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1.
Diabet Med ; 35(5): 595-601, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29460298

RESUMEN

AIMS: Insulin resistance may contribute to the pathogenesis of autoimmune-mediated diabetes. Antibodies against ß-cell-associated molecules, comprising islet cell antigen (ICA), glutamic acid decarboxylase (GAD) and insulin, characterize the autoimmune process. Because the link between insulin resistance and autoimmunity might be relevant for disease progression and treatment, we hypothesized that insulin resistance associates positively with ß-cell-directed antibodies in newly diagnosed Type 1 diabetes. METHODS: Within the German Diabetes Study, an observational study including adults with newly diagnosed diabetes, 142 adults [84 men, 58 women; age 33.1 (26.4, 41.9) years; diabetes duration 6.3 (4.2, 9.1) months] positive for at least one antibody against ICA, GAD or insulin underwent hyperinsulinaemic-euglycaemic clamp tests to assess insulin sensitivity (M-value) in a cross-sectional setting. RESULTS: Insulin-directed antibodies were inversely correlated with M-values (ß = -0.039). Albeit not strong, the association persisted after adjustment for age, sex and BMI, and even after further adjustment for confounders reflecting exposure to exogenous insulin and residual ß-cell secretory capacity. Correlation network-based analyses revealed a complex interaction between levels of fasting insulin and of insulin antibodies with respect to their relationship with the M-value. GAD- or ICA-directed antibodies did not correlate with insulin sensitivity. CONCLUSIONS: In adults with recent-onset Type 1 diabetes expressing at least one ß-cell-directed antibody, insulin sensitivity is inversely related to insulin antibody titres, but not to other autoantibodies. Our finding may allow for the identification of insulin resistance in adults with high levels of insulin antibodies.


Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/inmunología , Anticuerpos Insulínicos/inmunología , Resistencia a la Insulina , Adulto , Autoinmunidad , Estudios Transversales , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Masculino
2.
MMW Fortschr Med ; 158(19): 45, 2016 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-27797039
3.
Diabetes Obes Metab ; 18 Suppl 2: 43-49, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27393722

RESUMEN

AIMS: To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). MATERIALS AND METHODS: This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. RESULTS: During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (-0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. CONCLUSIONS: Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemiantes/administración & dosificación , Insulina Lispro/análogos & derivados , Polietilenglicoles/administración & dosificación , Adulto , Glucemia/metabolismo , Estudios Cruzados , Diabetes Mellitus Tipo 1/metabolismo , Esquema de Medicación , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Insulina Lispro/administración & dosificación , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
5.
Eur J Endocrinol ; 172(2): 107-13, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25378371

RESUMEN

OBJECTIVE: Body weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis. DESIGN: Multicentre longitudinal study carried out at diagnosis and up to 1-year follow-up. METHODS: Data on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c. RESULTS: In individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10-18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (ß 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m(2) higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (ß=0.026, 95% CI=0.0097, 0.042; P=0.002). CONCLUSIONS: These observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10-18 years. This should be considered in studies of ß-cell function in type 1 diabetes.


Asunto(s)
Índice de Masa Corporal , Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/diagnóstico , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Adolescente , Biomarcadores/sangre , Recuento de Células/métodos , Niño , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino
6.
Exp Clin Endocrinol Diabetes ; 122(2): 92-9, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24558019

RESUMEN

To investigate the risk of macro- and microvascular complications in patients with type 2 diabetes receiving rapid-acting insulin analogues (IA) or human regular insulin (HI).General practice diabetes patients with continuous prescription of any IA or HI for ≥3 years were selected from the German Disease Analyzer database (IMS Health). Logistic and Cox regression models were applied to analyze the incidence and time to onset of vascular outcomes (IA vs. HI).2764 patients on IA (insulin lispro, glulisine, aspart) and 4193 patients on HI were included (age, mean [SD]: 61.0 [11.3] and 64.7 [10.5] years, follow-up [Q1,Q3]: 4.6 [3.7,6.1] and 4.7 [3.7,5.9] years). No significant differences were detected between IA and HI regarding the incidence of vascular complications (OR [95%CI]: macrovascular 0.92 [0.72-1.18], microvascular 0.95 [0.77-1.17]) or regarding time to their onset, after adjustment for sex, age, comorbidities and time on IA/HI, or by propensity-score-based matching. However, in an additional short-term analysis (median [Q1,Q3] follow-up (IA 2.9 [1.2,4.6], HI 2.4 [0.8,4.4] years) of a larger sample (no continuous insulin treatment required) with more comorbidities, time to onset of macrovascular complications was significantly longer for AI than HI (HR 0.88 [0.81-0.97], p=0.009; microvascular complications: no difference).After long-term continuous treatment with IA or HI under real-life conditions, there was no different risk of macro- or microvascular complications, contradicting previous short-term analyses. Further prospective studies are needed to clarify whether selection bias may have been introduced by using strict entry criteria.


Asunto(s)
Bases de Datos Factuales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Insulina Regular Humana/administración & dosificación , Insulina de Acción Corta/administración & dosificación , Microcirculación/efectos de los fármacos , Adulto , Factores de Edad , Anciano , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemiantes/efectos adversos , Insulina Regular Humana/efectos adversos , Insulina de Acción Corta/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores Sexuales
7.
Diabetes Obes Metab ; 16(3): 262-7, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24118704

RESUMEN

AIMS: C-peptide secretion is currently the only available clinical biomarker to measure residual ß-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. METHODS: We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on ß-cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. RESULTS: Fasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (p < 0.0001). CONCLUSIONS: This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of ß-cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.


Asunto(s)
Envejecimiento , Péptido C/sangre , Diabetes Mellitus Tipo 1/metabolismo , Hipoglucemiantes/uso terapéutico , Anticuerpos Insulínicos/sangre , Células Secretoras de Insulina/metabolismo , Insulina/uso terapéutico , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Envejecimiento/metabolismo , Biomarcadores/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Europa (Continente) , Ayuno , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino
8.
J Hum Nutr Diet ; 27 Suppl 2: 21-7, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23909831

RESUMEN

BACKGROUND: Despite high insulin doses, good glycaemic control is often lacking in type 2 diabetes patients and new therapeutic options are needed. METHODS: In a proof of principle study, an energy-restricted, protein-rich meal replacement (PRMR) was examined as a means of reducing insulin requirement, HbA1C and body weight. Obese type 2 diabetes patients (n = 22) with >100 U insulin per day replaced, in week 1, the three main meals with 50 g of PRMR (Almased-Vitalkost) each (= 4903 kJ day(-1) ). In weeks 2-4, breakfast and dinner were replaced, and, in weeks 5-12, only dinner was replaced. Clinical parameters were determined at baseline, and after 4, 8 and 12 weeks, as well as after 1.5 years of follow-up. The Wilcoxon signed-rank test was used for the intention-to-treat analysis and the Mann-Whitney U-test for subgroup analyses. RESULTS: The 12-week-programme was completed by 15 participants (68%). After 1 week, the mean insulin dose was reduced from 147 (75) U to 91 (55) U day(-1) (P = 0.0001), and to 65 (32) U (P < 0.0001) after 12 weeks of study. Over a period of 12 weeks, HbA1c decreased from 8.8% (1.4%) to 8.1% (1.6%) (P = 0.048) and weight decreased from 118.0 (19.7) kg to 107.4 (19.2) kg (P < 0.0001). Moreover, body mass index, waist and hip circumference, fasting blood glucose, triglycerides and high-density lipoprotein cholesterol improved significantly. After 1.5 years, insulin requirement and weight remained significantly lower than baseline. Participants who continued PRMR further reduced their HbA1c, weight and insulin dose. Two patients were able to stop insulin therapy altogether. CONCLUSIONS: Energy-restricted PRMR was effective in reducing insulin requirement of type 2 diabetes patients with intensified insulin therapy accompanied by a reduction of HbA1c, weight and other cardiometabolic risk factors. With the continuous use of PRMR, glycaemic control might be improved in the long term.


Asunto(s)
Peso Corporal , Diabetes Mellitus Tipo 2/dietoterapia , Alimentos Formulados , Hemoglobina Glucada/metabolismo , Insulina/administración & dosificación , Adulto , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Dieta , Proteínas en la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Ayuno , Femenino , Estudios de Seguimiento , Humanos , Insulina/sangre , Masculino , Comidas , Persona de Mediana Edad , Obesidad/sangre , Obesidad/dietoterapia , Proyectos Piloto , Triglicéridos/sangre
9.
Clin Exp Immunol ; 172(3): 383-93, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23600826

RESUMEN

Fatty acids, uric acid and glucose are thought to contribute to subclinical inflammation associated with diabetes mellitus. We tested whether co-incubation of free fatty acids and uric acid or glucose influences the secretion of immune mediators from stimulated human whole blood in vitro. Fresh whole blood samples from 20 healthy subjects, 20 patients with type 1 diabetes and 23 patients with type 2 diabetes were incubated for 24 h with palmitic acid (PAL), linolenic acid (LIN) or eicosapentaenoic acid (EPA) alone or together with elevated concentrations of uric acid or glucose. Concentrations of proinflammatory cytokines interleukin (IL)-1ß, IL-2, IL-12(p70), IL-18, IFN-γ, of regulatory cytokines IL-4, IL-10, IL-17 and chemokine CCL2 (MCP-1) were measured by multiplex-bead technology from supernatants. Co-incubation of fatty acids with uric acid resulted in a significant reduction of IL-10, IL-12(p70), IFN-γ and CCL2 (MCP-1) concentrations in supernatants compared to incubation with uric acid alone (P < 0·0001). In contrast, IL-18 was up-regulated upon co-stimulation with fatty acids and uric acid. Similarly, co-incubation of fatty acids with glucose diminished secretion of IL-10, IFN-γ and CCL2 (monocyte chemotactic protein-1), while IL-8 was up-regulated (P < 0·001). Samples from healthy and diabetic subjects did not differ after adjustment for age, sex, body mass index and diabetes type. All three fatty acids similarly influenced whole blood cytokine release in vitro and modulated uric acid or glucose-stimulated cytokine secretion. Although the ω-3-fatty acid EPA showed slightly stronger effects, further studies are required to elaborate the differential effects of PAL, LIN and EPA on disease risk observed previously in epidemiological studies.


Asunto(s)
Quimiocinas/sangre , Citocinas/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos no Esterificados/farmacología , Adulto , Estudios de Casos y Controles , Interacciones Farmacológicas , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos no Esterificados/administración & dosificación , Femenino , Glucosa/administración & dosificación , Glucosa/farmacología , Humanos , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Ácido Palmítico/administración & dosificación , Ácido Palmítico/farmacología , Fitohemaglutininas/farmacología , Ácido Úrico/administración & dosificación , Ácido Úrico/farmacología , Ácido alfa-Linolénico/administración & dosificación , Ácido alfa-Linolénico/farmacología
10.
Diabetologia ; 56(6): 1356-63, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23494449

RESUMEN

AIMS/HYPOTHESIS: Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. METHODS: The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-ß1-3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA1c and fasting blood glucose. RESULTS: High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-ß1 and TGF-ß2 were associated with lower fasting and stimulated C-peptide levels (p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p < 0.001) while those of IL-10 and TGF-ß1 decreased (p < 0.02) and IL-1RA and TGF-ß2 remained unchanged. CONCLUSIONS/INTERPRETATION: The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.


Asunto(s)
Citocinas/sangre , Diabetes Mellitus Tipo 1/sangre , Ayuno , Regulación de la Expresión Génica , Células Secretoras de Insulina/citología , Adolescente , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Péptido C/sangre , Niño , Diabetes Mellitus Tipo 1/metabolismo , Dieta , Femenino , Humanos , Inflamación , Masculino , Factores de Tiempo , Adulto Joven
11.
Vet Pathol ; 50(5): 909-13, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23381923

RESUMEN

A 9-year-old cynomolgus monkey (Macaca fascicularis) infected orally with bovine spongiform encephalopathy (BSE) was presented for necropsy following euthanasia 4 years post infection (p.i.). This macaque R984 was exposed to a BSE dose that causes a simian form of variant Creutzfeldt-Jakob disease (vCJD) within 5 years p.i. in other macaques. All orally BSE-infected macaques developed a significant weight gain within the first 2 years p.i. compared with non-BSE-infected age- and sex-matched control animals, suggesting increased risk of type 2 diabetes (T2D). In contrast, macaque R984 developed rapid weight loss, hyperglycemia, and glucosuria and had to be euthanatized 4 years p.i. before clinical signs of vCJD. Pancreas histopathological evaluation revealed severe islet degeneration but, remarkably, no islet amyloid deposits were present. Immunostaining of pancreas sections for insulin and glucagon confirmed the loss of endocrine cells. In addition, prions were present in the adenohypophysis but not in other areas of the brain, indicating centripetal prion spread from the gut during the preclinical phase of BSE infection. Plasma glucose and insulin concentrations of macaque R984 became abnormal with age and resembled T2D. This unusual case of spontaneous T2D in the absence of islet amyloid deposits could have been due to early prion spread from the periphery to the endocrine system or could have occurred spontaneously.


Asunto(s)
Diabetes Mellitus Tipo 2/patología , Encefalopatía Espongiforme Bovina/complicaciones , Macaca fascicularis , Enfermedades de los Monos/patología , Obesidad/complicaciones , Animales , Glucemia/metabolismo , Peso Corporal , Bovinos , Diabetes Mellitus Tipo 2/etiología , Femenino , Técnicas Histológicas/veterinaria , Insulina/sangre , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Páncreas/patología , Factores Sexuales
12.
Diabet Med ; 29(4): 470-8, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22150724

RESUMEN

AIMS: Systemic concentrations of adhesion molecules and chemokines are associated with increased risk of cardiovascular complications. We compared these factors between patients with Type 2 diabetes vs. Type 1 diabetes or latent autoimmune diabetes in adults. METHODS: Serum concentrations of adhesion molecules sE-selectin, sICAM-1 and sVCAM-1, and chemokines CCL2, CCL3 and CCL4 were measured in 61 patients with latent autoimmune diabetes in adults, 90 with Type 1 diabetes, 465 with Type 2 diabetes and in 41 control subjects, using multiple regression models to adjust for possible confounders. RESULTS: Patients with Type 2 diabetes exhibited greater concentrations of adhesion molecules (P < 0.02) than those with Type 1 diabetes, latent autoimmune diabetes in adults and control subjects. These differences persisted upon adjustments for age, sex, BMI, blood pressure and diabetes duration (P < 0.04). Higher BMI positively correlated with concentrations of adhesion molecules in all subjects (P < 0.0001). Concentrations of sE-selectin positively related to diastolic (ß = 0.31) and systolic (ß = 0.28) blood pressure in the adjusted model (P < 0.04). Concentrations of the chemokines, CCL2 and CCL4, did not differ between groups, while CCL3 was higher in patients with latent autoimmune diabetes in adults and Type 1 diabetes than in those with Type 2 diabetes and control subjects (P < 0.05). CONCLUSIONS: Systemic concentrations of adhesion molecules, but not chemokines, relate to cardiovascular risk factors, but remain higher after adjustments in Type 2 diabetes, suggesting a diabetes-type specific effect without difference between latent autoimmune diabetes in adults and Type 1 diabetes, despite their dissimilar phenotype.


Asunto(s)
Enfermedades Cardiovasculares/sangre , Quimiocinas/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/sangre , Molécula 1 de Adhesión Celular Vascular/sangre , Adulto , Anciano , Presión Sanguínea , Índice de Masa Corporal , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/fisiopatología , Estudios Transversales , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/inmunología , Angiopatías Diabéticas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo
13.
Diabet Med ; 29(6): 734-41, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22150609

RESUMEN

AIMS: The relation of disease progression and age, serum interleukin 10 (IL-10) and interferon gamma (IFNγ) and their genetic correlates were studied in paediatric patients with newly diagnosed Type 1 diabetes. METHODS: Two hundred and twenty-seven patients from the Hvidoere Study Group were classified in four different progression groups as assessed by change in stimulated C-peptide from 1 to 6 months. CA repeat variants of the IL-10 and IFNγ gene were genotyped and serum levels of IL-10 and IFNγ were measured at 1, 6 and 12 months. RESULTS: IL-10 decreased (P < 0.001) by 7.7% (1 month), 10.4% (6 months) and 8.6% (12 months) per year increase in age of child, while a twofold higher C-peptide concentration at 1 month (p = 0.06), 6 months (P = 0.0003) and 12 months (P = 0.02) was associated with 9.7%, 18.6% and 9.7% lower IL-10 levels, independent of each other. IL-10 concentrations did not associate with the disease progression groups. By contrast, IFNγ concentrations differed between the four progression groups at 6 and 12 months (P = 0.02 and P = 0.01, respectively); patients with rapid progressing disease had the highest levels at both time points. Distribution of IL-10 and IFNγ genotypes was equal among patients from the progression groups. CONCLUSION: IL-10 serum levels associate inversely with age and C-peptide. As age and C-peptide also associate, a triangular association is proposed. Genetic influence on IL-10 production seems to be masked by distinct disease mechanisms. Increased serum IFNγ concentrations associate with rapid disease progression. Functional genetic variants do not associate with a single progression pattern group, implying that disease processes override genetically predisposed cytokine production.


Asunto(s)
Envejecimiento/sangre , Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Interferón gamma/sangre , Interleucina-10/sangre , Adolescente , Envejecimiento/genética , Biomarcadores/sangre , Péptido C/genética , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatología , Progresión de la Enfermedad , Ayuno , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Interferón gamma/genética , Interleucina-10/genética , Masculino
14.
Diabetes Metab Res Rev ; 27(8): 727-36, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22069252

RESUMEN

BACKGROUND: Islet-antigen-specific CD4+ T cells are known to promote auto-immune destruction in T1D. Measuring T-cell number and function provides an important biomarker. In response to this need, we evaluated responses to proinsulin and GAD epitopes in a multicentre study. METHODS: A tetramer-based assay was used in five participating centres to measure T-cell reactivities to DR0401-restricted epitopes. Three participating centres concurrently performed ELISPOT or immunoblot assays. Each centre used blind-coded, centrally distributed peptide and tetramer reagents. RESULTS: All participating centres detected responses to auto-antigens and the positive control antigen, and in some cases cloned the corresponding T cells. However, response rates varied among centres. In total, 74% of patients were positive for at least one islet epitope. The most commonly recognized epitope was GAD270-285. Only a minority of the patients tested by tetramer and ELISPOT were concordant for both assays. CONCLUSIONS: This study successfully detected GAD and proinsulin responses using centrally distributed blind-coded reagents. Centres with little previous experience using class II tetramer reagents implemented the assay. The variability in response rates observed for different centres suggests technical difficulties and/or heterogeneity within the local patient populations tested. Dual analysis by tetramer and ELISPOT or immunoblot assays was frequently discordant, suggesting that these assays detect distinct cell populations. Future efforts should investigate shared blood samples to evaluate assay reproducibility and longitudinal samples to identify changes in T-cell phenotype that correlate with changes in disease course.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos de Linfocito T/inmunología , Antígenos HLA-DR/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Adulto , Ensayo de Immunospot Ligado a Enzimas , Humanos , Proinsulina/inmunología
15.
Diabetes Metab Res Rev ; 27(8): 737-45, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22069253

RESUMEN

BACKGROUND: Type 1 diabetes (T1D) is a cell-mediated autoimmune disease characterized by destruction of the pancreatic islet cells. The use of cryopreserved cells is preferable to the use of freshly isolated cells to monitor clinical trials to decrease assay and laboratory variability. METHODS: The T-Cell Workshop Committee of the Immunology of Diabetes Society compared two widely accepted T-cell freezing protocols (warm and cold) to freshly isolated peripheral blood mononuclear cells from patients with T1D and controls in terms of recovery, viability, cell subset composition, and performance in functional assays currently in use in T1D-related research. Nine laboratories participated in the study with four different functional assays included. RESULTS: The cold freezing method yielded higher recovery and viability compared with the warm freezing method. Irrespective of freezing protocol, B cells and CD8+ T cells were enriched, monocyte fraction decreased, and islet antigen-reactive responses were lower in frozen versus fresh cells. However, these results need to take in to account that the overall response to islet autoantigens was low in some assays. CONCLUSIONS: In the current study, none of the tested T-cell functional assays performed well using frozen samples. More research is required to identify a freezing method and a T-cell functional assay that will produce responses in patients with T1D comparable to responses using fresh peripheral blood mononuclear cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Criopreservación/métodos , Diabetes Mellitus Tipo 1/inmunología , Islotes Pancreáticos/inmunología , Supervivencia Celular , Humanos , Proinsulina/inmunología
16.
Diabetologia ; 54(7): 1630-8, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21347621

RESUMEN

AIMS/HYPOTHESIS: Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI. METHODS: The pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration. RESULTS: Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-α cytokines than patients with either LADA or type 1 diabetes (p < 0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (p < 0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (p < 0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (p < 0.04). CONCLUSIONS/INTERPRETATION: Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.


Asunto(s)
Citocinas/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Adulto , Anciano , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1/sangre , Interleucina-10/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangre
17.
Dtsch Med Wochenschr ; 136(5): 172-5, 2011 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-21271474

RESUMEN

INTERVENTIONAL APPROACHES TO BETA CELL PRESERVATION: In a pilot study, initial attempts at primary prevention by preserving islet beta cells have been successful with highly hydrolyzed milk formula in children who are at high genetic risk of diabetes. Attempts at secondary prevention by intranasal application in children with a high-risk HLA genotype and positive islet autoantibodies have been disappointing. But in tertiary prevention anti-inflammatory, antigen-directed and T-cell targeted treatment has been partially successful in slowing down the destruction of beta cells. BIOLOGICAL BETA CELL SUBSTITUTION: Transplantation of a vascularised pancreas or islet cells results in disease regression and the prevention of secondary/tertiary complications of diabetes. A principal aim is the avoidance of frequent, severe hypoglycaemic episodes resulting from markedly reduced awareness of hypoglycaemia or its counter-regulation.


Asunto(s)
Diabetes Mellitus Tipo 1/terapia , Administración Intranasal , Administración Oral , Adolescente , Adulto , Autoanticuerpos/sangre , Supervivencia Celular/fisiología , Niño , Preescolar , Complicaciones de la Diabetes/inmunología , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Genotipo , Humanos , Hidrólisis , Hipoglucemiantes/administración & dosificación , Lactante , Fórmulas Infantiles/administración & dosificación , Insulina/administración & dosificación , Insulina/sangre , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/fisiología , Células Secretoras de Insulina/trasplante , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Trasplante de Islotes Pancreáticos , Proteínas de la Leche , Estudios Multicéntricos como Asunto , Trasplante de Páncreas , Proyectos Piloto , Receptores de Interleucina-1/antagonistas & inhibidores , Factores de Riesgo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Adulto Joven
18.
Clin Exp Immunol ; 163(1): 33-49, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20939860

RESUMEN

Autoimmune T cell responses directed against insulin-producing ß cells are central to the pathogenesis of type 1 diabetes (T1D). Detection of such responses is therefore critical to provide novel biomarkers for T1D 'immune staging' and to understand the mechanisms underlying the disease. While different T cell assays are being developed for these purposes, it is important to optimize and standardize methods for processing human blood samples for these assays. To this end, we review data relevant to critical parameters in peripheral blood mononuclear cell (PBMC) isolation, (cryo)preservation, distribution and usage for detecting antigen-specific T cell responses. Based on these data, we propose recommendations on processing blood samples for T cell assays and identify gaps in knowledge that need to be addressed. These recommendations may be relevant not only for the analysis of T cell responses in autoimmune disease, but also in cancer and infectious disease, particularly in the context of clinical trials.


Asunto(s)
Conservación de la Sangre/métodos , Separación Celular/métodos , Criopreservación/métodos , Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/inmunología , Monocitos/inmunología , Linfocitos T/inmunología , Animales , Antígenos de Superficie/inmunología , Enfermedades Autoinmunes/inmunología , Conservación de la Sangre/normas , Separación Celular/normas , Ensayos Clínicos como Asunto , Criopreservación/normas , Humanos , Infecciones/inmunología , Ratones , Neoplasias/inmunología
19.
Clin Exp Immunol ; 162(2): 197-209, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20846160

RESUMEN

Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell-mediated destruction of the pancreatic insulin-producing beta cells. Currently there are no widely accepted and standardized assays available to analyse the function of autoreactive T cells involved in T1D. The development of such an assay would greatly aid efforts to understand the pathogenesis of T1D and is also urgently required to guide the development of antigen-based therapies intended to prevent, or cure, T1D. Here we describe some of the assays used currently to detect autoreactive T cells in human blood and review critically their strengths and weaknesses. The challenges and future prospects for the T cell assays are discussed.


Asunto(s)
Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Pruebas Inmunológicas/métodos , Islotes Pancreáticos/inmunología , Linfocitos T/inmunología , Humanos , Activación de Linfocitos , Linfocitos T/citología
20.
Clin Exp Immunol ; 161(3): 444-52, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20529086

RESUMEN

The progression of type 1 diabetes after diagnosis is poorly understood. Our aim was to assess the relation of disease progression of juvenile-onset type 1 diabetes, determined by preserved beta cell function the first year after diagnosis, with systemic cytokine concentrations and number of autoantibodies. Juvenile patients (n = 227) had a meal-stimulated C-peptide test 1 and 6 months after diagnosis. On the basis of the C-peptide course for the duration of 1-6 months, four progression groups were defined: patients with persistently low beta cell function ('stable-low'), rapid progressers, slow progressers and remitters. Serum concentrations of adiponectin, interleukin (IL)-1ra, inducible protein 10 (IP-10), IL-6 and glutamic acid decarboxylase (GAD), IA-2A and islet-cell antibodies (ICA) were measured at 1, 6 and 12 months. We found that adiponectin concentrations at 1 month predicted disease progression at 6 months (P = 0·04). Patients with low adiponectin had a higher probability of becoming remitters than rapid progressers, odds ratio 3·1 (1·3-7·6). At 6 and 12 months, adiponectin differed significantly between the groups, with highest concentrations among stable-low and rapid progressers patients (P = 0·03 and P = 0·006). IL-1ra, IP-10 and IL-6 did not differ between the groups at any time-point. The number of autoantibodies differed significantly between the groups at 1 month (P = 0·04), where rapid progressers had the largest number. There was no difference between the groups in human leucocyte antigen-associated risk. We define progression patterns distinguishing patients diagnosed with low beta cell function from those with rapid decline, slow decline or actual increase in beta cell function, pointing to different mechanisms of disease progression. We find that adiponectin concentration at 1 month predicts, and at 6 and 12 months associates with, distinct progression patterns.


Asunto(s)
Adiponectina/sangre , Autoanticuerpos/sangre , Quimiocina CXCL10/sangre , Diabetes Mellitus Tipo 1/sangre , Proteína Antagonista del Receptor de Interleucina 1/sangre , Interleucina-6/sangre , Adolescente , Péptido C/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/inmunología , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Tiempo
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