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Resistance training attenuates circulating FGF-21 and myostatin and improves insulin resistance in elderly men with and without type 2 diabetes mellitus: A randomised controlled clinical trial.
Shabkhiz, F, Khalafi, M, Rosenkranz, S, Karimi, P, Moghadami, K
European journal of sport science. 2021;(4):636-645
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Abstract
Fibroblast growth factor 21 (FGF-21) and myostatin have been proposed to be potential therapeutic target for insulin resistance in age-related metabolic disorders including type 2 diabetes (T2D). Moreover, despite the potential metabolic effect of resistance training on insulin resistance, aging, and T2D; the effect of this type of exercise training on FGF-21 and myostatin in elderly men with and without T2D are unknown. Forty-four elderly men were assigned to either the RT training (RT; without T2D: 12, with TD2 = 10) or the control group (C; without T2D: 12, with TD2 = 10). The RT group performed 12-wk resistance training intervention, 3 days/wk, 10 repetitions with 70% 1RM. At the baseline, the elderly men with T2D had a higher FGF-21 (p = 0.002) and myostatin (p = 0.02) concentrations and lower muscle strength (p = 0.01) than the elderly men without T2D. RT resulted in significant decrease in FGF-21 and myostatin concentration and increase in muscle strength in both elderly men with and without T2D (P = 0.001, for all) as well as decrease in HOMA-IR in only elderly men without T2D (P = 0.001). There was no significant difference in the RT-induced FGF-21 reduction between elderly men with and without T2D (p = 0.77, p = 0.28, respectively), but, RT caused a larger reduction in circulating myostatin in elderly men without T2D than with T2D (P = 0.007). Taken together, our results demonstrated that 12 weeks of RT induced an overall significant reduction of FGF-21 and myostatin in elderly men with and without T2D; with higher reduction of myostatin in elderly men without T2D.
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Acute effects of dietary phosphorus intake on markers of mineral metabolism in hemodialysis patients: post hoc analysis of a randomized crossover trial.
Tsai, WC, Wu, HY, Chiu, YL, Yang, JY, Pai, MF, Wu, YR, Lin, WY, Hung, KY, Chien, KL, Hsu, SP, et al
Renal failure. 2021;(1):141-148
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Abstract
BACKGROUND Long-term dietary phosphorus excess influences disturbances in mineral metabolism, but it is unclear how rapidly the mineral metabolism responds to short-term dietary change in dialysis populations. METHODS This was a post hoc analysis of a randomized crossover trial that evaluated the short-term effects of low-phosphorus diets on mineral parameters in hemodialysis patients. Within a 9-day period, we obtained a total of 4 repeated measurements for each participant regarding dietary intake parameters, including calorie, phosphorus, and calcium intake, and markers of mineral metabolism, including phosphate, calcium, intact parathyroid hormone (iPTH), intact fibroblast growth factor 23 (iFGF23), and C-terminal fibroblast growth factor 23 (cFGF23). The correlations between dietary phosphorus intake and serum mineral parameters were assessed by using mixed-effects models. RESULTS Thirty-four patients were analyzed. In the fully adjusted model, we found that an increase in dietary phosphorus intake of 100 mg was associated with an increase in serum phosphate of 0.3 mg/dL (95% confidence intervals [CI], 0.2-0.4, p < .001), a decrease in serum calcium of 0.06 mg/dL (95% CI, -0.11 to -0.01, p = .01), an increase in iPTH of 5.4% (95% CI, 1.4-9.3, p = .01), and an increase in iFGF23 of 5.0% (95% CI, 2.0-8.0, p = .001). Dietary phosphorus intake was not related to cFGF23. CONCLUSIONS Increased dietary phosphorus intake acutely increases serum phosphate, iPTH, and iFGF23 levels and decreases serum calcium levels, highlighting the important role of daily fluctuations of dietary habits in disturbed mineral homeostasis in hemodialysis patients.
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Effects of dapagliflozin on the serum levels of fibroblast growth factor 21 and myokines and muscle mass in Japanese patients with type 2 diabetes: A randomized, controlled trial.
Yamakage, H, Tanaka, M, Inoue, T, Odori, S, Kusakabe, T, Satoh-Asahara, N
Journal of diabetes investigation. 2020;(3):653-661
Abstract
AIMS/INTRODUCTION Our aims were to examine the add-on effects of a sodium-glucose cotransporter 2 inhibitor, dapagliflozin, compared with existing antidiabetes treatments, on anthropometric/metabolic parameters, the levels of an endocrine regulator, fibroblast growth factor 21 (FGF21); a skeletal muscle mass (SMM) negative regulator, myostatin; and a metabolic regulator, irisin, in patients with type 2 diabetes. MATERIALS AND METHODS A total of 54 patients with type 2 diabetes were randomly divided into dapagliflozin and control groups. The dapagliflozin group received dapagliflozin 5 mg/day in addition to conventional therapy for 24 weeks. The primary outcome was the change in the level of serum FGF21 from baseline. The secondary outcomes included changes from baseline in anthropometric/metabolic parameters and serum levels of myostatin and irisin. RESULTS Bodyweight decreased in the dapagliflozin group compared with the control group (P < 0.001), but the changes in SMM were not significant between the groups (P = 0.611), thereby elevating the ratio of SMM-to-bodyweight in the dapagliflozin group (P = 0.028). Myostatin levels were significantly decreased (P = 0.010), and irisin levels showed a nearly significant reduction (P = 0.052) in the dapagliflozin group compared with the control group, whereas FGF21 levels did not change significantly from baseline to the end of the intervention in both the dapagliflozin (P = 0.673) and the control (P = 0.823) groups. CONCLUSIONS Dapagliflozin add-on therapy in patients with type 2 diabetes reduced myostatin levels significantly and maintained SMM, without significant changes in FGF21 levels.
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The Effects of Intensive Blood Pressure Lowering on Markers of Mineral Metabolism in Persons with CKD in SPRINT.
Ginsberg, C, Katz, R, Chonchol, MB, Bullen, AL, Raphael, KL, Zhang, WR, Ambrosius, WT, Bates, JT, Neyra, JA, Killeen, AA, et al
Clinical journal of the American Society of Nephrology : CJASN. 2020;(6):852-854
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FGF23 and the PTH response to paricalcitol in chronic kidney disease.
D'Arrigo, G, Pizzini, P, Cutrupi, S, Tripepi, R, Tripepi, G, Mallamaci, F, Zoccali, C
European journal of clinical investigation. 2020;(2):e13196
Abstract
BACKGROUND The parathyroid glands are endowed both with receptors responsive to FGF23 and to 1,25 vitamin D. Vitamin D receptor (VDR) activation, besides lowering PTH, also raises serum FGF23. FGF23 has been implicated in parathyroid resistance to VDR activation but the issue has never been investigated in predialysis CKD patients. METHODS In the Paricalcitol and Endothelial Functio in Chronic Kidney Disease (PENNY) study (NCT01680198), a 12-week randomized trial in stage G3-4 CKD patients (placebo n = 44 and paricalcitol n = 44), we measured PTH and the active form of FGF23 with no missing value across the trial. RESULTS At baseline, serum FGF23 and PTH were inter-related (r = .54, P < .01). Paricalcitol reduced serum PTH (-75.1 pg/mL, 95% CI: -90.4 to -59.8; P < .001) and increased FGF23 (+107 pg/mL, 95% CI: 44-170 pg/mL, P = .001). Changes in the Ca × P product in response to paricalcitol were closely related to simultaneous FGF23 changes in an analysis adjusted for changes in serum calcium and phosphate (P < .001). Of note, baseline FGF23, appropriately adjusted for baseline PTH, was unrelated with the PTH response to paricalcitol (r = -.06, P = .72). Placebo did not change neither PTH nor FGF23. CONCLUSION Serum FGF23 and PTH are inter-related and changes in the Ca × P product induced by paricalcitol per se correlate with the FGF23 response to this drug. Independently of serum FGF23, the parathyroid glands of patients with moderate to severe CKD maintain an intact ability to respond to VDR activation.
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Effects of Weight Loss on FGF-21 in Human Subjects: An Exploratory Study.
Headland, ML, Clifton, PM, Keogh, JB
International journal of environmental research and public health. 2019;(23)
Abstract
Fibroblast growth factor-21 (FGF-21), is a protein involved in cell growth and differentiation, development, wound repair and metabolism. Research looking at the impact of weight loss on FGF-21 levels is limited. The objective of this exploratory study was to determine changes in serum FGF-21 levels following weight loss induced by either continuous energy restriction or intermittent energy restriction. A sub cohort of participants who completed a 12-month dietary intervention trial following continuous energy restriction, or a week-on week-off energy restriction pattern, were selected for analysis. FGF-21 levels were not altered by weight loss and were not correlated with body weight or BMI at baseline or 12 months. Weight loss after 12 months either through continuous energy restriction or intermittent energy restriction was -5.9 ± 4.5 and -4.9 ± 3.4 kg, respectively. There was no change in FGF-21 levels, 0.3 ± 0.9 and 0.04 ± 0.2 ng/mL (p = 0.2). In conclusion, weight loss in healthy overweight or obesity subjects did not affect FGF-21 levels.
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Cholecalciferol supplementation increases FGF23 in peritoneal dialysis patients with hypovitaminosis D: a randomized clinical trial.
Ramirez-Sandoval, JC, Arvizu-Hernandez, M, Cruz, C, Vazquez-Cantu, B, Rojas-Concha, LJ, Tamez, L, Reynerio, F, Gomez, FE, Correa-Rotter, R
Journal of nephrology. 2019;(4):645-659
Abstract
BACKGROUND Vitamin D deficiency is common in peritoneal dialysis (PD) patients, so its supplementation has been advocated as potentially beneficial. METHODS Double-blind, placebo-controlled, randomized clinical trial. Subjects on PD treated with high calcium peritoneal dialysate (Ca 3.5 mEq/l) and serum levels of 25-hydroxi vitamin D (25D) < 20 ng/ml were randomized to receive cholecalciferol (4800 IU/daily) or placebo for 16 weeks. The outcome measures were the effects on the osteogenic biomarkers osteoprotegerin (primary endpoint), intact fibroblast growth factor-23 (iFGF23), osteocalcin, osteopontin, iPTH, 1,25-dyhydroxivitamin D (1,25D), and interleukin-6. RESULTS Fifty-eight subjects were randomly assigned. Baseline characteristics were similar in both groups. Cholecalciferol supplemented subjects had a significant increase in serum 25D (from 11.4 ± 5.0 to 28.3 ± 10.3 ng/ml), 1,25D and iFGF23 compared with placebo group. iFGF23 levels increased an average of 10,875 pg/ml per month (95% CI 11,778-88,414) in the cholecalciferol group and was unchanged in the placebo group (2829 pg/ml, 95% CI - 2181 to 14,972). Extremely high iFGF23 levels (> 30,000 pg/ml) were observed in 74% of subjects receiving cholecalciferol although iFGF23 returned to baseline values after 32 weeks of withdrawal. The observed changes in iFGF23 correlated with 1,25D levels and were not modified by other variables. No difference was observed between groups in osteoprotegerin or other osteogenic biomarkers levels. CONCLUSIONS Cholecalciferol supplementation increases serum 25D levels in subjects on PD exposed to high calcium dialysate, yet it induces an exponential increase of iFGF23 in most patients, which disappear after withdrawal of supplementation and may be a major concern for this maneuver.
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Effects of the Potassium-Binding Polymer Patiromer on Markers of Mineral Metabolism.
Bushinsky, DA, Spiegel, DM, Yuan, J, Warren, S, Fogli, J, Pergola, PE
Clinical journal of the American Society of Nephrology : CJASN. 2019;(1):103-110
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Abstract
BACKGROUND AND OBJECTIVES Patiromer is a sodium-free, nonabsorbed, potassium-binding polymer that uses calcium as the counter-exchange ion and is approved for treatment of hyperkalemia. The 4-week TOURMALINE study in patients with hyperkalemia previously demonstrated that patiromer administered once daily reduces serum potassium similarly when given with or without food. We report a prespecified exploratory efficacy analysis as well as a post hoc efficacy and safety analysis of the TOURMALINE study on circulating markers of mineral metabolism. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Adults with hyperkalemia (potassium >5.0 mEq/L) were randomized to once-daily patiromer 8.4 g without/with food for 4 weeks, with doses adjusted to achieve and maintain serum potassium 3.8-5.0 mEq/L. Baseline and week 4 serum and 24-hour urine markers of mineral metabolism are reported for all patients combined (evaluable for efficacy, n=112; evaluable for safety, n=113). P values were calculated using a paired t test for change from baseline, unless otherwise specified. RESULTS Mean (SD) baseline eGFR was 41±26 ml/min per 1.73 m2. Mean (SD) changes from baseline to week 4 were 0.0±0.5 mg/dl (P=0.78; n=100) for albumin-corrected serum calcium, -0.2±0.2 mg/dl (P<0.001; n=100) for serum magnesium, and -0.1±0.7 mg/dl (P=0.47; n=100) for serum phosphate. Median (quartile 1, quartile 3) changes in 24-hour creatinine-normalized urine calcium and phosphate from baseline to week 4 were 2.5 (-11.5, 23.7) mg/24 h (P=0.10; n=69) and -43.0 (-162.6, 35.7) mg/24 h (P=0.004; n=95), respectively. Median (quartile 1, quartile 3) changes in intact parathyroid hormone and 1,25-dihydroxyvitamin D from baseline to week 4 were -13 (-31, 4) pg/ml (P<0.001; n=97) and -2 (-9, 3) pg/ml (P=0.05; n=96), respectively. There were no changes in fibroblast growth factor-23 or 25-hydroxyvitamin D. In patients (n=16) with baseline serum phosphate >4.8 mg/dL, the mean (SD) changes in serum and 24-hour creatinine-normalized urine phosphate from baseline to Week 4 were -0.6±0.8 mg/dl (n=13) and -149.1±162.6 mg/24hr (n=9), respectively. CONCLUSIONS Patiromer lowered urine phosphate in all patients, and lowered both serum and urine phosphate in a small subset of patients with hyperphosphatemia. Intact parathyroid hormone and 1,25-dihydroxyvitamin D decreased, with no change in serum calcium.
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Fibroblast Growth Factor 23 Trajectories in Chronic Hemodialysis Patients: Lessons from the HEMO Study.
Jovanovich, A, You, Z, Isakova, T, Nowak, K, Cheung, A, Wolf, M, Chonchol, M, Kendrick, J
American journal of nephrology. 2019;(4):263-270
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Abstract
BACKGROUND Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients. OBJECTIVES To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients. METHODS The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality. RESULTS We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI -0.41-0.91) compared to the elevated stable trajectory group. CONCLUSIONS We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality.
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The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia.
Block, GA, Rosenbaum, DP, Yan, A, Greasley, PJ, Chertow, GM, Wolf, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(2):339-346
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Abstract
BACKGROUND Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study. METHODS After 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study. RESULTS After phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P ≤ 0.001-0.04). CONCLUSIONS Following a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor.