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The early identification of type 2 diabetic (T2D) patients at risk of developing coronary artery disease (CAD) remains a challenge. The coronary artery calcium score (CACs) is considered the most sensitive tool for assessing CAD risk in diabetic population, and the identification of a more targeted population in which the CACs would be more cost-efficient seems warranted. The accumulation of advanced glycation end products plays an important role in the pathogenesis of cardiovascular disease (CVD) in patients with diabetes. The aim of this study was to evaluate whether the assessment of skin autofluorescence (SAF) could be useful tool to identify those diabetic patients in whom CACs assessment should be prioritized. Prospective case–control study, comprising 156 subjects with T2D with no history of clinical CVD and 52 non-diabetic subjects matched by age. A value of CACs ≥ 400 Agatston Units (AU) was considered as “high CVD risk.” Logistic regression analysis to predict a CACs ≥ 400 AU was performed. Sensibility and specificity were calculated using the optimal cutoff point based on ROC curve. T2D patients had higher value of SAF compared to controls (p = 0.011). Among subjects with diabetes, 122 presented CACs

The response to Glucagon-like peptide-1 receptor agonists (GLP-1RAs) is highly varia-ble among patients. Thus, the identification of predictive biomarkers of therapeutic response to GLP-1 RA could help us to optimize the use of this class of drugs. GLP-1RAs increase exchange proteins directly activated by cAMP (EPAC). The aim of the present study was to assess whether the increase of EPAC1 after GLP-1RAs treatment could be a biomarker of clinical response.After showing that GLP-1 (10 ng/mL) significantly increased the expression of EPAC1 in human endo-thelial vascular cells (HUVEC), a pilot clinical study was planned. For this purpose 49 patients with type 2 diabetes who started treatment with liraglutide were included. EPAC1 concentration was determined by ELISA before and at one month of liraglutide treatment.We found that serum concentration of EPAC1 increased significantly after treatment with liraglutide. Only in those patients in whom EPAC1 increased (64%), a significant decrease in HbA1c, LDL-C, body mass index (BMI), and waist circumference was shown.This pilot study suggests that the increase of circulating EPAC1 after GLP-1RAs treatment could be a useful biomarker to predict clinical GLP1-RAs response.

Patients with type 2 diabetes have been considered a susceptible group for pulmonary dysfunction. Our aim was to assess pulmonary function on the prediabetes stage. Pulmonary function was assessed in 4,459 non-diabetic subjects, aged between 45 and 70 years, without cardiovascular disease or chronic pulmonary obstructive disease from the ongoing study ILERVAS. A “restrictive spirometric pattern”, an “abnormal FEV1” and an “obstructive ventilatory defect” were assessed. Prediabetes was defined by glycosylated hemoglobin (HbA1c) between 5.7 and 6.4% according to the American Diabetes Association criteria. Population was composed of 52.1% women, aged 57 [53;63] years, a BMI of 28.6 [25.8;31.8] kg/m2, and with a prevalence of prediabetes of 29.9% (n = 1392). Subjects with prediabetes had lower forced vital capacity (FVC: 93 [82;105] vs. 96 [84;106], p

Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are two of the most common diseases of aging around the world. Given the frequency with which T2D and AD occur, the notion that people with T2D may be at increased risk for AD has large societal consequences, and understanding the mechanistic links between these diseases is imperative for the development of effective AD prevention and treatment strategies. Apart from being an accelerator of AD, T2D is associated with a progressive cognitive decline. Impaired insulin signaling, inflammation, the accumulation of advanced glycation end-products and oxidative stress all play an essential role in the pathogenesis of both AD and diabetic complications. Therefore, it is reasonable to postulate that these pathways are involved in the increased risk of dementia that occurs in the T2D population. The early diagnosis of cognitive impairment and the identification of the subset of patients at a higher risk of developing AD is a challenge for healthcare providers, and meeting it will permit us to implement a personalized medicine, which is an essential issue in diabetes care with significant therapeutic implications. The main gaps that should be filled to achieve this objective are examined.

There is clinical evidence that fenofibrate, a PPARα agonist, arrests the progression of diabetic macular edema (DME). However, the underlying mechanisms of this beneficial effect remain to be elucidated. We previously reported that fenofibric acid (FA), the active metabolite of fenofibrate, prevents the disorganization of tight junction proteins and the hyperpermeability provoked by the diabetic milieu in the retinal pigment epithelium (RPE). The aim of the present study was to evaluate whether this effect is mediated by inhibiting the proinflammatory transcription factor NF-κB, as well as the expression of several proinflammatory cytokines involved in the pathogenesis of DME.Human RPE cells were cultured under standard conditions and under conditions leading to the disruption of the monolayer [IL-1β (10 ng/ml)]. The effect of FA, QNZ (a NF-κB inhibitor), WY14643 (a PPARα agonist), and MK-866 (a PPARα antagonist) in the disruption of the monolayer was determined by dextran permeability and immunohistochemistry analyses. The effect of FA on NF-κB activity was assessed by EMSA and by NF-κB/p65 nuclear translocation analyses. The expression of cytokines (IL-6, IL-8, MCP-1) was measured by RT-PCR.FA prevented RPE monolayer disruption, and the consequent hyperpermeability induced by IL-1β, through inhibition of NF-κB activity. This effect was due to PPARα activation and was associated with a significant downregulation of the expression of proinflammatory cytokines.Our findings suggest that the anti-inflammatory effects of FA through inhibition of NF-κB activity play a key role in the beneficial effect of fenofibrate for treating DME.

Liver and muscle glycogen content is reduced in diabetic patients but there is no information on the effect of diabetes on the glycogen content in the retinal pigment epithelium (RPE). The main aim of the study was to compare the glycogen content in the RPE between diabetic and non-diabetic human donors. Glycogen synthase (GS) and glycogen phosphorylase (GP), the key enzymes of glycogen metabolism, as well as their isoforms, were also assessed. For this purpose, 44 human postmortem eye cups were included (22 from 11 type 2 diabetic and 22 from 11 non-diabetic donors matched by age). Human RPE cells cultured in normoglycemic and hyperglycemic conditions were also analyzed. Glycogen content as well as the mRNA, protein content and enzyme activity of GS and GP were determined. In addition, GS and GP isoforms were characterized. In the RPE from diabetic donors, as well as in RPE cells grown in hyperglycemic conditions, the glycogen content was increased. The increase in glycogen content was associated with an increase in GS without changes in GP levels. In RPE form human donors, the muscle GS isoform but not the liver GS isoform was detected. Regarding GP, the muscle and brain isoform of GP but not the liver GP isoform were detected. We conclude that glycogen storage is increased in the RPE of diabetic patients, and it is associated with an increase in GS activity. Further studies aimed at determining the role of glycogen deposits in the pathogenesis of diabetic retinopathy are warranted., This study was supported by grants from the Ministerio de Economía y Competitividad (PI10/01219) and from CIBERDEM (CIBER de Diabetes y Enfermedades Metabólicas Asociadas). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

Data regarding the prevalence of eating disorders (ED) and their influence on clinical outcomes among patients with type 2 diabetes (T2DM) are scarce. Our aim is to investigate the frequency of positive screening for ED, specifically binge eating disorder (BED), in a T2DM sample and analyze whether there are any differences among T2DM subjects with a positive screening for ED or BED. Three hundred and twenty subjects with T2DM were recruited randomly. All participants were evaluated for the presence of ED by completing the “Eating Attitudes Test-26” (EAT-26). In addition, the “Questionnaire of Eating and Weight Patterns–Revised” (QEWP-R) for the screening of BED was also implemented. Sociodemographic, clinical and biochemical parameters were also recorded. According to EAT-26, 14 % of subjects screened positive for ED. Regarding QEWP-R, 16 % had a positive screening for ED, with BED having a frequency of 12.2 %, being the most prevalent one. There was a positive correlation between the scores obtained with the EAT-26 and the Beck Depression Inventory (p = 0.0014). Patients with BED were younger (57.5 ± 11.1 vs 63.3 ± 10.3 years; p = 0.004), with a lesser T2DM duration (8.5 ± 6.1 vs 12.1 ± 9.6 years; p = 0.002). Weight and BMI among subjects with BED were greater (89.1 ± 1.3 vs 82.4 ± 16.7 kg; p = 0.04 and 39.4 ± 10.3 vs 30.7 ± 5.5 kg/m2; p = 0.01). The frequency of subjects with one admission related to T2DM or any other condition during the last year was higher (10 vs 3 %; p = 0.04 and 33 vs 21 %; p = 0.01). ED among T2DM are frequent. Due to their deleterious effect on different metabolic and psychological outcomes, they should be diagnosed promptly, especially BED.

There is now consistent evidence from two major clinical trials (the Fenofibrate Intervention and Event Lowering in Diabetes and the Action to Control Cardiovascular Risk in Diabetes Eye) that fenofibrate arrests the progression of diabetic retinopathy in type 2 diabetic patients. However, the underlying mechanisms of this beneficial effect remain to be elucidated. The aim of the study was to evaluate the potential effect of fenofibric acid (FA), the active metabolite of fenofibrate, in preventing retinal neurodegeneration in an experimental mouse model of type 2 diabetes. For this purpose, we evaluated a total of 24 diabetic mice (db/db) aged 8 weeks that were randomly assigned to daily oral treatment (by gavage) with FA (100 mg/kg/day) (n = 12) or vehicle (n = 12) for 1 week. Ten non-diabetic mice (db/+) were used as control group. Retinal neurodegeneration was evaluated by measuring glial activation (immunofluorescence and Western blot) and apoptosis. Glutamate/aspartate transporter (GLAST) was assessed by immunofluorescence. Functional abnormalities were assessed by electroretinography (ERG). We observed that diabetic mice presented significantly higher glial activation and apoptosis in ganglion cell layer (GCL) than in age-matched non-diabetic mice. Treatment with FA resulted in a significant decrease in both glial activation and the rate of apoptosis in GCL in comparison with diabetic mice treated with vehicle. In addition, FA prevented GLAST downregulation induced by diabetes. Furthermore, a significant improvement of ERG parameters (oscillatory potential amplitudes and b-wave implicit time) was observed. We conclude that FA prevents retinal neurodegeneration induced by diabetes. Our results suggest that neuroprotection is one of the underlying mechanisms by which fenofibrate exerts its beneficial actions in diabetic retinopathy.

The aim of this study was to test whether the augmentation index adjusted for heart rate (AIx@HR75) can be used as a substitute for aortic pulse wave velocity (aPWV) in the measurement of arterial stiffness (AS) in type 1 diabetes. Sixty-eight patients with type 1 diabetes and 68 age- and sex-matched controls were evaluated. AS was assessed by aPWV and AIx@HR75 using applanation tonometry. Subjects with type 1 diabetes had higher aPWV compared to controls, but no differences were found between groups regarding AIx@HR75 [men: 10.75 % (2.63–20.75) vs. 8.25 % (4.00–11.38); p = 0.462. Women: 20.75 % (5.00–30.16) vs. 14.50 % (11.38–22.16); p = 0.418]. In univariate analyses, aPWV correlated positively with AIx@HR75 in both groups (type 1: r = 0.340, p = 0.005; healthy subjects: r = 0.451, p < 0.001). However, AIx@HR75 was not associated with aPWV after adjustment for cardiovascular risk factors in multivariate models (type 1: p = 0.342; healthy subjects: p = 0.976). Our findings suggest that AIx@HR75 should not be used as a substitute for aPWV for measuring AS in type 1 diabetes.