Clinical and endocrine correlates of circulating sclerostin levels in patients with type 1 diabetes mellitus

Neumann, Thomas; Hofbauer, Lorenz C.; Rauner, Martina; Lodes, S.; Kästner, B.; Franke, Sybille; Kiehntopf, Michael; Lehmann, Thomas; Müller, Ulrich A.; Wolf, Günter; Hamann, Christine; Sämann, A.

doi:10.1111/cen.12364

Cited by 51 publications

(52 citation statements)

References 36 publications

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“…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. Otherwise, after adjusting for age, no differences in sclerostin serum levels by gender were found in subjects with T1DM in the study by Neumann et al (17). In our opinion, the fact that the women we studied had higher sclerostin levels was not a coincidence, because i) we performed serum sclerostin measurements using the same method and the same commercially available kit that was also used by Gennari et al and ii) the women we studied showed a higher bone turnover rate when compared with men, and we can reasonably hypothesize that sclerostin may have contributed to the increased bone resorption.…”

Section: Discussionmentioning

confidence: 76%

“…Sclerostin works by binding to the LDL receptor-related proteins 5 and 6 (LRP5 and LRP6), leading to translocation of b-catenin into the nucleus and to regulation of targeted gene expression (4,5,6). To date, few data have been published on sclerostin in diabetes and only two studies have reported sclerostin serum levels in subjects with T1DM analyzing their relationship with bone turnover markers and bone mass (16,17). However, these cohorts were heterogenous for a number of participants, age, and duration of disease ranges when compared with our study population.…”

Section: Discussionmentioning

confidence: 99%

“…Differently, Neumann et al (17) have recently reported that subjects with T1DM exhibited higher sclerostin concentrations in comparison with controls.…”

Section: Introductionmentioning

confidence: 90%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Catalano

Pintaudi

Morabito

et al. 2014

European Journal of Endocrinology

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Background: Sclerostin is an osteocyte-derived inhibitor of the Wnt/b-catenin signaling pathway, which acts as a negative regulator of bone formation. Published data on sclerostin levels in type 1 diabetes mellitus (T1DM) are few. Objective: To evaluate gender differences in sclerostin serum levels and the association among sclerostin, bone mass, bone metabolism, and the main clinical characteristics of subjects with T1DM. Design and methods: A total of 69 patients with T1DM (mean age, 33.7G8.1; 49% males) were enrolled in this cross-sectional study in a clinical research center. Bone mineral density was measured by phalangeal quantitative ultrasound (QUS); bone turnover markers (urinary pyridinoline, deoxypyridinoline (D-PYR), and urine hydroxyproline (OH-PRO) to evaluate bone resorption; serum bone alkaline phosphatase and BGP to evaluate bone formation) and sclerostin were assessed. Results: D-PYR and sclerostin were significantly higher in women when compared with men (PZ0.04). A disease duration

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

“…Differently, Neumann et al (17) have recently reported that subjects with T1DM exhibited higher sclerostin concentrations in comparison with controls.…”

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Catalano

Pintaudi

Morabito

et al. 2014

European Journal of Endocrinology

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“…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). Hyperglycemia has a detrimental effect on bone health, acting directly on bone cells and indirectly through the formation of advanced glycation end products that have been shown to reduce bone strength and increase the risk of falls and fractures.…”

Section: Discussionmentioning

confidence: 97%

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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Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model

et al. 2021

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Patients with type 1 diabetes mellitus (T1DM) exhibit reduced BMD and significant increases in fracture risk. Changes in BMD are attributed to blunted osteoblast activity and inhibited bone remodeling, but these cannot fully explain the impaired bone integrity in T1DM. The goal of this study was to determine the cellular mechanisms that contribute to impaired bone morphology and composition in T1DM. Nonobese diabetic (NOD) mice were used, along with μCT, histomorphometry, histology, Raman spectroscopy, and RNAseq analyses of several skeletal sites in response to naturally occurring hyperglycemia and insulin treatment. The bone volume in the axial skeleton was found to be severely reduced in diabetic NOD mice and was not completely resolved with insulin treatment. Decreased bone volume in diabetic mice was associated with increased sclerostin expression in osteocytes and attenuation of bone formation indices without changes in bone resorption. In the face of blunted bone remodeling, decreases in the mineral:matrix ratio were found in cortical bones of diabetic mice by Raman microspectroscopy, suggesting that T1DM did not affect the bone mineralization process per se, but rather resulted in microenvironmental alterations that favored mineral loss. Bone transcriptome analysis indicated metabolic shifts in response to T1DM. Dysregulation of genes involved in fatty acid oxidation, transport, and synthesis was found in diabetic NOD mice. Specifically, pyruvate dehydrogenase kinase isoenzyme 4 and glucose transporter 1 levels were increased, whereas phosphorylated‐AKT levels were significantly reduced in diabetic NOD mice. In conclusion, in addition to the blunted bone formation, osteoblasts and osteocytes undergo metabolic shifts in response to T1DM that may alter the microenvironment and contribute to mineral loss from the bone matrix. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Clinical and endocrine correlates of circulating sclerostin levels in patients with type 1 diabetes mellitus

Abstract: Sclerostin serum levels were increased in patients with T1DM, and the positive correlation of age with serum sclerostin levels was stronger in T1DM. There was no effect of serum sclerostin levels on markers of bone metabolism and they do not explain the detrimental effects of T1DM on BMD.

Cited by 51 publications

References 36 publications

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

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

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

Skeletal Response to Insulin in the Naturally Occurring Type 1 Diabetes Mellitus Mouse Model

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