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1.
Clin Ter ; 170(6): e465-e471, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31696911

RESUMO

In Type 1 Diabetes (T1D), the monokine induced by interferon (IFN)-γ (MIG)/(C-X-C motif) receptor (CXCR)3 axis has a crucial role in ß-cell destruction and in the autoimmune process of the disease, like many papers have reported. In fact, in T1D subjects the serum levels of the Type helper 1 chemokine MIG is increased, suggesting that this chemokine could be a predictive marker of T1D. Moreover, the pathophysiology of the disease course could be assessed by measuring MIG serum levels. A potential approach for T1D therapy could be the block of MIG expression at the beginning of the disease. Anyway, the chemokines-cytokines interactions in the T1D pathogenesis need to be further investigated.


Assuntos
Quimiocina CXCL9/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Biomarcadores/metabolismo , Progressão da Doença , Humanos , Receptores CXCR3/metabolismo
2.
Int J Sports Med ; 40(14): 909-920, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639864

RESUMO

The aim of this study was to investigate the ameliorative effect of moderate-intensity exercise training in sole and simultaneous forms with insulin on experimental type 1 diabetes (T1D)-induced apoptosis. A total of 36 mature male Wistar rats were divided into six equally sized groups, including sedentary control (Con), moderate-intensity exercise training (E-sole), sedentary T1D-induced (D-sole), moderate-exercise-trained T1D-induced (DE), insulin-treated sedentary T1D-induced (DI) and exercise-trained, and insulin-treated T1D-induced (DEI) groups. The 6-week exercise training intervention was involved 30 min of moderate-intensity running on a treadmill once daily (5 days/week). Next, tubular differentiation (TDI) and spermiogenesis (SPI) indices were assessed. The Bcl-2, Bax and caspase-3 expressions were determined using RT-PCR, immunohistochemistry and western blot techniques. Finally, the TUNEL staining was used to analyze the apoptosis ratio. The moderate-intensity exercise training in the sole and when simultaneously considered with insulin (DEI) maintained testicular cellularity, up-regulated Bcl-2 expression, reduced Bax expression and ameliorated the diabetes-induced apoptosis. We failed to show remarkable alterations in caspase-3 mRNA and protein levels in the DE group versus D-sole animals. In conclusion, the moderate-intensity exercise training is able to potentially protect testicular cells from T1D-induced intrinsic apoptosis via up-regulating Bcl-2 and downregulating Bax expressions. Moreover, it amplifies the insulin-induced anti-apoptotic impacts.


Assuntos
Apoptose , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Condicionamento Físico Animal , Testículo/patologia , Animais , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Regulação para Baixo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Ratos Wistar , Espermatogênese/fisiologia , Regulação para Cima , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
3.
Invest Ophthalmol Vis Sci ; 60(12): 4063-4073, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31560762

RESUMO

Purpose: The balance of neuronal excitation and inhibition is important for proper retinal signaling. A previous report showed that diabetes selectively reduces light-evoked inhibition to the retinal dim light rod pathway, changing this balance. Here, changes in mechanisms of retinal inhibitory synaptic transmission after 6 weeks of diabetes are investigated. Methods: Diabetes was induced in C57BL/6J mice by three intraperitoneal injections of streptozotocin (STZ, 75 mg/kg), and confirmed by blood glucose levels more than 200 mg/dL. After 6 weeks, whole-cell voltage-clamp recordings of electrically evoked inhibitory postsynaptic currents from rod bipolar cells and light-evoked excitatory postsynaptic currents from A17-amacrine cells were made in dark-adapted retinal slices. Results: Diabetes shortened the timecourse of directly activated lateral GABAergic inhibitory amacrine cell inputs to rod bipolar cells. The timing of GABA release onto rod bipolar cells depends on a prolonged amacrine cell calcium signal that is reduced by slow calcium buffering. Therefore, the effects of calcium buffering with EGTA-acetoxymethyl ester (AM) on diabetic GABAergic signaling were tested. EGTA-AM reduced GABAergic signaling in diabetic retinas more strongly, suggesting that diabetic amacrine cells have reduced calcium signals. Additionally, the timing of release from reciprocal inhibitory inputs to diabetic rod bipolar cells was reduced, but the activation of the A17 amacrine cells responsible for this inhibition was not changed. Conclusions: These results suggest that reduced light-evoked inhibitory input to rod bipolar cells is due to reduced and shortened calcium signals in presynaptic GABAergic amacrine cells. A reduction in calcium signaling may be a common mechanism limiting inhibition in the retina.


Assuntos
Sinalização do Cálcio/fisiologia , Retinopatia Diabética/metabolismo , Células Bipolares da Retina/metabolismo , Células Amácrinas/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Estimulação Luminosa , Estreptozocina , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
4.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500224

RESUMO

Since diabetes is a global epidemic, the development of novel therapeutic strategies for the treatment of this disease is of major clinical interest. Diabetes is differentiated in two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM arises from an autoimmune destruction of insulin-producing ß-cells whereas T2DM is characterized by an insulin resistance, an impaired insulin reaction of the target cells, and/or dysregulated insulin secretion. In the past, a growing number of studies have reported on the important role of the protein kinase CK2 in the regulation of the survival and endocrine function of pancreatic ß-cells. In fact, inhibition of CK2 is capable of reducing cytokine-induced loss of ß-cells and increases insulin expression as well as secretion by various pathways that are regulated by reversible phosphorylation of proteins. Moreover, CK2 inhibition modulates pathways that are involved in the development of diabetes and prevents signal transduction, leading to late complications such as diabetic retinopathy. Hence, targeting CK2 may represent a novel therapeutic strategy for the treatment of diabetes.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos
5.
Life Sci ; 234: 116738, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398418

RESUMO

AIMS: Oxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization. MAIN METHODS: A rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment. KEY FINDINGS: Sitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals. SIGNIFICANCE: The results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologia
6.
Int J Mol Sci ; 20(16)2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398795

RESUMO

Islet autoantibody (iAb)-positive individuals have a high risk of progression to type 1 diabetes (T1D), although the rate of progression is highly variable and factors involved in the rate of progression are largely unknown. The ratio of unmethylated/methylated insulin DNA levels (unmethylated INS ratio) has been shown to be higher in participants at high risk of T1D compared to healthy controls. We aimed to evaluate whether an unmethylated INS ratio may be a useful biomarker of beta cell death and rate of progression to T1D. In TrialNet participants who were followed in the Pathway to Prevention Study and progressed to diabetes (n = 57, median age of onset 15.3 years), we measured unmethylated INS ratio and autoantibodies by electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA, and ECL-IA2) and radioimmunoassays (RIA) (mIAA, GADA, IA2A, and ZnT8A) longitudinally for 24 months prior to diagnosis. Linear models were used to test the association between unmethylated INS ratio and the age at T1D diagnosis and unmethylated INS ratio and iAb over time. Close to diabetes onset, the unmethylated INS ratio was associated with mIAA (p = 0.003), ECL-IAA (p = 0.002), and IA2A (p = 0.01) levels, but not with GADA, ECL-GADA, ECL-IA2, or ZnT8A levels. No significant associations were found at baseline (24 months prior to T1D diagnosis). Only mIAA levels were significantly associated with an unmethylated INS ratio over time, with a 0.24 change in the ratio for each 0.1 change in mIAA z-score (p = 0.02). Adjusting for a baseline unmethylated INS ratio, an increased rate of change in unmethylated INS ratio from baseline to diabetes onset was associated with a five-year decrease in age at T1D diagnosis (p = 0.04).


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adolescente , Idade de Início , Autoanticorpos/sangue , Autoanticorpos/imunologia , Biomarcadores , Morte Celular , Criança , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Humanos , Células Secretoras de Insulina/imunologia , Masculino , Metilação , Risco , Adulto Jovem
7.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370156

RESUMO

Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes.


Assuntos
Fatores Biológicos/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Canais de Potássio Cálcio-Ativados/genética , Animais , Fatores Biológicos/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Regulação da Expressão Gênica , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Potenciais da Membrana/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Canais de Potássio Cálcio-Ativados/metabolismo , Fatores de Risco , Transdução de Sinais , Vasodilatação/efeitos dos fármacos
8.
J Diabetes Res ; 2019: 2813489, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467926

RESUMO

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to ß-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect ß-cell mass against glucotoxicity and to increase ß-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-ß cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on ß-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of ß-cell mass after new-onset T1D.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucosídeos/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Compostos Benzidrílicos/administração & dosagem , Glicemia/metabolismo , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Esquema de Medicação , Quimioterapia Combinada , Intervenção Médica Precoce , Teste de Tolerância a Glucose , Glucosídeos/administração & dosagem , Injeções Intraperitoneais , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiologia , Masculino , Camundongos , Estreptozocina , Fatores de Tempo , Ácido gama-Aminobutírico/administração & dosagem
9.
J Immunol Res ; 2019: 1780567, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467932

RESUMO

This study analyzed the expression of membrane OX40 and OX40L (mOX40 and mOX40L) and levels of soluble OX40 and OX40L (sOX40 and sOX40L) in T1D patients to determine their clinical significance. Peripheral blood (PB) was collected from patients with T1D and healthy control participants. Expression of mOX40 and mOX40L on immune cells was detected by flow cytometry. Levels of sOX40 and sOX40L in sera were measured by ELISA. We demonstrated for the first time enhanced sOX40 and sOX40L expression and reduced mOX40 and mOX40L levels in T1D patients which correlated with the clinical characteristics and inflammatory factors. These results suggest that OX40/OX40L signal may be promising biomarkers and associated with the pathogenesis of T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Ligante OX40/metabolismo , Receptores OX40/metabolismo , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Ligante OX40/sangue , Receptores OX40/sangue , Adulto Jovem
10.
Mol Immunol ; 114: 289-298, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31419705

RESUMO

Programmed cell death 1 ligand 1 (PD-L1) plays a critical role in mediating autoimmune diseases, including type I diabetes (T1D). B cells are important antigen-presenting cells (APCs) that make a major contribution to T1D development. However, B cells expressing low levels of PD-L1 that infiltrate insulitic islets in NOD mice may not inhibit effector T cells and prevent T1D. Here, we generated PD-L1 transgenic NOD (NOD.PD-L1Tg) mice, in which most immune cells overexpress PD-L1, to investigate the ability of B cells overexpressing PD-L1 to inhibit diabetic CD4+ T cells and prevent T1D. The severity of insulitis in NOD.PD-L1Tg mice was significantly lower than in NOD mice and none developed diabetes. In addition, there were no differences in expression of activity markers by APCs following LPS stimulation between two groups. In vitro studies revealed that B cells expressing high levels of PD-L1 inhibited proliferation of and cytokine secretion by pre-diabetic CD4+ T cells, whereas in vivo studies showed that NOD/SCID mice receiving diabetic CD4+ T cells mixed with B cells overexpressing PD-L1 became diabetic at a slower rate. Thus, we propose that B cells showing high expression of PD-L1 protect NOD mice against T1D and downregulate diabetogenic CD4+ T cells.


Assuntos
Linfócitos B/metabolismo , Antígeno B7-H1/metabolismo , Diabetes Mellitus Experimental/metabolismo , Camundongos Endogâmicos NOD/metabolismo , Animais , Doenças Autoimunes/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Regulação para Baixo/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Estado Pré-Diabético/metabolismo
11.
Transplant Proc ; 51(8): 2787-2792, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445766

RESUMO

BACKGROUND: Diabetes is an autoimmunologic disease that may have a different background. The aim of our study was to show that type 1 diabetes is accompanied by changes in gene expression in peripheral blood mononuclear cells. We analyzed the genes characteristic of pancreatic islet cells and genes playing a big part in autoimmune diseases and cancer. DESIGN: The study included 21 patients and was performed to examine the expression of 9 genes. The patients were divided into 3 research groups: people with type 1 diabetes, people with diabetes after pancreas transplant, and a control group of healthy patients. To assess the level of expression, RNA material was obtained from peripheral blood collected from individuals qualified for the study. RESULTS: The results of the study showed many interesting changes in the expression level of the analyzed genes. It was demonstrated that CASR gene expression was significantly higher in transplant patients than in diabetic patients. Differences in the level of activity are also noted in genes that take part in autoimmune diseases. PROPOSAL: Profiling gene expression in peripheral blood samples may be a useful and noninvasive diagnostic tool that allows early detection of changes leading to the onset or resumption of diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Perfilação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Transplante de Pâncreas , Adulto , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/cirurgia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Receptores de Detecção de Cálcio/metabolismo
12.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
13.
Arch Endocrinol Metab ; 63(4): 376-384, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365624

RESUMO

OBJECTIVE: To test the influence of oral fructose and glucose dose-response solutions in blood glucose (BG), glucagon, triglycerides, uricaemia, and malondialdehyde in postprandial states in type 1 diabetes mellitus (T1DM) patients. SUBJECTS AND METHODS: The study had a simple-blind, randomized, two-way crossover design in which T1DM patients were selected to receive fructose and glucose solutions (75g of sugars dissolved in 200 mL of mineral-water) in two separate study days, with 2-7 weeks washout period. In each day, blood samples were drawn after 8h fasting and at 180 min postprandial to obtain glucose, glucagon, triglycerides, uric acid, lactate, and malondialdehyde levels. RESULTS: Sixteen T1DM patients (seven men) were evaluated, with a mean age of 25.19 ± 8.8 years, a mean duration of disease of 14.88 ± 4.73 years, and glycated hemoglobin of 8.13 ± 1.84%. Fructose resulted in lower postprandial BG levels than glucose (4.4 ± 5.5 mmol/L; and 12.9 ± 4.1 mmol/L, respectively; p < 0.01). Uric acid levels increased after fructose (26.1 ± 49.9 µmol/L; p < 0.01) and reduced after glucose (-13.6 ± 9.5 µmol/L; p < 0.01). The malondialdehyde increased after fructose (1.4 ± 1.6 µmol/L; p < 0.01) and did not change after glucose solution (-0.2 ± 1.6 µmol/L; p = 0.40). Other variables did not change. CONCLUSIONS: Fructose and glucose had similar sweetness, flavor and aftertaste characteristics and did not change triglycerides, lactate or glucagon levels. Although fructose resulted in lower postprandial BG than glucose, it increased uric acid and malondialdehyde levels in T1DM patients. Therefore it should be used with caution. ClinicalTrials.gov registration: NCT01713023.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Frutose/metabolismo , Glucose/metabolismo , Período Pós-Prandial/efeitos dos fármacos , Edulcorantes/metabolismo , Adolescente , Adulto , Glicemia/análise , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Feminino , Frutose/farmacologia , Glucose/farmacologia , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Projetos Piloto , Método Simples-Cego , Soluções/farmacologia , Edulcorantes/farmacologia , Paladar/efeitos dos fármacos , Triglicerídeos/sangue , Ácido Úrico/sangue , Adulto Jovem
14.
Nutrients ; 11(7)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295897

RESUMO

The achievement of optimal post-prandial (PP) glucose control in patients with type 1 diabetes (T1DM) remains a great challenge. This review summarizes the main factors contributing to PP glucose response and discusses the likely reasons why PP glucose control is rarely achieved in T1DM patients. The macronutrient composition of the meal, the rate of gastric emptying and premeal insulin administration are key factors affecting the PP glucose response in T1DM. Although the use of continuous insulin infusion systems has improved PP glucose control compared to conventional insulin therapy, there is still need for further ameliorations. T1DM patients frequently present a delayed gastric emptying (GE) that produces a lower but more prolonged PP hyperglycemia. In addition, delayed GE is associated with a longer time to reach the glycemic peak, with a consequent mismatch between PP glucose elevation and the timing of premeal insulin action. On this basis, including GE time and meal composition in the algorithms for insulin bolus calculation of the insulin delivery systems could be an important step forward for optimization of PP glucose control in T1DM.


Assuntos
Glicemia/fisiologia , Diabetes Mellitus Tipo 1 , Esvaziamento Gástrico/fisiologia , Período Pós-Prandial/fisiologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Humanos , Insulina/fisiologia , Refeições/fisiologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31322069

RESUMO

BACKGROUND: Monocytes are the main blood innate mononuclear phagocyte and one of the most important effector cells expressing Fcγ receptor, which is critical for the interaction with Fc domain of antibodies. OBJECTIVE: To evaluate the effect of Rituximab (RTX, a chimeric human anti-CD20 monoclonal antibody) on the functional activities of Monocytes (MOs) at the onset of human Type 1 Diabetes (T1D). METHODS: MOs were isolated from peripheral blood mononuclear cells (PBMCs) obtained from volunteer patients with recent-onset T1D and healthy control donors. RESULTS: The levels of the production of Interleukin 1ß (IL-1ß) and IL-6 were significantly increased in MOs from patients with T1D when compared to MOs from healthy controls (respectively, p < 0.01 and p < 0.05). Similarly, Interferon γ (IFN-γ), and intracellular free Calcium Ion (ifCa2+) levels were increased in T1D MOs than in control MOs, but the difference did not reach a significant level. Conversely, the production levels of IL-4 and catalase activity, as well as of both phagocytosis and killing capacities were decreased in MOs of T1D patients compared to MOs from healthy controls, but the difference was not significant for catalase activity and killing capacity (respectively, p < 0.01, p > 0.05, p < 0.01, and p > 0.05). Additionally, treatment with RTX significantly upregulated phagocytosis (p < 0.05), markedly downregulated the release of IL-1ß (p < 0.01), ifCa2+, hydrogen peroxide (H2O2), and slightly downregulated the Nitric Oxide Synthase (NOS) activity, NOS activity-to-arginase activity ratio, the levels of Lactate Dehydrogenase (LDH)-based cytotoxicity, and the production of IL-6 and IFN-γ. Moreover, RTX treatment significantly upregulated the production of IL-4 (p < 0.05), IL-10 (p < 0.01) and the catalase activity (p < 0.05). CONCLUSION: Our study has shown for the first time that RTX can reverse the abnormal functional activities of MOs as well as their production of proinflammatory cytokines at the onset of T1D. From a therapeutic point of view, RTX may potentially be suggested at the beginning of T1D to immunomodulate innate immunity and inflammatory conditions.


Assuntos
Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Peróxido de Hidrogênio/metabolismo , Monócitos/efeitos dos fármacos , Rituximab/farmacologia , Adolescente , Arginase/metabolismo , Estudos de Casos e Controles , Catalase/metabolismo , Células Cultivadas , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Monócitos/metabolismo , Óxido Nítrico/metabolismo
16.
Phytomedicine ; 63: 153002, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301539

RESUMO

BACKGROUND: Type 1 diabetes is an autoimmune disease directed to the pancreatic islets where inflammation leads to the death of insulin-producing ß cells and insulin deficiency. Type 2 diabetes, which is closely related to overweight, is characterized by insulin resistance. In both cases, proinflammatory cytokines play an important role by causing insulitis and insulin resistance. The gum resin of Boswellia species and its pharmacologically active compounds, including 11-keto-ß-boswellic acids have been shown to suppress the expression of proinflammatory cytokines in various immune-competent cells. PURPOSE: To review the present evidence of the therapeutic effects of boswellic extracts (BE) and/or 11-keto-ß-boswellic acids in the prevention/treatment of diabetes mellitus and to provide comprehensive insights into the underlying molecular mechanisms. METHODS: This review considers all available informations from preclinical and clinical studies concerning BEs, 11-keto-ß-boswellic acids, proinflammatory cytokines and diabetes mellitus collected via electronic search (PubMed) and related publications of the author. RESULTS: Type 1 diabetes: Studies in mice with autoimmune diabetes revealed that in the model of multiple injections of low doses of streptozotocin (MLD-STZ), an extract of the gum resin of Boswellia serrata and 11-keto-ß-boswellic acid (KBA) suppressed the increase in proinflammatory cytokines in the blood, infiltration of lymphocytes into pancreatic islets and increase in blood glucose. In a second model, i.e. the nonobese diabetic (NOD) mouse, KBA prevented the infiltration of lymphocytes into pancreatic islets. Regarding the clinical effects, a case report provided evidence that BE suppressed the blood levels of tyrosine phosphatase antibody (IA2-A), a marker for insulitis, in a patient with late-onset autoimmune diabetes of the adult (LADA). Type 2 diabetes: In a preclinical study in rats where obesity was alimentary induced, the administration of BE significantly reduced food intake, overweight, proinflammatory cytokines such as interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) and ameliorated the parameters of glucose and lipid metabolism. Similar results were obtained in a second animal study, where type 2 diabetes was induced by a combination of a high-fat/high-fructose diet and a single dose of streptozotocin. Two clinical trials with patients with type 2 diabetes receiving the resin of Boswellia serrata demonstrated improvement in the blood glucose, HbA1c and lipid parameters. CONCLUSION: Preclinical and clinical data suggest that BE and/or 11-keto-ß-boswellic acids by inhibiting the expression of proinflammatory cytokines from immune-competent cells, may prevent insulitis and insulin resistance in type 1 and type 2 diabetes, respectively, and therefore may be an option in the treatment/prevention of type 1 and type 2 diabetes. It is hypothesized that molecularly, BE and 11-keto-ß-boswellic acids act via interference with the IκB kinase/Nuclear Transcription Factor-κB (IKK/NF-κB) signaling pathway through inhibition of the phosphorylation activity of IKK. However, further investigations and well-designed clinical studies are required.


Assuntos
Boswellia/química , Diabetes Mellitus Tipo 1/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Citocinas/sangue , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Camundongos , Camundongos Endogâmicos NOD , NF-kappa B/metabolismo , Extratos Vegetais/química , Ratos , Resinas Vegetais/química , Resinas Vegetais/farmacologia , Triterpenos/farmacologia
17.
Diabetes Res Clin Pract ; 155: 107781, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279959

RESUMO

AIMS: To analyze the factors associated with non-albuminuric reduced estimated glomerular filtration rate (NAeGFR-) phenotype in young people with type 1 diabetes (T1DM). METHODS: In this cross-sectional study were enrolled 140 outpatient diabetic children (age 7-18 years), consecutively observed in the period 2016-2017. Eighteen subjects with microalbuminuria (defined as albumin excretion rate ≥ 30 mg/24 h) were excluded. Fasting HbA1c, uric acid (UA), neutrophils and lymphocytes count were recorded. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz's bed-side formula and reduced eGFR was defined by a value <90 mL/min/1.73 m2. RESULTS: Out of 122 subjects analyzed, 76 (62%) showed normal eGFR and 46 (38%) showed NAeGFR- phenotype. They were characterized by higher prevalence of male sex (57% vs 33%, p = 0.010), autoimmune diseases (26% vs 12%, p = 0.043), high UA levels (4.0 ±â€¯0.9 vs 3.3 ±â€¯0.9 mg/dl, p < 0.0001) and high Neutrophils/Lymphocytes ratio (1.5 [1.2-2.0] vs 1.3 [1.0-1.8], p = 0.023). CONCLUSIONS: In our population, the prevalence on NAeGFR- phenotype is 38% and it is associated with male sex, high levels of UA, presence of other autoimmune diseases and low-grade inflammation. It should encourage pediatricians to monitor early both eGFR and UA in order to intercept diabetic youth more likely prone to develop progressive renal impairment.


Assuntos
Albuminas/análise , Diabetes Mellitus Tipo 1/fisiopatologia , Taxa de Filtração Glomerular , Insuficiência Renal/epidemiologia , Adolescente , Criança , Estudos Transversais , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobina A Glicada/análise , Humanos , Incidência , Itália/epidemiologia , Masculino , Fenótipo , Prevalência , Ácido Úrico/análise
18.
J Immunol Res ; 2019: 8785263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281853

RESUMO

Regulatory T cells (Tregs) play a critical role in controlling autoreactive T cells, and quantitative and/or qualitative deficiencies in Tregs are associated with autoimmune diseases, including type 1 diabetes (T1D), in both humans and mice. Both the incidence of T1D and percentages of peripheral Tregs in NOD mice vary considerably between animal facilities. In our animal facility, the incidence of T1D in NOD mice is high at 90-100% and the percentages of peripheral CD4+Foxp3+ cells in ~9-10-week-old female NOD mice are decreased compared to control (B6) mice shortly before high glucose is first detected (~12 weeks). These data suggest that there is an imbalance between Tregs and potentially pathogenic effector T cells at this age that could have significant impact on disease progression to overt diabetes. The goal of the current study was to investigate mechanisms that play a role in peripheral Treg : T effector cell balance in NOD mice, including differences in persistence/survival, peripheral homeostatic proliferation, and thymic production and output of CD4+ T cells. We found no differences in persistence/survival or homeostatic proliferation of either Tregs or effector T cells between NOD and B6 mice. Furthermore, although the percentages and absolute numbers of CD4+Foxp3+ cells in thymus were not decreased in NOD compared to B6 mice, the percentage of CD4+ recent thymic emigrants (RTE) that were Foxp3+ was significantly lower in 9-week-old NOD mice. Interestingly, the thymic output of CD4+Foxp3+ cells was not lower in NOD mice, whereas the thymic output of CD4+Foxp3- cells was significantly higher in NOD mice at that age compared to B6 mice. These data suggest that the higher thymic output of CD4+Foxp3- T cells contributes, at least in part, to the lower percentages of peripheral CD4+Foxp3+ Tregs in NOD mice and an imbalance between Tregs and T effector cells that may contribute to the development of full-blown diabetes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Biomarcadores , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Imunomodulação , Imunofenotipagem , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Especificidade da Espécie , Linfócitos T Reguladores/metabolismo , Timo/metabolismo
19.
J Neuroinflammation ; 16(1): 138, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286987

RESUMO

BACKGROUND: Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration. METHODS: Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) (n = 13), active proliferative DR (aPDR) (n = 14), inactive PDR (iPDR) (n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3fl/fl and LysMCre/+SOCS3fl/fl mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining. RESULTS: Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysMCre/+SOCS3fl/fl mice and SOCS3fl/fl mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysMCre/+SOCS3fl/fl diabetic mice. CONCLUSION: STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Retinopatia Diabética/metabolismo , Leucócitos Mononucleares/metabolismo , Microvasos/metabolismo , Vasos Retinianos/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Estudos Transversais , Diabetes Mellitus Tipo 1/imunologia , Retinopatia Diabética/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/imunologia , Vasos Retinianos/imunologia
20.
EBioMedicine ; 46: 512-521, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257149

RESUMO

The steep increase in the incidence of type 1 diabetes (T1D), in the Western world after World War II, cannot be explained solely by genetic factors but implies that this rise must be due to crucial interactions between predisposing genes and environmental changes. Three parallel phenomena in early childhood - the dynamic development of the immune system, maturation of the gut microbiome, and the appearance of the first T1D-associated autoantibodies - raise the question whether these phenomena might reflect causative relationships. Plenty of novel data on the role of the microbiome in the development of T1D has been published over recent years and this review summarizes recent findings regarding the associations between islet autoimmunity, T1D, and the intestinal microbiota.


Assuntos
Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Microbiota , Animais , Autoimunidade , Disbiose , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/imunologia , Microbiota/imunologia
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