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Lindegaard B.,Copenhagen University | Lindegaard B.,Baker IDI Heart and Diabetes Institute | Matthews V.B.,Baker IDI Heart and Diabetes Institute | Matthews V.B.,University of Western Australia | And 17 more authors.
Diabetes | Year: 2013

Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-induced insulin resistance by activating AMP-activated protein kinase (AMPK). We studied mice with a global deletion of the a-isoform of the IL-18 receptor (IL-18R-/-) fed a standard chow or HFD. We next performed gain-of-function experiments in skeletal muscle, in vitro, ex vivo, and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation, and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R-/- mice display increased weight gain, ectopic lipid deposition, inflammation, and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL-18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited HFD-induced weight gain. In summary, IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis. © 2013 by the American Diabetes Association.

O'Flaherty D.,GSTS Pathology | Sankaralingam A.,GSTS Pathology | Scully P.,Renal Unit | Manghat P.,Darenth Valley Hospital | And 3 more authors.
Clinical Biochemistry | Year: 2013

Objectives: Abnormalities in PTH are implicated in the pathogenesis of bone abnormalities in chronic kidney disease (CKD)-mineral bone disorder (CKD-MBD). PTH concentrations are important in clinical decision and management. This emphasises the importance of providing an assay which measures biologically active PTH. We compared concentrations of intact PTH with biointact PTH (1-84) in CKD and end stage renal disease (ESRD) and investigated the relationship between the 2 PTH assays with bone and mineral laboratory parameters and bone mineral density (BMD) in CKD. Design and methods: We assessed 140 patients (61 in ESRD and 79 with CKD stages 1-4) in this cross-sectional study. We measured biointact PTH (1-84) as well as routine biochemical parameters on all subjects. In the CKD cohort, bone turnover markers; bone alkaline phosphatase (BAP) and tartrate resistant acid phosphatase (TRACP)-5b and bone mineral density (BMD) were also determined. Results: In ESRD, intact PTH concentration was significantly higher compared to biointact PTH (1-84) (422 [443] v/s 266 [251] pg/mL, (p< 0.001) with an average bias of 60%. In CKD, intact PTH concentration was also higher compared to biointact PTH (1-84) (79[55] v/s 68[49] pg/mL p<. 0.001) with an average bias of 18%. Only the biointact PTH (1-84) assay showed any significant correlation with serum calcium concentrations (r=-0.26, p< 0.05) and phosphate (r= 0.25, p< 0.05) in CKD. Following multilinear regression analysis and adjustment for all significant co-variables, only eGFR, BAP and 25 (OH)vitamin remained significantly associated with intact PTH and biointact PTH (1-84). The strength of association was stronger between BAP and biointact PTH (1-84) (biointact PTH (1-84): p=0.007, intact PTH: p= 0.01). In adjusted analyses, only biointact PTH (1-84) was significantly associated with BMD at the fore-arm (FARM) (p= 0.049). Conclusions: The study confirms the differences between intact PTH and biointact PTH (1-84) in ESRD. Whilst there may be similarities in the diagnostic ability of both intact and biointact PTH (1-84), our data suggest that biointact PTH (1-84) assay may better reflect bone metabolism and BMD in CKD. Further longitudinal studies are needed. © 2013 The Canadian Society of Clinical Chemists.

Ishtiaq S.,St. Thomas Hospital | Edwards S.,Osteoporosis Unit | Sankaralingam A.,St. Thomas Hospital | Evans B.A.J.,University of Cardiff | And 5 more authors.
Cytokine | Year: 2015

Bisphosphonates (BPs) have been shown to influence angiogenesis. This may contribute to BP-associated side-effects such as osteonecrosis of the jaw (ONJ) or atypical femoral fractures (AFF). The effect of BPs on the production of angiogenic factors by osteoblasts is unclear. The aims were to investigate the effect of (1) alendronate on circulating angiogenic factors; vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) in vivo and (2) zoledronate and alendronate on the production of VEGF and ANG-1 by osteoblasts in vitro. We studied 18 post-menopausal women with T score≤-2 randomized to calcium/vitamin D only (control arm, n=8) or calcium/vitamin D and alendronate 70mg weekly (treatment arm, n=10). Circulating concentrations of VEGF and ANG-1 were measured at baseline, 3, 6 and 12months. Two human osteoblastic cell lines (MG-63 and HCC1) and a murine osteocytic cell line (MLO-Y4) were treated with zoledronate or alendronate at concentrations of 10-12-10-6M. VEGF and ANG-1 were measured in the cell culture supernatant. We observed a trend towards a decline in VEGF and ANG-1 at 6 and 12months following treatment with alendronate (p=0.08). Production of VEGF and ANG-1 by the MG-63 and HCC1 cells decreased significantly by 34-39% (p<0.01) following treatment with zoledronate (10-9-10-6M). Treatment of the MG-63 cells with alendronate (10-7 and 10-6) led to a smaller decrease (25-28%) in VEGF (p<0.05). Zoledronate (10-10-10- 6M) suppressed the production of ANG-1 by MG-63 cells with a decrease of 43-49% (p<0.01). Co-treatment with calcitriol (10-8M) partially reversed this zoledronate-induced inhibition. BPs suppress osteoblastic production of angiogenic factors. This may explain, in part, the pathogenesis of the BP-associated side-effects. © 2014 Elsevier Ltd.

Mosali P.,St. Thomas Hospital | Mosali P.,The London Clinic | Bernard L.,St. Thomas Hospital | Bernard L.,The London Clinic | And 9 more authors.
Calcified Tissue International | Year: 2014

Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab. © 2014 Springer Science+Business Media New York.

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