Sclerostin Levels Associated with Inhibition of the Wnt/β-Catenin Signaling and Reduced Bone Turnover in Type 2 Diabetes Mellitus

Gaudio, Agostino; Privitera, F.; Battaglia, Katia; Torrisi, Venerando; Sidoti, Maria Helga; Pulvirenti, Ivana; Canzonieri, Elena; Tringali, Giovanni; Fiore, Carmelo Erio

doi:10.1210/jc.2012-1901

Cited by 160 publications

(123 citation statements)

References 42 publications

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“…Although a strong correlation between serum sclerostin levels, bone density, and body fat was previously demonstrated in healthy subjects and in patients with T2DM (31,39,40), our results could not confirm these findings. Our study is limited by the sole measurement of whole-body minus head bone density and not the individual sites such as the spine, hip, and forearm.…”

Section: Discussioncontrasting

confidence: 99%

“…In a small recent study evaluating a group of healthy offspring of patients with T2DM, serum sclerostin levels were consistently correlated with FPG, although they were not correlated with 2-h PG (30). Another study demonstrated that compared with healthy controls, circulating levels of sclerostin were increased in patients with T2DM, positively associated with duration of T2DM and glycated hemoglobin, and inversely related to bone turnover markers (31,32). Similarly, serum sclerostin levels were elevated in subjects with type 1 diabetes compared with normal control subjects and correlated with HbA 1c (33).…”

Section: Discussionmentioning

confidence: 96%

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Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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OBJECTIVEA gene mutation of the Wnt/b-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/b-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and b-cell function. RESEARCH DESIGN AND METHODSWe performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTSSclerostin levels were higher in IGR compared with NGT (50.8 6 2.4 vs. 38.7 6 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = 20.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = 20.52 and r = 20.44, respectively; both P < 0.001). Sclerostin levels were not correlated with b-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r 2 associated with HOMA-IR (r 2 change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r 2 change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONSSclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

et al. 2015

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“…On the other hand, increased sclerostin (SOST) expression supports the idea that Wnt signalling is suppressed in the patients in our study. Namely, increased SOST is related to the inhibition of Wnt signalling [33]. Therefore, increased SOST level fits very well with increased WIF1 what decreases activity of Wnt signalling.…”

Section: Discussionmentioning

confidence: 55%

Transcriptome analysis of osteosarcoma identifies suppression of wnt pathway and up-regulation of adiponectin as potential biomarker

Märtson¹,

Kõks²,

Reimann³

et al. 2013

Genomics Discov

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Osteosarcoma (OS) is primary malignant bone tumour with complicated early diagnosis. There are no specific markers currently available for predicting the prognosis and chemosensitivity of OS. In present study we performed transcriptome profiling of single patient tumour tissue with RNA-seq technology. We analysed surgically removed sarcoma sample from single 16 years old male patient. Transciptome analysis was done with RNA-seq technology, bioinformatics with Lifescope and R Bioconductor. Validation experiments were done with quantitative real-time PCR (QRTPCR). After quality and coverage filtering, RNA-seq experiment resulted 29,311,899 mapped reads for sarcoma and 22,099,159 mapped reads for normal bone tissue. 65 genes were differentially expressed with FDR corrected statistical significance below 0.05. Seven genes were down-regulated and 58 genes were up-regulated in sarcoma. The most highly up-regulated gene in sarcoma was adiponectin, ADIPOQ (with adjusted p-value 5.5E-07, log2 fold change was 7.9). Many of the genes we found are related to the adipose tissue metabolism (ADIPOQ, PLIN1, FABP4) and to the Wnt signalling suppression (WIF1, SOST). We also found novel fusion transcript between the genes LMTK2 and ZSWIM5. LMTK2 is lemur tyrosine kinase 2, and it has been shown to be involved in NGF-TrkA signalling. Interestingly, studies support the involvement of LMTK2 in development of prostate cancer. ZSWIM5 is zinc finger SWIM domain protein 5 and its function is not known. Immunohistochemical analysis confirmed positive staining for adiponectin in osteosarcoma. This paper is a good illustration how transcriptome analysis can find new biomarkers and targets for complex diseases.

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“…Reduced Wnt signaling and increased Wnt antagonism have been associated with increased oxidative stress, and reduced osteoblast activity [50,162,163]. Oxidative stress activates FOXO signaling, which competes for b-catenin in the cell, to reduce activation of Wnt target genes.…”

Section: Discussionmentioning

confidence: 99%

Determining the Role of Sost and Sostdc1 During Fracture Healing

Yee¹

2016

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Sclerostin Levels Associated with Inhibition of the Wnt/β-Catenin Signaling and Reduced Bone Turnover in Type 2 Diabetes Mellitus

Abstract: These results show for the first time that T2DM patients have serum concentrations of β-catenin lower than controls. The negative association of β-catenin with sclerostin suggests a biological effect of increased sclerostin on the Wnt signaling, which appears impaired in T2DM.

Cited by 160 publications

References 42 publications

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism

Transcriptome analysis of osteosarcoma identifies suppression of wnt pathway and up-regulation of adiponectin as potential biomarker

Determining the Role of Sost and Sostdc1 During Fracture Healing

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