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1.
Rev. Hosp. Ital. B. Aires (2004) ; 40(3): 95-104, sept. 2020. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1128985

RESUMO

La relación entre inmunidad y cáncer es compleja. Las células tumorales desarrollan mecanismos de evasión a las respuestas del sistema inmunitario. Esta capacidad permite su supervivencia y crecimiento. La inmunoterapia ha transformado el tratamiento oncológico mejorando la respuesta inmunitaria contra la célula tumoral. Esta se basa en el bloqueo de los puntos de control inmunitario mediante anticuerpos monoclonales contra la molécula inhibidora CTLA-4 (antígeno 4 del linfocito T citotóxico [CTLA-4]) y la proteína 1 de muerte celular programada y su ligando (PD-1/PD-L1). Aunque los inhibidores de los puntos de control inmunitario (ICIs) son fármacos bien tolerados, tienen un perfil de efectos adversos conocido como eventos adversos inmunorrelacionados (EAI). Estos afectan varios sistemas, incluyendo las glándulas endocrinas. Los eventos adversos endocrinos más frecuentes son la disfunción tiroidea, la insuficiencia hipofisaria, la diabetes mellitus autoinmune y la insuficiencia suprarrenal primaria. El creciente conocimiento de estos efectos adversos endocrinos ha llevado a estrategias de tratamiento efectivo con el reemplazo hormonal correspondiente. El objetivo de esta revisión es reconocer la incidencia de estas nuevas endocrinopatías, la fisiopatología, su valoración clínica y el manejo terapéutico. (AU)


The relationship between immunity and cancer is complex. Tumor cells develop evasion mechanisms to the immune system responses. This ability allows their survival and progression. Immunotherapy has transformed cancer treatment by improving the immune response against tumor cells. This is achieved by blocking immune checkpoints with monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 and its ligand (PD-1 / PD-L1). Although the immune checkpoint inhibitors (ICIs) are well tolerated drugs, they have a profile of adverse effects known as immune-related adverse events (irAES). These involve diverse systems, including the endocrine glands. The most frequent endocrine immune-related adverse events are thyroid and pituitary dysfunction, autoimmune diabetes mellitus and primary adrenal insufficiency. The increasing knowledge of these irAES has led to effective treatment strategies with the corresponding hormonal replacement. The objective of this review is to recognize the incidence of these new endocrinopathies, the physiopathology, their clinical evaluation, and therapeutic management. (AU)


Assuntos
Humanos , Doenças do Sistema Endócrino/induzido quimicamente , Imunoterapia/efeitos adversos , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/patologia , Doenças da Glândula Tireoide/terapia , Tiroxina/administração & dosagem , Tri-Iodotironina/uso terapêutico , Corticosteroides/administração & dosagem , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/patologia , Insuficiência Adrenal/terapia , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/fisiopatologia , Doenças do Sistema Endócrino/terapia , Hipofisite/diagnóstico , Hipofisite/induzido quimicamente , Hipofisite/patologia , Hipofisite/terapia , Glucocorticoides/administração & dosagem , Insulina/uso terapêutico , Metimazol/uso terapêutico , Mineralocorticoides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias/imunologia
2.
PLoS One ; 15(8): e0237305, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822421

RESUMO

Diabetes can elicit direct deleterious effects on the myocardium, independent of coronary artery disease or hypertension. These cardiac disturbances are termed diabetic cardiomyopathy showing increased risk of heart failure with or without reduced ejection fraction. Presently, there is no specific treatment for this type of cardiomyopathy and in the case of type I diabetes, it may start in early childhood independent of glycemic control. We hypothesized that alterations in isolated myocyte contractility and cardiac function are present in the early stages of experimental diabetes in rats before overt changes in myocardium structure occur. Diabetes was induced by single-dose injection of streptozotocin (STZ) in rats with data collected from control and diabetic animals 3 weeks after injection. Left ventricle myocyte contractility was measured by single-cell length variation under electrical stimulation. Cardiac function and morphology were studied by high-resolution echocardiography with pulsed-wave tissue Doppler imaging (TDI) measurements and three-lead surface electrocardiogram. Triglycerides, cholesterol and liver enzyme levels were measured from plasma samples obtained from both groups. Myocardial collagen content and perivascular fibrosis of atria and ventricle were studied by histological analysis after picrosirius red staining. Diabetes resulted in altered contractility of isolated cardiac myocytes with increased contraction and relaxation time intervals. Echocardiography showed left atrium dilation, increased end-diastolic LV and posterior wall thickness, with reduced longitudinal systolic peak velocity (S') of the septum mitral annulus at the apical four-chamber view obtained by TDI. Triglycerides, aspartate aminotransferase and alkaline phosphatase were elevated in diabetic animals. Intertitial collagen content was higher in atria of both groups and did not differ among control and diabetic animals. Perivascular intramyocardial arterioles collagen did not differ between groups. These results suggest that alterations in cardiac function are present in the early phase in this model of diabetes type 1 and occur before overt changes in myocardium structure appear as evaluated by intersticial collagen deposition and perivascular fibrosis of intramyocardial arterioles.


Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Cardiomiopatias Diabéticas/fisiopatologia , Contração Miocárdica , Miócitos Cardíacos/patologia , Animais , Células Cultivadas , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Cardiomiopatias Diabéticas/induzido quimicamente , Cardiomiopatias Diabéticas/patologia , Ratos , Estreptozocina
3.
PLoS One ; 15(8): e0237667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833960

RESUMO

BACKGROUND AND AIMS: This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when ß-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early ß-cell damage. MATERIALS AND METHODS: We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis. RESULTS: We demonstrated by western blot, Transmission Electron Microscopy and cell viability experiments that RIAO circulate in the blood and can be measured by ELISA; are elevated in serum of childhood obesity and diabetes; are neurotoxics and works as biomarkers of early ß-cell failure. We explored the range of evidence-based medicine clusters that included the RIAO level, which allowed us to classify and stratify the obesity patients with high cardiometabolic risk. CONCLUSIONS: RIAO level increases as the number of complications rises; RIAOs > 3.35 µg/ml is a predictor of changes in the current indicators of ß-cell damage. We proposed a novel physio-pathological pathway and shows that PCD affect not only elderly patients but also children. Here we reduced the gap between basic biomedical research, clinical practice and health decision making.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Obesidade/patologia , Estrutura Quaternária de Proteína , Adolescente , Animais , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade , Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura , Microscopia Eletrônica de Transmissão , Neurônios/efeitos dos fármacos , Obesidade/sangue , Obesidade/complicações , Projetos Piloto , Cultura Primária de Células , Multimerização Proteica , Ratos , Testes de Toxicidade Aguda
5.
Niger J Clin Pract ; 23(7): 970-974, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620727

RESUMO

Background: Diabetes mellitus is one of the most common metabolic disorders with a rising prevalence. It cuts across all ages and socioeconomic status. Various skin lesions are frequently observed in diabetic patients. Aims: This study was carried out to determine the prevalence, pattern, and determinants of skin diseases in diabetic patients at the Barau Dikko Teaching Hospital, Kaduna, North West Nigeria. Materials and Methods: One hundred consecutive diabetic patients attending the clinic were included in the study. Results: Many of the patients had more than one skin condition at a time. The most prevalent skin diseases were idiopathic guttate hypomelanosis which was seen in 61% of patients, infections from fungal, bacterial, and viral causes occurred in 30% of patients, other skin disorders were diabetic dermopathy seen in 17% of patients, palmoplantar hyperpigmentation was seen in 13% of patients, while pruritus occurred in 12% of patients and xerosis was seen in 10% of patients. Conclusion: Skin disorders are common among diabetic patients at Barau Dikko Teaching Hospital, Kaduna, North West Nigeria.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Dermatopatias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Hospitais de Ensino , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Prevalência , Prurido/epidemiologia , Pele/patologia , Adulto Jovem
6.
Life Sci ; 256: 117985, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32562692

RESUMO

AIMS: To assess the combination therapy of anti-CD20 mabs and adenovirus-mediated interleukin-10 (IL-10) gene delivery on the prevention of type 1 diabetes (T1D) in non-obese diabetes (NOD) mice. MAIN METHODS: In present study, we simultaneously blocked the B cell interactions and recovered the Th cell subset proportion by using through anti-CD20 Mab and adenovirus-mediated gene delivery of IL-10, respectively. After 9 consecutive days of combination therapy, various measurements, including hematoxylin-eosin staining (HE), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay (TUNEL), immunohistochemistry, ELISA, PCR and western blot were applied to further assess the efficacy. KEY FINDINGS: The results suggested that the combination intervention reduced the T1D-associated morbidity of NOD mice, promote insulin secretion, control blood glucose and ease pancreatitis. Moreover, the combination therapy might play a protective role in pancreatic ß cells by suppressing the expression of TNF-α and Fas, blocking the Caspase-8 and Caspase-3 apoptotic pathways and activating the Bcl-2 anti-apoptotic pathway. Finally, the combination intervention may up-regulate the gene expression of CK-19 and PDX-1 and further accelerate the differentiation and proliferation of pancreatic ß cells. SIGNIFICANCE: Therefore, the combination intervention with anti-CD20 mabs and the IL-10 gene plays a role in the prevention of T1D to some extent in NOD mice.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD20/administração & dosagem , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Interleucina-10/administração & dosagem , Pancreatite/tratamento farmacológico , Adenoviridae/genética , Animais , Anticorpos Monoclonais/genética , Antígenos CD20/genética , Apoptose/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Quimioterapia Combinada , Feminino , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pancreatite/genética , Pancreatite/patologia
7.
Nat Commun ; 11(1): 2475, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424134

RESUMO

Autoimmune ß-cell destruction leads to type 1 diabetes, but the pathophysiological mechanisms remain unclear. To help address this void, we created an open-access online repository, unprecedented in its size, composed of large-scale electron microscopy images ('nanotomy') of human pancreas tissue obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD; www.nanotomy.org). Nanotomy allows analyses of complete donor islets with up to macromolecular resolution. Anomalies we found in type 1 diabetes included (i) an increase of 'intermediate cells' containing granules resembling those of exocrine zymogen and endocrine hormone secreting cells; and (ii) elevated presence of innate immune cells. These are our first results of mining the database and support recent findings that suggest that type 1 diabetes includes abnormalities in the exocrine pancreas that may induce endocrine cellular stress as a trigger for autoimmunity.


Assuntos
Bases de Dados como Assunto , Diabetes Mellitus Tipo 1/patologia , Ilhotas Pancreáticas/ultraestrutura , Microscopia Eletrônica , Autoanticorpos/metabolismo , Grânulos Citoplasmáticos/ultraestrutura , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Granulócitos/imunologia , Humanos , Imunidade Inata , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Doadores de Tecidos
8.
PLoS One ; 15(5): e0233639, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453760

RESUMO

Diabetes is the leading cause of end-stage renal disease worldwide. Our understanding of the early kidney response to chronic hyperglycemia remains incomplete. To address this, we first investigated the urinary proteomes of otherwise healthy youths with and without type 1 diabetes and subsequently examined the enriched pathways that might be dysregulated in early disease using systems biology approaches. This cross-sectional study included two separate cohorts for the discovery (N = 30) and internal validation (N = 30) of differentially excreted proteins. Discovery proteomics was performed on a Q Exactive Plus hybrid quadrupole-orbitrap mass spectrometer. We then searched the pathDIP, KEGG, and Reactome databases to identify enriched pathways in early diabetes; the Integrated Interactions Database to retrieve protein-protein interaction data; and the PubMed database to compare fold changes of our signature proteins with those published in similarly designed studies. Proteins were selected for internal validation based on pathway enrichment and availability of commercial enzyme-linked immunosorbent assay kits. Of the 2451 proteins identified, 576 were quantified in all samples from the discovery cohort; 34 comprised the urinary signature for early diabetes after Benjamini-Hochberg adjustment (Q < 0.05). The top pathways associated with this signature included lysosome, glycosaminoglycan degradation, and innate immune system (Q < 0.01). Notably, all enzymes involved in keratan sulfate degradation were significantly elevated in urines from youths with diabetes (|fold change| > 1.6). Increased urinary excretion of monocyte differentiation antigen CD14, hexosaminidase A, and lumican was also observed in the validation cohort (P < 0.05). Twenty-one proteins from our signature have been reported elsewhere as potential mediators of early diabetes. In this study, we identified a urinary proteomic signature for early type 1 diabetes, of which lysosomal enzymes were major constituents. Our findings highlight novel pathways such as keratan sulfate degradation in the early kidney response to hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 1/urina , Sulfato de Ceratano/metabolismo , Proteinúria/genética , Proteômica , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Proteínas da Matriz Extracelular/urina , Feminino , Humanos , Sulfato de Ceratano/genética , Rim/metabolismo , Rim/patologia , Lisossomos/metabolismo , Lisossomos/patologia , Masculino , Espectrometria de Massas , Proteinúria/metabolismo , Proteinúria/urina , Proteoma/genética , Proteoma/metabolismo , Adulto Jovem
10.
Nat Rev Endocrinol ; 16(7): 349-362, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398822

RESUMO

Loss of functional ß-cell mass is the key mechanism leading to the two main forms of diabetes mellitus - type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind ß-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early ß-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on ß-cells in human disease. These advances include studies of islet morphology and human ß-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the ß-cell level and the endoplasmic reticulum stress signalling that contributes to ß-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK-eIF2α dependent). Here, we review these new findings, focusing on studies performed on human ß-cells or on samples obtained from patients with diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Pancreática Exócrina/etiologia , Células Secretoras de Insulina/fisiologia , Animais , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Insuficiência Pancreática Exócrina/fisiopatologia , Humanos , Células Secretoras de Insulina/patologia , Transdução de Sinais/fisiologia
11.
Nat Commun ; 11(1): 2238, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382089

RESUMO

In type1 diabetes (T1D) autoreactive T-cells infiltrate the islets of Langerhans, depleting insulin-secreting ß-cells (insulitis). Insulitis arises during an asymptomatic phase, prior to clinical diagnosis of T1D. Methods to diagnose insulitis and ß-cell mass changes during this asymptomatic phase are limited, precluding early therapeutic intervention. During T1D the islet microvasculature increases permeability, allowing nanoparticles to access the microenvironment. Contrast enhanced ultrasound (CEUS) uses shell-stabilized gas bubbles to provide acoustic backscatter in vasculature. Here, we report that sub-micron sized 'nanobubble' ultrasound contrast agents can be used to measure increased islet microvasculature permeability and indicate asymptomatic T1D. Through CEUS and histological analysis, pre-clinical models of T1D show accumulation of nanobubbles specifically within pancreatic islets, correlating with insulitis. Importantly, accumulation is detected early in disease progression and decreases with successful therapeutic intervention. Thus, sub-micron sized nanobubble ultrasound contrast agents provide a predicative marker for disease progression and therapeutic reversal early in asymptomatic T1D.


Assuntos
Meios de Contraste , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/patologia , Animais , Feminino , Humanos , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/diagnóstico por imagem , Ilhotas Pancreáticas/patologia , Camundongos , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Ultrassonografia
13.
Immunity ; 52(5): 872-884.e5, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32433950

RESUMO

Some endocrine organs are frequent targets of autoimmune attack. Here, we addressed the origin of autoimmune disease from the viewpoint of feedback control. Endocrine tissues maintain mass through feedback loops that balance cell proliferation and removal according to hormone-driven regulatory signals. We hypothesized the existence of a dedicated mechanism that detects and removes mutant cells that missense the signal and therefore hyperproliferate and hypersecrete with potential to disrupt organismal homeostasis. In this mechanism, hypersecreting cells are preferentially eliminated by autoreactive T cells at the cost of a fragility to autoimmune disease. The "autoimmune surveillance of hypersecreting mutants" (ASHM) hypothesis predicts the presence of autoreactive T cells in healthy individuals and the nature of self-antigens as peptides from hormone secretion pathway. It explains why some tissues get prevalent autoimmune disease, whereas others do not and instead show prevalent mutant-expansion disease (e.g., hyperparathyroidism). The ASHM hypothesis is testable, and we discuss experimental follow-up.


Assuntos
Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Glândulas Endócrinas/imunologia , Sistema Endócrino/imunologia , Vigilância Imunológica/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Glândulas Endócrinas/citologia , Glândulas Endócrinas/metabolismo , Sistema Endócrino/citologia , Sistema Endócrino/metabolismo , Feminino , Humanos , Vigilância Imunológica/genética , Masculino , Mutação , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Adv Exp Med Biol ; 1221: 607-630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274728

RESUMO

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing beta cells in pancreatic islets. The degradation of the glycosaminoglycan heparan sulfate (HS) by the endo-ß-D-glycosidase heparanase plays a critical role in multiple stages of the disease process. Heparanase aids (i) migration of inflammatory leukocytes from the vasculature to the islets, (ii) intra-islet invasion by insulitis leukocytes, and (iii) selective destruction of beta cells. These disease stages are marked by the solubilization of HS in the subendothelial basement membrane (BM), HS breakdown in the peri-islet BM, and the degradation of HS inside beta cells, respectively. Significantly, healthy islet beta cells are enriched in highly sulfated HS which is essential for their viability, protection from damage by reactive oxygen species (ROS), beta cell function and differentiation. Consequently, mouse and human beta cells but not glucagon-producing alpha cells (which contain less-sulfated HS) are exquisitely vulnerable to heparanase-mediated damage. In vitro, the death of HS-depleted mouse and human beta cells can be prevented by HS replacement using highly sulfated HS mimetics or analogues. T1D progression in NOD mice and recent-onset T1D in humans correlate with increased expression of heparanase by circulating leukocytes of myeloid origin and heparanase-expressing insulitis leukocytes. Treatment of NOD mice with the heparanase inhibitor and HS replacer, PI-88, significantly reduced T1D incidence by 50%, impaired the development of insulitis and preserved beta cell HS. These outcomes identified heparanase as a novel destructive tool in T1D, distinct from the conventional cytotoxic and apoptosis-inducing mechanisms of autoreactive T cells. In contrast to exogenous catalytically active heparanase, endogenous heparanase may function in HS homeostasis, gene expression and insulin secretion in normal beta cells and immune gene expression in leukocytes. In established diabetes, the interplay between hyperglycemia, local inflammatory cells (e.g. macrophages) and heparanase contributes to secondary micro- and macro-vascular disease. We have identified dual activity heparanase inhibitors/HS replacers as a novel class of therapeutic for preventing T1D progression and potentially for mitigating secondary vascular disease that develops with long-term T1D.


Assuntos
Diabetes Mellitus Tipo 1/enzimologia , Glucuronidase/metabolismo , Animais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Glucuronidase/antagonistas & inibidores , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/patologia
15.
Invest Ophthalmol Vis Sci ; 61(3): 48, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32232351

RESUMO

Purpose: We hypothesized that longitudinal changes in corneal nerve morphology would differ between the central cornea and inferior whorl in relation to other measures of diabetic neuropathy. Methods: Thirty patients with diabetes (age: 54.08 ± 15.86, duration: 23.95 ± 14.2, HbA1c: 7.51 ± 1.37) and 19 age-matched healthy controls (age: 49.47 ± 13.25) underwent assessment of neuropathy disability score (NDS), vibration perception threshold (VPT), cold (CPT) and warm (WPT) perception thresholds, peroneal motor nerve conduction velocity (PMNCV), corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), inferior whorl length (IWL), and the average of CNFL and IWL (ANFL) at baseline and after 1 to 8 years. Results: In patients with diabetes, between baseline and follow-up, there was a significant reduction in CNBD (57.72 ± 30.08 vs. 44.04 ± 23.69; P = 0.02), CNFL (21.77 ± 5.19 vs. 15.65 ± 4.7; P < 0.0001), IWL (24.69 ± 8.67 vs. 14.23 ± 6.13; P < 0.0001), ANFL (23.26 ± 5.53 vs. 15.09 ± 4.48; P < 0.0001), and WPT (43.56 ± 4.43 vs. 40.78 ± 4.93; P = 0.01), and an increase in VPT (12.9 ± 8.96 vs. 13.78 ± 8.99; P = 0.02). There was no significant change in CNFD (27.12 ± 8.2 vs. 25.43 ± 7.11; P = 0.2), NDS (3.38 ± 3.35 vs. 2.61 ± 2.8; P = 0.08), CPT (17.7 ± 10.59 vs. 22.45 ± 9.23; P = 0.06), or PMNCV (42.4 ± 4.21 vs. 42.16 ± 6.3; P = 0.2). Conclusions: There is evidence of corneal nerve loss in patients with diabetes, particularly at the inferior whorl during follow-up.


Assuntos
Córnea/inervação , Neuropatias Diabéticas/diagnóstico , Fibras Nervosas/patologia , Doenças do Nervo Trigêmeo/patologia , Nervo Trigêmeo/patologia , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade
16.
Exp Mol Pathol ; 114: 104432, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32243891

RESUMO

BACKGROUND: Type 1 diabetes (T1DM) severely threatens human health, and the dysfunction of insulin-secreting ß cells in islets is related to the reduced PDX-1 expression. It has been reported that long non-coding RNA MALAT1 regulates ß cell function, while the potential mechanism is unclear. METHODS: Islets were isolated from non-obese diabetic (NOD) mice and wild type (WT) mice. Mouse islets and ß cell line (Min6) were stimulated by IL-1ß. The expression of MALAT1 was determined using real-time PCR, while the PDX-1 protein expression was determined using western blotting. ChIP-qPCR was carried out to determine the histone acetylation of the PDX-1 promoter. RESULTS: In NOD islets and IL-1ß-stimulated Min6 cells, the expression of MALAT1 was increased, while the mRNA and protein levels of PDX-1 were decreased at an age/time-dependent manner. Overexpressing MALAT1 suppressed the H3 histone acetylation of the PDX-1 promoter, inhibiting both mRNA and protein expressions of PDX-1. Knocking down MALAT1 restored the decrease of the histone acetylation of the PDX-1 promoter, as well as the PDX-1 expression, which was reduced by IL-1ß stimulation. Under high glucose stimulation, the overexpression of PDX-1 alone restored the insulin secretion which was inhibited by the simultaneous overexpression of MALAT1 and PDX-1. Under high glucose and IL-1ß stimulation, the simultaneous knockdown of MALAT1 and PDX-1 reduced the enhancement of the insulin secretion which was raised by knocking down MALAT1 alone. CONCLUSION: MALAT1 induces the dysfunction of ß cells via reducing the H3 histone acetylation of the PDX-1 promoter and subsequently inhibiting the expression of PDX-1, thus suppressing the insulin secretion.


Assuntos
Diabetes Mellitus Tipo 1/genética , Proteínas de Homeodomínio/genética , Células Secretoras de Insulina/metabolismo , RNA Longo não Codificante/genética , Transativadores/genética , Acetilação , Animais , Linhagem Celular , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Glucose/metabolismo , Histonas/genética , Humanos , Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD , Regiões Promotoras Genéticas/genética
17.
Arch Immunol Ther Exp (Warsz) ; 68(2): 13, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32297019

RESUMO

Interactions between the immune system and the pancreas are pivotal in understanding how and why ß cells' damage causes problems with pancreas functioning. Pancreatic islets are crucial in maintaining glucose homeostasis in organs, tissue and cells. Autoimmune aggression towards pancreatic islets, mainly ß cells, leads to type 1 diabetes-one of the most prevalent autoimmune disease in the world, being a worldwide risk to health of many people. In this review, we highlight the role of immune cells and its influence in the development of autoimmunity in Langerhans islets. Moreover, we discuss the impact of the immunological factors on future understanding possible recurrence of autoimmunity on 3D-bioprinted bionic pancreas.


Assuntos
Bioimpressão/tendências , Diabetes Mellitus Tipo 1/terapia , Sistema Imunitário/citologia , Pâncreas/imunologia , Células-Tronco/citologia , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Humanos , Células Secretoras de Insulina/citologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas , Pâncreas/patologia
18.
PLoS One ; 15(3): e0230627, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208453

RESUMO

The gene encoding eukaryotic initiation factor 5A (EIF5A) is found in diabetes-susceptibility loci in mouse and human. eIF5A is the only protein known to contain hypusine (hydroxyputrescine lysine), a polyamine-derived amino acid formed post-translationally in a reaction catalyzed by deoxyhypusine synthase (DHPS). Previous studies showed pharmacologic blockade of DHPS in type 1 diabetic NOD mice and type 2 diabetic db/db mice improved glucose tolerance and preserved beta cell mass, which suggests that hypusinated eIF5A (eIF5AHyp) may play a role in diabetes pathogenesis by direct action on the beta cells and/or altering the adaptive or innate immune responses. To translate these findings to human, we examined tissue from individuals with and without type 1 and type 2 diabetes to determine the expression of eIF5AHyp. We detected eIF5AHyp in beta cells, exocrine cells and immune cells; however, there was also unexpected enrichment of eIF5AHyp in pancreatic polypeptide-expressing PP cells. Interestingly, the presence of eIF5AHyp co-expressing PP cells was not enhanced with disease. These data identify new aspects of eIF5A biology and highlight the need to examine human tissue to understand disease.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Lisina/análogos & derivados , Pâncreas/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Baço/metabolismo , Adulto , Animais , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Células Secretoras de Polipeptídeo Pancreático/citologia , Células Secretoras de Polipeptídeo Pancreático/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Adulto Jovem
19.
PLoS One ; 15(3): e0230488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176740

RESUMO

Pregnant women with diabetes mellitus (DM) are at high risk for hypertensive disorder of pregnancy (HDP). Women with poor control DM sometimes have heavy-for-dates infants. However, women with HDP sometimes have light-for-dates infants. We aim to clarify the relationship between glycemic control and fetal growth in women with DM and/or subsequent HDP. Of 7893 women gave singleton birth at or after 22 gestational weeks, we enrolled 154 women with type 1 DM (T1DM) or type 2 DM (T2DM) whose infants did not have fetal abnormalities. Among women with T1DM or T2DM, characteristics of the three groups (with HDP, without HDP, and with chronic hypertension [CH]) were compared. No women with T1DM had CH, but 19 (17.4%) of 109 with T2DM did. HDP incidence was similar between women with T1DM (22.2%) and T2DM without CH (16.7%). Among women with T1DM, the incidences of fetal growth restriction (FGR) with and without HDP were similar. However, among women with T2DM without CH, this incidence was significantly higher among those with HDP (33.3%) than among those without HDP (5.3%), was significantly more common with HbA1c levels at first trimester ≥ 7.2% (33.3%) than with those < 7.2% (5.6%), and significantly more numerous without pre-pregnancy therapies for DM (23.3%) than with them (3.3%). Among women with T2DM and HDP, those with FGR had smaller placenta SDs and higher insulin dosages at delivery than those without light-for-dates. In multivariate analysis, the presence of diabetic nephropathy was a predictor of T1DM and HDP (P = 0.0105), whereas HbA1c levels ≥ 7.2% before pregnancy was a predictor of T2DM and HDP (P = 0.0009). Insulin dosage ≥ 50U/day at delivery (P = 0.0297) and the presence of HDP (P = 0.0116) independently predicted T2DM, HDP, and FGR development. Insufficient pre-pregnancy treatment of DM increased the risk of HDP.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Retardo do Crescimento Fetal , Insulina/administração & dosagem , Pré-Eclâmpsia , Gravidez em Diabéticas , Adulto , Doença Crônica , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/patologia , Humanos , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/patologia , Gravidez , Gravidez em Diabéticas/sangue , Gravidez em Diabéticas/tratamento farmacológico , Gravidez em Diabéticas/epidemiologia , Gravidez em Diabéticas/patologia , Estudos Retrospectivos , Fatores de Risco
20.
BMC Med Genet ; 21(1): 61, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32216767

RESUMO

BACKGROUND: Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene. METHODS: Genetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry. RESULTS: The first cases in Hungary, - two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11- intron 11-12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver. CONCLUSIONS: The novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.


Assuntos
Diabetes Mellitus Tipo 1/genética , Epífises/anormalidades , Mutação INDEL , Osteocondrodisplasias/genética , Sítios de Splice de RNA/genética , eIF-2 Quinase/genética , Pré-Escolar , Consanguinidade , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/patologia , Estresse do Retículo Endoplasmático/genética , Epífises/patologia , Evolução Fatal , Feminino , Mutação da Fase de Leitura , Humanos , Hungria , Lactente , Falência Hepática/complicações , Falência Hepática/genética , Falência Hepática/patologia , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Linhagem , Irmãos , Viroses/complicações , Viroses/patologia
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