% CI 0.77-0.97). When results of the EXSCEL trial were omitted, the pooled rate ratio for cardiovascular events and mortality was 0.80 (95% CI 0.40-1.63) and 0.75 (95% CI 0.30-1.84), respectively. CONCLUSIONS: Treatment with ELAR does not increase the risk of cardiovascular events and may reduce all-cause mortality.


Assuntos
Preparações de Ação Retardada/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/epidemiologia , Exenatida/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Sistema Cardiovascular/efeitos dos fármacos , Causas de Morte , Preparações de Ação Retardada/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/mortalidade , Exenatida/administração & dosagem , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Incidência , Liraglutida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade
13.
Wien Klin Wochenschr ; 131(Suppl 1): 139-140, 2019 May.
Artigo em Alemão | MEDLINE | ID: mdl-30980156

RESUMO

Acute thrombotic complications as a key feature of accelerated atherothrombotic disease typically precipitate cardiovascular events and therefore strongly contribute to cardiovascular morbidity and mortality in diabetic patients. Inhibition of platelet aggregation can reduce the risk for acute atherothrombosis. The present article represents the recommendations of the Austrian Diabetes Association for the use of antiplatelet drugs in diabetic patients according to current scientific evidence.


Assuntos
Angiopatias Diabéticas/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Trombose , Áustria , Plaquetas , Angiopatias Diabéticas/prevenção & controle , Humanos , Agregação Plaquetária , Guias de Prática Clínica como Assunto , Trombose/tratamento farmacológico , Trombose/prevenção & controle
14.
Int J Clin Pharm ; 41(2): 563-573, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30864083

RESUMO

Background Diabetes is a major cause of microvascular complications. Renin-angiotensin-aldosterone blockers have been known to have the benefits of delaying onset and progression of diabetic complications including nephropathy. Objective To evaluate the effect of sarpogrelate, an antiplatelet agent, on the new onset diabetic complications in patients with type 2 diabetes mellitus. Setting A 1108-bed tertiary university hospital in Korea. Methods A retrospective cohort study was conducted using electronic medical records between 2010 and 2015 in Korea. The study cohort of the propensity score matched patients with or without sarpogrelate was evaluated for the diabetic complications identified with the diagnosis codes in T2DM patients on the metformin based antidiabetic therapy. Nephropathy was further evaluated for progression of kidney function. Main outcome measure The incidence of composite microvascular complications included nephropathy, neuropathy, and retinopathy. Results The 1:2 propensity score matched 478 out of 14,440 patients were included in the final analysis with or without sarpogrelate (162 vs. 316 patients). The incidence of nephropathy, neuropathy, and retinopathy was 1.23% versus 5.38% (HR 0.21, 95% CI 0.05-0.92), 1.23% versus 4.43% (HR 0.26, 95% CI 0.06-1.14), and 6.17% versus 6.33% (HR 0.93, 95% CI 0.43-1.97) with sarpogrelate and without sarpogrelate, respectively. Changes in the estimated glomerular filtration rate and urine albumin creatinine ratio were not significantly different between the groups. Conclusion In Korean patients, sarpogrelate, an antiplatelet agent, was associated with reducing the incidence and progression of nephropathyin type 2 diabetes, but not associated with the composite endpoints including neuropathy and retinopathy.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Registros Eletrônicos de Saúde/estatística & dados numéricos , Succinatos/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/complicações , Nefropatias Diabéticas/complicações , Neuropatias Diabéticas/complicações , Retinopatia Diabética/complicações , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos
15.
BMC Endocr Disord ; 19(1): 5, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621663

RESUMO

BACKGROUND: Insulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these "IAS-like" insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia. CASE PRESENTATION: A 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 µU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart → regular human insulin→ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output. CONCLUSIONS: Proper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Secreção de Insulina , Insulina/sangue , Período Pós-Prandial , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Quimioterapia Combinada , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Hiperglicemia/etiologia , Hipoglicemia/etiologia , Inositol/análogos & derivados , Inositol/uso terapêutico , Insulina/uso terapêutico , Anticorpos Anti-Insulina/sangue , Isoindóis/uso terapêutico , Liraglutida/uso terapêutico , Masculino , Resultado do Tratamento
16.
BMC Endocr Disord ; 19(1): 3, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611254

RESUMO

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors could effectively reduce HbA1C and postprandial hyperglycemia and could incur only minimal danger of hypoglycemia. Patients with uncontrolled diabetes might be treated by the complementary action of insulin plus DPP-4 inhibitors. Here, we compared the all-cause mortality risk between DPP-4 inhibitor users and nonusers with underlying insulin therapy. METHODS: Using the population-based National Health Insurance Research Database of Taiwan, we conducted an 11-year retrospective cohort study. A total of 3120 patients undergoing insulin therapy for type 2 diabetes mellitus (T2DM) during 2000-2010 were enrolled. The overall incidence rates for all-cause mortality of 1560 DPP-4 inhibitor users and 1560 matched DPP-4 inhibitor nonusers were compared. RESULTS: No significant difference was found in the baseline demographic and clinical variables of the two groups of patients. Median follow-up period for the matched cohort was 1.67 years. All-cause mortality was observed in 93 (6.0%) of 1560 DPP-4 inhibitor nonusers and 36 (2.3%) of 1560 DPP-4 users. The incidence rate of mortality was 11.72 for DPP-4 inhibitor users and 38.16 per 1000 person-years for DPP-4 inhibitor nonusers. After multivariate adjustment, DPP-4 inhibitor users ran a reduced mortality risk (adjusted hazard ratio 0.32, 95% CI 0.22-0.47; p < 0.0001) than did the nonusers. CONCLUSION: Risk of all-cause mortality may be reduced when using insulin plus DPP-4 inhibitors than when using insulin plus non-DPP-4 inhibitors.


Assuntos
Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/mortalidade , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adulto , Idoso , Causas de Morte , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/fisiopatologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Hiperglicemia/mortalidade , Hiperglicemia/fisiopatologia , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taiwan/epidemiologia , Resultado do Tratamento , Adulto Jovem
17.
Exp Clin Endocrinol Diabetes ; 127(4): 255-262, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29529692

RESUMO

BACKGROUND: miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated. METHODS: In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Immunohistochemical staining was performed to measure NOTCH1 expression in the diabetic endothelium. RESULTS: miR-34a was significantly up-regulated, and NOTCH1 down-regulated, in the thoracic aorta from STZ-induced diabetic rats compared with control group. As compared to model group, the mRNA of NOTCH1 was significantly decreased or increased by miR-34a mimics or inhibitors ex vivo, respectively. Bioinformatics methods further demonstrated that NOTCH1 was a potential target of miR-34a, which was confirmed by dual-luciferase reporter assay. Moreover, both serum ET and NO were significantly increased in diabetic rats as compared to control group. miR-34a inhibitors ex vivo treatment resulted in significant down-regulation ofserum ET and NO levels in diabetic rats as compared to model group. CONCLUSION: These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , MicroRNAs/farmacologia , Receptor Notch1/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/sangue , Angiopatias Diabéticas/sangue , Injeções Intravenosas , Masculino , MicroRNAs/administração & dosagem , Ratos , Ratos Sprague-Dawley
18.
Tissue Eng Part A ; 25(1-2): 44-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29644938

RESUMO

In diabetes-associated chronic wounds, the normal response to hypoxia is impaired and many cellular processes involved in wound healing are hindered. Central to the hypoxia response is hypoxia-inducible factor-1α (HIF-1α), which activates multiple factors that enhance wound healing by promoting cellular motility and proliferation, new vessel formation, and re-epithelialization. Prolyl hydroxylase domain-containing protein 2 (PHD2) regulates HIF-1α activity by targeting it for degradation under normoxia. HIF-1α also upregulates microRNA miR-210, which in turn regulates proteins involved in cell cycle control, DNA repair, and mitochondrial respiration in ways that are antagonistic to wound repair. We have identified a highly potent short synthetic hairpin RNA (sshRNA) that inhibits expression of PHD2 and an antisense oligonucleotide (antimiR) that inhibits miR-210. Both oligonucleotides were chemically modified for improved biostability and to mitigate potential immunostimulatory effects. Using the sshRNA to silence PHD2 transcripts stabilizes HIF-1α and, in combination with the antimiR targeting miR-210, increases proliferation and migration of keratinocytes in vitro. To assess activity and delivery in an impaired wound healing model in diabetic mice, PHD2-targeting sshRNAs and miR-210 antimiRs both alone and in combination were formulated for local delivery to wounds using layer-by-layer (LbL) technology. LbL nanofabrication was applied to incorporate sshRNA into a thin polymer coating on a Tegaderm mesh. This coating gradually degrades under physiological conditions, releasing sshRNA and antimiR for sustained cellular uptake. Formulated treatments were applied directly to splinted full-thickness excisional wounds in db/db mice. Cellular uptake was confirmed using fluorescent sshRNA. Wounds treated with a single application of PHD2 sshRNA or antimiR-210 closed 4 days faster than untreated wounds, and wounds treated with both oligonucleotides closed on average 4.75 days faster. Markers for neovascularization and cell proliferation (CD31 and Ki67, respectively) were increased in the wound area following treatment, and vascular endothelial growth factor (VEGF) was increased in sshRNA-treated wounds. Our results suggest that silencing of PHD2 and miR-210 either together or separately by localized delivery of sshRNAs and antimiRs is a promising approach for the treatment of chronic wounds, with the potential for rapid clinical translation.


Assuntos
Diabetes Mellitus Experimental , Angiopatias Diabéticas , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Células NIH 3T3 , Oligonucleotídeos Antissenso/genética , Cicatrização/genética
19.
Clin Exp Hypertens ; 41(3): 244-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29781736

RESUMO

This study aimed to compare the real-world effectiveness of valsartan and non renin-angiotensin system (non-RAS) agent monotherapy on the incidence of new on-set diabetes (NOD) in Chinese hypertensive patients. It was based on an electronic Health Recording System database from Minhang District of Shanghai. Hypertensive patients aged ≥18 years continuously taking either valsartan or non-RAS agent monotherapy for >12 months were included. Hazard ratios (HR) of NOD events were estimated using propensity score matching method and multivariate regression. Of 29295 patients, there were 2107 in valsartan group, 21397 in CCB group, 4094 in ß-blockers group and 1697 in diuretics group. Two-year follow-up revealed NOD rates of 11.09 and 14.22 per 100 persons per year in valsartan and non-RAS inhibitor groups (HR = 0.77, 95% confidence interval 0.65-0.93, P = 0.006), respectively. Among non-RAS agents, CCB group had the highest incidence of NOD (21.72 per 100 persons per year). Comparisons between CCB sub-groups revealed the highest NOD incidence for nifedipine, followed by amlodipine and felodipine. NOD incidences in ß-blockers and diuretics groups (11.70 and 10.50 per 100 persons per year, respectively) were not significantly different from valsartan group. Compared with non-RAS inhibitors, particularly CCBs, valsartan could significantly reduce the incidence of NOD.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Valsartana/uso terapêutico , Adolescente , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Anlodipino/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , China , Angiopatias Diabéticas/tratamento farmacológico , Diuréticos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Curr Drug Targets ; 20(1): 51-59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30129410

RESUMO

Diabetes is one of the most concerning diseases in modern times. Despite considerable advances in therapeutic management, the prevalence of diabetes and its contribution to death and disability continue to be a major health problem. Diabetic vasculopathies are the leading cause of mortality and morbidity in diabetic patients. Its pathophysiology includes oxidative stress, advanced glycation end products, and a low-grade inflammatory state. Lately, actions of the innate immune system via Toll-like receptors (TLRs) have been suggested as a new insight in this field. TLRs are pattern recognition receptors activated by highly conserved structural motifs of exogenous or endogenous ligands. Heat-shock proteins (HSPs), normally known for their ability to protect cells during stressful conditions, when released from injured cells bind to TLR4 and trigger the release of pro-inflammatory cytokines in a MyD88-dependent pathway. This pathway had been investigated in pancreatic beta cells and skeletal muscle, but it has not yet been explored in the vascular system and deserves investigation. In this work, the interplay between TLR4 and HSP70 in the vasculature during diabetes is reviewed and discussed. The current literature and preliminary results from our laboratory led us to hypothesize that hyperglycemia-associated HSP70 plays an important role in the pathophysiology of diabetic vasculopathies via the TLR4 pathway and might be a new target for therapeutic intervention.


Assuntos
Angiopatias Diabéticas/tratamento farmacológico , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/patologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Produtos Finais de Glicação Avançada/imunologia , Produtos Finais de Glicação Avançada/metabolismo , Proteínas de Choque Térmico HSP70/imunologia , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
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