Didac Mauricio

High prevalence of ischaemia, infection and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study

Aims/hypothesisLarge clinical studies describing the typical clinical presentation of diabetic foot ulcers are limited and most studies were performed in single centres with the possibility of selection of specific subgroups. The aim of this study was to investigate the characteristics of diabetic patients with a foot ulcer in 14 European hospitals in ten countries.MethodsThe study population included 1,229 consecutive patients presenting with a new foot ulcer between 1 September 2003 and 1 October 2004. Standardised data on patient characteristics, as well as foot and ulcer characteristics, were obtained. Foot disease was categorised into four stages according to the presence or absence of peripheral arterial disease (PAD) and infection: A: PAD −, infection −; B: PAD −, infection +; C: PAD +, infection −; D: PAD +, infection +.ResultsPAD was diagnosed in 49% of the subjects, infection in 58%. The majority of ulcers (52%) were located on the non-plantar surface of the foot. With regard to severity, 24% had stage A, 27% had stage B, 18% had stage C and 31% had stage D foot disease. Patients in the latter group had a distinct profile: they were older, had more non-plantar ulcers, greater tissue loss and more serious comorbidity.Conclusions/interpretationAccording to our results in this European cohort, the severity of diabetic foot ulcers at presentation is greater than previously reported, as one-third had both PAD and infection. Non-plantar foot ulcers were more common than plantar ulcers, especially in patients with severe disease, and serious comorbidity increased significantly with increasing severity of foot disease. Further research is needed to obtain insight into the clinical outcome of these patients.

Role of vitamin D in the pathogenesis of type 2 diabetes mellitus

Vitamin D deficiency has been shown to alter insulin synthesis and secretion in both humans and animal models. It has been reported that vitamin D deficiency may predispose to glucose intolerance, altered insulin secretion and type 2 diabetes mellitus. Vitamin D replenishment improves glycaemia and insulin secretion in patients with type 2 diabetes with established hypovitaminosis D, thereby suggesting a role for vitamin D in the pathogenesis of type 2 diabetes mellitus. The presence of vitamin D receptors (VDR) and vitamin D–binding proteins (DBP) in pancreatic tissue and the relationship between certain allelic variations in the VDR and DBP genes with glucose tolerance and insulin secretion have further supported this hypothesis. The mechanism of action of vitamin D in type 2 diabetes is thought to be mediated not only through regulation of plasma calcium levels, which regulate insulin synthesis and secretion, but also through a direct action on pancreatic β‐cell function. Therefore, owing to its increasing relevance, this review focuses on the role of vitamin D in the pathogenesis of type 2 diabetes mellitus.

Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

BACKGROUND Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. METHODS We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING National Institutes of Health and Juvenile Diabetes Research Foundation.

Resource utilisation and costs associated with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale Study

Aims/hypothesisThe aim of the present study was to investigate resource utilisation and associated costs in patients with diabetic foot ulcers and to analyse differences in resource utilisation between individuals with or without peripheral arterial disease (PAD) and/or infection.MethodsData on resource utilisation were collected prospectively in a European multicentre study. Data on 1,088 patients were available for the analysis of resource use, and data on 821 patients were included in the costing analysis. Costs were calculated for each patient by multiplying the country-specific direct and indirect unit costs by the number of resources used from inclusion into the study up to a defined endpoint. Country-specific costs were converted into purchasing power standards.ResultsResource use and costs varied between outcome groups and between disease severity groups. The highest costs per patient were for hospitalisation, antibiotics, amputations and other surgery. All types of resource utilisation and costs increased with the severity of disease. The total cost per patient was more than four times higher for patients with infection and PAD at inclusion than for patients in the least severe group, who had neither.Conclusions/interpretationImportant differences in resource use and costs were found between different patient groups. The costs are highest for individuals with both peripheral arterial disease and infection, and these are mainly related to substantial costs for hospitalisation. In view of the magnitude of the costs associated with in-hospital stay, reducing the number and duration of hospital admissions seems an attractive option to decrease costs in diabetic foot disease.

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype: Action LADA 7

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Control of Glycemia and Cardiovascular Risk Factors in Patients With Type 2 Diabetes in Primary Care in Catalonia (Spain)

OBJECTIVE The objective of this study was to analyze the clinical characteristics and levels of glycemic and cardiovascular risk factor control in patients with type 2 diabetes that are in primary health care centers in Catalonia (Spain). RESEARCH DESIGN AND METHODS This was a cross-sectional study of a total population of 3,755,038 individuals aged 31–90 years at the end of 2009. Clinical data were obtained retrospectively from electronic clinical records. RESULTS A total of 286,791 patients with type 2 diabetes were identified (7.6%). Fifty-four percent were men, mean (SD) age was 68.2 (11.4) years, and mean duration of disease was 6.5 (5.1) years. The mean (SD) A1C value was 7.15 (1.5)%, and 56% of the patients had A1C values ≤7%. The mean (SD) blood pressure (BP) values were 137.2 (13.8)/76.4 (8.3) mmHg, mean total cholesterol concentration was 192 (38.6) mg/dL, mean HDL cholesterol concentration was 49.3 (13.2) mg/dL, mean LDL cholesterol (LDL-C) concentration was 112.5 (32.4) mg/dL, and mean BMI was 29.6 (5) kg/m2. Thirty-one percent of the patients had BP values ≤130/80 mmHg, 37.9% had LDL-C values ≤100 mg/dL, and 45.4% had BMI values ≤30 kg/m2. Twenty-two percent were managed exclusively with lifestyle changes. Regarding medicated diabetic patients, 46.9, 22.9, and 2.8% were prescribed one, two, or three antidiabetic drugs, respectively, and 23.4% received insulin therapy. CONCLUSIONS The results from this study indicate a similar or improved control of glycemia, lipids, and BP in patients with type 2 diabetes when compared with previous studies performed in Spain and elsewhere.

Delivery of care to diabetic patients with foot ulcers in daily practice: results of the Eurodiale Study, a prospective cohort study

Aims  To determine current management and to identify patient‐related factors and barriers that influence management strategies in diabetic foot disease.

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype Action LADA 7

OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3). CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

Diabetes classification: grey zones, sound and smoke: Action LADA 1

Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis‐prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.