Circulating Levels of Sclerostin Are Increased in Patients with Type 2 Diabetes Mellitus

García-Martín, Antonia; Rozas-Moreno, Pedro; Reyes-García, Rebeca; Morales-Santana, Sonia; García-Fontana, Beatriz; García‐Salcedo, José A.; Muñóz-Torres, Manuel

doi:10.1210/jc.2011-2186

Cited by 286 publications

(225 citation statements)

References 35 publications

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“…Interestingly, sclerostin levels are increased in diabetes and can be regulated by GLP-1 agonists (6,35). We show here that Ex-4 treatment reduces serum sclerostin in mice.…”

Section: Discussionmentioning

confidence: 57%

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Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Pereira

Jeyabalan

Jorgensen

et al. 2015

Bone

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“…Interestingly, sclerostin levels are increased in diabetes and can be regulated by GLP-1 agonists (6,35). We show here that Ex-4 treatment reduces serum sclerostin in mice.…”

Section: Discussionmentioning

confidence: 57%

“…Clinical data indicate that bone of diabetic patients is fragile and of poor quality, despite a bone mineral density (BMD) that is often normal. Circulating levels of sclerostin, a negative regulator of bone formation produced by osteocytes, are elevated in type 2 diabetic patients (6).…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Pereira

Jeyabalan

Jorgensen

et al. 2015

Bone

View full text Add to dashboard Cite

“…In patients with T2DM, the increase of serum sclerostin is associated with a significant decrease in the b-catenin serum concentration, suggesting, indeed, that sclerostin signaling is modulated in diabetes (31). On one hand, this gives support to the hypothesis that bone, which produces almost all the available sclerostin, may play a role also in glucose metabolism and insulin resistance (8,32,35). On the other hand, it can be speculated that anti-sclerostin antibody treatment, which is a promising option for severe osteoporosis and surgical implant fixation, might have a role in T2DM treatment (36).…”

Section: Discussionmentioning

confidence: 64%

“…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%

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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“…Finally, our data suggest that Wnt targeted therapeutics might have a beneficial impact on metabolism. The increased levels of circulating sclerostin, a bone-derived inhibitor of Wnt signaling (77), in metabolic diseases (78)(79)(80) suggest that therapies designed to increase bone mass by targeting sclerostin (81,82) might also impact circulating lipid levels. To date, body composition has not been a major endpoint in the studies designed to examine antisclerostin agents as a bone anabolic therapy.…”

Section: Discussionmentioning

confidence: 99%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

125

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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Circulating Levels of Sclerostin Are Increased in Patients with Type 2 Diabetes Mellitus

Cited by 286 publications

References 35 publications

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

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

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

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