Increased levels of Dickkopf-1 are indicative of Wnt/β-catenin downregulation and lower osteoblast signaling in children and adolescents with type 1 diabetes mellitus, contributing to lower bone mineral density

Tsentidis, Charalampos; Gourgiotis, Dimitrios; Kossiva, Lydia; Marmarinos, Antonios; Doulgeraki, Artemis; Karavanaki, Kyriaki

doi:10.1007/s00198-016-3802-5

Cited by 39 publications

(22 citation statements)

References 32 publications

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“…T1DM is characterised as a state of low bone turnover [ 68 ], as determined by osteoblast dysfunction [ 65 – 67 ]. Of note is that insulin deficiency and insulin-like growth factor-1 (IGF-1) reduction [ 27 , 46 – 48 ] and hyperglycaemia-induced oxidative stress and accumulation of advanced glycation end-products (AGEs) that compromise collagen properties [ 69 , 70 ], low osteocalcin levels [ 62 , 63 ], and/or Wnt signalling pathway [ 71 , 72 ] seem to be causing these changes, resulting in a reduction in the mature osteoblast numbers and thus bone formation, leading to low peak bone mass at a young age [ 31 – 34 ]. Other factors such as inflammatory systemic diseases are characterised by increased levels of proinflammatory cytokines [ 73 ] that uncouple the bone remodelling cycle, also interfering with bone mass acquisition [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Skeletal Status, Body Composition, and Glycaemic Control in Adolescents with Type 1 Diabetes Mellitus

Wierzbicka

Świercz

Płudowski

et al. 2018

Journal of Diabetes Research

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Background Disturbed bone turnover, osteoporosis, and increased fracture risk are late complications of insulin-dependent diabetes mellitus. Little is known about how far and to what extent can glycaemic control of type 1 diabetes mellitus (T1DM) prevent disturbances of bone health and body composition during the growth and maturation period. Objective The aim of this cross-sectional study was to compare the skeletal status outcomes and body composition between patients stratified by glycaemic control (1-year HbA1c levels) into well- and poorly-controlled subgroups in a population of T1DM adolescents, that is, <8% and ≥8%, respectively. Subjects and Methods Skeletal status and body composition were evaluated in 60 adolescents with T1DM (53.3% female; mean aged: 15.1 ± 1.9 years; disease duration: 5.1 ± 3.9 years) using dual energy X-ray absorptiometry (GE Prodigy). The results were compared to age- and sex-adjusted reference values for healthy controls. The calculated Z-scores of different metabolic control subgroups were compared. Clinical data was also assessed. Results As evidenced by Z-scores, patients with T1DM revealed a significantly lower TBBMD (total body bone mineral density), TBBMC (total body bone mineral content), S24BMD (bone mineral density of lumbar spine L2–L4), and TBBMC/LBM ratio (total body bone mineral content/lean body mass), but higher FM (fat mass) and FM/LBM ratio (fat mass/lean body mass) values compared to an age- and sex-adjusted general population. The subset (43.3% patients) with poor metabolic control (HbA1c ≥ 8%) had lower TBBMD, TBBMC, and LBM compared to respective values noted in the HbA1c < 8% group, after adjusting for confounders (mean Z-scores: −0.74 vs. −0.10, p = 0.037; −0.67 vs. +0.01, p = 0.026; and −0.45 vs. +0.20, p = 0.043, respectively). Additionally, we found a significant difference in the TBBMC/LBM ratio (relative bone strength index) between the metabolic groups (−0.58 vs. −0.07; p = 0.021). A statistically significant negative correlation between 1-year HbA1c levels and Z-scores of TBBMD, TBBMC, and LBM was also observed. In patients with longer disease duration, a significant negative correlation was established only for TBBMD, after adjusting for confounders. The relationships between densitometric values and age at onset of T1DM and sex were not significant and showed no relation to any of the analysed parameters of the disease course. Conclusion Findings from this study of adolescents with T1DM indicate that the lower Z-scores of TBBMD, TBBMC, and LBM as well as the TBBMC/LBM ratio are associated with increased HbA1c levels. Their recognition can be crucial in directing strategies to optimise metabolic control and improve diabetes management for bone development and maintenance in adolescents with T1DM.

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Section: Discussionmentioning

confidence: 99%

Skeletal Status, Body Composition, and Glycaemic Control in Adolescents with Type 1 Diabetes Mellitus

Wierzbicka

Świercz

Płudowski

et al. 2018

Journal of Diabetes Research

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“…It has been observed that osteoblasts in T1DM onset undergo transdifferentiation, dedifferentiation and cell death due to defects in the bone marrow stromal cell function . However, a plausible explanation for the reduced osteoblast function is evidenced by elevated levels of Dickkopf‐1 in T1DM, a known inhibitor of the Wnt/β‐catenin signalling pathway . The Wnt/β‐catenin signalling pathway regulates osteoblast differentiation and function whereby its downregulation in mice models has been correlated with reduced bone mineral density and increased frequency of osteocyte apoptosis .…”

Section: Bone Defects In Diabetic Patientsmentioning

confidence: 99%

“…[20] The Wnt/b-catenin signalling pathway regulates osteoblast differentiation and function whereby its downregulation in mice models has been correlated with reduced bone mineral density and increased frequency of osteocyte apoptosis. [20] In contrast, osteoclasts in type 1 diabetic mouse models demonstrated hypersensitivity to the effects of the RANKL, one of two major mediators of osteoclast differentiation with the second being the macrophage colony-stimulating factor. [21] Consequently, this causes extensive bone resorption via the upregulated expression of cathepsin K, matrix metalloproteinase-9 (MMP-9) and pro-osteoclast soluble mediators.…”

Section: Type 1 Diabetes Mellitusmentioning

confidence: 99%

Weak bones in diabetes mellitus – an update on pharmaceutical treatment options

Lin

Dass

2017

Journal of Pharmacy and Pharmacology

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Objectives Diabetes mellitus is often associated with a number of complications such as nephropathy, neuropathy, retinopathy and foot ulcers. However, weak bone is a diabetic complication that is often overlooked. Although the exact mechanism for weak bones within diabetes mellitus is unclear, studies have shown that the mechanism does differ in both type I (T1DM) and type II diabetes (T2DM). This review, however, investigates the application of mesenchymal stem cells, recombinant human bone morphogenetic protein-2, teriparatide, insulin administration and the effectiveness of a peroxisome proliferator-activated receptor-ϒ modulator, netoglitazone in the context of diabetic weak bones. Key findings In T1DM, weak bones may be the result of defective osteoblast activity, the absence of insulin's anabolic effects on bone, the deregulation of the bone-pancreas negative feedback loop and advanced glycation end product (AGE) aggregation within the bone matrix as a result of hyperglycaemia. Interestingly, T2DM patients placed on insulin administration, thiazolidinediones, SGLT2 inhibitors and sulfonylureas have an associated increased fracture risk. T2DM patients are also observed to have high sclerostin levels that impair osteoblast gene transcription, AGE aggregation within bone, which compromises bone strength and a decrease in esRAGE concentration resulting in a negative association with vertebral fractures. Summary Effective treatment options for weak bones in the context of diabetes are currently lacking. There is certainly scope for discovery and development of novel agents that could alleviate this complication in diabetes patients.

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“…Peroxisome proliferator-activated receptor γ (PPARγ) and the WNT/β-catenin pathway act in an opposite manner in many diseases, including MS [ 17 , 18 ]. Numerous autoimmune disorders present this opposed interplay, such as type 1 diabetes [ 19 , 20 ], thyroid autoimmunity [ 21 , 22 ] and rheumatoid arthritis [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

Vallée

Lecarpentier²,

Guillevin

et al. 2018

IJMS

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Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

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Increased levels of Dickkopf-1 are indicative of Wnt/β-catenin downregulation and lower osteoblast signaling in children and adolescents with type 1 diabetes mellitus, contributing to lower bone mineral density

Cited by 39 publications

References 32 publications

Skeletal Status, Body Composition, and Glycaemic Control in Adolescents with Type 1 Diabetes Mellitus

Skeletal Status, Body Composition, and Glycaemic Control in Adolescents with Type 1 Diabetes Mellitus

Weak bones in diabetes mellitus – an update on pharmaceutical treatment options

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

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