RESUMO
AIMS/HYPOTHESIS: The proinflammatory cytokines IFN-α, IFN-γ, IL-1ß and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown. METHODS: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes. RESULTS: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1ß and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells. CONCLUSIONS/INTERPRETATION: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.
Assuntos
Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Humanos , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Interferons/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Interferon gama/metabolismo , Ilhotas Pancreáticas/metabolismoRESUMO
AIM: To assess how long participants with type 2 diabetes spent with HbA1c less than 7.0% and how likely they were to maintain this target with oral semaglutide 7 mg versus sitagliptin 100 mg or oral semaglutide 14 mg versus empagliflozin 25 mg, sitagliptin 100 mg or subcutaneous liraglutide 1.8 mg. MATERIALS AND METHODS: Analyses used on-treatment data without rescue medication for all randomized participants (semaglutide [approved maintenance doses], n = 1880; comparators [not including placebo], n = 1412). Duration of time with HbA1c less than 7.0% was calculated using an HbA1c time curve. A binary endpoint of achieving HbA1c less than 7.0% at weeks 26 (week 24 for PIONEER 7) and 52 of each trial (and week 78 for PIONEER 3) was analysed. RESULTS: Mean duration of time with HbA1c less than 7.0% was greater with oral semaglutide 7 mg versus sitagliptin in PIONEER 3 (27 vs. 22 weeks) and with oral semaglutide 14 mg versus empagliflozin and sitagliptin (27-34 vs. 19 vs. 22 weeks, respectively), and similar versus subcutaneous liraglutide. A greater proportion of participants achieved and maintained HbA1c less than 7.0% for more than 75% of the trial with oral semaglutide 14 mg versus oral comparators. The odds of achieving HbA1c less than 7.0% at weeks 24/26 and 52/78 were significantly greater with oral semaglutide 14 mg versus oral comparators or subcutaneous liraglutide, and with oral semaglutide 7 mg versus sitagliptin. CONCLUSIONS: Oral semaglutide 7 and 14 mg resulted in greater time spent with HbA1c less than 7.0%, and a greater likelihood of achieving and maintaining HbA1c less than 7.0% versus oral comparators.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hemoglobinas Glicadas , Liraglutida/efeitos adversos , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Fosfato de Sitagliptina/efeitos adversosRESUMO
AIM: To evaluate the cross-sectional association between severe periodontitis and diabetes mellitus (DM), in a representative sample of Spanish population. MATERIALS AND METHODS: The di@bet.es epidemiological study is a population-based cohort study aimed to determine the prevalence and incidence of DM in the adult population of Spain. The at-risk sample at the final examination (2016-2017) included 1751 subjects who completed an oral health questionnaire. This questionnaire, together with demographic and risk factors, had been previously validated to build an algorithm to predict severe periodontitis in the Spanish population. Logistic regression models were used to evaluate the association between severe periodontitis and DM with adjustment for confounding factors. RESULTS: In total, 144 subjects developed DM, which yielded 8.2% cumulative incidence. Severe periodontitis was detected in 59.0%, 54.7% or 68.8% of the subjects depending on three different selected criteria at the 2016-2017 exam. All criteria used to define severe periodontitis were associated with DM in unadjusted analysis, but the magnitude of the association decreased after adjusting for significant confounders. The criteria '≥50% of teeth with clinical attachment loss ≥5 mm' presented an odds ratio of 4.9 (95% confidence interval: 2.2-10.7; p ≤ .001) for DM. CONCLUSIONS: Severe periodontitis is associated with DM in the Spanish population.
Assuntos
Diabetes Mellitus , Periodontite , Adulto , Humanos , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus/epidemiologia , Periodontite/complicações , Periodontite/epidemiologia , Fatores de RiscoRESUMO
AIMS: To evaluate the efficacy and safety of oral semaglutide versus comparators by patient characteristic subgroups in patients with type 2 diabetes. MATERIALS AND METHODS: Change from baseline in glycated haemoglobin (HbA1c) and body weight, and achievement of HbA1c <7.0% with oral semaglutide 7 mg, oral semaglutide 14 mg, flexibly dosed oral semaglutide (flex) and comparators were assessed across baseline subgroups (age, race, ethnicity, diabetes duration, body mass index and HbA1c) from the PIONEER programme. Treatment differences were analysed using a mixed model for repeated measurements for continuous variables and a logistic regression model for the binary endpoint. Pooled safety data were analysed descriptively. RESULTS: Changes from baseline in HbA1c and body weight, and the odds of achieving HbA1c <7.0%, were greater with oral semaglutide 14 mg/flex (n = 1934) and higher or similar with oral semaglutide 7 mg (n = 823) versus comparators (n = 2077) across most subgroups. Changes in HbA1c with oral semaglutide 14 mg/flex were greater for patients with higher baseline HbA1c (HbA1c >9.0%: -1.7% to -2.6%; HbA1c <8.0%: -0.7% to -1.2%). In some trials, Asian patients experienced greater HbA1c reductions with oral semaglutide 14 mg/flex (-1.5% to -1.8%) than other racial groups (-0.6% to -1.6%). The overall incidence of adverse events (AEs) with oral semaglutide was similar to that with comparators and was consistent across subgroups. More gastrointestinal AEs were observed with oral semaglutide, versus comparators, across subgroups. CONCLUSIONS: Oral semaglutide demonstrated consistently greater HbA1c and body weight reductions across a range of patient characteristics, with greater HbA1c reductions seen at higher baseline HbA1c levels.
Assuntos
Diabetes Mellitus Tipo 2 , Peso Corporal , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVE: Use of self-reported questionnaires in Dentistry may be useful to estimate the prevalence of periodontitis in epidemiological studies. This study aims to assess the accuracy of self-reporting for predicting the prevalence of periodontitis in a Spanish population participating in a diabetes incidence study. MATERIALS AND METHODS: Data were collected from 231 patients participating in the Di@bet.es study. Eight questions about periodontal health were included in a health patient-reported questionnaire. The outcomes from self-reporting were validated against a full-mouth periodontal examination. Multivariable logistic regression predictive modeling was used to determine the sensitivity, specificity, and area under the receiver operator characteristic curve (AUROCC). RESULTS: Self-reported gum health, loose teeth, tooth appearance, and use of dental floss were associated with different definitions of severe periodontitis. Correlations between responses to the questions were weak. The question "Do you think you might have gum disease?" combined with demographic and well-established risk factors resulted in an AUC value of 0.75, sensitivity of 75.2%, and specificity of 60.6% for severe periodontitis. The answer to 4 questions combined with age, educational level, smoking status, and tooth loss was 76.4% sensitive and 63.5% specific, with an AUC of 0.75 in predicting prevalence of ≥25% of teeth with probing pocket depth (PPD) ≥6 mm. CONCLUSION: Predictive models, combining self-reporting on oral health status with demographic and risk factors, were useful for estimating the prevalence of severe periodontitis in the Spanish population.
Assuntos
Periodontite/diagnóstico , Autorrelato , Humanos , Prevalência , Sensibilidade e Especificidade , Espanha , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy. METHODS: One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and Cox proportional models and log-rank test were used. RESULTS: With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07-1.19, p < 0.001) and 31 months (HR 1.09; 95% CI 1.04-1.15; p < 0.001) respectively, for patients with FPG < 7 mmol/L. In the multivariate analysis of the entire cohort adjusted by platinum compound and comorbidities, high levels of FPG as a continuous variable (HR 1.14; 95% CI 1.07-1.21; p < 0.001), the presence of comorbidity (HR 1.72; 95% CI 1.12-2.63; p = 0.012), and treatment with carboplatin (HR 1.95; 95% CI 1.26-2.99; p = 0.002) were independent predictors for shorter OS. In additional multivariate models considering non-diabetic patients as a reference group, diabetic patients with poor metabolic control (HbA1c > 8.5%) (HR 4.53; 95% CI 2.21-9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90-5.46 p < 0.001) had significantly independent worse OS. CONCLUSION: Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association.
Assuntos
Biomarcadores/análise , Glicemia/análise , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Quimiorradioterapia , Neoplasias Pulmonares/diagnóstico , Platina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
This international, randomized, double-blind trial (NCT01864174) compared the efficacy and safety of metformin extended-release (XR) and immediate-release (IR) in patients with type 2 diabetes. After a 4-week placebo lead-in, pharmacotherapy-naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once-daily metformin XR 2000 mg or twice-daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: -0.93% vs -0.96%; -21.1 vs -20.6 mg/dL (-1.2 vs -1.1 mmol/L); -24.7 vs -27.1 mg/dL (-1.4 vs -1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once-daily dosing.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Glicemia/análise , Automonitorização da Glicemia , Terapia Combinada/efeitos adversos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos , Exercício Físico , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Método Simples-CegoRESUMO
BACKGROUND: Diabetes and periodontitis are chronic non-communicable diseases independently associated with mortality and have a bidirectional relationship. AIMS: To update the evidence for their epidemiological and mechanistic associations and re-examine the impact of effective periodontal therapy upon metabolic control (glycated haemoglobin, HbA1C). EPIDEMIOLOGY: There is strong evidence that people with periodontitis have elevated risk for dysglycaemia and insulin resistance. Cohort studies among people with diabetes demonstrate significantly higher HbA1C levels in patients with periodontitis (versus periodontally healthy patients), but there are insufficient data among people with type 1 diabetes. Periodontitis is also associated with an increased risk of incident type 2 diabetes. MECHANISMS: Mechanistic links between periodontitis and diabetes involve elevations in interleukin (IL)-1-ß, tumour necrosis factor-α, IL-6, receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio, oxidative stress and Toll-like receptor (TLR) 2/4 expression. INTERVENTIONS: Periodontal therapy is safe and effective in people with diabetes, and it is associated with reductions in HbA1C of 0.27-0.48% after 3 months, although studies involving longer-term follow-up are inconclusive. CONCLUSIONS: The European Federation of Periodontology (EFP) and the International Diabetes Federation (IDF) report consensus guidelines for physicians, oral healthcare professionals and patients to improve early diagnosis, prevention and comanagement of diabetes and periodontitis.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Doenças Periodontais/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas/análise , Humanos , Resistência à Insulina , Doenças Periodontais/diagnóstico , Doenças Periodontais/etiologia , Doenças Periodontais/terapia , Periodontite/complicações , Periodontite/etiologiaRESUMO
Limitations in ß-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated ß-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. ß-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, ß-cell mass did not change after Px or after gastrin treatment in middle-aged rats. ß-Cell replication and individual ß-cell size were similarly increased after Px in young and middle-aged animals, and ß-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet ß-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory ß-cell hyperplasia and hypertrophy was retained in middle-aged rats, but ß-cell dedifferentiation and impaired duct cell plasticity limited ß-cell regeneration.
Assuntos
Desdiferenciação Celular/fisiologia , Células Secretoras de Insulina/fisiologia , Ductos Pancreáticos/citologia , Ductos Pancreáticos/fisiologia , Regeneração/fisiologia , Envelhecimento/fisiologia , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Plasticidade Celular , Tamanho Celular , Gastrinas/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Proteínas do Tecido Nervoso/metabolismo , Pancreatectomia , Ratos , Ratos Wistar , Fatores de Transcrição SOX9/metabolismo , Regulação para CimaRESUMO
AIMS: Incretin-based therapies have been associated with an increased risk of pancreatitis. Recently, various histological abnormalities have been reported in human pancreatic tissue from brain-dead organ donors who had been exposed to incretin-based drugs. In the present study we examined pancreatic tissue collected at surgery. METHODS: Human pancreatic tissue from 7 type 2-diabetic patients treated with incretin-based drugs (type 2-I), 6 diabetic patients without incretin treatment (type 2-NI), 11 patients without diabetes (no diabetes group) and 9 brain-dead organ donors (BDOD group) was examined. RESULTS: Fractional beta-cell area was reduced in the type 2-NI group compared to the group without diabetes (P < .05), but there was no difference compared to the type 2-I patients. Alpha-cell area (P = .30), beta-cell replication (P = .17) and alpha-cell replication (P = .91) were not different. There were also no differences in acinar cell (P = .13) and duct cell replication (P = .099). Insulin-positive duct cells were more frequent in the type 2-I and the BDOD groups (P = .034). No co-expression of insulin and glucagon was detected. Pancreatic intraepithelial neoplasia (PanIN) lesions were very rare, all low-grade (PanIN 1a and 1b) and tended to occur more frequently in the type 2-I group (P = .084). CONCLUSIONS: The present results did not reveal marked histological abnormalities in the pancreas of incretin-treated patients with type 2 diabetes. Low numbers of specimens available and a large inter-individual variability of the findings warrant caution regarding the interpretation of histological data concerning drug effects on the human pancreas.
Assuntos
Células Acinares/patologia , Carcinoma in Situ/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Incretinas/uso terapêutico , Ilhotas Pancreáticas/patologia , Pâncreas Exócrino/patologia , Pâncreas/cirurgia , Neoplasias Pancreáticas/patologia , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Adenocarcinoma/cirurgia , Adulto , Idoso , Carcinoma in Situ/epidemiologia , Carcinoma in Situ/cirurgia , Estudos de Casos e Controles , Cistadenoma/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório , Dipeptídeos/uso terapêutico , Exenatida , Feminino , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/cirurgia , Nitrilas/uso terapêutico , Tamanho do Órgão , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/cirurgia , Pancreatite Crônica/cirurgia , Peptídeos/uso terapêutico , Pirrolidinas/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Doadores de Tecidos , Peçonhas/uso terapêutico , VildagliptinaRESUMO
The existence of functional connexin36 (Cx36) hemichannels in ß-cells was investigated in pancreatic islets of rat and wild-type (Cx36(+/+)), monoallelic (Cx36(+/-)), and biallelic (Cx36(-/-)) knockout mice. Hemichannel opening by KCl depolarization was studied by measuring ATP release and changes of intracellular ATP (ADP). Cx36(+/+) islets lost ATP after depolarization with 70 mM KCl at 5 mM glucose; ATP loss was prevented by 8 and 20 mM glucose or 50 µM mefloquine (connexin inhibitor). ATP content was higher in Cx36(-/-) than Cx36(+/+) islets and was not decreased by KCl depolarization; Cx36(+/-) islets showed values between that of control and homozygous islets. Five minimolar extracellular ATP increased ATP content and ATP/ADP ratio and induced a biphasic insulin secretion in depolarized Cx36(+/+) and Cx36(+/-) but not Cx36(-/-) islets. Cx36 hemichannels expressed in oocytes opened upon depolarization of membrane potential, and their activation was inhibited by mefloquine and glucose (IC50 â¼8 mM). It is postulated that glucose-induced inhibition of Cx36 hemichannels in islet ß-cells might avoid depolarization-induced ATP loss, allowing an optimum increase of the ATP/ADP ratio by sugar metabolism and a biphasic stimulation of insulin secretion. Gradual suppression of glucose-induced insulin release in Cx36(+/-) and Cx36(-/-) islets confirms that Cx36 gap junction channels are necessary for a full secretory stimulation and might account for the glucose intolerance observed in mice with defective Cx36 expression. Mefloquine targeting of Cx36 on both gap junctions and hemichannels also suppresses glucose-stimulated secretion. By contrast, glucose stimulation of insulin secretion requires Cx36 hemichannels' closure but keeping gap junction channels opened.
Assuntos
Glicemia/metabolismo , Conexinas/antagonistas & inibidores , Intolerância à Glucose/metabolismo , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Regulação para Cima , Trifosfato de Adenosina/metabolismo , Animais , Glicemia/análise , Conexinas/genética , Conexinas/metabolismo , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Intolerância à Glucose/sangue , Heterozigoto , Hiperglicemia/etiologia , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Moduladores de Transporte de Membrana/farmacologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Wistar , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Técnicas de Cultura de Tecidos , Regulação para Cima/efeitos dos fármacos , Proteína delta-2 de Junções ComunicantesRESUMO
Pancreatic ß-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in ß-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human ß-cells. Mice with ß-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.
RESUMO
Insulinomas are rare neuroendocrine tumors arising from pancreatic ß cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in ß cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of ß cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.
Assuntos
Insulinoma , Humanos , Insulinoma/genética , Insulinoma/patologia , Insulinoma/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Mutação , Regulação Neoplásica da Expressão Gênica , Epigênese Genética , Montagem e Desmontagem da Cromatina/genéticaRESUMO
AIMS: We used N-terminal pro-B-type natriuretic peptide (NT-proBNP) point-of-care testing (POCT) for heart failure risk stratification of individuals with type 2 diabetes for >10 years and hypertension. METHODS: Overall 259 participants aged 50 years or older with type 2 diabetes (duration of >10 years), hypertension, and no overt cardiovascular disease (CVD) were recruited at two study centers. Patients' data were acquired and NT-proBNP levels were measured using the CARDIAC proBNP+ test (Roche) and the cobas h232 instrument (Roche). Participants were clustered into two groups according to their NT-proBNP concentration value: with NT-proBNP <125 pg/ml and with NT-proBNP ≥125 pg/ml. RESULTS: Mean age of the participants was 66.1 ± 9.2 years, 55.2 % were female, 60.6 % (n = 157) had a NT-proBNP <125 pg/ml and 39.4 % (n = 102 ≥ 125 pg/ml). Differences were observed among those with low and high NT-proBNP in mean age (63.4 ± 8.8 years vs. 70.1 ± 8.2 years, p < 0.001), diabetes duration (15.4 ± 5.9 years vs. 17.9 ± 7.3 years, p = 0.003), and estimated glomerular filtration rate (eGFR) (86 ± 16 ml/min/1.73 m2 vs. 76 ± 20 ml/min/1.73 m2, p < 0.001). CONCLUSIONS: NT-proBNP POCT is practical and can be pragmatically targeted for screening people with type 2 diabetes and hypertension for heart failure risk stratification in routine clinical practice.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Hipertensão , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Peptídeo Natriurético Encefálico , Sistemas Automatizados de Assistência Junto ao Leito , Biomarcadores , Insuficiência Cardíaca/diagnóstico , Fragmentos de PeptídeosRESUMO
The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt ß-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity. However, a precise understanding of the pancreatic ß-cell response in ageing is still lacking. In this review, we summarize the age-related alterations, adaptations and/or failures of ß-cells at the molecular, morphological and functional levels in mouse and human. Age-associated alterations include processes such as ß-cell proliferation, apoptosis and cell identity that can influence ß-cell mass. Age-related changes also affect ß-cell function at distinct steps including electrical activity, Ca2+ signaling and insulin secretion, among others. We will consider the potential impact of these alterations and those mediated by senescence pathways on ß-cells and their implications in age-related T2D. Finally, given the great diversity of results in the field of ß-cell ageing, we will discuss the sources of this heterogeneity. A better understanding of ß-cell biology during ageing, particularly at older ages, will improve our insight into the contribution of ß-cells to age-associated T2D and may boost new therapeutic strategies.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Células Secretoras de Insulina , Envelhecimento/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , CamundongosRESUMO
BACKGROUND: Agonists of the glucagon-like peptide-1 (GLP-1) receptor provide pharmacological levels of GLP-1 activity, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors increase concentrations of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide. We aimed to assess the efficacy and safety of the human GLP-1 analogue liraglutide versus the DPP-4 inhibitor sitagliptin, as adjunct treatments to metformin, in individuals with type 2 diabetes who did not achieve adequate glycaemic control with metformin alone. METHODS: In this parallel-group, open-label trial, participants (aged 18-80 years) with type 2 diabetes mellitus who had inadequate glycaemic control (glycosylated haemoglobin [HbA(1c)] 7.5-10.0%) on metformin (>or=1500 mg daily for >or=3 months) were enrolled and treated at office-based sites in Europe, the USA, and Canada. Participants were randomly allocated to receive 26 weeks' treatment with 1.2 mg (n=225) or 1.8 mg (n=221) subcutaneous liraglutide once daily, or 100 mg oral sitagliptin once daily (n=219). The primary endpoint was change in HbA(1c) from baseline to week 26. The efficacy of liraglutide versus sitagliptin was assessed hierarchically by a non-inferiority comparison, with a margin of 0.4%, followed by a superiority comparison. Analyses were done on the full analysis set with missing values imputed by last observation carried forward; seven patients assigned to liraglutide did not receive treatment and thus did not meet criteria for inclusion in the full analysis set. This trial is registered with ClinicalTrials.gov, number NCT00700817. FINDINGS: Greater lowering of mean HbA(1c) (8.5% at baseline) was achieved with 1.8 mg liraglutide (-1.50%, 95% CI -1.63 to -1.37, n=218) and 1.2 mg liraglutide (-1.24%, -1.37 to -1.11, n=221) than with sitagliptin (-0.90%, -1.03 to -0.77, n=219). Estimated mean treatment differences for liraglutide versus sitagliptin were -0.60% (95% CI -0.77 to -0.43, p<0.0001) for 1.8 mg and -0.34% (-0.51 to -0.16, p<0.0001) for 1.2 mg liraglutide. Nausea was more common with liraglutide (59 [27%] patients on 1.8 mg; 46 [21%] on 1.2 mg) than with sitagliptin (10 [5%]). Minor hypoglycaemia was recorded in about 5% of participants in each treatment group. INTERPRETATION: Liraglutide was superior to sitagliptin for reduction of HbA(1c), and was well tolerated with minimum risk of hypoglycaemia. These findings support the use of liraglutide as an effective GLP-1 agent to add to metformin. FUNDING: Novo Nordisk.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Pirazinas/uso terapêutico , Triazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Liraglutida , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fosfato de Sitagliptina , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
Exposure to air particulate matter has been linked with hypertension and blood pressure levels. The metabolic risks of air pollution could vary according to the specific characteristics of each area, and has not been sufficiently evaluated in Spain. We analyzed 1103 individuals, participants in a Spanish nationwide population based cohort study (di@bet.es), who were free of hypertension at baseline (2008-2010) and completed a follow-up exam of the cohort (2016-2017). Cohort participants were assigned air pollution concentrations for particulate matter < 10 µm (PM10) and < 2.5 µm (PM2.5) during follow-up (2008-2016) obtained through modeling combined with measurements taken at air quality stations (CHIMERE chemistry-transport model). Mean and SD concentrations of PM10 and PM2.5 were 20.17 ± 3.91 µg/m3 and 10.83 ± 2.08 µg/m3 respectively. During follow-up 282 cases of incident hypertension were recorded. In the fully adjusted model, compared with the lowest quartile of PM10, the multivariate weighted ORs (95% CIs) for developing hypertension with increasing PM10 exposures were 0.82 (0.59-1.14), 1.28 (0.93-1.78) and 1.45 (1.05-2.01) in quartile 2, 3 and 4 respectively (p for a trend of 0.003). The corresponding weighted ORs according to PM2.5 exposures were 0.80 (0.57-1.13), 1.11 (0.80-1.53) and 1.48 (1.09-2.00) (p for trend 0.004). For each 5-µg/m3 increment in PM10 and PM2.5 concentrations, the odds for incident hypertension increased 1.22 (1.06-1.41) p = 0.007 and 1.39 (1.07-1.81) p = 0.02 respectively. In conclusion, our study contributes to assessing the impact of particulate pollution on the incidence of hypertension in Spain, reinforcing the need for improving air quality as much as possible in order to decrease the risk of cardiometabolic disease in the population.
Assuntos
Exposição Ambiental/efeitos adversos , Hipertensão/epidemiologia , Hipertensão/etiologia , Material Particulado/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Poluentes Atmosféricos , Poluição do Ar , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Vigilância em Saúde Pública , Medição de Risco , Fatores de Risco , Espanha/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. FUNDING: Novo Nordisk A/S.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Peptídeos/uso terapêutico , Peçonhas/uso terapêutico , Análise de Variância , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Exenatida , Feminino , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/química , Injeções Subcutâneas , Modelos Lineares , Liraglutida , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Peptídeos/efeitos adversos , Peptídeos/química , Resultado do Tratamento , Peçonhas/efeitos adversos , Peçonhas/química , Redução de Peso/efeitos dos fármacosRESUMO
Pancreatic beta cells have a significant remodeling capacity which plays an essential role in the maintenance of glucose homeostasis. Beta cell apoptosis, replication, size, dedifferentiation, and (neo)generation contribute to the beta cell mass regulation. However, the extent of their respective contribution varies significantly depending on the specific condition, and it is the balance among them that determines the eventual change in beta cell mass. Thus, the study of the pancreatic beta cell mass regulation requires the determination of all these factors. In this chapter, we describe the quantification of beta cell replication based on the incorporation of thymidine analogs into replicated DNA strands and on the expression of Ki67 antigen and phosphorylation of histone H3. Beta cell apoptosis is analyzed by the TUNEL technique, and beta cell mass and cross-sectional area of individual beta cells are determined by computerized image processing methods.