Beta-cell function is disrupted in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate how markers of beta-cell secretion (proinsulin-processing metabolites) are expressed in SLE patients and their potential relation to features associated with the disease such as activity or damage. METHODS: One hundred and forty-four SLE patients and 69 nondiabetic sex- and age-matched controls were assessed. Beta-cell secretion molecules, as measured by insulin, split and intact proinsulins, and C-peptide levels were analysed in both groups. Multiple regression analysis was performed to compare proinsulin propeptides between groups and to explore the interrelations with SLE features. Analyses were adjusted for glucocorticoid intake and for insulin resistance classic risk factors. RESULTS: Fully multivariable analysis demonstrated that regardless of glucocorticoid use, SLE patients exhibited higher levels of split proinsulin. Likewise, the split proinsulin-to-insulin ratio was upregulated in patients with SLE undergoing glucocorticoid therapy [beta coeficient 0.19 (95% Confidence Interval 0.07, 0.30), P = 0.002] or not [beta coef. 0.09 (95% CI: 0.01, 0.17), P = 0.025]. Similar results were found for the intact proinsulin-to-insulin ratio, although differences were only statistically significant for patients taking glucocorticoids [beta coef. 0.08 (95% CI: 0.03, 0.12), P = 0.001]. SLE damage score was associated with higher serum levels of intact [beta coef. 0.51 (95% CI 0.17, 0.86) pmol/l, P = 0.004] and split proinsulins [beta coef. 1.65 (95% CI 0.24, 3.06) pmol/l, P = 0.022] after multivariable analysis, including disease duration and prednisone use. CONCLUSION: Among patients with SLE, proinsulin-processing metabolites, a marker of beta-cell disruption, are upregulated compared with matched controls. This disproportionate hyperproinsulinemia can be explained by the damage produced by the disease and occurs independently of prednisone use.

Relationship Between Insulin Sensitivity and ß-Cell Secretion in Nondiabetic Subjects with Rheumatoid Arthritis.

OBJECTIVE: In nondiabetic healthy individuals, insulin secretion and sensitivity are linked by a negative feedback loop characterized by a hyperbolic function. We aimed to study the association of traditional insulin resistance (IR) factors with insulin secretion and sensitivity, and to determine whether the hyperbolic equilibrium of this relation is preserved in patients with rheumatoid arthritis (RA). METHODS: This was a cross-sectional study encompassing 361 nondiabetic individuals: 151 with RA and 210 controls. Insulin, C-peptide, and IR indices by homeostatic model (HOMA2) were assessed. A multivariable analysis was performed to evaluate the differences in the correlation of traditional IR-related factors with glucose homeostasis molecules, as well as IR indices between patients and controls. Nonlinear regression analysis was used to assess the hyperbolic relation of insulin sensitivity and secretion. RESULTS: HOMA2-IR indices were higher in patients with RA than controls. Hepatic insulin extraction, as assessed by the insulin:C-peptide molar ratio, was lower in patients with RA after multivariable analysis (0.08 ± 0.02 vs 0.14 ± 0.07, p < 0.001). Traditional IR-related factors showed significantly lower adjusted correlation coefficients with IR indices in patients with RA. The association between insulin sensitivity and secretion showed a different hyperbolic relation in patients with RA: the variability explained by the curve was lower in RA (nonlinear r2 = 0.845 vs r2 = 0.928, p = 0.001) and ß coefficients (-0.74, 95% CI -0.77 to -0.70 vs -1.09, 95% CI -1.17 to -1.02, ng/ml, p < 0.001) were different in RA. CONCLUSION: The traditional factors associated with IR in healthy individuals are less related to IR in patients with RA. Insulin sensitivity and secretion yield a different hyperbolic equilibrium in RA.

Amylin in the insulin resistance of patients with rheumatoid arthritis.

OBJECTIVES: Amylin, which is co-secreted with insulin, plays a role in glycemic regulation and is impaired in type 2 diabetes. In the present study we assess, for the first time, the implication of amylin in the development of insulin resistance (IR) in rheumatoid arthritis (RA). METHODS: This was a cross-sectional study involving 361 non-diabetic individuals, 151 patients with RA and 210 sex-matched controls. Insulin, C-peptide, amylin, lipoprotein serum concentrations, and IR indexes by homeostatic model assessment (HOMA2) were evaluated in patients and controls. A multivariable analysis, adjusted for IR-related factors, was performed to determine the differences between patients and controls vis-à-vis amylin and how it is related to IR in RA. RESULTS: Insulin, C-peptide and HOMA2-IR indexes were higher in RA patients than in controls. Amylin serum levels were found to be upregulated in RA patients compared to controls (1.36 ± 0.81 vs. 1.79 ± 1.51 ng/ml, p=0.011), although this difference was lost after adjusting for covariates (p=0.46). While amylin positively correlated with the presence of rheumatoid factor (beta coef. 0.90 [95%CI -0.23-1.56], p=0.009) and SDAI (beta coef 0.01 [95%CI 0.00-0.03], p=0.034), no significant association with other disease activity scores, glucocorticoid intake, methotrexate use or TNF-alpha inhibitors was found. CONCLUSIONS: IR in RA does not appear to be mediated by amylin. This would imply that the mechanisms associated with IR in RA patients differ from those at work in type 2 diabetes.

Incretins in patients with rheumatoid arthritis.

BACKGROUND: The precise mechanism linking systemic inflammation with insulin resistance (IR) in rheumatoid arthritis (RA) remains elusive. In the present study, we determined whether the incretin-insulin axis and incretin effect are disrupted in patients with RA and if they are related to the IR found in these patients. METHODS: We conducted a cross-sectional study that encompassed 361 subjects without diabetes, 151 patients with RA, and 210 sex-matched control subjects. Insulin, C-peptide, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), dipeptidyl peptidase 4 (DPP-4) soluble form, and IR indexes by homeostatic model assessment (HOMA2) were assessed. A multivariable analysis adjusted for IR-related factors was performed. Additionally, ten patients and ten control subjects underwent a 566-kcal meal test so that we could further study the postprandial differences of these molecules between patients and control subjects. RESULTS: Insulin, C-peptide, and HOMA2-IR indexes were higher in patients than in control subjects. This was also the case for GLP-1 (0.49 ± 1.28 vs. 0.71 ± 0.22 ng/ml, p = 0.000) and GIP (0.37 ± 0.40 vs. 1.78 ± 0.51 ng/ml, p = 0.000). These differences remained significant after multivariable adjustment including glucocorticoid intake. Disease Activity Score in 28 joints with erythrocyte sedimentation rate (ß coefficient 46, 95% CI 6-87, p = 0.026) and Clinical Disease Activity Index (ß coefficient 7.74, 95% CI 1.29-14.20, p = 0.019) were associated with DPP-4 serum levels. GLP-1 positively correlated with ß-cell function (HOMA2 of ß-cell production calculated with C-peptide) in patients but not in control subjects (interaction p = 0.003). The meal test in patients with RA revealed a higher total and late response AUC for glucose response, a later maximal response of C-peptide, and a flatter curve in GIP response. CONCLUSIONS: The incretin-insulin axis, both during fasting and postprandial, is impaired in patients with RA.

Proprotein convertase subtilisin/kexin type 9 in rheumatoid arthritis.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation and that has been linked with cardiovascular risk. The purpose of the present study was to examine whether PCSK9 levels are related to both abnormalities in the lipid profile and the severe atherosclerosis that occur in rheumatoid arthritis (RA) patients. METHODS: Cross-sectional study that encompassed 520 individuals; 326 patients with RA and 194 age- and sex-matched controls. PCSK9 and lipoproteins serum concentrations, standard lipid profile and carotid intima-media thickness (cIMT) and carotid plaques were assessed in patients and controls. A multivariable analysis, adjusted for standard cardiovascular risk factors, was performed to evaluate the influence of PCSK9 on RA related dyslipidaemia and subclinical carotid atherosclerosis. RESULTS: After adjusting for classical cardiovascular risk factors, lipid profile and statins, RA patients showed lower PCSK9 serum concentrations than controls (beta coefficient -45 95%CI [-53, -38] ng/ml, p=0.00). PCSK9 was associated with both cIMT and the presence of carotid plaques in RA patients. However, this association was lost after adjusting for classical cardiovascular risk factors. CONCLUSIONS: PCSK9 is down-regulated in patients with RA.

Serum cathepsin S and cystatin C: relationship to subclinical carotid atherosclerosis in rheumatoid arthritis.

OBJECTIVES: To assess whether serum cathepsin S and cystatin C, two novel markers of cardiovascular disease risk, are associated with subclinical carotid atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Serum cystatin C and cathepsin S levels, carotid intima-media thickness (cIMT) and carotid plaques were assessed in a cross-sectional study involving 178 RA patients. RESULTS: An association between disease activity scores with higher levels of cystatin C, but not with cathepsin S, was found. Cystatin C levels were also associated with cIMT in the patient subgroup included in the higher quartile of Cimt (OR 1.31, 95%CI [1.00-1.72], p=0.04) after adjusting for traditional cardiovascular risk factors, age and sex. An association between serum cystatin C levels and carotid plaques was also found in the univariate analysis (OR 1.37, 95%CI [1.06-1.76], p=0.02). However, this significant association was lost after adjusting for traditional cardiovascular risk factors and age. Cathepsin S was not associated with cIMT or carotid plaques. CONCLUSIONS: High cystatin C serum levels identify a subgroup of RA patients with a high risk of subclinical atherosclerotic disease.

Relationship between endothelial dysfunction and osteoprotegerin, vitamin D, and bone mineral density in patients with rheumatoid arthritis.

OBJECTIVES: We aimed to investigate whether the abnormalities in bone mineral density (BMD) that occur in patients with rheumatoid arthritis (RA) are associated with the presence of endothelial dysfunction. METHODS: Cross-sectional study encompassing 216 subjects (111 patients with RA and 105 age- and sex-matched controls) without history of cardiovascular disease. Endothelial function was determined by brachial artery flow-mediated dilatation (FMD) and BMD by dual x-ray absorptiometry (DXA) measurements. Plasma vitamin D and osteoprotegerin serum (OPG) levels were assessed in patients and controls. Multiple regression analysis was performed to study the relationship between BMD with endothelial function, taking into account vitamin D and OPG levels. RESULTS: After adjusting for traditional cardiovascular risk factors, vitamin D and OPG levels, BMD emerged as an independent factor associated with lower FMD values in controls, but not in patients with RA. Although OPG levels were inversely associated with FMD values in both RA patients and controls after adjusting for BMD, vitamin D showed this relationship only in the controls. CONCLUSIONS: Whilst OPG is associated with endothelial function in RA patients and controls, vitamin D levels and BMD are related to endothelial function in controls but not in patients with RA.

Tecnologías auditivas actuales y desarrollo gramatical infantil / Current auditory technologies and childhood gramatical development

Las nuevas tecnologías audioprotésicas proporcionan a los niños sordos una discriminación de la palabra impensable hace unos años. El objetivo de este estudio es analizar el desarrollo gramatical de niños sordos que emplean dichas tecnologías y comprobar qué variables inciden en las diferencias interindividuales. Se ha evaluado a 32 niños de entre 3 y 7 años con pérdidas auditivas prelocutivas bilaterales superiores a 70 dB, que emplean audífono de programación digital o implante coclear unilateral o bilateral. A cada participante se le administró la prueba Escalas de Desarrollo del Lenguaje de Reynell III, que incluye una escala de comprensión verbal y otra de lenguaje expresivo. Los resultados muestran que solo un 30% de los participantes alcanza un desarrollo lingüístico normalizado. En la escala de comprensión, la dificultad comienza en oraciones que relacionan más de 2 elementos, y se hace muy patente en pasivas y subordinadas. En expresión, la gramática que resulta más compleja a la mayoría es la correspondiente a la edad de 3 años. Y también se detectan dificultades importantes en la flexión de verbos en pasado, tercera persona y plural de sustantivos. La edad de colocación de la prótesis o el implante resulta ser la variable más explicativa, y a ella se suma el nivel sociocultural familiar (AU)

The new auditory technologies provide deaf children with auditory speech discrimination that was unthinkable a few years ago. The aim of this study was to analyze grammatical development in deaf children using new auditory technologies, and to confirm which variables account for intersubject differences. We evaluated 32 children (aged 3-7 years) with bilateral and congenital or pre-speech deafness and hearing loss greater than 70 dB, who used digital hearing aids or cochlear implants. The Reynell Developmental Language Scales III was administered in each child. The results showed that only 30% of the participants demonstrated age-appropriate language skills. In language comprehension, sentences connecting more than 2 elements caused difficulties, which were greater when these sentences were passive and subordinate. In expressive language, a grammatical level equivalent to that in 3-year-olds caused the most difficulty for most of the participants. Expressive language related to inflections of past tense and third person verbs, and plural noun construction also caused difficulties. The most explanatory variable was age at implantation and at prosthesis fitting in deaf children. The family's sociocultural level was also important (AU)