RESUMEN
AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS: This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.
Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Adolescente , Adulto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hemoglobina Glucada , Péptidos Similares al Glucagón/efectos adversos , China/epidemiologíaRESUMEN
AIMS: To report Type 2 diabetes-related outcomes after the implantation of a duodenal-jejunal bypass liner device and to investigate the role of proximal gut exclusion from food in glucose homeostasis using the model of this device. METHODS: Sixteen patients with Type 2 diabetes and BMI <36 kg/m(2) were evaluated before and 1, 12 and 52 weeks after duodenal-jejunal bypass liner implantation and 26 weeks after explantation. Mixed-meal tolerance tests were conducted over a period of 120 min and glucose, insulin and C-peptide levels were measured. The Matsuda index and the homeostatic model of assessment of insulin resistance were used for the estimation of insulin sensitivity and insulin resistance. The insulin secretion rate was calculated using deconvolution of C-peptide levels. RESULTS: Body weight decreased by 1.3 kg after 1 week and by 2.4 kg after 52 weeks (P < 0.001). One year after duodenal-jejunal bypass liner implantation, the mean (sem) HbA(1c) level decreased from 71.3 (2.4) mmol/mol (8.6[0.2]%) to 58.1 (4.4) mmol/mol (7.5 [0.4]%) and mean (sem) fasting glucose levels decreased from 203.3 (13.5) mg/dl to 155.1 (13.1) mg/dl (both P < 0.001). Insulin sensitivity improved by >50% as early as 1 week after implantation as measured by the Matsuda index and the homeostatic model of assessment of insulin resistance (P < 0.001), but there was a trend towards deterioration in all the above-mentioned variables 26 weeks after explantation. Fasting insulin levels, insulin area under the curve, fasting C-peptide, C-peptide area under the curve, fasting insulin and total insulin secretion rates did not change during the duodenal-jejunal bypass liner implantation period or after explantation. CONCLUSIONS: The duodenal-jejunal bypass liner improves glycaemia in overweight and obese patients with Type 2 diabetes by rapidly improving insulin sensitivity. A reduction in hepatic glucose output is the most likely explanation for this improvement.
Asunto(s)
Glucemia/metabolismo , Péptido C/sangre , Diabetes Mellitus Tipo 2/sangre , Derivación Gástrica , Hemoglobina Glucada/metabolismo , Obesidad/cirugía , Área Bajo la Curva , Remoción de Dispositivos , Diabetes Mellitus Tipo 2/cirugía , Duodeno/cirugía , Ayuno , Femenino , Homeostasis , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Yeyuno/cirugía , Masculino , Persona de Mediana Edad , Obesidad/sangre , Estudios Prospectivos , Resultado del Tratamiento , Pérdida de PesoRESUMEN
A protocol consisting of a single donor-specific transfusion (DST) plus a brief course of anti-CD154 monoclonal antibody (anti-CD40 ligand mAb) induces permanent islet allograft survival in chemically diabetic mice, but its efficacy in mice with autoimmune diabetes is unknown. Confirming a previous report, we first observed that treatment of young female NOD mice with anti-CD154 mAb reduced the frequency of diabetes through 1 year of age to 43%, compared with 73% in untreated controls. We also confirmed that spontaneously diabetic NOD mice transplanted with syngeneic (NOD-Prkdc(scid)/Prkdc(scid)) or allogeneic (BALB/c) islets rapidly reject their grafts. Graft survival was not prolonged, however, by pretreatment with either anti-CD154 mAb alone or anti-CD154 mAb plus DST. In addition, allograft rejection in NOD mice was not restricted to islet grafts. Anti-CD154 mAb plus DST treatment failed to prolong skin allograft survival in nondiabetic male NOD mice. The inability to induce transplantation tolerance in NOD (H2g7) mice was associated with non-major histocompatibility complex (MHC) genes. Treatment with DST and anti-CD154 mAb prolonged skin allograft survival in both C57BL/6 (H2b) and C57BL/6.NOD-H2g7 mice, but it was ineffective in NOD, NOD.SWR-H2q, and NOR (H2g7) mice. Mitogen-stimulated interleukin-1beta production by antigen-presenting cells was greater in strains susceptible to tolerance induction than in the strains resistant to tolerance induction. The results suggest the existence of a general defect in tolerance mechanisms in NOD mice. This genetic defect involves defective antigen-presenting cell maturation, leads to spontaneous autoimmune diabetes in the presence of the H2g7 MHC, and precludes the induction of transplantation tolerance irrespective of MHC haplotype. Promising islet transplantation methods based on overcoming the alloimmune response by interference with costimulation may require modification or amplification for use in the setting of autoimmune diabetes.
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Diabetes Mellitus Tipo 1/inmunología , Tolerancia Inmunológica , Trasplante de Islotes Pancreáticos , Trasplante de Piel , Animales , Anticuerpos Monoclonales/uso terapéutico , Transfusión Sanguínea , Ligando de CD40 , Femenino , Rechazo de Injerto/prevención & control , Masculino , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Timectomía , Donantes de Tejidos , Acondicionamiento PretrasplanteRESUMEN
The p35 protein which is hyperexpressed on hairy leukemic cells was determined to be Ii, the electrophoretically invariant glycoprotein that is associated with class II major histocompatibility complex (Ia) antigens from the time of their synthesis. The principal function of class II MHC antigens is to present to T cell receptors those digested foreign antigenic peptides that probably fold as amphipathic alpha-helices and adsorb to a hydrophobic surface (desetope) on Ia. By a novel strip-of-helix hydrophobicity algorithm we found that the sequence Leu-142 to His-170 in Ii formed a five-cycle, amphipathic, alpha-helix, the highest scoring one among a series of proteins commonly used as experimental antigens. This finding led to the hypothesis that this sequence in Ii bound to the antigen-binding site (desetope) of Ia until release and self-aggregation in the endosome in order that digested foreign peptides could then bind to Ia. Abundant expression of Ii in leukemic cells might be associated with an altered capacity of those cells to present foreign or leukemic antigens to the host's immune system.
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Antígenos de Diferenciación de Linfocitos B , Antígenos de Histocompatibilidad Clase II/metabolismo , Leucemia de Células Pilosas/metabolismo , Proteínas de la Membrana/metabolismo , Línea Celular Transformada , Transformación Celular Viral , Herpesvirus Humano 4 , Humanos , Peso Molecular , Sialoglicoproteínas/metabolismo , Células Tumorales CultivadasRESUMEN
Two proteins, p70 and p80, were found in chemically crosslinked complexes with class II MHC molecules and Ii after 3-12 hr labelings with [35S]methionine. Two-dimensional, nonreduced/reduced SDS gel electrophoresis of immunoprecipitated complexes revealed 1) endogenous disulfide linkages between Ii-Ii and Ii-p70 and 2) chemically crosslinked, nearest neighbors of alpha-beta, alpha-Ii, Ii-p70, and alpha-p80. Although such nearest neighbors within multimeric complexes were identified as dimers in nonreduced/reduced 2D gels, stoichiometries could not be determined in the high molecular weight complex(es), which included alpha, beta, Ii, p70, and p80, and were not separated in the first dimension. p80 was not the chondroitin-sulfate form of Ii (Ii-CS) because it was not electrophoretically heterogeneous and was not sensitive to chondroitinase ABC. p70 was not hsp72/74 detected with C92 or N27 mAbs, and p80 was not BiP detected with its respective mAb. While only these two proteins associated prominently with class II MHC antigens and Ii late after synthesis, their functions are unknown.
Asunto(s)
Antígenos de Diferenciación de Linfocitos B , Antígenos de Histocompatibilidad Clase II/aislamiento & purificación , Proteínas/aislamiento & purificación , Anticuerpos Monoclonales , Antígenos de Neoplasias/aislamiento & purificación , Línea Celular , Electroforesis en Gel Bidimensional , Proteínas de Choque Térmico/aislamiento & purificación , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Cinética , Metionina/metabolismo , Peso Molecular , Unión Proteica , Biosíntesis de ProteínasRESUMEN
Antibodies to either Ii or class II major histocompatibility complex (MHC) antigens did not recognize cell surface forms of Ii in immunoprecipitates of cells that had been radioiodinated by the lactoperoxidase method, whereas they bound [35S]methionine metabolically labeled molecules. N-hydroxysuccinimidobiotin (NHS-B) and biotin hydrazide (B-H) were used to react more generally with cell surface proteins via amino groups and nitrene coupling, respectively. Each of these latter compounds labeled alpha and beta chains of class II MHC antigens as seen in Western-blotted, electrophoresed immunoprecipitates probed with 125I-labeled streptavidin but not Ii or its associated forms. Although tyrosine residues might have been inaccessible to radioiodination in carbohydrate-derivatized forms of Ii, the lack of Ii biotinylation in these controlled, sensitive studies was consistent with the view that Ii forms were not surface expressed, with the possible exception of the chondroitin sulfate-derivatized forms of Ii (Ii-CS).
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Antígenos de Superficie/análisis , Biotina , Técnica del Anticuerpo Fluorescente , Antígenos HLA/análisis , Radioisótopos de Yodo , Biotina/análogos & derivados , Butiratos/farmacología , Ácido Butírico , Línea Celular , Antígenos HLA/clasificación , HumanosRESUMEN
The enzyme cyclooxygenase (COX)-1 is constitutive whereas COX-2 is regulated in virtually all tissues. To assess whether this dogma holds true in the pancreatic islet, we examined basal and interleukin (IL)-1-regulated expression of COX-2 in HIT-T15 cells, Syrian hamster and human islets, and other Syrian hamster tissues. We found that COX-2, and not COX-1, gene expression is dominant in pancreatic islet tissue under both basal and IL-1-stimulated conditions. Control tissues (liver, spleen, and kidney) showed the expected predominance of COX-1 gene expression. Basal and IL-1-stimulated prostaglandin E2 synthesis were blocked by a specific COX-2 inhibitor. IL-1 stimulation had a biphasic effect on COX-2 mRNA levels with an initial mild increase at 2-4 hr followed by a more dramatic decrease below basal level by 24 hr. The IL-1-induced increase in COX-2 mRNA levels was accompanied by a parallel increase in NF-kappaB binding to COX-2 promoter elements. The subsequent decrease in COX-2 mRNA levels was accompanied by a parallel decrease in NF-IL-6 binding activity and COX-2 promoter activity. Specific mutation of the NF-IL-6 binding motif within the COX-2 promoter reduced basal promoter activity by 50% whereas mutation of the NF-kappaB motif had no effect. These studies provide documentation of NF-IL-6 in the pancreatic islet and that COX-2, rather than COX-1, is dominantly expressed. They suggest coordinate regulation by IL-1 of COX-2 mRNA, NF-kappaB, and NF-IL-6 and raise the issue of whether intrinsically high levels of COX-2 gene expression predisposes the normal islet for microenvironmentally induced overproduction of islet prostaglandin E2.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Interleucina-1/fisiología , Islotes Pancreáticos/metabolismo , Isoenzimas/genética , Proteínas Nucleares/metabolismo , Prostaglandina-Endoperóxido Sintasas/genética , Animales , Proteínas Potenciadoras de Unión a CCAAT , Células Cultivadas , Cricetinae , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Dinoprostona/metabolismo , Regulación Enzimológica de la Expresión Génica , Humanos , Isoenzimas/metabolismo , Proteínas de la Membrana , Mutagénesis , FN-kappa B/fisiología , Regiones Promotoras Genéticas , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/genética , Factores de TiempoRESUMEN
A role for the Epstein-Barr virus in initiating Type 1 (insulin-dependent) diabetes mellitus has been proposed since Epstein-Barr virus BOLF1 (497-513) AVTPL RIFIVPPAAEY has an 11 amino acid identity with HLA-DQw8 beta (49-60) AVTPL GPPAAEY. Rabbit antisera to the BOLF1 (496-515) peptide crossreacted with the homologous DQw8 beta (44-63) peptide but not with the related DQw7 beta (44-63) peptide, which differed from the DQw8 peptide only in an ALA to ASP substitution in position 57. Antisera to DQw8 beta (49-60) reacted with the DQw8 beta (44-63) peptide and BOLF1 (496-515), but not with DQw7 beta (44-63). The antiserum to the BOLF1 peptide bound to denatured class II major histocompatibility complex beta chains from Epstein-Barr virus-transformed DQw8-positive lymphocytes in an immunoblotting analysis. Epstein-Barr virus antibodies were detected at equal frequencies and similar titres in sera of 30 patients with Type 1 diabetes (16 of 30; 63%) and in sera of 20 non-diabetic control subjects (13 of 20; 65%). Sera from diabetic patients did not bind to DQw8 beta (44-63) or BOLF1 (496-515) peptides. From these data we conclude that there is no simple relationship between serological evidence of Epstein-Barr virus infection and crossreactions between homologous Epstein-Barr virus and class II major histocompatibility complex peptides.