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1.
Environ Pollut ; 256: 113342, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31676093

RESUMO

PM2.5 exposure aggravates type 2 diabetes, in which inflammatory factors play an important role. In this study, we aimed to explore the mechanisms responsible for aggravating diabetes after PM2.5 exposure, and study the roles of inflammatory factors in insulin-resistant type 2 diabetes. Our study indicated that short-time PM2.5 exposure enhances insulin resistance in type 2 diabetic rats and significantly raises inflammatory factors, including IL-6, TNF-α, and MCP-1, in lungs. However, we found that of these inflammatory factors only IL-6 levels are elevated in blood, liver, adipose tissue, and macrophages, but not in skeletal muscle. IL-6 induced activation of the STAT3/SOCS3 pathway in liver, but not other downstream pathways including STAT1, ERK1/2, and PI3K. Both STAT3 inhibition and IL-6 neutralization effectively alleviated the disorders of glucose metabolism after PM2.5 exposure. Taken together, this suggests that the systemic increase in IL-6 may play an important role in the deterioration of the type 2 diabetes via IL-6/STAT3/SOCS3 pathway in liver after short-time exposure to PM2.5. Besides, we unexpectedly found a stronger resistance to the PM2.5 exposure-induced increase in IL-6 in skeleton muscle than those of many other tissues.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Interleucina-6/sangue , Material Particulado/toxicidade , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/imunologia , Material Particulado/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
2.
Life Sci ; 241: 117152, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837333

RESUMO

GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase 4 inhibitors (DPP-4i) are two classes of antidiabetic agents used in the management of diabetes based on incretin hormones. There is emerging evidence that they have anti-inflammatory effects. Since most long-term complications of diabetes have a background of chronic inflammation, these agents may be beneficial against diabetic complications not only due to their hypoglycemic potential but also via their anti-inflammatory effects. However, the exact molecular mechanisms by which GLP-1RAs and DPP-4i exert their anti-inflammatory effects are not clearly understood. In this review, we discuss the potential molecular pathways by which these incretin-based therapies exert their anti-inflammatory effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Inflamação/prevenção & controle , Diabetes Mellitus Tipo 2/imunologia , Humanos
3.
PLoS Pathog ; 15(12): e1008140, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31809521

RESUMO

Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice. Similarly, serum IL-22 levels were significantly lower in tuberculosis (TB) patients with T2DM than in TB patients without T2DM. ILC3s were an important source of IL-22 in mice infected with Mtb, and recombinant IL-22 treatment or adoptive transfer of ILC3s prolonged the survival of Mtb-infected T2DM mice. Recombinant IL-22 treatment reduced serum insulin levels and improved lipid metabolism. Recombinant IL-22 treatment or ILC3 transfer prevented neutrophil accumulation near alveoli, inhibited neutrophil elastase 2 (ELA2) production and prevented epithelial cell damage, identifying a novel mechanism for IL-22 and ILC3-mediated inhibition of inflammation in T2DM mice infected with an intracellular pathogen. Our findings suggest that the IL-22 pathway may be a novel target for therapeutic intervention in T2DM patients with active TB disease.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/microbiologia , Interleucinas/imunologia , Linfócitos/imunologia , Tuberculose/imunologia , Animais , Diabetes Mellitus Tipo 2/complicações , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Tuberculose/complicações
5.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(10): 966-971, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31630495

RESUMO

Objective: To analyze the clinicopathological features of type 2 diabetes mellitus complicated with colorectal cancer (DCRC). Methods: A case-control study was conducted. Inclusion criteria: (1) hospitalized patients receiving fibrocolonoscopy; (2) adenocarcinoma and mucinous adenocarcinoma diagnosed by pathology; (3) with preoperative cTNM clinical staging; (4) colorectal cancer patients undergoing surgical treatment; (5) with postoperative pTNM staging; (6) no smoking or drinking habits. Exclusion criteria: (1) familial adenomatous polyposis (FAP); (2) Lynch syndrome; (3) carcinoma of anal canal and perianal carcinoma; (4) multiple primary cancer; (5) with serious cardiocerebrovascular diseases or multiple organ failure. Clinicopathlogical data of 32 DCRC patients who were diagnosed and treated in Peking University Shougang Hospital from December 2017 to December 2018 were retrospectively collected and analyzed. Forty nondiabetic colorectal cancer (CRC) patients during the same period were selected as control group according to the sex ratio and the age difference less than 5 years. Student's t test and χ(2) test were used to compare the difference between the two groups in baseline clinicopathological data, clinical test results, tumor markers and infiltration status of T cells in tumor immune microenvironment. Results: Among 32 DCRC patients, 24 were males and 8 were females with a mean age of (63.0±1.7) years; among 40 CRC patients, 30 were males and 10 were females with a mean age of (60.5±1.6) years. The duration of diabetes mellitus in DCRC patients (from the diagnosis of diabetes mellitus to the diagnosis of colorectal cancer) was (9.2±1.3) years. The body mass index (BMI) of DCRC group was significantly higher than that of CRC group [(24.8±0.6) kg/m(2) vs. (23.2±0.4) kg/m(2), t=2.372, P=0.020]. There were no significant differences in other baseline data (sex, age, primary site of tumor, R0 resection rate, pathological stage, pathological type, differentiation degree of tumor, preoperative intestinal obstruction) between the two groups (all P>0.05). Serum triglyceride level in DCRC group was higher than that in CRC group [(2.1±0.2) mmol/L vs. (1.5±0.1) mmol/L, t=3.085, P=0.003], while hemoglobin [(120.3±5.2) g/L vs. (132.7±2.8) g/L, t=-2.224, P=0.029], anti- thrombin III [(94.2±3.7)% vs. (103.5±2.4)%, t=-2.197, P=0.031], and red blood cell count [(4.2±0.1)×10(12)/L vs. (4.5±0.1)×10(12)L, t=-2.055, P=0.044] were all lower than those in CRC group. The preoperative carcinoembryonic antigen (CEA) level in DCRC group was higher than that in CRC group [(50.3±21.8) µg/L vs. (5.6±1.0) µg/L, t=2.339, P=0.022]. There were no significant differences in preoperative levels of other four tumor molecular markers (CA199, CA242, CA724 and CA125) between the two groups (all P>0.05). The expression of Foxp3 [specific markers of CD4+, CD25+ regulatory T cells (Treg)] in DCRC group was higher than that in CRC group [(82.7±6.2) cell/HPF vs. (62.6±4.9) cell/HPF, t=2.586, P=0.012]. There were no significant differences in the infiltration of CD4, CD8, PD-1 and PD-L1 positive cells between two groups (all P>0.05). Conclusions: The average diabetic history of DCRC patients is nearly 10 years. They have higher BMI and serum CEA level, and more Treg cell infiltration in the tumor. Close attention should be paid to these patients in clinical practice.


Assuntos
Neoplasias Colorretais/cirurgia , Diabetes Mellitus Tipo 2/diagnóstico , Adenocarcinoma/sangue , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Idoso , Índice de Massa Corporal , Antígeno Carcinoembrionário/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/complicações , Neoplasias Colorretais/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/fisiologia
6.
Trans Am Clin Climatol Assoc ; 130: 145-155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31516178

RESUMO

Ketosis-prone diabetes (KPD) is a heterogeneous condition characterized by patients who present with diabetic ketoacidosis but lack the phenotype of autoimmune type 1 diabetes. Here I review progress in our understanding of KPD and its place in the expanding universe of "atypical diabetes." I focus on investigations of our collaborative research group at Baylor College of Medicine and the University of Washington using a longitudinally followed, heterogeneous, multiethnic cohort of KPD patients. We have identified clinically and pathophysiologically distinct KPD subgroups, separable by the presence or absence of islet autoimmunity and the presence or absence of beta cell functional reserve. The resulting "Aß" classification of KPD accurately predicts long-term glycemic control and insulin dependence. I describe key characteristics of the KPD subgroups, their natural histories, and our investigations into their immunologic, genetic, and metabolic etiologies. These studies serve as a paradigm for the investigation of atypical forms of diabetes.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus/classificação , Cetoacidose Diabética/metabolismo , Células Secretoras de Insulina/metabolismo , Afro-Americanos , Americanos Asiáticos , Autoimunidade/imunologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Cetoacidose Diabética/imunologia , Grupo com Ancestrais do Continente Europeu , Hispano-Americanos , Humanos , Secreção de Insulina , Síndrome
7.
PLoS Med ; 16(9): e1002901, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513665

RESUMO

BACKGROUND: The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis). METHODS AND FINDINGS: This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (ß: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (ß: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (ß: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (ß: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. CONCLUSIONS: In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. TRIAL REGISTRATION: The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , /uso terapêutico , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/imunologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Itália , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-1/imunologia , Fatores de Tempo , Resultado do Tratamento , /efeitos adversos
8.
Mol Med Rep ; 20(4): 3951-3958, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485663

RESUMO

Polygonatum sibiricum polysaccharide (PSP) has been shown to alleviate hyperglycemia and reduce oxidative stress to delay the progression of diabetic retinopathy and cataracts. However, its role and underlying mechanisms in regulating type 2 diabetes mellitus (T2DM) remain unclear. Nuclear factor erythroid 2­related factor 2 (Nrf2) activation plays a protective role in T2DM. The present study focused on the effect of PSP on inflammatory cytokine secretion and Nrf2 expression in the adipocytes of T2DM patients. In this study, high­glucose­ and high­insulin­induced 3T3­L1 adipocytes were used to mimic insulin­resistant (IR)­3T3­L1 adipocytes. Furthermore, the effect and underlying mechanisms of PSP on inflammation and glucose uptake in IR­3T3­L1 adipocytes were investigated. The present study found that proliferation after 50, 100 and 250 µg/ml PSP treatment had no significant change in normal 3T3­L1 adipocytes. A total of 50, 100 and 250 µg/ml of PSP also alleviated IL­1ß, IL­6, and TNF­α levels and promoted proliferation, glucose uptake, and glucose transporter 4 expression in IR­3T3­L1 adipocytes. Furthermore, 50, 100 and 250 µg/ml PSP promoted Nrf2 and HO­1 expression. However, silencing Nrf2 expression reversed the effect of 100 µg/ml PSP in IR­3T3­L1 adipocytes. In conclusion, these results suggest that PSP alleviates inflammatory cytokines and promotes glucose uptake in IR­3T3­L1 adipocytes by promoting Nrf2 expression. PSP may be a potential therapeutic agent for T2DM treatment by promoting Nrf2 expression.


Assuntos
Adipócitos/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Citocinas/imunologia , Fator 2 Relacionado a NF-E2/genética , Polissacarídeos/farmacologia , Células 3T3-L1 , Adipócitos/imunologia , Animais , Anti-Inflamatórios/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/imunologia , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/imunologia , Camundongos , Polygonatum/química , Polissacarídeos/química , Regulação para Cima/efeitos dos fármacos
9.
Biomed Pharmacother ; 118: 109131, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545226

RESUMO

Berberine and metformin, both established pharmaceutical agents with herbal origins, have incidental beneficial effects on multiple diseases, including diabetes. These effects have been speculated to occur via the gut microbiome. In this study, we administered either berberine or metformin to db/db mice and investigated changes in body weight, food intake, and blood glucose levels. Fresh stool samples were analyzed using 16 s rDNA high-throughput sequencing to evaluate the gut microbiome. Short-chain fatty acids (SCFA) in the stool were quantified using gas chromatography. The expression of NF-κB signaling pathway and tight junction (ZO1 and occludin) proteins in the intestinal epithelium was determined using qPCR and western blotting. The intestinal barrier structure was examined using transmission electron microscopy and serum lipopolysaccharide (LPS) was measured using a commercial kit. Both berberine and metformin reduced food intake, body weight, and blood glucose and HbA1c levels. Both treatments effectively restored the intestinal SCFA content, reduced the level of serum LPS, relieved intestinal inflammation, and repaired intestinal barrier structure. Intervention with metformin or berberine modified the gut microbiome in db/db mice, increasing the number of SCFA-producing bacteria (e.g., Butyricimonas, Coprococcus, Ruminococcus) and reducing opportunistic pathogens (e.g., Prevotella, Proteus). An increased abundance of other probiotics including Lactobacillus and Akkermansia was also observed. Berberine and metformin can modulate the composition of the gut microbiome and reduce body weight, blood glucose levels, and intestinal inflammation in db/db mice, which demonstrates their effectiveness in the reduction of diabetic complications in this model.


Assuntos
Berberina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gastroenterite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/microbiologia , Ingestão de Alimentos/efeitos dos fármacos , Gastroenterite/microbiologia , Hemoglobina A Glicada/análise , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Obesidade/imunologia , Obesidade/microbiologia , Obesidade/prevenção & controle , Permeabilidade
10.
BMC Oral Health ; 19(1): 175, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387562

RESUMO

BACKGROUND: Oral health is related to general health and one of the most prevalent chronic diseases is diabetes mellitus. Diabetes can have adverse effects on oral health and vice versa. Saliva analysis can be used as a non-invasive method to obtain information about diseases status like diabetes. The aim of present study was to evaluate the salivary immunoglobulin-A (s-IgA) and salivary amylase levels and their associations with oral-dental manifestations in patients with controlled and non-controlled type 2 diabetes. METHODS: This case-control study was carried out on 90 subjects who referred to the Diabetes Center of Shahid Bahonar Hospital, Kerman University of Medical Sciences, Kerman, Iran. Participants were divided into three groups: 1) uncontrolled diabetic patients (n = 30); 2) controlled diabetic patients (n = 30); and 3) healthy individuals (n = 30). Unstimulated salivary levels of I-A and amylase were measured. All participants underwent a dental and periodontal examination to explore the oral and dental manifestations. T-test, chi-square and ANOVA tests were used for data analysis in SPSS 18. RESULTS: Significant higher level of s-IgA was found in uncontrolled diabetic patients compared to controlled diabetic (P ≤ 0.0001) and the control group (P = 0.004). Moreover, the mean levels of s-amylase in uncontrolled patients was significantly higher compared to controlled diabetic (P = 0.01) and the control group (P ≤ 0.0001). Uncontrolled diabetic patients with oral candidiasis, erythematous candidiasis, abscesses, or xerostomia had higher s-IgA levels compared to the controlled diabetic participants. Moreover, uncontrolled diabetic patients with oral candidiasis or erythematous candidiasis showed a significant higher levels of s-amylase compared to controlled diabetic patients. Also, significant positive correlations were found between s-IgA and DMFT and s-IgA and PDI (r = 0.444, P = 0.014 and r = 0.386, P = 0.035, respectively). CONCLUSION: In conclusion, higher s-amylase and s-IgA concentrations may reflect oral-dental manifestations in T2DM. Moreover, the current findings suggest that s-amylase and s-IgA may serve as a complementary and alternative fluid in screening for diabetes mellitus.


Assuntos
Amilases/análise , Diabetes Mellitus Tipo 2/imunologia , Imunoglobulina A/análise , Saliva/enzimologia , Saliva/imunologia , Amilases/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Irã (Geográfico)
11.
Arkh Patol ; 81(4): 78-82, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31407723

RESUMO

The study of the sociomedical problems of diabetes mellitus led to the discovery of latent autoimmune diabetes in adults (LADA), a special form of the disease. The slow onset of the disease, the clinical signs of type 2 diabetes mellitus concurrent with the autoantibody pancreatic ß-cell destruction mechanism that is characteristic of type 1 diabetes. Genetic factors play an important role in the genesis of the disease. Insulitis concurrent with intact or hypertrophic islets of the gland originally develops morphologically. Subsequently, the phenomena of islet atrophy and sclerosis are progressive. The disease is typical for young people (generally those aged 25-35 years) with normal body mass index, low blood C-peptide levels, with antibodies against ß-cells, primarily to glutamate decarboxylase, being detected. Insulin preparations should be used to treat these patients.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Adulto , Autoanticorpos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/imunologia , Glutamato Descarboxilase , Humanos , Diabetes Autoimune Latente em Adultos/diagnóstico , Diabetes Autoimune Latente em Adultos/imunologia , Adulto Jovem
12.
Acta Diabetol ; 56(11): 1225-1230, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31367990

RESUMO

AIMS: To investigate the possibility of identifying a subtype of latent autoimmune diabetes in adults (LADA), T-LADA (T cell responses-positive and autoantibody-negative) from patients with phenotypic type 2 diabetes (T2D) by enzyme-linked immunospot (ELISPOT). METHODS: Eighty-two patients with phenotypic T2D were studied. Autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 and zinc transporter 8 were measured by radioligand assay. Thirty-nine Ab+ and 43 Ab- patients with phenotypic T2D were enrolled for T cell assay of responses to GAD65 and C-peptide antigen by ELISPOT. RESULTS: (1) Eleven of 43 Ab- participants with phenotypic T2D were demonstrated interferon (IFN)-γ secreting T cells by ELISPOT, while 13 of 39 Ab+ patients with phenotypic T2D were positive for T cells responses to islet antigens. (2) The onset ages of T cell+ people with phenotypic T2D were younger than that of T cell- individuals (42.7 ± 9.3 vs. 48.2 ± 10.2 years, P = 0.025). Moreover, T cell+ patients with T2D displayed a significantly lower fasting C-peptide (FCP) compared with T cell- participants [0.28 (0.02-0.84) vs. 0.42 (0.05-1.26) nmol/L, P = 0.013]. (3) Ab-T+ group had a significantly lower FCP compared with Ab-T- group [0.31 (0.13-0.84) vs. 0.51 (0.07-1.26) nmol/L, P = 0.023]. CONCLUSIONS: By measuring T cell responses to islet antigens in patients with phenotypic T2D, we identified a specific subtype of LADA who may be associated with worse basal ß-cell function than classic T2D (Ab-T-).


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Diabetes Autoimune Latente em Adultos/imunologia , Fenótipo , Linfócitos T/imunologia , Adulto , Autoanticorpos/imunologia , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/sangue , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Diabetes Autoimune Latente em Adultos/sangue , Diabetes Autoimune Latente em Adultos/classificação , Masculino , Pessoa de Meia-Idade , Transportador 8 de Zinco/imunologia
13.
Acta Diabetol ; 56(12): 1239-1245, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31423559

RESUMO

Immune checkpoint inhibitors (CPI) are increasingly being used in oncology, and many autoimmune side effects have been described. Diabetes mellitus (DM) has been reported in approximately 1% of subjects treated with programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors, alone or in association with CTLA-4 inhibitors. In the present mini-review, we aimed to describe different clinical pictures and pathophysiology associated with these forms of diabetes. Data on CPI-related DM was gathered from the largest case series in the literature and from our centre dedicated to immunotherapy complications (ImmuCare-Hospices Civils de Lyon). Most cases are acute autoimmune insulin-dependent diabetes which are similar to fulminant diabetes (extremely acute onset with concomitant near-normal HbA1c levels). Other cases, however, have a phenotype close to type 2 diabetes or appear as a decompensation of previously known type 2 diabetes. The occurrence of diabetes can also be a complication of autoimmune pancreatitis induced by CPI use. Finally, two cases of diabetes in a context of autoimmune lipoatrophy have recently been described. Regarding the wide variety of CPI-induced diabetes, the discovery of a glucose disorder under CPI should motivate specialised care for aetiological diagnosis and appropriate treatment.


Assuntos
Pontos de Checagem do Ciclo Celular , Diabetes Mellitus Tipo 2/induzido quimicamente , Imunoterapia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Diabetes Mellitus Lipoatrófica/induzido quimicamente , Diabetes Mellitus Lipoatrófica/epidemiologia , Diabetes Mellitus Lipoatrófica/imunologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/imunologia , Humanos , Inibidores de Proteínas Quinases/uso terapêutico
14.
Mol Immunol ; 114: 270-277, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400630

RESUMO

Accumulating evidence suggests a role for the complement system in the pathogenesis of diabetes and the vascular complications that characterise this condition. Complement proteins contribute to the development of type 1 diabetes (T1D) by enhancing the underlying organ-specific autoimmune processes. Complement upregulation and activation is also an important feature of insulin resistance and the development of type 2 diabetes (T2D). Moreover, animal and human studies indicate that complement proteins are involved in the pathogenic mechanisms leading to diabetic microvascular and macrovascular complications. The adverse vascular effects of complement appear to be related to enhancement of the inflammatory process and the predisposition to a thrombotic environment, eventually leading to vascular occlusion. Complement proteins have been considered as therapeutic targets to prevent or treat vascular disease but studies have been mainly conducted in animal models, while human work has been both limited and inconclusive so far. Further studies are needed to understand the potential role of complement proteins as therapeutic targets for reversal of the pathological processes leading to T1D and T2D and for the prevention/treatment of diabetic vascular complications.


Assuntos
Proteínas do Sistema Complemento/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Animais , Humanos , Resistência à Insulina/imunologia , Doenças Vasculares/imunologia
15.
Folia Med (Plovdiv) ; 61(2): 231-239, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301656

RESUMO

BACKGROUND AND AIMS: An important factor in the development of vascular wall lesions is the degradation of the major protein of connective tissue - type IV collagen. Type IV collagen peptides (CIVDP) derived from this degradation are present in the circulation and are a stimulus for production of anti-collagen type IV antibodies (ACIVAbs) IgM, IgG and IgA. The aim of this study was to find a possible association between ACIVAbs, lipid indices and the development of microvascular complications. MATERIALS AND METHODS: Sera of 93 patients (mean age 61.4±11.3 yrs, diabetes duration 9.88±3.12 yrs; hypertension duration 9.28±4.98) with type 2 diabetes mellitus (T2DM) and arterial hypertension (AH) were investigated. ACIVAbs was determined using ELISA and then compared to serum ACIVAbs in 42 age- and sex-matched controls. Diabetics were divided into two groups according to presence (group 1, n=67) or absence (group 2, n=26) of microangiopathy. Lipid profile and lipid indices (log TG/HDL, LDL/HDL, TC/HDL and TG/HDL) were examined too. RESULTS: Patients with T2DM and AH showed statistically significant higher levels of serum ACIVAbs IgG than healthy controls [0.298 (0.237÷0.381) vs 0.210 (0.149÷0.262), KW=14.01, p<0.0001]. Group 1 had statistically significant higher levels of ACIVAbs IgG than patients without microangiopathy [0.323 (0.243÷0.391) vs 0.241 (0.207÷0.291), KW=7.66, p=0.006] and healthy controls [0.210 (0.149÷0.262), KW=17.52, p<0.0001). ACIVAbs IgG showed correlation with duration of diabetes (r=0.49, p=0.01), retinopathy (r=-0.20, p=0.04) and BMI (r=-0.24, p=0.05), HbA1c (r=0.21, p=0.04), SBP (r=0.16, p=0.05). ACIVAbs IgG correlated with log TG/HDL (r=0.21, p=0.01), LDL/HDL (r=0.19, p=0.02) TC/HDL (r=0.16, p=0.05) and with TG/HDL (r=0.15, p=0.05). CONCLUSION: Our study shows relationship between elevation of ACIVAbs IgG, high lipid indices and development of microvascular complications in patients with type 2 diabetes mellitus and arterial hypertension.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Neuropatias Diabéticas/metabolismo , Retinopatia Diabética/metabolismo , Hipertensão/metabolismo , Idoso , Autoanticorpos/imunologia , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Colágeno Tipo IV/imunologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/metabolismo , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/imunologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/imunologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/imunologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Triglicerídeos/metabolismo
16.
Nat Commun ; 10(1): 3254, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332184

RESUMO

Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood. Group 1 innate lymphoid cells (ILC1s) are effectors of innate immunity and enriched in inflamed tissues. Here we show that the number of adipose ILC1s increases in obese T2D patients and correlates with glycemic parameters and with the number of ILC1s in the blood; circulating ILC1 numbers decrease as a result of metabolic improvements after bariatric surgery. In vitro co-culture experiments show that human adipose ILC1s promote adipose fibrogenesis and CD11c+ macrophage activation. Reconstruction of the adipose ILC1 population in Prkdc-/-IL2rg-/- mice by adoptive transfer drives adipose fibrogenesis through activation of TGFß1 signaling; however, transfer of Ifng-/- ILC1s has no effect on adipose fibrogenesis. Furthermore, inhibiting adipose accumulation of ILC1s using IL-12 neutralizing antibodies attenuates adipose tissue fibrosis and improves glycemic tolerance. Our data present insights into the mechanisms of local immune disturbances in obesity-related T2D.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Imunidade Inata , Linfócitos/metabolismo , Obesidade/metabolismo , Adipócitos/citologia , Adipócitos/imunologia , Adipócitos/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Cirurgia Bariátrica , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Fibrose , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Ativação de Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/imunologia
17.
Inflamm Res ; 68(10): 857-866, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31236602

RESUMO

OBJECTIVE: The probably effects of sitagliptin and vitamin D3 (VitD3) on proliferation capacity and cytokines production were investigated in type 2 diabetes mellitus (T2DM) in vitro. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 35 patients with T2DM and 26 healthy controls (HCs). CFSE-labeled PBMCs stimulated with phytohamagglutinin (PHA, 5 µg/mL) in the presence/absence of sitagliptin (200 mg/mL) with/without VitD3 (10-8 M) for 4 days. The proliferation of CD4+ T helper cells and non-CD4+ cells was analyzed using flow cytometry. The supernatant levels of IFN-γ, IL-17, IL-4, TGB-ß and IL-37 were detected using ELISA. RESULTS: The proliferation of CD4+ T cells in response to PHA was higher in T2DM patients compared with HCs. The production of IFN-γ and IL-17 in PHA-stimulated cultures was higher, and the levels of IL-4 and IL-37 were lower in T2DM patients compared to HCs. The addition of sitagliptin or VitD3 to the cultures decreased the CD4+ T cells and non-CD4+ cells proliferation in patients and HCs. Sitagliptin with VitD3 was more effective in suppression of proliferation, decreasing of IL-17 and enhancing of IL-37 production. CONCLUSION: Sitagliptin plus VitD3 effectively reduces the proliferative T cells response and modulates pro-inflammatory/anti-inflammatory cytokines production.


Assuntos
Colecalciferol/farmacologia , Diabetes Mellitus Tipo 2/imunologia , Hipoglicemiantes/farmacologia , Fosfato de Sitagliptina/farmacologia , Linfócitos T/efeitos dos fármacos , Vitaminas/farmacologia , Adulto , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia
18.
Mediators Inflamm ; 2019: 5481725, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210749

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells contributing to regulation of lymphocyte immune response. DCs are divided into two subtypes: CD11c-positive conventional or myeloid (cDCs) and CD123-positive plasmacytoid (pDCs) DCs. The aim of the study was to assess DCs (HLA-DR+ lineage-) and their subtypes by flow cytometry in peripheral blood and subcutaneous (SAT) and epicardial (EAT) adipose tissue in subjects with (T2DM, n = 12) and without (non-T2DM, n = 17) type 2 diabetes mellitus undergoing elective cardiac surgery. Subjects with T2DM had higher fasting glycemia (8.6 ± 0.7 vs. 5.8 ± 0.2 mmol/l, p < 0.001) and glycated hemoglobin (52.0 ± 3.4 vs. 36.9 ± 1.0 mmol/mol, p < 0.001) and tended to have more pronounced inflammation (hsCRP: 9.8 ± 3.1 vs. 5.1 ± 1.9 mg/ml, p = 0.177) compared with subjects without T2DM. T2DM was associated with reduced total DCs in SAT (1.57 ± 0.65 vs. 4.45 ± 1.56% for T2DM vs. non-T2DM, p = 0.041) with a similar, albeit insignificant, trend in EAT (0.996 ± 0.33 vs. 2.46 ± 0.78% for T2DM vs. non-T2DM, p = 0.171). When analyzing DC subsets, no difference in cDCs was seen between any of the studied groups or adipose tissue pools. In contrast, pDCs were increased in both SAT (13.5 ± 2.0 vs. 4.6 ± 1.9% of DC cells, p = 0.005) and EAT (29.1 ± 8.7 vs. 8.4 ± 2.4% of DC, p = 0.045) of T2DM relative to non-T2DM subjects as well as in EAT of the T2DM group compared with corresponding SAT (29.1 ± 8.7 vs. 13.5 ± 2.0% of DC, p = 0.020). Neither obesity nor coronary artery disease (CAD) significantly influenced the number of total, cDC, or pDC in SAT or EAT according to multiple regression analysis. In summary, T2DM decreased the amount of total dendritic cells in subcutaneous adipose tissue and increased plasmacytoid dendritic cells in subcutaneous and even more in epicardial adipose tissue. These findings suggest a potential role of pDCs in the development of T2DM-associated adipose tissue low-grade inflammation.


Assuntos
Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/metabolismo , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Tecido Adiposo/imunologia , Idoso , Doença da Artéria Coronariana/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/imunologia , Pericárdio/imunologia , Pericárdio/metabolismo , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo
19.
Afr Health Sci ; 19(1): 1602-1606, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31148989

RESUMO

Background: Type 2 diabetes mellitus is associated with chronic low grade inflammation. One of the novel inflammatory markers is hemogram derived neutrophil to lymphocyte ratio (NLR). Objective: We aimed to compare NLR levels of diabetic subjects and healthy controls and to observe possible correlation between NLR and HbA1c. Methods: Medical data of type 2 diabetic subjects admitted to out-patient clinics of our institution between April to July in 2017 were obtained from database and retrospectively analyzed. Control group was chosen from healthy subjects who visited our institution for a routine check-up. Anthropometric measures, laboratory data, including, HbA1c, NLR were recorded. Results: Median NLR of the type 2 DM group 2.44 (1.9) was significantly elevated when compared to healthy controls (1.5 (0.9), (p<0.001). In addition, a Pearson's correlation test revealed that NLR was strongly correlated with age (r=0.26, p=0.008), fasting plasma glucose (r=0.38, p<0.001), and HbA1c (r=0.49, p<0.001). Conclusion: Elevated NLR in otherwise healthy subjects may be indicative of underlying impaired glucose metabolism and moreover, NLR should be used as a marker of diabetic control level in addition to HbA1c in type 2 diabetic subjects.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Intolerância à Glucose/imunologia , Inflamação/sangue , Linfócitos/citologia , Neutrófilos/citologia , Adolescente , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estudos Retrospectivos
20.
Mol Immunol ; 112: 322-329, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31238287

RESUMO

OBJECTIVE: The morbidity and prevalence of type 2 diabetes mellitus (DM) are increasing in the elderly population. Interleukin 37 (IL-37) play important roles in anti-inflammatory and anti-bacteria immune responses, but its role in the development of type 2 DM in the elderly is unclear. Therefore, we investigated whether IL-37 is associated with type 2 DM in the elderly and the underlying mechanism. METHODS: Hospitalized patients (aged 65-95 years) with recently diagnosed type 2 diabetes mellitus were studied retrospectively and compared with healthy subjects without glucose metabolism abnormalities. A diabetic mouse model was established by feeding ob/ob mice (C57BL/6) a high-fat, carbohydrate-free diet. Plasma glucose and insulin levels were determined by glucose oxidase assay and radioimmunoassay, respectively. The IL-37 expression level was determined by real-time PCR, western blot and ELISA (Enzyme-linked immunoassay). RESULTS: Statistic analysis showed that the IL-37 level was significantly associated with type 2 DM and insulin resistance in the elderly. The patients were then divided into insulin therapy sensitive and resistant group according to their response to insulin therapy. Data showed that the IL-37 was highly expressed in the insulin therapy sensitive group. And this was related to the less severe gut microbiota dysbiosis. In the mice model, overexpressing the IL-37 could suppress the gut microbiota dysbiosis and also the diabetes development. CONCLUSION: Thus our results showed that higher IL-37 was associated with increased insulin sensitive in elderly type 2 DM patients through suppressing the gut microbiota dysbiosis.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Interleucina-1/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Feminino , Células HEK293 , Humanos , Resistência à Insulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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