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OBJECTIVE Cardiovascular disease (CVD) accounts for most deaths in patients with type 1 diabetes (T1D); however, the determinants of plaque composition are unknown. MicroRNAs (miRNAs) regulate gene expression, participate in the development of atherosclerosis and represent promising CVD biomarkers. This study analyzed the circulating miRNA expression profile in T1D with carotid either calcified (CCP) or fibrous (CFP) plaque. RESEARCH DESIGN AND METHODS Circulating small non-coding RNA were sequenced and quantified using NGS and bioinformatic analysis in an exploratory set of 26 T1D with CCP and in 25 with CFP. Then, in a validation set of 40 CCP, 40 CFP and 24 controls T1D, selected miRNAs expression was measured by digital droplet PCR. Putative gene targets enriched for pathways implicated in atherosclerosis/vascular calcification/diabetes were analyzed. Patient’s main clinical characteristics were also recorded. RESULTS miR-503-5p, let-7d-5p, miR-106b-3p, miR-93-5p were significantly up-regulated, while miR-10a-5p downregulated in CCP patients compared to CFP (all FC>±1.5, p CONCLUSIONS These findings characterize miRNAs and their signature in the regulatory network of carotid plaque phenotype, in T1D, providing new insights into plaque pathophysiology, and possibly novel biomarkers of plaque composition.

Type 2 diabetes is characterized by a two- to fourfold increased risk of cardiovascular disease. This is generally attributed to the adverse effects of hyperglycemia and oxidative stress on vascular biology. It has also been shown that patients with prediabetic conditions, such as impaired fasting glucose and impaired glucose tolerance, are at increased risk of cardiovascular disease as well (1). This result suggests that abnormalities in carbohydrate metabolism form a continuum that progressively worsens cardiovascular health; the first step of the adverse sequence of events that leads to the atherosclerotic process is thought to be endothelial dysfunction (2). Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis. In addition to providing a physical barrier between the vessel wall and lumen, the endothelium secretes a number of mediators that regulate platelet aggregation, coagulation, fibrinolysis, and vascular tone. The term “endothelial dysfunction” refers to a condition in which the endothelium loses its physiological properties: the tendency to promote vasodilation, fibrinolysis, and anti-aggregation. Endothelial cells secrete several mediators that can alternatively mediate either vasoconstriction, such as endothelin-1 and thromboxane A2, or vasodilation, such as nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor. NO is the major contributor to endothelium-dependent relaxation in conduit arteries, whereas the contribution of endothelium-derived hyperpolarizing factor predominates in smaller resistance vessels. In patients with diabetes, endothelial dysfunction appears to be a consistent finding; indeed, there is general agreement that hyperglycemia and diabetes lead to an impairment of NO production and activity. The endothelium has a limited intrinsic capacity of self-repair, being built up by terminally differentiated cells with a low proliferative potential. That is why endothelial repair is accomplished through the contribution of circulating cells, namely endothelial progenitor cells (EPCs), in physiological and pathological conditions. In this review, we will outline the mechanisms of endothelial dysfunction …

Defective endothelium is a key event in the development of atherosclerosis in diabetes: alteration of the l-arginine-nitric oxide (NO) pathway has been suggested. We propose a modeling approach of the l-arginine-NO pathway in vivo in both control and type 2 diabetic subjects based on the intravenous bolus injection of l-[15N]arginine and subsequent noncompartmental and compartmental model analysis of l-[15N] arginine in plasma and [15N]nitrate in the urine. No differences in arginine kinetics were observed between normal subjects and diabetic patients. [15N]nitrates were detectable up to 48 h from the l-15[N]arginine administration; no differences were found in the tracer-to-tracee ratio in each urine collection. However, the NO synthesis in plasma from arginine was lower (P = 0.05 for the noncompartmental and 0.1208 for the compartmental analysis, by Mann-Whitney test) in diabetic patients than in control subjects when expressed both in absolute terms (50% decrease) and as percentage of NO turnover (30% decrease). This new modeling approach of l-arginine-NO pathway provides a detailed picture of arginine kinetics and nitrate metabolism. From our data, it appears that noncomplicated type 2 diabetic patients have a decreased conversion of arginine to NO.

OBJECTIVE Vasculoprotective endothelial progenitor cells (EPCs) are regulated by stromal-derived factor-1α (SDF-1α) and are reduced in type 2 diabetes. Because SDF-1α is a substrate of dipeptidyl-peptidase-4 (DPP-4), we investigated whether the DPP-4 inhibitor sitagliptin modulates EPC levels in type 2 diabetic patients. RESEARCH DESIGN AND METHODS This was a controlled, nonrandomized clinical trial comparing 4-week sitagliptin (n = 16) versus no additional treatment (n = 16) in addition to metformin and/or secretagogues in type 2 diabetic patients. We determined circulating EPC levels and plasma concentrations of SDF-1α, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and nitrites/nitrates. RESULTS There was no difference in clinical baseline data between the sitagliptin and control arms. After 4 weeks, as compared with control subjects, patients receiving sitagliptin showed a significant increase in EPCs and SDF-1α and a decrease in MCP-1. CONCLUSIONS Sitagliptin increases circulating EPCs in type 2 diabetic patients with concomitant upregulation of SDF-1α. This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular implications.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β superfamily, has been recently described as a soluble rejuvenation factor for the heart, muscle, and brain. In fact, GDF11 declines in aged mice, while its replenishment improves vascular, brain, muscle, and cardiac function (1–3). As type 2 diabetes (T2D) increases with age and is characterized by accelerated aging (4), we cross-sectionally explored the effects of age, diabetes, and vascular disease on plasma GDF11 concentrations. The study was approved by the local ethics committee and conducted in accordance with the principles of the Declaration of Helsinki. Plasma GDF11 concentrations were measured by ELISA (MBS2502734, MyBioSource) in a previously described cohort of T2D patients and age- and sex-matched control subjects without diabetes (5). As the distribution of GDF11 concentrations was skewed, it was log-transformed before statistical analyses. On average, plasma GDF11 concentrations were higher in T2D patients than …