Atherosclerotic Disease in Type 2 Diabetes Is Associated With an Increase in Sclerostin Levels

Abstract

OBJECTIVEWnt/β-catenin signaling is related to the pathogenesis of several diseases. Sclerostin is an inhibitor of Wnt/β-catenin signaling. However, there are few data regarding the sclerostin levels and vascular disease. Our aim was to examine the relationship between serum sclerostin and atherosclerotic disease (AD) in type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 78 T2DM patients (45.3% females, mean age 59 ± 5.7 years; 54.7% males, 57.4 ± 6.7 years).RESULTSSerum sclerostin concentrations of T2DM patients in the AD group were significantly higher than in the non-AD group (P = 0.006). For each increase of 1 pmol/L in sclerostin level, there was a 4% increase of the risk of AD in T2DM patients. A concentration of ≥42.3 pmol/L showed a sensitivity of 69% and a specificity of 54.8% to detect an increased risk of AD. In males, sclerostin levels were higher in those with AD (P = 0.04), abnormal intima-media thickness (IMT) (P = 0.004), carotid plaques (P < 0.001), and aortic calcification (P < 0.001). In females, higher levels of sclerostin were related to abnormal IMT (P = 0.03) and aortic calcifications (P = 0.004). Homocysteine (β = 0.319 [95% CI 0.561–2.586], P = 0.003) and IMT (β = 0.330 [14.237–67.693], P = 0.003) were positively correlated with sclerostin.CONCLUSIONSCirculating sclerostin is increased in T2DM patients with atherosclerotic lesions. Although the sample size of our study was small, these data suggest that sclerostin levels could be a major modulator of Wnt signaling in AD with implications in T2DM patients.

Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus

“…Our first interesting and furthermore innovative result was that circulating sclerostin levels were significantly increased in women when compared with men with T1DM. With few exceptions (22), most of the existing data in the literature (23,24) showed higher sclerostin levels in men to an extent diametrically opposed with our findings; furthermore, they are based on studies involving subjects affected by T2DM (30). Even Gennari et al (16) showed higher sclerostin levels in men but the overall cohort also included T2DM subjects and healthy controls; for this reason, their results are not generalizable to T1DM.…”

“…In our study, women exhibited higher sclerostin levels and a lower prevalence of macroangiopathy when compared with men who, on the other hand, showed higher homocysteine levels. Sclerostin was negatively associated with homocysteine in the whole population of T1DM, in contrast to what has recently been observed in T2DM (30). These data may account for an increased cardiovascular risk in men in comparison with women with T1DM.…”

“…Recently, but in a population of subjects with T2DM, Morales-Santana et al (30) have observed an association between circulating sclerostin and surrogate markers of atherosclerotic disease such as abnormal carotid intima-media thickness (IMT), carotid plaque, and aortic calcification. Sclerostin has been found to be involved in vascular calcification (VC) (13,14), and higher sclerostin levels were detected in postmenopausal women with a higher pulse wave velocity (34).…”

“…A reduced bone formation as a consequence of reduced osteoblast activity has been identified as the mean pathogenetic effect or for low bone mineral density (BMD) in subjects with T1DM (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39). intimal thickening in atherosclerosis, and Wnt/b-catenin signaling is a regulator of VSMC behavior (9).…”

The relationship between inhibitors of the Wnt signalling pathway (sclerostin and Dickkopf-1) and carotid intima-media thickness in postmenopausal women with type 2 diabetes mellitus

“…Adjusting for potential confounders, sclerostin and Dkk-1 levels showed inverse significant association with CIMT. The negative association between sclerostin and CIMT contrasts with the findings by Morales-Santana et al 17 We used the same kits to measure sclerostin, and therefore, we do not believe that differences in the methodology for measuring sclerostin explain the differences in the findings from our study and that of Morales-Santana. Gender difference may influence association as sclerostin levels are higher in males compared with females.…”