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1.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
2.
Nat Genet ; 51(11): 1588-1595, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676868

RESUMO

The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ß cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the ß-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the ß-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the ß-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human ß cells. Our study illustrates how ß cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.


Assuntos
Cromatina/genética , Citocinas/farmacologia , Diabetes Mellitus Tipo 1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Células Secretoras de Insulina/metabolismo , Transcriptoma , Cromatina/química , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Elementos Facilitadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Fatores de Transcrição
4.
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
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.
Indian J Med Res ; 149(4): 479-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31411171

RESUMO

Background & objectives: In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools. Methods: In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing. Results: Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients. Interpretation & conclusions: The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Adulto , Idade de Início , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Índia/epidemiologia , Ilhotas Pancreáticas/patologia , Masculino , Pâncreas/patologia , Estudos Prospectivos , Adulto Jovem
7.
Diabetes Res Clin Pract ; 155: 107818, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31425769

RESUMO

AIMS: Low-carbohydrate diet (LCD) has gained interest among individuals with diabetes as a means to manage glycaemia. We investigated the adherence to LCD in the Finnish Diabetic Nephropathy Study and whether carbohydrate restriction is associated with cardio-metabolic risk factors. METHODS: Cross-sectional data were available from 902 individuals with type 1 diabetes (44% men, age 47 ±â€¯13 years). Dietary data were collected twice with a 3-day diet record. Mean of the measurements was used. Carbohydrate intake <130 g/day or <26 E% was used as indication of LCD. Individuals reporting LCD were compared to sex-, diabetes duration- and eGFR-matched controls with higher carbohydrate intakes (>253 g/day or >48 E%). In the whole population, carbohydrate-to-fat ratio was calculated and its association with health variables was investigated. RESULTS: Higher carbohydrate-to-fat ratio was associated with higher blood glucose variability, higher blood pressure, lower HDL cholesterol concentration, and in men with lower waist-to-hip ratio. LCD adherence (n = 69) was associated with lower BMI (25.6 vs. 27.8 kg/m2, p = 0.030), lower variability of blood glucose measurements (0.38 vs. 0.45 mmol/l, p = 0.030), and lower diastolic blood pressure (74 vs. 79 mmHg, p = 0.048). Men reporting LCD had higher total (5.1 vs. 4.0 mmol/l, p = 0.007) and non-HDL cholesterol (3.4 vs. 2.7 mmol/l, p = 0.021). Women with LCD had higher HDL-cholesterol concentration (1.9 vs. 1.5 mmol/l, p = 0.014). CONCLUSIONS: Reduced blood glucose variability, related to LCD, could have clinical relevance to individuals with type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/dietoterapia , Dieta com Restrição de Carboidratos/métodos , Carboidratos da Dieta/efeitos adversos , Estudos Transversais , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Biomed Res Int ; 2019: 7689642, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467911

RESUMO

Objectives: The purpose of this study was to explore the association between rs2292239 polymorphism in ERBB3 gene and type 1 diabetes (T1D). Methods: A systematic search of studies on the association of rs2292239 polymorphism in ERBB3 gene with T1D susceptibility was conducted in PubMed, Web of science, Elsevier Science Direct, and Cochrane Library. Eventually, 9 published studies were included. The strength of association between rs2292239 polymorphism and T1D susceptibility was assessed by odds ratios (ORs) with its 95% confidence intervals (CIs). Results: A total of 9 case-control studies, consisting of 5369 T1D patients and 6920 controls, were included in the meta-analysis. This meta-analysis showed significant association between ERBB3 rs2292239 polymorphism and T1D susceptibility in overall population (A vs. C, OR: 1.292, 95% CI= 1.224-1.364, P H=0.450, P H is P value for the heterogeneity test). Similar results were found in subgroup analysis by ethnicity. Conclusions: ERBB3 rs2292239 polymorphism is associated with T1D susceptibility and rs2292239-A allele is a risk factor for T1D. However, more large-scale studies are warranted to replicate our findings.


Assuntos
Diabetes Mellitus Tipo 1/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Receptor ErbB-3/genética , Alelos , Diabetes Mellitus Tipo 1/patologia , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
9.
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
10.
Nutrients ; 11(8)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366063

RESUMO

The relationship between added sugar and arterial stiffness in youth with type 1 diabetes (T1D) has not been well-described. We used data from the SEARCH for Diabetes in Youth Study (SEARCH), an ongoing observational cohort study, to determine the association between added sugar and arterial stiffness in individuals diagnosed with T1D <20 years of age (n = 1539; mean diabetes duration of 7.9 ± 1.9 years). Added sugar intake was assessed by a food frequency questionnaire, and arterial stiffness measures included pulse wave velocity (PWV) and augmentation index. Separate multivariate linear regression models were used to evaluate the association between added sugar and arterial stiffness. Separate interaction terms were included to test for effect modification by body mass index (BMI) z-score and physical activity (PA). Overall, there was no association between added sugar and arterial stiffness (P > 0.05); however, the association between added sugar and arterial stiffness differed by BMI z-score (P for interaction = 0.003). For participants with lower BMI z-scores, added sugar intake was positively associated with PWV trunk measurements, whereas there was no association for those who had a higher BMI z-score. PA did not significantly modify the association between added sugar and arterial stiffness. Further research is needed to determine the longitudinal relationship and to confirm that obesity differentially affects this association.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Carboidratos da Dieta/administração & dosagem , Açúcares/administração & dosagem , Rigidez Vascular , Adolescente , Índice de Massa Corporal , Estudos de Coortes , Ingestão de Alimentos , Exercício , Feminino , Humanos , Masculino , Adulto Jovem
11.
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
12.
Sensors (Basel) ; 19(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323886

RESUMO

In the daily management of type 1 diabetes (T1D), determining the correct insulin dose to be injected at meal-time is fundamental to achieve optimal glycemic control. Wearable sensors, such as continuous glucose monitoring (CGM) devices, are instrumental to achieve this purpose. In this paper, we show how CGM data, together with commonly recorded inputs (carbohydrate intake and bolus insulin), can be used to develop an algorithm that allows classifying, at meal-time, the post-prandial glycemic status (i.e., blood glucose concentration being too low, too high, or within target range). Such an outcome can then be used to improve the efficacy of insulin therapy by reducing or increasing the corresponding meal bolus dose. A state-of-the-art T1D simulation environment, including intraday variability and a behavioral model, was used to generate a rich in silico dataset corresponding to 100 subjects over a two-month scenario. Then, an extreme gradient-boosted tree (XGB) algorithm was employed to classify the post-prandial glycemic status. Finally, we demonstrate how the XGB algorithm outcome can be exploited to improve glycemic control in T1D through real-time adjustment of the meal insulin bolus. The proposed XGB algorithm obtained good accuracy at classifying post-prandial glycemic status (AUROC = 0.84 [0.78, 0.87]). Consequently, when used to adjust, in real-time, meal insulin boluses obtained with a bolus calculator, the proposed approach improves glycemic control when compared to the baseline bolus calculator. In particular, percentage time in target [70, 180] mg/dL was improved from 61.98 (± 13.89) to 67.00 (± 11.54; p < 0.01) without increasing hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Algoritmos , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia , Simulação por Computador , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/patologia , Relação Dose-Resposta a Droga , Humanos , Hiperglicemia/sangue , Hiperglicemia/patologia , Sistemas de Infusão de Insulina , Período Pós-Prandial , Estudo de Prova de Conceito
13.
J Korean Med Sci ; 34(29): e202, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31347313

RESUMO

BACKGROUND: Diabetes mellitus (DM) causes macro- and microvasculopathy, but data on cardiac microvascular changes in large animals are scarce. We sought to determine the effect of DM on macro- and microvascular changes in diabetic pigs and humans. METHODS: Eight domestic pigs (4 with type I diabetes and 4 controls) underwent coronary angiography with optical coherence tomography (OCT; at baseline and 1 and 2 months), coronary computed tomography angiography, cardiac magnet resonance (CMR) imaging, and histologic examination. RESULTS: The diabetic pigs had more irregular capillaries with acellular capillaries and a smaller capillary diameter (11.7 ± 0.33 µm vs. 13.5 ± 0.53 µm; P < 0.001) than those of the control pigs. The OCT showed no significant epicardial stenosis in either group; however diabetic pigs had a greater intima-media thickness. CMR results showed that diabetic pigs had a lower relative upslope at rest (31.3 ± 5.9 vs. 37.9 ± 8.1; P = 0.011) and during stress (18.0 ± 3.0 vs. 21.6 ± 2.8; P = 0.007) than the control pigs, implying decreased myocardial perfusion. Among the 79 patients with ST elevation myocardial infarction, 25 had diabetes and they had lower myocardial perfusion on CMR as well. CONCLUSION: DM causes microvascular remodeling and a decrease in myocardial perfusion in large animals at a very early stage of the disease course. Early and effective interventions are necessary to interrupt the progression of vascular complications in diabetic patients.


Assuntos
Circulação Coronária/fisiologia , Diabetes Mellitus Tipo 1/patologia , Hiperglicemia/patologia , Infarto do Miocárdio/patologia , Idoso , Animais , Capilares/diagnóstico por imagem , Capilares/fisiologia , Espessura Intima-Media Carotídea , Angiografia Coronária , Diabetes Mellitus Tipo 1/complicações , Modelos Animais de Doenças , Feminino , Hemoglobina A Glicada/análise , Coração/diagnóstico por imagem , Coração/fisiopatologia , Humanos , Hiperglicemia/complicações , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Estudos Retrospectivos , Suínos , Tomografia de Coerência Óptica
14.
Rom J Ophthalmol ; 63(2): 153-160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31334394

RESUMO

Purpose: To assess the variation in cone photoreceptor density on the basis of age compatibility between healthy subjects, on one side, and type 1 diabetic patients with no diabetic retinopathy, on the other. Methods: A high resolution adaptive optics retinal camera in flood illumination regime was employed to image cones of 15 type I diabetic patients and 16 healthy controls. For each subject we scanned the cone mosaic in 4 perifoveal areas (nasally, temporally, superiorly and inferiorly) at 2, 3 and 4 degrees eccentricity. The impact of diabetes duration, gender and age were evaluated. Results: In the type I diabetic group we found a meaningful lower cone density (p<0.05), except for the temporal meridian at 2 and 4 degrees eccentricity. Moreover, a significant asymmetry of cone photoreceptor densities was proved between the horizontal and vertical meridians in both diabetic and control groups. Conclusion: The rtx1 retinal image evaluation demonstrated photoreceptors loss in DM1 diabetic patients prior to any clinical changes. Abbreviations: AO = adaptive optics, SS = swept source, OCT = optical coherence tomography, BCVA= best corrected visual acuity, DM = diabetes mellitus, DR = diabetic retinopathy.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Oftalmoscopia/métodos , Óptica e Fotônica , Células Fotorreceptoras Retinianas Cones/patologia , Tomografia de Coerência Óptica/instrumentação , Adolescente , Adulto , Contagem de Células , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acuidade Visual , Adulto Jovem
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.
Acta Diabetol ; 56(11): 1209-1216, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31313005

RESUMO

AIMS: Diabetic retinopathy remains asymptomatic until its late stages but remains a leading cause of vision impairment and blindness. We studied quality of life and the ability to deal with the discomfort deriving from the presence of a chronic disease in patients with type 1 diabetes and different stages of retinopathy. METHODS: Multicenter collaborative observational study involving nine centers screening for retinopathy in different areas of Italy. The National Eye Institute 25-item visual functioning questionnaire and the locus of control tool were administered to 449 people with type 1 diabetes between February 2016 and March 2018. Socio-demographic and clinical data were collected. RESULTS: On multivariable analysis, severe retinopathy is associated with worse scores for general vision, ocular pain, near vision activities, distance vision activities, driving, color vision, peripheral vision and lower values of internal control, independently of visual acuity. Women had a perception of worse general health, distance vision activities and driving, and lower internal control and trust in others. Worse scores for visual-specific social functioning, visual-specific mental health, visual-specific role difficulties, visual-specific dependency and peripheral vision were associated with higher HbA1c levels. Fatalism increased with rising HbA1c levels. CONCLUSIONS: These results confirm that a gap exists between patients' knowledge and expectations on retinopathy and providers' expertise and assumptions. To bridge this gap, patient-centered education and engaging approaches may be more effective than simple information given during consultations.


Assuntos
Diabetes Mellitus Tipo 1/psicologia , Retinopatia Diabética/psicologia , Qualidade de Vida , Acuidade Visual , Adaptação Psicológica , Idoso , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/patologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
BMC Med ; 17(1): 125, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31286933

RESUMO

BACKGROUND: Autoimmune diseases are often preceded by an asymptomatic autoantibody-positive phase. In type 1 diabetes, the detection of autoantibodies to pancreatic islet antigens in genetically at-risk children is prognostic for future clinical diabetes. Testing for islet autoantibodies is, therefore, performed in a range of clinical studies. Accurate risk estimates that consider the a priori genetic risk and other risk modifiers are an important component of screening. The age of an individual is an under-appreciated risk modifier. The aim of this study was to provide age-adjusted risk estimates for the development of autoantibodies across childhood in genetically at-risk children. METHODS: The prospective BABYDIAB and BABYDIET studies included 2441 children from birth who had a first-degree relative with type 1 diabetes. Children were born between 1989 and 2006 and were regularly followed from birth for the development of islet autoantibodies and diabetes. A landmark analysis was performed to estimate the risk of islet autoantibodies at birth and at the age 3.5, 6.5 and 12.5 years. Exponential decay curves were fitted for the risk by the age of 20 years. RESULTS: The risk of islet autoantibodies by the age of 20 years was 8%, 4.6%, 2.6% and 0.9%, at the landmark ages of birth, 3.5, 6.5 and 12.5 years, respectively. The short-term risks (within 6 years of follow-up) at these landmark ages were 5.3%, 2.9%, 1.8% and 1%, respectively. The decline in autoantibody risk with age was modelled using a one-phase exponential decay curve (r = 0.99) with a risk half-life of 3.7 years. This risk decay model was remarkably consistent when the outcome was defined as islet autoantibody-positive or multiple islet autoantibody-positive and when the study cohort was stratified by HLA risk genotype. A similar decay model was observed for coeliac disease-associated transglutaminase antibodies in the same cohort. Unlike the risk of developing islet autoantibodies, the rate of developing clinical diabetes in children who were islet autoantibody-positive did not decline with age. CONCLUSION: The risk of developing autoantibodies drops exponentially with age in children with a first-degree relative with type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos
19.
Diabetes Res Clin Pract ; 153: 157-165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150719

RESUMO

BACKGROUND AND AIMS: Although people with type 1 diabetes are exempt from fasting the month of Ramadan due to the risk to their health, many wish to fast nonetheless. Little is known about the impact of structured education on the fasting experiences of people with type 1 diabetes. This study aimed to explore how the Dose Adjustment for Normal Eating (DAFNE) course affected people with type 1 diabetes' fasting experiences to provide insight into the benefits of structured education for people wishing to fast while managing their diabetes. METHODS: Semi-structured interviews were conducted with 40 DAFNE graduates who fasted Ramadan. The purposive sample was selected from the DAFNE registry at Dasman Diabetes Institute in Kuwait. The interviews were transcribed verbatim and analysed thematically in an iterative process. Topics discussed included fasting experiences prior to attending the DAFNE course, fasting experiences this year, and how DAFNE affected their fasting. RESULTS: Five themes emerged; (1) Reduction in fluctuations and complications, (2) Improvement in confidence and self-reliance, (3) Tailored support for dose and pump programming adjustments, (4) Positive effect on wellbeing, and (5) Encouraging informed-decision making about fasting. CONCLUSIONS: The findings have provided insight into the impact of DAFNE structured education on the fasting experiences of people with type 1 diabetes and has shown how overall, DAFNE had enhanced the quality of fasting. In addition, by assisting them in fulfilling their fasting wishes, DAFNE has had a positive effect on their wellbeing.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Jejum , Adulto , Idoso , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Islamismo , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Adulto Jovem
20.
Biol Pharm Bull ; 42(8): 1337-1344, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31167987

RESUMO

Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and features myocardial fibrosis as its main pathological feature. Calcium sensing receptor (CaSR) is a G protein-coupled receptor, which involves in myocardial fibrosis by regulation of calcium homeostasis. Calhex231, the CaSR inhibitor, is not clear whether it regulates myocardial fibrosis in DCM. In the present study, type 1 diabetic (T1D) rats and primary neonatal rat cardiac fibroblasts were used to observe the role of Calhex231. In vivo experiments showed that in the T1D group, contractile dysfunction and the deposition of collagen I and III were obvious after 12 weeks. In vitro experiments, we found that high glucose (HG) could increase the expression of CaSR, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) collagen I/III, matrix metalloproteinase-2 (MMP-2), MMP9, along with cardiac fibroblast migration and proliferation. We further demonstrated that CaSR activation increased intracellular Ca2+ concentration and upregulated the expression of Itch (atrophin-1 interacting protein 4), which resulted in increasing the ubiquitination levels of Smad7 and upregulating the expression of p-Smad2, p-Smad3. However, treatment with Calhex231 clearly inhibited the above-mentioned changes. Collectively these results suggest that Calhex231 could inhibit Itch-ubiquitin proteasome and TGF-ß1/Smads pathways, and then depress the proliferation of cardiac fibroblasts, along with the reduction deposition of collagen, alleviate glucose-induced myocardial fibrosis. Our findings indicate an important new mechanism for myocardial fibrosis, and suggest Calhex231 would be a new therapeutic agent for the treatment of DCM.


Assuntos
Benzamidas/farmacologia , Cicloexilaminas/farmacologia , Cardiomiopatias Diabéticas/patologia , Fibrose/tratamento farmacológico , Miocárdio/patologia , Receptores de Detecção de Cálcio/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Animais , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/induzido quimicamente , Cardiomiopatias Diabéticas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/metabolismo , Glucose/metabolismo , Coração , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Modelos Animais , Miocárdio/metabolismo , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitinas/metabolismo
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