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1.
PLoS One ; 15(4): e0231196, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32282852

RESUMO

OBJECTIVES: To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. METHODS: Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. PARTICIPANTS: Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. INTERVENTION: Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. RESULTS: One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. CONCLUSIONS: ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. REGISTRATION: - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/complicações , Microcirculação , Idoso , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas , Neuropatias Diabéticas/prevenção & controle , Retinopatia Diabética/prevenção & controle , Método Duplo-Cego , Europa (Continente)/epidemiologia , Feminino , Resposta Galvânica da Pele , Humanos , Cooperação Internacional , Estilo de Vida , Linagliptina/administração & dosagem , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Seleção de Pacientes , Projetos de Pesquisa , Fatores de Risco
2.
Diabetes ; 69(3): 291-299, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32079705

RESUMO

The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.


Assuntos
Glicemia/metabolismo , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Estudos de Coortes , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/prevenção & controle , Retinopatia Diabética/metabolismo , Retinopatia Diabética/prevenção & controle , Humanos , Planejamento de Assistência ao Paciente , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
3.
Endocr Regul ; 53(1): 14-25, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517620

RESUMO

OBJECTIVE: Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. METHODS: In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2-4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. RESULTS: Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrate or insulin treatment led to a significant decrease (p<0.01) in blood glucose levels, as well as a significant (p<0.05) increase in the body weight and serum NOx. Moreover, nitrate treatment significantly increased serum insulin levels (p<0.001) compared to the other groups. CONCLUSION: Chronic nitrate treatment modified the thermal and mechanical sensitivities in diabetic animals.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Nitratos/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/patologia , Masculino , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Nitratos/uso terapêutico , Nociceptividade/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Estreptozocina
4.
Endocr J ; 66(9): 753-762, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31406090

RESUMO

Exercise is a fundamental component of diabetes management. However, choosing inappropriate type or timing of exercise is associated with mild or severe hypoglycemia either during exercise or several hours after exercise. Several studies have shown that impaired counterregulatory responses triggers hypoglycemia. Therefore, in this investigation, we explored the appropriate intensity and time of exercise in patients with diabetes. The mechanisms of counterregulatory responses and hypoglycemia associated autonomic failure (HAAF), as well as the strategies for preventing episodes of hypoglycemia after exercise were also investigated. In this study, we obtained the following results: 1) High intensity interval exercise is more suitable for diabetic patients. 2) Morning exercise reduces nocturnal hypoglycemia risks compared with midday, afternoon and evening exercise. 3) Hypoglycemia can be prevented by dietary approach, reduction or suspension of insulin dose, use of mini dose glucagon, caffeine, mitigation methods, prediction algorithm, autonomic feedback controlled close-loop insulin delivery, real time continuous glucose monitoring. Based on these results we concluded that exercise may cause severe hypoglycemia or induce blunted response in patients with diabetes. For Diabetes Mellitus (DM) patients, the intensity and time of exercise influence the occurrence of hypoglycemia. This review summarizes the clinical characteristics of different types of exercises and time of exercise that can be potentially used to educate and guide patients regarding the role of exercise in standard of care.


Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/prevenção & controle , Diabetes Mellitus Tipo 1/terapia , Neuropatias Diabéticas , Exercício Físico/fisiologia , Hipoglicemia/etiologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/prevenção & controle , Humanos , Hipoglicemia/sangue , Hipoglicemia/prevenção & controle , Insulina/uso terapêutico
5.
Diabetes Metab Syndr ; 13(2): 1011-1014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336436

RESUMO

Bioelectronic medicines are a newer way to treat and diagnose the diseases associated with biological systems. All vital organs of the body are innervated, commanding brain to regulate the homeostasis functions. Bioelectronic medicines rely on implications of electrical stimulations or signals associated with the nervous system for real-time treatment. Diabetic peripheral neuropathy (DPN) is a most prevalent micro-vascular complication associated with diabetes mellitus. Complex plexus of nerves were affected in this complication with impaired function. Bioelectronic medicines are future hope for effective treatment of DPN.


Assuntos
Fontes de Energia Bioelétrica , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/prevenção & controle , Terapia por Estimulação Elétrica/métodos , Neuroestimuladores Implantáveis , Dor/prevenção & controle , Neuropatias Diabéticas/etiologia , Humanos , Dor/etiologia
6.
Diabetes Metab Syndr ; 13(2): 913-923, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336545

RESUMO

BACKGROUND: Therapeutic footwear is built on a model of patient's foot, for people with diabetes suffering with neuropathy. Can the footwear helps to improve plantar pressure in neuropathic foot? This study focussed on available data on therapeutic footwear as an intervention for improving and offloading plantar pressure in neuropathic diabetic foot. METHODS: Relevant scientific literature in PubMed, Medline and Google Scholar published between 2000 and 2017 were searched. The keywords searched were therapeutic footwear, plantar pressure, neuropathic foot, rocker sole, ulcer healing and offloading of plantar pressure. Articles on randomized controlled trials, observational, cohort, feasibility and factorial studies were reviewed. RESULTS: One hundred and twenty five (125) articles were identified. The article comprised of 6 randomized controlled trials, 2 observational, 1 cohort, 1 feasibility and 1 factorial study met the inclusion criteria and were critiqued with a total enrolment of 1380 study subjects. CONCLUSIONS: The review of the collated literature demonstrated that, therapeutic footwear can improve the healing of neuropathic diabetic foot ulcer by redistributing plantar pressure. However, the efficacy of therapeutic footwear requires the inclusion of technical features that should not be compromised from the design to the production of the footwear.


Assuntos
Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/fisiopatologia , Pé Diabético/prevenção & controle , Neuropatias Diabéticas/prevenção & controle , Órtoses do Pé/estatística & dados numéricos , Sapatos , Complicações do Diabetes/etiologia , Pé Diabético/etiologia , Neuropatias Diabéticas/etiologia , Humanos , Cicatrização
7.
Neurotoxicology ; 74: 196-202, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323241

RESUMO

OBJECTIVE: Diabetic neuropathy (DN) is the most common complication of diabetes mellitus. It is thought that neuronal cell death which is mainly due to reactive oxygen species (ROS) overproduction in the cells is responsible for most symptoms of this disorder. Nesfatin-1 has identified recently as a novel endogenous neuropeptide which recent studies have shown that it may have a protective effect. Therefore, we postulated that Nesfatin-1 might adequately prevent from high glucose-induced cell injury via inhibition of apoptotic, autophagy, and ROS responses. METHODS: In this study, PC12 cells were pretreated with different concentrations of Nesfatin-1 (1-100 ng/ml) and then co-treated with Nesfatin-1 and glucose (125 mM) for 48 h, and downstream pathways then were evaluated to investigate ROS, apoptosis, and autophagy. RESULTS: Results of this study showed that Nesfatin-1 can not only inhibit from intracellular ROS overproduction-induced by high glucose in PC12 cells (p < 0.0001) but also reduce the apoptotic cell death in PC12 cells following high glucose exposure by increasing cell viability and reducing apoptotic rates (p < 0.05). Furthermore, Nesfatin-1 decreased the LC3-II levels by western blotting (p < 0.0001), which showed a reduction in autophagy. CONCLUSION: These results support the idea that Nasfatin-1can protect PC12 cells against high glucose-induced cell injury by inhibition of apoptosis, autophagy and ROS production and can be considered as a potential drug for treatment of diabetic neuropathy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glucose/toxicidade , Fármacos Neuroprotetores/toxicidade , Nucleobindinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Neuropatias Diabéticas/prevenção & controle , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Necrose/patologia , Necrose/prevenção & controle , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia
8.
Cell Physiol Biochem ; 53(1): 76-86, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31192545

RESUMO

BACKGROUND/AIMS: Diabetes causes damage to the enteric nervous system. The enteric nervous system consists of neurons and enteric glial cells (EGCs). The present study evaluated the effects of an ethyl-acetate fraction (EAF) from Trichilia catigua (T. catigua; 200 mg/kg) on the total population of enteric neurons (HuC/D-immunoreactive [IR]) and EGCs (S100-IR and glial fibrillary acidic protein [GFAP]-IR) in the total preparation and jejunal mucosa in diabetic rats. METHODS: The animals were distributed into four groups: normoglycemic rats (N), diabetic rats (D), normoglycemic rats that received the EAF (NC), and diabetic rats that received the EAF (DC). The jejunum was processed for immunohistochemistry to evaluate HuC/D, S100, and GFAP immunoreactivity. The expression of S100 and GFAP proteins was also quantified by Western blot. RESULTS: The D group exhibited a decrease in the number of neurons and EGCs, an increase in the area of cell bodies, an increase in S100 protein expression, a decrease in GFAP protein expression, and a decrease in S100-IR and GFAP-IR EGCs in the jejunal mucosa. The DC group exhibited a decrease in the number of neurons and EGCs, a decrease in the area of cell bodies, a decrease in S100 and GFAP protein expression, and a decrease in S100-IR and GFAP-IR EGCs in the jejunal mucosa. The NC group exhibited maintenance of the number of neurons and EGCs, an increase in the area of cell bodies, and a decrease in S100 and GFAP protein expression. CONCLUSION: The EAF from T. catigua partially conferred protection against diabetic neuropathy in the enteric nervous system.


Assuntos
Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/prevenção & controle , Jejuno/inervação , Meliaceae/química , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetatos/química , Animais , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/patologia , Sistema Nervoso Entérico/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/análise , Jejuno/efeitos dos fármacos , Jejuno/patologia , Masculino , Neuroglia/patologia , Neurônios/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Proteínas S100/análise
9.
Int Immunopharmacol ; 74: 105672, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31195189

RESUMO

Metformin is the first line drug in the treatment of type 2 diabetes, however, little is known about its therapeutic potential to prevent or delay damage to the peripheral nerve. Thus, the aim of this study was to investigate whether metformin is able to attenuate the neuroinflammatory response in sciatic nerve of insulin-dependent diabetic mice. Swiss Webster mice were divided into four groups: Control, Diabetic (STZ), Diabetic +100 mg/kg/day of metformin (STZ + M100) and Diabetic +200 mg/kg/day of metformin. Diabetes was induced by streptozotocin (90 mg/kg, i.p.). Only animals with glycemia ≥270 mg/dl were considered diabetics. Metformin prevented atrophy of myelinated axons, and reduced expression of inflammatory mediators (interleukin-1ß, inducible nitric oxide synthase and nitric oxide). However, treatment with 200 mg of metformin was more effective in increasing neurotrophic (myelin basic protein and neural growth factor), angiogenic (vascular endothelial growth factor) and anti-inflammatory (inhibitor kappa B-alpha and interleukin 10) factors. Thus, metformin treatment, especially at the dose of 200 mg, protected the nerve from damages related to chronic hyperglycemia.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Camundongos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo
10.
J Diabetes Investig ; 10(5): 1199-1208, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30892819

RESUMO

AIMS/INTRODUCTION: Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC-conditioned media (DPSC-CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. MATERIALS AND METHODS: DPSCs were isolated from the dental pulp of Sprague-Dawley rats. Eight weeks after the induction of diabetes, DPSC-CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC-CM on diabetic polyneuropathy were assessed 4 weeks after DPSC-CM injection. To confirm the angiogenic effect of DPSC-CM, the effect of DPSC-CM on cultured human umbilical vascular endothelial cell proliferation was investigated. RESULTS: The administration of DPSC-CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC-CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro-inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC-CM significantly increased the proliferation of umbilical vascular endothelial cells. CONCLUSIONS: We showed that DPSC-CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti-inflammatory actions. DPSC-CM could be a novel cell-free regenerative medicine treatment for diabetic polyneuropathy.


Assuntos
Indutores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Meios de Cultivo Condicionados/farmacologia , Polpa Dentária/citologia , Neuropatias Diabéticas/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Medicina Regenerativa , Células-Tronco/citologia , Animais , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Condução Nervosa , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/irrigação sanguínea , Nervo Isquiático/efeitos dos fármacos
11.
Endokrynol Pol ; 70(4): 323-329, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845344

RESUMO

INTRODUCTION: Long-term poor metabolic control promotes the occurrence of microvascular complications, such as cardiovascular autonomic neuropathy (CAN) and atherogenic hyperlipidaemia, which translates into increased mortality in patients with type 1 diabetes mellitus (T1DM). The aim of the study was to assess the prevalence of CAN in patients with T1DM in relation to treatment method (continuous subcutaneous insulin infusion, CSII, versus multiple daily injections using pens, MDI) and metabolic control. MATERIAL AND METHODS: The study group comprised 93 adults (60 women, 33 men), mean age 31 years, with T1DM being treated at a local clinical centre from 2011 to 2015. The presence of CAN, the results of laboratory tests, and anthropometric data were analysed. The subjects were divided into two groups according to treatment method (CSII, MDI). RESULTS: The median duration of diabetes was 16 years. 61% of the subjects used MDI and 39% used CSII. 41% of the subjects presented with CAN (confirmed with the Ewing test using ProSciCard apparatus), with a significantly lower prevalence in the group of patients treated with CSII (15.4% vs. 60.4%; p < 0.001). The mean HbA1c level in the CSII-treated group was noticeably lower (7.44 ± 1.67% vs.8.55 ± 1.1%, p < 0.001), and these patients also had lower triglyceride levels (0.71 vs. 1.32 mmol/L, p < 0.001). Regardless of the treatment method, 72% of all patients under 40 years of age achieved their therapeutic target of LDL cholesterol level < 2.6 mmol/L, whereas only 13% of all those over 40 years old achieved an LDL cholesterol level < 1.8 mmol/L. CONCLUSIONS: The presented results draw attention to the high prevalence of CAN among T1DM patients. The study reveals the need for more intensive monitoring and treatment of hyperlipidaemia, despite good glycaemic control, especially in those over the age of 40 years.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Insulina/uso terapêutico , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/etiologia , Feminino , Humanos , Injeções Subcutâneas , Insulina/administração & dosagem , Sistemas de Infusão de Insulina , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Resultado do Tratamento , Triglicerídeos/sangue , Adulto Jovem
12.
J Diabetes ; 11(12): 928-937, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30884162

RESUMO

BACKGROUND: The clinical efficacy of electroacupuncture in treating diabetic peripheral neuropathy (DPN) is significant, but the underlying mechanism of action is not clear. Considering that glucose-regulated protein 78 (GRP78) and caspase-12 are major proteins participating in cell apoptosis, we investigated the effects of "adjusting internal organs and dredging channel" electroacupuncture therapy on GRP78 and caspase-12 levels in streptozotocin (STZ)-diabetic rats to elucidate the mechanism of action. METHODS: Rats were first divided into two groups: one group was rendered diabetic with a single injection of 50 mg/kg STZ, whereas the other normal control group was injected with an equivalent volume of citrate buffer. The STZ-diabetic rats were randomly divided into three groups: model control and electroacupuncture- and mecobalamin-treated groups. After 12 weeks treatment, the therapeutic efficacy of electroacupuncture was assessed using sciatic nerves isolated from rats. In the electroacupuncture group, rats were treated by electroacupuncture for 20 minutes once daily for 6 days each week, with 1 day off, for 12 consecutive weeks. The selected acupressure points include bilateral acupressure points of BL13 (Fehu), BL20 (Pishu), BL23 (Shenshu), LI4 (Hegu), LR3 (faichong), ST36 (Zusanli), and SP6 (Sanyiniiao). Acupressure points were stimulated using a HuaTuo SDZ-V Electric Acupuncture Therapy Apparatus. The acupressure points of BL13 and BL23, as well as SP6 and LR3, were connected on the same side with a dilatational wave of 3 Hz (frequency ratio of 1 : 5) to stimulate the parts of the body to the extent that could be tolerated by the rat. As for the mecobalamin-treated groups, mecobalamin was administrated to rats intragastrically at a dose of 20 mg/kg once daily for 12 consecutive weeks. Immunofluorescence and western blot analysis were used to determine GRP78 and caspase-12 levels in sciatic nerves. In addition, cell apoptosis in sciatic nerves was determined using the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay. RESULTS: Electroacupuncture markedly reduced the pathological injury to sciatic nerves in STZ-diabetic rats. Moreover, electroacupuncture significantly downregulated GRP78 and caspase-12 and reduced cell apoptosis of sciatic nerves in DPN rats. CONCLUSIONS: Electroacupuncture improved DPN by downregulating GRP78 and caspase-12 and reducing cell apoptosis of sciatic nerves in STZ-diabetic rats, and further inhibited the occurrence of endoplasmic reticulum stress, thus preventing sciatic nerve injuries.


Assuntos
Caspase 12/metabolismo , Diabetes Mellitus Experimental/terapia , Neuropatias Diabéticas/prevenção & controle , Eletroacupuntura , Proteínas de Choque Térmico/metabolismo , Nervo Isquiático/enzimologia , Estreptozocina , Pontos de Acupuntura , Animais , Apoptose , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/enzimologia , Neuropatias Diabéticas/patologia , Regulação para Baixo , Masculino , Ratos Sprague-Dawley , Nervo Isquiático/ultraestrutura , Transdução de Sinais
13.
Mayo Clin Proc ; 94(3): 484-489, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718068

RESUMO

Postherpetic neuralgia (PHN) is the most common complication of varicella zoster virus (VZV) reactivation and a cause of considerable physical and psychosocial morbidity. No known treatment effectively prevents the development of PHN in patients with VZV reactivation. In this study, our objective was to evaluate the efficacy of premedication with gabapentin for reducing the risk of PHN in patients with diabetic and nondiabetic neuropathy. We retrospectively searched the electronic health records of patients with diabetic and nondiabetic neuropathy treated with gabapentin at Mayo Clinic before diagnosis of VZV reactivation. In total, PHN developed in 7 patients with diabetic neuropathy receiving gabapentin (n=62 [11.3%]) compared with 26 not receiving premedication with gabapentin (n=50 [52.0%]) (odds ratio, 0.12; 95% CI, 0.05-0.31; P<.001); PHN developed in 11 patients with nondiabetic neuropathy receiving gabapentin (n=109 [10.1%]) compared with 108 not receiving premedication with gabapentin (n=217 [49.8%]) (odds ratio, 0.11; 95% CI, 0.06-0.22; P<.001). In this cohort of patients with neuropathy, gabapentin administration before the onset of VZV reactivation significantly reduced the risk of PHN.


Assuntos
Antivirais/administração & dosagem , Neuropatias Diabéticas/prevenção & controle , Gabapentina/administração & dosagem , Herpes Zoster/tratamento farmacológico , Neuralgia Pós-Herpética/prevenção & controle , Neuropatias Diabéticas/virologia , Feminino , Herpes Zoster/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia Pós-Herpética/virologia , Resultado do Tratamento
14.
Lipids Health Dis ; 18(1): 43, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736810

RESUMO

BACKGROUND: Diabetic encephalopathy is a chronic complications of diabetes mellitus that affects the central nervous system. We evaluated the effect of ω3 and ω6 polyunsaturated fatty acids (PUFAs) supplementation plus the antioxidant agent nordihydroguaiaretic acid (NDGA) on the etiopathology of diabetic encephalopathy in eSS rats, a spontaneous model of type 2 diabetes. METHODS: One hundred twenty spontaneous diabetic eSS male rats and 38 non-diabetic Wistar, used as healthy control, received monthly by intraperitoneal route, ω3 or ω6 PUFA (6.25 mg/kg) alone or plus NDGA (1.19 mg/kg) for 12 months. Diabetic rats had a worse performance in behavioural Hole-Board test. Histopathological analysis confirmed lesions in diabetic rats brain tissues. We also detected low expression of synaptophysin, a protein linked to release of neurotransmitters, by immunohistochemically techniques in eSS rats brain. Biochemical and histopathological studies of brain were performed at 12th month. Biochemical analysis showed altered parameters related to metabolism. High levels of markers of oxidative stress and inflammation were detected in plasma and brain tissues. Data were analysed by ANOVA test and paired t test was used by comparison of measurements of the same parameter at different times. RESULTS: The data obtained in this work showed that behavioural, biochemical and morphological alterations observed in eSS rats are compatible with previously reported indices in diabetic encephalopathy and are associated with increased glucolipotoxicity, chronic low-grade inflammation and oxidative stress burden. Experimental treatments assayed modulated the values of studied parameters. CONCLUSIONS: The treatments tested with ω3 or ω3 plus NDGA showed improvement in the values of the studied parameters in eSS diabetic rats. These observations may form the basis to help in prevent and manage the diabetic encephalopathy.


Assuntos
Encefalopatias/etiologia , Neuropatias Diabéticas/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Masoprocol/uso terapêutico , Animais , Glicemia/análise , Encéfalo/patologia , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Neuropatias Diabéticas/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Hipocampo/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
15.
Phytomedicine ; 56: 229-245, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668344

RESUMO

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder associated with persistent increased level of glucose in the blood. According to a report by World Health Organisation (WHO), prevalence of diabetes among adults over 18 years of age had reached to 8.5% in year 2014 which was 4.7% in 1980s. The Prolong increased level of glucose in blood leads to development of microvascular (blindness, nephropathy and neuropathy) and macrovascular (cardiovascular and stroke) degenerative complications because of uncontrolled level of glucose in blood. This also leads to the progression of oxidative stress and affecting metabolic, genetic and haemodynamic system by activation of polyol pathway, protein kinase C pathway, hexosamine pathway and increases advanced glycation end products (AGEs) formation. Diabetes mellitus and its associated complications are one of the major leading causes of mortality worldwide. Various natural products like alkaloids, glycosides, flavonoids, terpenoids and polyphenols are reported for their activity in management of diabetes and its associated diabetic complications. Tannins are systematically studied by many researchers in past few decades for their effect in diabetes and its complications. AIM: The present review was designed to compile the data of tannins and their beneficial effects in the management of diabetic complications. METHOD: Literature search was performed using various dataset like pubmed, EBSCO, proQuest Scopus and selected websites including the National Institutes of Health (NIH) and the World Health Organization (WHO). RESULTS: Globally, more than 400 natural products have been investigated in diabetes and its complications. Tannins are the polyphenolic compounds present in many medicinal plants and various dietary sources like fruits, nuts, grains, spices and beverages. Various reports have shown that compounds like gallic acid, ellagic acid, catechin, epicatechin and procynidins from medicinal plants play major role in controlling progression of diabetes and its related complications by acting on molecular pathways and key targets involved in progression. Many chemists used above mentioned phyto-constituents as a pharmacophore for the developing new chemical entities having higher therapeutic benefits in management of diabetic complications. CONCLUSION: This review focuses on the role of various tannins in prevention and management of diabetic complications like diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic cardiomyopathy. It will help researchers to find some leads for the development of new cost effective therapy using dietary source for the management of diabetic complications.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Complicações do Diabetes/complicações , Nefropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/prevenção & controle , Plantas Medicinais/química , Taninos/farmacologia , Adolescente , Adulto , Doenças Cardiovasculares/etiologia , Nefropatias Diabéticas/etiologia , Neuropatias Diabéticas/etiologia , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Estresse Oxidativo , Proteína Quinase C/metabolismo
16.
Diabetes Metab Res Rev ; 35(2): e3099, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30462877

RESUMO

Diabetic neuropathy is a major complication of type 2 diabetes. Emerging evidence also suggests that people with pre-diabetes may develop similar symptoms related to nerve dysfunction. While regular exercise provides many benefits to patients with diabetes, whether exercise influences nerve function has not been established. As such, the aim of this systematic review was to evaluate current evidence regarding the effect of exercise training on the progression and development of diabetic neuropathy. A systematic search of MEDLINE (Ovid), CINAHL, AMED, PEDro, the Cochrane Library, Embase, and Scopus databases identified a total of 12 studies that were eligible for inclusion in this systematic review. Quality rating and data extraction were performed by two independent reviewers. The 12 included studies examined people with pre-diabetes (n = 1) and with type 2 diabetes (n = 11). There was heterogeneity of study quality and exercise type and dosage among these studies. Eleven studies reported that exercise training had a positive influence on nerve function or neuropathy-related symptoms; and only one study reported mild adverse events. Evidence from this systematic review suggests aerobic exercise training may positively influence nerve function among people with type 2 diabetes, with minimal risk of adverse events. Further research will be required to determine the optimal dosage of exercise training and the effect on nerve function in pre-diabetes and in women with previous gestational diabetes. This review is registered on PROSPERO (CRD42018088182).


Assuntos
Diabetes Mellitus Tipo 2/terapia , Neuropatias Diabéticas/prevenção & controle , Exercício Físico , Estado Pré-Diabético/terapia , Treinamento de Resistência , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Estado Pré-Diabético/fisiopatologia
17.
J Cell Physiol ; 234(4): 3814-3828, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30256388

RESUMO

Glycosaminoglycans are extracellular matrix components related to several biological functions and diseases. Chondroitin sulfate is a sulphated glycosaminoglycan synthesized as part of proteoglycan molecules. They are frequently associated with amyloid deposits and possess an active role in amyloid fibril formation. Recently, a neuroprotective effect of extracellular matrix components against amyloid toxicity and oxidative stress has been reported. Advanced glycation end products (AGEs), the end products of the glycation reaction, have been linked to amyloid-based neurodegenerative disease as associated with oxidative stress and inflammation. In this study we have analyzed the effect of chondroitin sulfate isolated from different species, in comparison with a new biotechnological unsulfated chondroitin, in the amyloid aggregation process of insulin, as well as the ability to prevent the formation of AGEs and related toxicity. The results have showed a determining role of chondroitin sulfate groups in modulating insulin amyloid aggregation. In addition, both sulfated and unsulfated chondroitins have shown protective properties against amyloid and AGEs-induced toxicity. These data are very relevant as a protective effect of these glycosaminoglycans in the AGE-induced toxicity was never observed before. Moreover, considering the issues related to the purity and safety of chondroitin from natural sources, this study suggests a new potential application for the biotechnological chondroitin.


Assuntos
Amiloide/toxicidade , Sulfatos de Condroitina/farmacologia , Neuropatias Diabéticas/prevenção & controle , Produtos Finais de Glicação Avançada/toxicidade , Insulina/toxicidade , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Bovinos , Linhagem Celular Tumoral , Sulfatos de Condroitina/isolamento & purificação , Citoproteção , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Humanos , Neurônios/metabolismo , Neurônios/ultraestrutura , Agregados Proteicos , Agregação Patológica de Proteínas , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Tubarões , Sus scrofa
18.
J Pharm Pharmacol ; 71(3): 417-428, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30537209

RESUMO

OBJECTIVES: The aim of this study was to evaluate the neuroprotective effects of SalB on high glucose (HG)-induced excessive autophagy and apoptosis in vitro. METHODS: The proliferation and apoptosis of RSC96 cells were determined using the MTT assay and flow cytometry, respectively. Western blot analysis was performed to examine the expression of autophagy and apoptosis-related proteins. RT-PCR and flow cytometry were manipulated to examine the level of Bcl-2. The signals of autophagy markers were detected using immunofluorescence methods. KEY FINDINGS: We found that HG significantly reduced RSC96 cell's proliferation and induced apoptosis. What's more, HG increased the level of autophagy and apoptosis-related proteins. However, these effects were reversed by SalB. In addition, we also found that 3-MA decreased the expression of LC3A/B and Beclin1, while the JNK inhibitor SP600125 reduced the levels of phosphorylated JNK, LC3A/B and Beclin1. CONCLUSIONS: High glucose not only induced apoptosis but also caused autophagic cell death by activating the JNK pathway. These effects prevented by SalB in an opposite manner.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzofuranos/farmacologia , Neuropatias Diabéticas/prevenção & controle , Doenças do Sistema Nervoso Periférico/prevenção & controle , Animais , Antracenos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neuropatias Diabéticas/metabolismo , Glucose/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
19.
Mol Med Rep ; 19(1): 743-751, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30431101

RESUMO

Diabetic peripheral neuropathy (DPN) is one of the common complications in diabetes, affecting more than half of patients with diabetes. L­carnitine (LC) was recently demonstrated to serve a positive role in ameliorating DPN. Therefore, the aim of the present study was to investigate the underlying mechanisms of LC in ameliorating DPN. Male Kunming mice were randomly assigned into five groups, including the control group, diabetes mellitus group, pre­treatment group, treatment group and post­treatment group. Type 2 diabetes was induced in mice using a combination of high­fat diet and streptozotocin injection. Subsequently, peripheral neuropathy was measured and the levels of LC, insulin and insulin­like growth factor­1 (IGF­1) were detected. When diabetic mice were treated with LC, the levels of IGF­1 in the plasma and pancreas were increased. In addition, hyperalgesia, as determined by the tail­flick test as well as food intake, body weight and blood glucose levels were decreased. An amelioration of demyelination, axonal atrophy and mitochondria swelling in the nerve fibres of diabetic mice was also observed. The present study demonstrated that LC ameliorated peripheral neuropathy in type 2 diabetic mice and the effect of LC may in part be mediated by an increase in local and circulatory IGF­1 levels.


Assuntos
Glicemia/metabolismo , Carnitina/farmacologia , Diabetes Mellitus Experimental/complicações , Neuropatias Diabéticas/prevenção & controle , Fator de Crescimento Insulin-Like I/metabolismo , Animais , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Masculino , Camundongos
20.
Agri ; 30(4): 165-170, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30403270

RESUMO

OBJECTIVES: Diabetic peripheral neuropathy (DPN) is the most common and troublesome complication of diabetes leading to great morbidity and resulting in a huge economic burden for diabetes care. Over half of people with diabetes develop neuropathy. Also, DPN is a major cause of reduced quality of life due to pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. The aim of this study was evaluating the effects of lifestyle interventions on diabetic neuropathy severity in diabetes type 2 outpatients. METHODS: This clinical trial conducted on 74 patients with DPN that divided with random allocation into intervention or control group. The lifestyle interventions applied in the intervention group beginning four educational sessions on lifestyle that emphasize strategies for lowering blood sugar, increasing physical activity, promoting weight loss, prudent diet, and foot caring. Each session was lasted for1.5 hour. Then patients followed for 12 weeks. During this period, they received counseling on mentioned lifestyle interventions. DPN severity in both groups measured using modified Toronto Clinical Neuropathy Score (mTCNS) at the beginning of study and at the end of counseling for 12 weeks. RESULTS: Comparing differences of mean of DNP severity before and after lifestyle intervention between two groups of study, there was a significant difference (p<0.001). DNP severity in control group had not any change or it increased in some participants, but DNP decreased in intervention group, after applying lifestyle intervention. CONCLUSION: Lifestyle interventions can contribute to reducing DPN severity, and consequently decreasing neuropathic pain.


Assuntos
Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas/prevenção & controle , Estilo de Vida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Índice de Gravidade de Doença , Resultado do Tratamento
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