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    Intact FGF23 and α-Klotho during acute inflammation/sepsis in CKD patients. Dounousi Evangelia,Torino Claudia,Pizzini Patrizia,Cutrupi Sebastiano,Panuccio Vincenzo,D'Arrigo Graziella,Abd ElHafeez Samar,Tripepi Giovanni,Mallamaci Francesca,Zoccali Carmine European journal of clinical investigation BACKGROUND:High FGF23 and low α-Klotho levels associate with systemic inflammation and reduced nitric oxide (NO) bioavailability, but the dynamics of this relationship in patients with CKD has not been investigated. METHODS:We sequentially measured serum intact FGF23 and carboxyl-terminal (iFGF23, cFGF23), the iFGF23/cFGF23 ratio, αKlotho, biomarkers of inflammation (hs-CRP, IL-6 and TNF-α) and sepsis (procalcitonin), nitrotyrosine (reflecting NO synthesis and oxidative stress), serum iron and ferritin and CKD-MBD biomarkers, PTH, 25(OH)VD, 1,25(OH)2 VD at peak of intercurrent sepsis and after complete resolution in a series of 17 patients with CKD. RESULTS:At peak infection, biomarkers of inflammation/sepsis, ferritin and nitrotyrosine were all very high (all P < 0·01) and declined towards the normal range thereafter (P < 0·01). iFGF23 was 191 ± 10 pg/ml (geometric mean, SD) and doubled to 371 ± 8 pg/ml (P = 0·003) after the resolution of infection, while cFGF23 did not change (246 ± 5 pg/mL vs. 248 ± 5 pg/mL, P = 0·50). As a consequence, the iFGF23/cFGF23 ratio, an indicator of the proteolytic cleavage of the FGF23 molecule, was 0·78 ± 3·87 at peak infection and increased to 1·49 ± 3·00 after resolution of infection (P < 0·001). In contrast, serum α-Klotho levels were upregulated at peak infection (peak infection: 526 ± 4 pg/ml, postinfection: 447 ± 4 pg/ml, P = 0·001). The eGFR, PTH and vitamin D did not change significantly throughout. CONCLUSIONS:Acute inflammation/sepsis suppresses the active form of FGF23 and activates α-Klotho, the latter effect being likely attributable to enhance proteolysis of FGF23 molecule. iFGF23 downregulation and α-Klotho upregulation during acute sepsis may participate into the counter-regulatory response to severe inflammation in CKD patients with sepsis. 10.1111/eci.12588
    Fibroblast growth factor-23 but not sKlotho levels are related to diastolic dysfunction in type 1 diabetic patients with early diabetic nephropathy. Dogan Burcu,Arikan Izzet Hakki,Guler Derya,Keles Nursen,Isbilen Banu,Isman Ferruh,Oguz Aytekin International urology and nephrology PURPOSE:To investigate the soluble Klotho (sKlotho) and fibroblast growth factor-23 (FGF-23) levels and echocardiographic findings in type 1 diabetic patients with no or early diabetic nephropathy. METHODS:A total of 147 subjects (mean age 34.1 ± 9.2 years, 55.8 % were females) including type 1 diabetic patients with glomerular filtration rate (GFR) >60 ml/min (n = 71, mean age 34.3 ± 9.5 years, 54.9 % were females) and healthy controls (n = 76, mean age 33.9 ± 9.1 years, 56.6 % were females) were included in this study. Data on demographic characteristics, blood biochemistry, urinalysis, diabetes-related complications and echocardiography were recorded. Serum levels for sKlotho and FGF-23 were determined by ELISA method. RESULTS:Patient and control groups were similar in terms of mean sKlotho (509.2 ± 183.5 and 547.6 ± 424.0 pg/ml, respectively) and FGF-23 (76.2 ± 15.6 and 77.2 ± 15.1 pg/ml, respectively) levels as well as echocardiographic findings. No significant correlation of sKlotho (pg/ml) and FGF-23 (pg/ml) levels with cardiac parameters was noted among diabetic patients. In subgroup analysis, the correlations between FGF-23 levels and isovolumic relaxation time (ms) and early diastolic velocity at medial/septal annulus (E'med) (m/s) were significant only in patients with early diabetic nephropathy (DN) but not in non-DN patients. No significant association of sKlotho levels with echocardiographic findings was noted. CONCLUSIONS:Our findings in young adult type 1 diabetic patients with GFR >60 ml/min versus healthy controls revealed no difference between groups in terms of sKlotho and FGF-23 levels and echocardiographic findings, while a significant correlation of FGF-23 (pg/ml) levels and diastolic dysfunction was noted only in patients with DN. 10.1007/s11255-015-1190-y
    Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children. Kunert Svenja Kristin,Hartmann Hans,Haffner Dieter,Leifheit-Nestler Maren Journal of bone and mineral metabolism The fibroblast growth factor (FGF) 23/Klotho axis is a principal regulator of phosphate hemostasis and vitamin D metabolism, but limited data is available on its role in the central nervous system. Here, we investigate soluble α-Klotho (sKlotho) and C-terminal as well as intact FGF23 in cerebrospinal fluid (CSF) and plasma and their relationship to mineral metabolism parameters in humans. In 39 children aged 0.3-16.8 years undergoing lumbar puncture for the exclusion of inflammatory neurological disease, sKlotho and FGF23 were investigated by Western blot analysis, followed by ELISA quantification in CSF and plasma. The percentage of intrathecal synthesis of both proteins was calculated by measuring both the expected and observed CSF/plasma ratios of sKlotho and FGF23. The secreted (KL1) and cleaved (KL1+KL2) isoforms of sKlotho, and FGF23 were clearly detected in CSF in all subjects, although protein levels were lower compared to those of plasma samples (each p < 0.01). The intrathecal percentage of CSF sKlotho and FGF23 synthesis amounted to 98 and 99 %, respectively. CSF sKlotho levels were higher in boys than in girls (p < 0.01), and correlated positively with plasma C-terminal FGF23 concentrations (p < 0.05) and standardized height (p < 0.01). Importantly, there were no significant correlations between plasma and CSF levels of sKlotho or FGF23. Plasma sKlotho as well as C-terminal and intact FGF23, respectively, were associated with parameters of mineral metabolism These results provide evidence that cleaved and secreted sKlotho and FGF23 are present in CSF, mainly derived from brain and affected by sex, height, and mineral metabolism parameters in children. Nevertheless, the absence of significant associations between plasma and CSF levels of Klotho and FGF23, respectively, suggest that the regulation of Klotho and FGF23 may be different between organs secreting these hormones into blood and CSF. 10.1007/s00774-016-0746-y
    Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. Muñoz-Castañeda Juan R,Herencia Carmen,Pendón-Ruiz de Mier Maria Victoria,Rodriguez-Ortiz Maria Encarnación,Diaz-Tocados Juan M,Vergara Noemi,Martínez-Moreno Julio M,Salmerón Maria Dolores,Richards William G,Felsenfeld Arnold,Kuro-O Makoto,Almadén Yolanda,Rodríguez Mariano FASEB journal : official publication of the Federation of American Societies for Experimental Biology In renal failure, hyperphosphatemia occurs despite a marked elevation in serum fibroblast growth factor (FGF)-23. Abnormal regulation of the FGFR1-Klotho receptor complex may cause a resistance to the phosphaturic action of FGF23. The purpose of the present study was to investigate the regulation of renal Klotho and FGF receptor (FEFR)-1 in healthy and uremic rats induced by 5/6 nephrectomy. In normal rats, the infusion of rat recombinant FGF23 enhanced phosphaturia and increased renal FGFR1 expression; however, Klotho expression was reduced. Uremic rats on a high-phosphate (HP) diet presented hyperphosphatemia with marked elevation of FGF23 and an increased fractional excretion of phosphate (P) that was associated with a marked reduction of Klotho expression and an increase in FGFR1. After neutralization of FGF23 by anti-FGF23 administration, phosphaturia was still abundant, Klotho expression remained low, and the FGFR1 level was reduced. These results suggest that the expression of renal Klotho is modulated by phosphaturia, whereas the FGFR1 expression is regulated by FGF23. Calcitriol (CTR) administration prevented a decrease in renal Klotho expression. In HEK293 cells HP produced nuclear translocation of β-catenin, together with a reduction in Klotho. Wnt/β-catenin inhibition with Dkk-1 prevented the P-induced down-regulation of Klotho. The addition of CTR to HP medium was able to recover Klotho expression. In summary, high FGF23 levels increase FGFR1, whereas phosphaturia decreases Klotho expression through the activation of Wnt/β-catenin pathway.-Muñoz-Castañeda, J. R., Herencia, C., Pendón-Ruiz de Mier, M. V., Rodriguez-Ortiz, M. E., Diaz-Tocados, J. M., Vergara, N., Martínez-Moreno, J. M., Salmerón, M. D., Richards, W. G., Felsenfeld, A., Kuro-O, M., Almadén, Y., Rodríguez, M. Differential regulation of renal Klotho and FGFR1 in normal and uremic rats. 10.1096/fj.201700006R
    Alpha Klotho and Fibroblast Growth Factor-23 Among Alcoholics. Quintero-Platt Geraldine,González-Reimers Emilio,Rodríguez-Gaspar Melchor,Martín-González Candelaria,Pérez-Hernández Onán,Romero-Acevedo Lucía,Espelosín-Ortega Elisa,Vega-Prieto María José de la,Santolaria-Fernández Francisco Alcohol and alcoholism (Oxford, Oxfordshire) AIMS:Alcoholism may be a cardiovascular risk factor. Osteocyte derived molecules such as fibroblast growth factor 23 (FGF-23) and soluble α Klotho have recently been associated with cardiovascular disease, but their role in alcoholics is unknown. We here analyze the behavior of FGF23 and α Klotho in alcoholics. METHODS:Ninety-seven alcoholic patients were assessed for liver function, presence of hypertension, diabetes, atrial fibrillation, left ventricular hypertrophy (LVH), vascular calcifications (assessed by chest X-ray) and nutritional status (lean and fat mass measured by densitometry). We measured plasma levels of FGF-23 and serum soluble α Klotho, using ELISA in 97 patients and 20 age- and sex-matched controls. RESULTS:FGF-23 levels were higher in patients than in controls (Z = 3.50; P < 0.001). FGF-23 (Z = 5.03; P < 0.001) and soluble α Klotho (Z = 5.61; P < 0.001) were higher in cirrhotics, and both were related to liver function, independently of serum creatinine FGF-23 levels were higher among alcoholics with diabetes (Z = 2.55; P = 0.011) or hypertension (Z = 2.56; P = 0.01), and increased body fat (ρ = 0.28; P = 0.022 for trunk fat), whereas α Klotho levels were higher in patients with LVH (Z = 2.17; P = 0.03) or atrial fibrillation (Z = 2.34; P = 0.019). CONCLUSIONS:FGF-23 was higher in alcoholics than in controls, especially among cirrhotics, and soluble α Klotho levels were also higher among cirrhotics. Both were related to liver function impairment, independently of serum creatinine levels, and also showed significant associations with vascular risk factors, such as hypertension, diabetes or trunk fat amount in the case of FGF-23, or LVH or atrial fibrillation in the case of α Klotho. SHORT SUMMARY:We report increased values of fibroblast growth factor 23 (FGF-23) and soluble α Klotho in cirrhotic alcoholics. Both molecules are associated with liver function impairment, and with some cardiovascular risk factors such as diabetes, hypertension, increased body fat, left ventricular hypertrophy and atrial fibrillation independently of serum creatinine. 10.1093/alcalc/agx041
    Fibroblast growth factor 23 and Klotho contribute to airway inflammation. Krick Stefanie,Grabner Alexander,Baumlin Nathalie,Yanucil Christopher,Helton Scott,Grosche Astrid,Sailland Juliette,Geraghty Patrick,Viera Liliana,Russell Derek W,Wells J Michael,Xu Xin,Gaggar Amit,Barnes Jarrod,King Gwendalyn D,Campos Michael,Faul Christian,Salathe Matthias The European respiratory journal Circulating levels of fibroblast growth factor (FGF)23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-Klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and Klotho-mediated FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised that FGF23 can potentiate airway inflammation Klotho-independent FGFR4 activation.FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients, and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model.Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in interleukin-1β release Klotho-independent FGFR4-mediated activation of phospholipase Cγ/nuclear factor of activated T-cells signalling. In addition, Klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of Klotho led to an attenuation of airway inflammation.Cigarette smoke induces airway inflammation by downregulation of Klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD. 10.1183/13993003.00236-2018
    Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23. Matsui Isao,Oka Tatsufumi,Kusunoki Yasuo,Mori Daisuke,Hashimoto Nobuhiro,Matsumoto Ayumi,Shimada Karin,Yamaguchi Satoshi,Kubota Keiichi,Yonemoto Sayoko,Higo Tomoaki,Sakaguchi Yusuke,Takabatake Yoshitsugu,Hamano Takayuki,Isaka Yoshitaka Kidney international Several experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Moreover, transverse aortic constriction also upregulated myocardial FGF23 expression in wild type mice. The promoter region of the FGF23 gene contains two putative nuclear factors of activated T cells (NFAT)-binding sites, with NFAT1 activating the promoter in a proximal NFAT-binding site dependent manner. Neither serum, urinary, or fractional excretion values of calcium and phosphate nor serum levels of 1,25(OH) vitamin D were different between wild type and transgenic mice. Moreover, the renal expression of FGF receptors and α-Klotho was comparable. However, plasma levels of antidiuretic hormone were significantly increased in the transgenic mice, and aquaporin-2 immunohistochemical staining was mainly positive in the apical membrane of the collecting duct, compared to a primarily cytoplasmic staining in wild type mice. Real-time PCR analyses of kidney CYP27B1 and CYP24A1 expression in wild type mice showed that exogenous antidiuretic hormone blocked FGF23's actions on these vitamin D activating or inactivating enzymes. Finally, the renal resistance of transgenic mice to FGF23 was partly overcome by tolvaptan. Thus, LVH in transgenic mice is associated with an increase in myocardial and serum intact FGF23, with the kidneys being protected against FGF23 excess by elevated antidiuretic hormone levels. 10.1016/j.kint.2018.02.018
    α-Klotho's effects on mineral homeostasis are fibroblast growth factor-23 dependent. Erben Reinhold G Current opinion in nephrology and hypertension PURPOSE OF REVIEW:α-Klotho (Klotho) occurs in three isoforms, a membrane-bound form acting as a coreceptor for fibroblast growth factor-23 (FGF23) signalling, a shed soluble form consisting of Klotho's large ectodomain thought to act as an enzyme or a hormone, and a secreted truncated form generated by alternative splicing of the Klotho mRNA with unknown function. The purpose of this review is to highlight the recent advances in our understanding of Klotho's function in mineral homeostasis. RECENT FINDINGS:A number of seminal discoveries have recently been made in this area, shifting existing paradigms. The crystal structure of the ternary FGF receptor (FGFR)-1c/Klotho/FGF23 complex has been uncovered, revealing how the ligand FGF23 interacts with FGFR1c and the coreceptor Klotho at atomic resolution. Furthermore, it was shown that soluble Klotho lacks any glycosidase activity and serves as a bona fide coreceptor for FGF23 signalling. Experiments with a combination of Klotho and Fgf23-deficient mouse models demonstrated that all isoforms of Klotho lack any physiologically relevant, FGF23-independent functions in mineral homeostasis or ageing. Finally, it was demonstrated that the alternatively spliced Klotho mRNA is degraded and is not translated into a secreted Klotho protein isoform in humans. SUMMARY:Taken together, there is now overwhelming evidence that the main physiological function of transmembrane and soluble Klotho for mineral homeostasis is their role as coreceptors mediating FGF23 actions. In light of these findings, the main pathophysiological consequence of the downregulation of Klotho observed in acute and chronic renal failure may be the induction of renal FGF23 resistance. 10.1097/MNH.0000000000000415
    Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Daryadel Arezoo,Bettoni Carla,Haider Thomas,Imenez Silva Pedro H,Schnitzbauer Udo,Pastor-Arroyo Eva Maria,Wenger Roland H,Gassmann Max,Wagner Carsten A Pflugers Archiv : European journal of physiology Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH) vitamin D metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH) vitamin D, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH) vitamin D are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH) D levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71 erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH) vitamin D levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism. 10.1007/s00424-018-2171-7
    Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters. Hu Ming Chang,Shi Mingjun,Moe Orson W Pflugers Archiv : European journal of physiology Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins: βKlotho and γKlotho; αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH and 1,25-(OH)D. The direct role of αKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na-dependent phosphate co-transporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones, and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease. 10.1007/s00424-018-2238-5
    Fibroblast Growth Factor 23 to Alpha-Klotho Index Correlates with Systemic Sclerosis Activity: A Proposal for Novel Disease Activity Marker. Kotyla Przemyslaw J,Kruszec-Zytniewska Aneta,Owczarek Aleksander J,Olszanecka-Glinianowicz Magdalena,Chudek Jerzy Journal of clinical medicine Systemic sclerosis, a connective tissue disease, is characterized by thickening of the skin, massive fibrosis of internal organs, vasculopathy, and immune system functioning aberration. Recently, vitamin D (VD) deficit, seen almost universally in patients with systemic sclerosis (SSc), has gained much attention. VD metabolism is precisely orchestrated at the level of the kidney by regulators: parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) and their receptors with a FGF23 co-receptor-α-Klotho. The aim of this study was to assess the levels of VD, α-Klotho, FGF23 in SSc patients and to find the relationship between those parameters and disease activity. We enrolled 48 SSc patients with a diffuse variant of SSc and 23 sex- and age-matched healthy volunteers that served as the control group (CG). Patients were characterized by lower level of VD in comparison to CG (19.8 (12.6⁻28.9) vs. 24.5 (21.3⁻31.5) ng/mL; < 0.01), significantly reduced levels of iFGF23 (19.3 (12.1⁻30.5) vs. 73.9 (59.7⁻110.2) pg/mL < 0.001), and similar α-Klotho concentrations (1415 ± 557 vs. 1526 ± 397 pg/mL), respective. None of these parameters correlated with the extent of skin involvement (modified Rodnan Skin Score) and disease activity according to Eustar 2017 guidelines. The FGF23/α-Klotho index was significantly reduced in SSc patients (0.013 (0.0081⁻0.025) vs. 0.055 (0.038⁻0.095); < 0.001), and its log correlated ( = 0.35; < 0.001) with disease activity score (Eular2017). Our data showed that the FGF23/α-Klotho index may be considered as a novel, potential marker of systemic sclerosis activity. 10.3390/jcm7120558
    Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy. Hum Julia M,O'Bryan Linda M,Tatiparthi Arun K,Clinkenbeard Erica L,Ni Pu,Cramer Martin S,Bhaskaran Manoj,Johnson Robert L,Wilson Jonathan M,Smith Rosamund C,White Kenneth E Journal of applied physiology (Bethesda, Md. : 1985) Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the "soluble" or "cleaved" form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN. 10.1152/japplphysiol.00838.2018
    Klotho protein function among patients with type 1 diabetes. Flotyńska Justyna,Uruska Aleksandra,Araszkiewicz Aleksandra,Zozulińska-Ziółkiewicz Dorota Endokrynologia Polska The fibroblast growth factor 23 (FGF23) and Klotho system play a very important role in the regulation of the human body metabolism. On the one hand, they promote longevity, and on the other hand they promote insulin resistance. Nowadays, accelerated aging in diabetes as the main consequence of chronic complications of the disease is postulated. Signalling pathways induced by insulin, insulin-like growth factor (IGF-1), and their homologues play an important role in controlling the aging process. Because FGF23/Klotho system affects glucose metabolism and gene expression of antioxidant enzymes, changes in its concentration may be a marker of chronic complications of diabetes or a treatment option. Despite huge improvements in the treatment of diabetes, its chronic complications remain an important clinical problem. An interesting issue is the relationship between the concentration of FGF23/Klotho and management of the disease, duration, insulin resistance, and development of complications in type 1 diabetes. 10.5603/EP.a2018.0070
    Klotho, fibroblast growth factor-23, and the renin-angiotensin system - an analysis from the PEACE trial. Bergmark Brian A,Udell Jacob A,Morrow David A,Jarolim Petr,Kuder Julia F,Solomon Scott D,Pfeffer Marc A,Braunwald Eugene,Sabatine Marc S European journal of heart failure AIMS:Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition. METHODS AND RESULTS:A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; P  < 0.01). CONCLUSIONS:Low Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril. 10.1002/ejhf.1424
    FGF23-Klotho axis in patients with rheumatoid arthritis. Alvarez-Cienfuegos Antonio,Cantero-Nieto Lucia,Garcia-Gomez Jose Alberto,Robledo Gema,González-Gay Miguel Angel,Ortego-Centeno Norberto Clinical and experimental rheumatology OBJECTIVES:We aimed to compare serum Klotho and fibroblast growth factor-23 (FGF-23) levels between rheumatoid arthritis (RA) patients and healthy controls. Possible association between FGF-23 and soluble Klotho with different characteristic of the disease as well as their potential role as surrogate markers of cardiovascular disease (CVD) were studied. METHODS:Sixty-three patients with RA recruited at Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018 and sixty-five age- and sex-matched healthy controls were included in this study. Serum Klotho and FGF-23 were analysed using ELISA. RESULTS:Patients had higher serum levels of Klotho than healthy controls (p˂0.0001). They were positively associated with the presence of anticitrullinated peptide antibody and rheumatic factor (p<0.05). Klotho serum levels were higher in RA patients treated with biologic agents than in those undergoing conventional therapy (p=0.008). However, no association with carotid intima media thickness was found. Although no significant differences in serum FGF-23 levels between patients and controls were found (p=0.43), FGF-23 levels were positively associated with low-density lipoprotein (LDL-c) level (p<0.05) and smoking (p=0.008) in patients with RA. CONCLUSIONS:The increased serum Klotho levels in RA patients, especially in those undergoing biologic therapy, may indicate a potential implication in the pathogenesis of the disease. Although levels of FGF-23 were related to LDL-c levels, the FGF-23-Klotho axis does not seem to be related to subclinical arteriosclerosis in RA.
    The relationship between serum FGF-23 concentration and insulin resistance, prediabetes and dyslipidemia in obese children and adolescents. Kutluturk Yesim,Akinci Aysehan,Ozerol Ibrahim Halil,Yologlu Saim Journal of pediatric endocrinology & metabolism : JPEM Background Obesity is known to cause metabolic disturbances including insulin resistance, dyslipidemia and alters bone mineralization. The effects of obesity on fibroblast growth factor 23 (FGF-23), which is important in bone mineralization, have not yet been clarified. Our aim was to investigate the association between FGF-23 concentration and obesity-associated dysmetabolism. Methods Subjects comprised 46 obese children and adolescents. The same number of age-matched, healthy controls were recruited. Markers of bone mineralization and glucose metabolism were measured. Thyroid function and insulin resistance were investigated in both groups. In obese subjects; an oral glucose tolerance test (OGTT) was performed and hemoglobin A1c and lipid fractions were measured. Bone mineral density and hepatic steatosis were investigated. Results Serum FGF-23, α-klotho and 1,25(OH)2D3 concentrations were significantly lower while fasting insulin, fasting glucose, C-peptide and alkaline phosphatase (ALP) concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly higher in the obese group compared to controls. A significant negative correlation was observed between free tri-iodothyronine (fT3) and both FGF-23 and α-klotho in the obese group. Significant negative correlation was found between FGF-23 and C-peptide and a positive correlation was found between FGF-23 and high density lipoprotein-cholesterol (HDL-c) in the obese subjects with impaired glucose tolerance (IGT). Significant negative correlations were found between FGF-23 and both fasting insulin levels and C-peptide levels in the obese subjects with hepatic steatosis. Conclusions In our study, insulin resistance-associated hyperinsulinism and/or lower 1,25(OH)2D3 levels, both present in obese children and adolescents, may lead to decreased serum FGF-23 concentrations in obese subjects. 10.1515/jpem-2018-0507
    Impaired function of fibroblast growth factor 23 / Klotho protein axis in prediabetes and diabetes mellitus: Promising predictor of cardiovascular risk. Berezin Alexander E,Berezin Alexander A Diabetes & metabolic syndrome The discovery of clear molecular mechanisms of early cardiac and vascular complications in patients with prediabetes and known diabetes mellitus are core element of stratification at risk with predictive model creation further. Previous clinical studies have shown a pivotal role of impaired signaling axis of fibroblast growth factor 23 (FGF23), FGF23 receptor isoforms and its co-factor Klotho protein in cardiovascular (CV) complications in prediabetes and diabetes. Although there were data received in clinical studies, which confirmed a causative role of altered function of FGF-23/Klotho protein axis in manifestation of CV disease in prediabetes and type 2 diabetes mellitus (T2DM), the target therapy of these diseases directing on improvement of metabolic profiles, systemic and adipokine-relating inflammation by beneficial restoring of dysregulation in FGF-23/Klotho protein axis remain to be not fully clear. The aim of the review was to summarize findings regarding the role of impaired FGF-23/Klotho protein axis in developing CV complications in patients with prediabetes and type 2 diabetes mellitus. It has been elucidated that elevated levels of FGF-23 and deficiency of Klotho protein in peripheral blood are predictors of CV disease and CV outcomes in patients with (pre) diabetes, while predictive values of dynamic changes of the concentrations of these biomarkers require to be elucidated in detail in the future. 10.1016/j.dsx.2019.07.018
    How do we sense phosphate to regulate serum phosphate level? Fukumoto Seiji,Takashi Yuichi,Tsoumpra Maria K,Sawatsubashi Shun,Matsumoto Toshio Journal of bone and mineral metabolism Abnormal phosphate levels result in several pathological conditions such as rickets/osteomalacia and ectopic calcification indicating that there must be a system that regulates phosphate level within a narrow range. FGF23 has been shown to be an essential hormone regulating serum phosphate level. FGF23 binds to Klotho-FGF receptor complex to reduce serum phosphate level. Several reports suggested that FGF receptor is involved in the regulation of FGF23 production. It has been also shown that high extracellular phosphate can activate several intracellular signaling pathways. However, it has been unclear whether and how phosphate regulates FGF23 production in vivo. Our recent results indicate that high extracellular phosphate directly activates FGF receptor 1 and the downstream intracellular signaling enhances FGF23 production. Thus, there is a negative feedback system for the regulation of serum phosphate level involving FGF receptor and FGF23. We propose that FGF receptor works at least as one of phosphate sensors in the maintenance of serum phosphate level. 10.1007/s00774-019-01066-0
    FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model. Xiao Zhousheng,King Gwendalyn,Mancarella Salvatore,Munkhsaikhan Undral,Cao Li,Cai Chun,Quarles Leigh Darryl JCI insight Observations in transgenic α-Klotho (Kl) mice (KlTg) defined the antiaging role of soluble Klotho (sKL130). A genetic translocation that elevates sKL levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 (FGF23) levels and the potential of both membrane KL (mKL135) and sKL130 to act as coreceptors for FGF23 activation of fibroblast growth factor receptors (FGFRs). Neither FGF23 expression nor the contributions of FGF23, mKL135, and sKL130 codependent and independent functions have been investigated in KlTg mice. In the current study, we examined the effects of Kl overexpression on FGF23 levels and functions in KlTg mice. We found that mKL135 but not sKL130 stimulated FGF23 expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated FGF23 suppressed 1,25(OH)2D and parathyroid hormone levels but did not cause hypophosphatemic rickets in KlTg mice. KlTg mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that mKL135 and sKL130 are essential cofactors for FGF23-mediated ERK activation but that they inhibited FGF23 stimulation of PLC-γ and PI3K/AKT signaling. Thus, increased longevity in KlTg mice occurs in the presence of excess FGF23 that interacts with mKL and sKL to bias FGFR pathways. 10.1172/jci.insight.132820
    [Potential application of fibroblast growth factor 23-klotho axis in chronic kidney disease]. Lacroix Jean Sébastien,Urena-Torres Pablo Nephrologie & therapeutique Membrane Alpha Klotho (α-klotho) is expressed in the kidney and functions as a co-receptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in mineral homeostasis. The extracellular domain of transmembrane αklotho can be cleaved by proteases and released into the circulation as soluble α-klotho. Klotho deficiency is a pathogenic factor for chronic kidney disease progression and cardiovascular diseases. The FGF23 excess may also contribute to cardiovascular diseases where its pathogenic effect acts via the FGFR4 and independently of α-klotho. The decline in serum α-klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease can serve as a robust predictor for risk of cardiovascular diseases and mortality in both CKD patients and the general population. The first randomized trials suggest the possibility to reduce FGF23 excess in chronic kidney disease by controlling the phosphate serum using phosphate binders and reducing PTH levels with calcimimetic drug. New strategies emerge, including the administration of α-klotho recombinant and the use of epidrugs in order to correct the klotho deficiency. The FGR4 inhibitors are promising to limit the development of left ventricular hypertrophy linked to FGF23 excess. Finally, a better understanding of the molecular mechanisms of FGF23/α-klotho axis will allow us to find new strategic approaches and improve the CKD patient's management and their outcomes. 10.1016/j.nephro.2019.05.003
    Changes in Fibroblast Growth Factor 23 and Soluble Klotho Levels After Hemodialysis Initiation. Kidney medicine RATIONALE & OBJECTIVE:Patients with chronic kidney failure have markedly elevated fibroblast growth factor 23 (FGF-23) levels and decreased soluble Klotho levels. However, no studies have examined the effects of hemodialysis initiation on the levels of these hormones and other parameters of mineral metabolism. STUDY DESIGN:Prospective single-arm study. SETTING & PARTICIPANTS:20 individuals with incident kidney failure initiating hemodialysis. EXPOSURE:Initiation of hemodialysis. Dose adjustments of phosphate binders and vitamin D receptor activators and use of calcimimetics, erythropoiesis-stimulating agents, and intravenous iron were prohibited. OUTCOMES:Changes in serum levels of FGF-23, soluble Klotho, and other biochemical parameters of mineral metabolism, measured before and after each hemodialysis session, for a total of 4 sessions over 5 days. ANALYTICAL APPROACH:Repeated-measures analysis of variance. RESULTS:At baseline, participants had 18-fold higher median FGF-23 levels and 1.6-fold lower mean soluble Klotho levels compared with age- and sex-matched healthy individuals. Initiation of hemodialysis led to progressive reductions in serum phosphorus, intact parathyroid hormone, and FGF-23 levels, with dialysis-related fluctuations. No reductions were observed in levels of α-microglobulin, which has molecular weight comparable to FGF-23. The magnitude of the FGF-23 level reductions was strongly associated with concomitant changes in serum phosphorus levels but not with the changes in intact parathyroid hormone levels. Soluble Klotho levels did not change after the initiation of hemodialysis. LIMITATIONS:Single-arm design, small sample size, short follow-up period. CONCLUSIONS:Initiation of hemodialysis in patients with chronic kidney failure led to progressive reductions in FGF-23 levels in association with reductions in serum phosphorus levels. These results suggest that phosphorus is a strong inducer of FGF-23 production and that regulation of FGF-23 production is a rapid process. 10.1016/j.xkme.2019.09.007
    Soluble Klotho and fibroblast growth factor 23 levels in diabetic nephropathy with different stages of albuminuria. Inci Ayca,Sari Funda,Coban Melahat,Olmaz Refik,Dolu Suleyman,Sarıkaya Metin,Yılmaz Necat Journal of investigative medicine : the official publication of the American Federation for Clinical Research The relationship between soluble Klotho (s-Klotho) levels, fibroblast growth factor 23 (FGF23) levels, and albuminuria in patients with diabetic chronic kidney disease (CKD) remains unclear. A total of 109 patients with type 2 diabetes (mean age 61.63±9.77 years), at the outpatient clinic of the Antalya Research and Training Hospital Nephrology Unit between January and June 2014, as well as 32 healthy controls (mean age 49.53±7.32 years) were enrolled for this cross-sectional study. Patients were classified into three groups according to their urinary albumin creatinine ratio (UACR), normoalbuminuria (UACR<30 mg/g), microalbuminuria (UACR 30-300 mg/g), and macroalbuminuria (UACR>300 mg/g). The blood was analyzed for FGF23, s-Klotho, parathyroid hormone (PTH), P, Ca, creatinine, and 25-hydroxyvitamin D3 (25hD) levels. Creatinine, s-Klotho, FGF23, and PTH levels were significantly higher and 25hD levels were significantly lower in the patient group than in the healthy controls (p<0.001). Between the groups according to UACR, 1-way analysis of variance revealed statistically significant differences for creatinine (p<0.001), 25hD (p<0.001), PTH (p=0.002), Ca (p=0.002), and albumin levels (p<0.001). A statistically significant positive correlation was found between s-Klotho and FGF23 (r=0.768; p=0.001), and between FGF23 levels and UACR (r=0.768; p=0.001). In conclusion, the results of the present study suggest that s-Klotho levels are significantly elevated in patients with diabetes and s-Klotho levels decreased with increasing albumin excretion in our patients despite a reduction in estimated glomerular filtration rate. 10.1136/jim-2016-000142
    Soluble Klotho levels in diabetic nephropathy: relationship with arterial stiffness. Inci A,Sari F,Olmaz R,Coban M,Dolu S,Sarikaya M,Ellidag H Y European review for medical and pharmacological sciences OBJECTIVE:In this cross-sectional study, we investigate the relationship between soluble Klotho (s-Klotho) levels, markers of bone mineral metabolism and arterial stiffness in 109 diabetic nephropathy patients (median age 61.00± 9.77 years) and 32 healthy controls (median age 49.23 ± 7.32 years). PATIENTS AND METHODS:Blood samples were collected to measure the levels of s-Klotho, and FGF23, serum creatinine, Calcium (Ca), Phosphorus (P), 25-hydroxyvitamin D3 (25hD) and parathyroid hormone (PTH). Pulse wave velocity (PWV) and blood pressure were also measured using a combined monitor. RESULTS:s-Klotho, FGF23 and PTH levels were significantly higher and 25hD was significantly lower in the patients than in controls (p < 0.001). Systolic blood pressure, pulse pressure and PWV were also significantly higher in the patients (p < 0.001). s-Klotho, FGF23 and 25hD levels significantly varied between sub-groups according to CKD stages, defined according to the CKD epidemiology collaboration equation. A strong positive correlation was found between s-Klotho and FGF23 (r = 0.768, p = 0.001) levels, but not with other bone mineral metabolism, blood pressure or arterial stiffness parameters. Creatinine levels significantly differed (p = 0.009) between three s-Klotho-level sub-groups, with the high creatinine levels in the sub-group with the lowest s-Klotho levels and estimated glomerular filtration rate (eGFR). CONCLUSIONS:There was no correlation between eGFR and s-Klotho levels. Arterial stiffness increased in CKD but was not related to s-Klotho or FGF23 levels. Among all parameters, FGF23 levels had the greatest effect on s-Klotho levels.
    Correlation between Soluble -Klotho and Renal Function in Patients with Chronic Kidney Disease: A Review and Meta-Analysis. Wang Qinglian,Su Wenyan,Shen Zhenwei,Wang Rong BioMed research international OBJECTIVE:Over decades, numerous inconsistent studies are reported on the relationship between soluble -Klotho and renal function in patients with chronic kidney disease (CKD). This study aims to perform a meta-analysis to figure out the correlations between soluble -Klotho and renal function in patients with CKD. MATERIALS AND METHODS:We searched medical and scientific literature databases, PubMed and EMBASE (from the inception to October 2017), for publications that reported studies on associations between soluble -Klotho and renal function in patients with CKD. Only publications in English were extracted. Summary correlation coefficient (r) values were extracted from each study, and 95% confidence intervals (CIs) were calculated. Publication bias was tested, and sensitivity and subgroup analyses were performed to investigate potential heterogeneity. RESULTS:Of 611 studies, 9 publications with 1457 patients were included into the analysis. The following data were extracted from the literature: first author, year of publication, research region, research index, sample size, average age and Pearson or Spearman correlation coefficient, study design, the Klotho/FGF23 assays utilized, full length, or the C-terminal fragment of FGF23. The pooled r between -Klotho and estimated glomerular filtration rate (eGFR), FGF-23 were 0.35 (95%CI, 0.23~0.46, and P<0.05), -0.10 (95%CI, -0.19~-0.01, and P<0.05) with remarkable significance, indicating moderate heterogeneity. There was no significant heterogeneity between subgroups in analyses of -Klotho and eGFR stratified by research region, mean age, and eGFR, but heterogeneity exists in analyses of -Klotho and FGF-23 stratified by research region. There was no significant correlation between a-klotho and Ca and PTH and PHOS. There was no evidence of publication bias with Egger's test (p=0.360) or with Begg's test (p=0.902) and the distribution of funnel plots was symmetrical in all of our analysis. CONCLUSIONS:There exists a significant positive correlation between soluble -Klotho and eGFR in patients with CKD. Also, a significant negative correlation between -Klotho and FGF23 levels is proven. This raises hope to employ Klotho and FGF23 as early biomarkers of CKD. However, further large prospective follow-up researches are needed to validate this hypothesis and to explore whether maintaining or elevating the Klotho level could improve renal function and complications in CKD patients. 10.1155/2018/9481475
    The relationship between serum fibroblast growth factor 23, Klotho, and lumbar spine bone mineral density in northern Chinese postmenopausal women. Han Wen,Bai Xiao-Juan,Han Lu-Lu,Sun Xue-Feng,Chen Xiang-Mei Menopause (New York, N.Y.) OBJECTIVES:Changes in serum protein levels of fibroblast growth factor 23 (FGF23) and Klotho resulting from bone metabolism are still controversial. The purpose of this study was to observe the relationship between FGF23 and Klotho serum proteins and lumbar spine bone mineral density (LBMD) in northern Chinese postmenopausal women. METHODS:This was a community-based cross-sectional study carried out in Shenyang, a northern Chinese city. The study included 355 postmenopausal women with an average age of 62.92 ± 8.78 years. FGF23 and Klotho serum proteins were measured using a sandwich enzyme immunoassay. LBMD was examined using dual-energy X-ray absorptiometry. Pearson's correlation and regression analyses were performed to investigate the associations among them. RESULTS:The LgKlotho was positively correlated with LBMD (r = 0.105). There was a linear relationship between LgKlotho serum levels and LBMD (P = 0.007) after adjusting for BMI, and the relationship still existed after adjustments for many confounding variables (P = 0.045), including age, BMI, systolic blood pressure, diastolic blood pressure, total protein, total bilirubin, high-density lipoprotein cholesterol, fasting blood glucose, serum calcium, estimated glomerular filtration rate, serum uric acid, estradiol, cigarette smoking, alcohol consumption, milk intake, calcium and vitamin D supplements, physical exercise, and fracture history in postmenopausal women. FGF23 serum levels were, however, not significantly associated with LBMD. CONCLUSIONS:Klotho was positively correlated with LBMD, and there was a linear relationship between Klotho serum protein levels and LBMD; however, the levels of serum Klotho were not independently associated with reduced LBMD in northern Chinese postmenopausal women. Moreover, serum FGF23 levels were not significantly related to LBMD in this sample population. 10.1097/GME.0000000000001276
    Circulating Levels of Soluble Klotho and Fibroblast Growth Factor 23 in Diabetic Patients and Its Association with Early Nephropathy. Farías-Basulto Alfonso,Martínez-Ramírez Héctor Ramón,Gómez-García Erika Fabiola,Cueto-Manzano Alfonso Martín,Cortés-Sanabria Laura,Hernández-Ramos Luis Eduardo,Ramírez-López Guadalupe,Mendoza-Carrera Francisco Archives of medical research INTRODUCTION:Diabetic nephropathy is a leading cause of chronic kidney disease (CKD). In diabetes, changes in serum levels of both soluble alpha Klotho (sKL) and fibroblast growth factor 23 (FGF-23) have been associated with CKD progression. OBJECTIVE:To evaluate the associations of circulating levels of sKL and FGF-23 with the presence of early nephropathy (EN) in diabetic patients. METHODS:A cross-sectional study in 136 Mexicans with type 2 diabetes mellitus (T2DM). Early nephropathy was defined as an estimated glomerular filtration rate (≥60 ml/min) and urinary albumin excretion (≥30 mg/g). Serum concentrations of sKL and FGF-23 were measured using ELISA. Associations were evaluated with multiple logistic regression. RESULTS:Fifty-two subjects had EN. Median values of sKL and FGF-23 for all individuals were 244 pg/mL (interquartile range [IQR]: 201-402) and 92 pg/mL (IQR: 39-507), respectively. A positive correlation was found between levels of sKL and FGF-23 (r = 0.38; p <0.001). FGF-23 levels correlated negatively with angiotensin-II receptor blocker therapy (ARB, r = 0.24; p <0.01). Subjects without EN were younger (59 vs. 63 years old, p = 0.02). Elevated concentrations of FGF-23 were negatively associated with EN (Odds Ratio [OR] = 0.29, 95% Confidence Interval [95% CI] = 0.13, 0.65). CONCLUSIONS:In Mexican diabetic patients, serum levels of FGF-23 were positively correlated with sKL but negatively correlated with ARB therapy. In addition, a higher concentration of FGF-23 reduced the odds of early nephropathy in patients with T2DM. 10.1016/j.arcmed.2019.01.008
    Expression and localization of fibroblast growth factor (FGF)23 and Klotho in the spleen: its physiological and functional implications. Nakashima Yuri,Mima Toru,Yashiro Mitsuru,Sonou Tomohiro,Ohya Masaki,Masumoto Asuka,Yamanaka Shintaro,Koreeda Daisuke,Tatsuta Koichi,Hanba Yoshiyuki,Moribata Mari,Negi Shigeo,Shigematsu Takashi Growth factors (Chur, Switzerland) The FGF23-Klotho signaling axis is known to exert anti-aging effects via calcium-phosphorus metabolism. In mice deficient in FGF23-Klotho signaling, however, the number of splenocytes is reduced. FGF23 is expressed in both bone and spleen, with regulation of its production differing in these organs. As FGF23-Klotho signaling may play an immunological role in the spleen, splenocytes in male C57BL/6J mice were assayed for expression of Klotho or FGF23 by flow cytometry and immunohistochemistry. Cells that expressed Klotho included CD45R/B220 CD21/CD35 CD1d CD43 marginal zone B cells. These cells also expressed FGF receptor 1, indicating that Klotho-positive B cells could respond to FGF23. Plasmacytoid dendritic cells (pDCs) with CD11c CD45R/B220 CD11b CD8α were found to produce FGF23. Klotho-positive cells and FGF23-producing cells were present in close proximity to each other, suggesting that FGF23 produced by pDCs may act within a limited area. These findings indicate that FGF23-Klotho signaling could play a biological or immunological role in the spleen. 10.1080/08977194.2016.1273222
    The production of fibroblast growth factor 23 is controlled by TGF-β2. Feger Martina,Hase Philipp,Zhang Bingbing,Hirche Frank,Glosse Philipp,Lang Florian,Föller Michael Scientific reports Transforming growth factor-β (TGF-β) is a cytokine produced by many cell types and implicated in cell growth, differentiation, apoptosis, and inflammation. It stimulates store-operated calcium entry (SOCE) through the calcium release-activated calcium (CRAC) channel Orai1/Stim1 in endometrial Ishikawa cells. Bone cells generate fibroblast growth factor (FGF) 23, which inhibits renal phosphate reabsorption and 1,25(OH)D formation in concert with its co-receptor Klotho. Moreover, Klotho and FGF23 counteract aging and age-related clinical conditions. FGF23 production is dependent on Orai1-mediated SOCE and inflammation. Here, we explored a putative role of TGF-β2 in FGF23 synthesis. To this end, UMR106 osteoblast-like cells were cultured, Fgf23 transcript levels determined by qRT-PCR, FGF23 protein measured by ELISA, and SOCE analyzed by fluorescence optics. UMR106 cells expressed TGF-β receptors 1 and 2. TGF-β2 enhanced SOCE and potently stimulated the production of FGF23, an effect significantly attenuated by SB431542, an inhibitor of the transforming growth factor-β (TGF-β) type I receptor activin receptor-like kinases ALK5, ALK4, and ALK7. Furthermore, the TGF-β2 effect on FGF23 production was blunted by SOCE inhibitor 2-APB. We conclude that TGF-β2 induces FGF23 production, an effect involving up-regulation of SOCE. 10.1038/s41598-017-05226-y
    Calcineurin inhibitors regulate fibroblast growth factor 23 (FGF23) synthesis. Bär Ludmilla,Großmann Claudia,Gekle Michael,Föller Michael Naunyn-Schmiedeberg's archives of pharmacology Fibroblast growth factor 23 (FGF23) inhibits renal phosphate reabsorption and calcitriol formation, effects depending on Klotho as a co-receptor for FGF23. In addition, FGF23/Klotho strongly influences aging and the onset of age-associated diseases. The synthesis of FGF23 by bone cells is induced by store-operated Ca entry (SOCE) through Orai1 in UMR106 osteoblast-like cells. Ca entry activates the phosphatase calcineurin in many cell types which dephosphorylates nuclear factor of activated T cells (NFAT) thereby stimulating its transcriptional activity. Here, we explored whether calcineurin-NFAT signaling impacts on FGF23 production. Fgf23 transcripts were determined by qRT-PCR and FGF23 protein by ELISA. Calcineurin as well as NFAT expression were quantified by RT-PCR in UMR106 cells. UMR106 cells expressed calcineurin subunits Ppp3r1, Ppp3ca, Ppp3cb, and Ppp3cc as well as NFATc1, NFATc3, and NFATc4. Calcineurin inhibitors ciclosporin A (CsA) and tacrolimus (FK-506) decreased Fgf23 gene expression and FGF23 protein production. Moreover, calcineurin-NFAT interaction inhibitor INCA-6 reduced the abundance of Fgf23 transcripts as well as FGF23 protein. Calcineurin-NFAT signaling is a potent regulator of FGF23 formation. 10.1007/s00210-017-1411-2
    New Insights into the Mechanism of Action of Soluble Klotho. Dalton George D,Xie Jian,An Sung-Wan,Huang Chou-Long Frontiers in endocrinology The gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full-length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for FGF23, which allows it to participate in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl's mechanism of action as a "hormone" has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl's mechanism of action, the mechanistic basis of sKl's protective, FGF23-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling. 10.3389/fendo.2017.00323
    Changes in expression of klotho affect physiological processes, diseases, and cancer. Xuan Nguyen Thi,Hai Nong Van Iranian journal of basic medical sciences encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of target genes. KL participates in modulation of the insulin/insulin-like growth factor-1 (IGF-1) signaling, which induces the growth hormone (GH) secretion. Accordingly, mutant mice display multiple aging-like phenotypes, which are ameliorated by overexpression of KL. Therefore, KL is an important contributor to lifespan. KL is further identified as a regulator of calcium (Ca) channel-dependent cell physiological processes. KL has been also shown to induce cancer cell apoptosis, thus, it is considered as a potential tumor suppressor. Our recent studies have indicated that KL modulates an influx of Ca from the extracellular space, leading to a change in CCL21-dependent migration in dendritic cells (DCs). Interestingly, the regulation of the expression of KL was mediated through a phosphoinositide 3-kinase (PI3K) pathway in DCs. Moreover, downregulating of KL expression by using siRNA knockdown technique, we observed that the expression of Ca channels including Orai3, but not Orai1, Orai2, TRPV5 and TRPV6 was significantly reduced in -silenced as compared to control BMDCs. Clearly, additional research is required to define the role of KL in the regulation of organismic and cellular functions through the PI3K signaling and the expression of the Ca channels.
    [Correlations of FGF23 and Klotho with cardiovascular injury in chronic kidney disease patients]. Gan Lu,Zhou Qiaoling Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences OBJECTIVE:To analyze the levels of serum calcium, phosphate, fibroblast growth factor 23 (FGF23), and Klotho proteins in patients with chronic kidney disease (CKD), and to investigate the correlations of FGF23 and Klotho proteins with cardiac complicates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD).
 Methods: A total of 180 CKD-MBD patients were enrolled for this study. Among them, 60 patients underwent regular hemodialysis, 60 patients did not undergo renal replacement therapy and 60 patients were diagnosed as second hyperparathyroidism (SHPT). Thirty age and gender-matched health volunteers served as controls. Serum samples were collected and tested, and the demographical, clinical and biochemical data were all recorded. FGF23 and Klotho levels in serum samples were analyzed by enzyme-linked immunosorbent assay. Data of echocardiography and plain abdominal X rays were collected as well. The influential factors for cardiovascular injury, the relationship between biochemical indexes and ectopic calcification, and the correlations of FGF23 and Klotho with cardiac complicates were analyzed
 Results: Patients, who kept hemodialysis, especially those with SHPT, exhibited an increase in serum FGF23 level while a decrease in serum Klotho protein levels (P<0.01). Patients with higher levels of serum FGF23 were more likely to have ectopic calcification (OR=4.667), while patients with lower levels of serum Klotho had high risks to get myocardial hypertrophy (OR=3.496). Receiver operator characteristic (ROC) curve analysis showed that the area under the curve (AUC) for FGF23 was 0.778 (P<0.01) while for Klotho was 0.715 (P<0.01).
 Conclusion: Patients, who kept hemodialysis, especially those with SHPT, have a significant increase in serum FGF23 protein levels and a significant decrease in serum Klotho protein levels. Serum FGF23 and Klotho protein levels are closely correlated with left ventricular enlargement and hypertrophy. Serum FGF23 and Klotho protein are risk factors for heart. 10.11817/j.issn.1672-7347.2017.09.011
    Plasma s-Klotho is related to kidney function and predicts adverse renal outcomes in patients with advanced chronic kidney disease. Liu Qi-Feng,Ye Jian-Ming,Yu Li-Xia,He Ao-Lin,Sun Qiang,He Da-Wei,Li Sha-Sha Journal of investigative medicine : the official publication of the American Federation for Clinical Research To investigate whether the soluble Klotho (s-Klotho) level in patients with chronic kidney disease (CKD) is related to kidney function and whether a low s-Klotho level can predict adverse renal outcomes or CKD progression in patients with advanced CKD. 112 patients with CKD stages 3-5 and 30 healthy volunteers were enrolled. Blood samples were collected to measure serum creatinine, calcium, phosphorus, intact parathyroid hormone, and hemoglobin. s-Klotho and fibroblast growth factor 23 (FGF23) were determined by ELISA. We first conducted a cross-sectional study to investigate correlations between s-Klotho and estimated glomerular filtration rate (eGFR) and other parameters. Patients were then followed prospectively for 20.1±10.1 months according to s-Klotho median level until serum creatinine doubled, or initiation of renal replacement therapy, or death. s-Klotho levels inpatients with CKD were significantly lower than that in the control group. For patients with CKD, there were no differences in age distribution among subgroups. However, s-Klotho level differed significantly across CKD stages, and it was lower in the advanced CKD group compared with the moderate CKD group. Correlation analysis revealed that s-Klotho was positively associated with eGFR, but inversely associated with FGF23. During the follow-up of 20.1±10.1 months, patients with higher s-Klotho levels showed a reduced risk of kidney adverse outcomes, including serum creatinine doubling and initiation of renal replacement therapy. Cox regression analysis revealed that low s-Klotho was an independent risk factor for CKD progression. s-Klotho level was closely correlated with kidney function, further, low s-Klotho level could predict adverse kidney disease outcomes in patients with progressive CKD. 10.1136/jim-2017-000560
    Protective Effect of Klotho against Ischemic Brain Injury Is Associated with Inhibition of RIG-I/NF-κB Signaling. Zhou Hong-Jing,Li Hui,Shi Meng-Qi,Mao Xiao-Na,Liu Dong-Ling,Chang Yi-Ran,Gan Yu-Miao,Kuang Xi,Du Jun-Rong Frontiers in pharmacology Aging is the greatest independent risk factor for the occurrence of stroke and poor outcomes, at least partially through progressive increases in oxidative stress and inflammation with advanced age. Klotho is an antiaging gene, the expression of which declines with age. Klotho may protect against neuronal oxidative damage that is induced by glutamate. The present study investigated the effects of Klotho overexpression and knockdown by an intracerebroventricular injection of a lentiviral vector that encoded murine Klotho (LV-KL) or rat Klotho short-hairpin RNA (LV-KL shRNA) on cerebral ischemia injury and the underlying anti-neuroinflammatory mechanism. The overexpression of Klotho induced by LV-KL significantly improved neurobehavioral deficits and increased the number of live neurons in the hippocampal CA1 and caudate putamen subregions 72 h after cerebral hypoperfusion that was induced by transient bilateral common carotid artery occlusion (2VO) in mice. The overexpression of Klotho significantly decreased the immunoreactivity of glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1, the expression of retinoic-acid-inducible gene-I, the nuclear translocation of nuclear factor-κB, and the production of proinflammatory cytokines (tumor necrosis factor α and interleukin-6) in 2VO mice. The knockdown of Klotho mediated by LV-KL shRNA in the brain exacerbated neurological dysfunction and cerebral infarct after 22 h of reperfusion following 2 h middle cerebral artery occlusion in rats. These findings suggest that Klotho itself or enhancers of Klotho may compensate for its aging-related decline, thus providing a promising therapeutic approach for acute ischemic stroke during advanced age. 10.3389/fphar.2017.00950
    Correlation of serum levels of fibroblast growth factor 23 and Klotho protein levels with bone mineral density in maintenance hemodialysis patients. Zheng Shubei,Chen Yan,Zheng Yu,Zhou Zhihong,Li Zhanyuan European journal of medical research OBJECTIVE:The correlation of serum fibroblast growth factor 23 (FGF-23) and Klotho protein levels with bone mineral density (BMD) in maintenance hemodialysis (MHD) patients was analyzed. METHODS:Between January 2015 and November 2015, 125 MHD patients in our hospital were enrolled. Dual-energy X-ray absorptiometry was used to examine the BMD in the femoral neck and lumbar spine of MHD patients. The patients were divided into three groups: a normal bone mass group, an osteopenia group, and an osteoporosis group. An ELISA was performed to measure serum FGF-23, Klotho protein, and 1,25(OH)VitD levels. Other parameters, including calcium (Ca), phosphorus (P), and parathyroid hormone, were also measured. RESULTS:Of the 125 MHD patients, 82.40% of patients had femoral neck osteopenia, and 56.00% of patients had lumbar spinal osteopenia. The serum FGF-23 level was highest in the osteoporosis group. However, there was no significant difference in serum FGF-23 levels among the three groups, depending on femoral neck and lumbar spinal BMD (P > 0.05). Spearman's correlation analysis also pointed to a lack of correlation between serum FGF-23 levels and BMD. Among the three groups, there were significant differences in serum Klotho protein levels and femoral neck BMD (P < 0.05). Serum Klotho protein levels in the osteoporosis group were clearly lower than those in the normal bone mass group and osteopenia group (P < 0.05). Similarly, serum Klotho protein levels were significantly lower in those with lumbar spinal osteopenia as compared with those in the normal group. There was a positive correlation between serum Klotho protein levels and BMD and T values for the femoral neck and lumbar spine. The results of a multiple linear regression analysis revealed that the serum Klotho protein level was one of the main factors affecting BMD in MHD patients. CONCLUSIONS:The serum level of FGF-23 was not correlated with a change in BMD of MHD patients, whereas the serum Klotho protein level was associated with the degree of BMD. A high Klotho protein level may decrease the severity of chronic kidney disease and mineral bone disorder (CKD-MBD) in MHD patients with low BMD. 10.1186/s40001-018-0315-z
    AMP-activated kinase is a regulator of fibroblast growth factor 23 production. Glosse Philipp,Feger Martina,Mutig Kerim,Chen Hong,Hirche Frank,Hasan Ahmed Abdallah,Gaballa Mohamed M S,Hocher Berthold,Lang Florian,Föller Michael Kidney international Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKα1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKα1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE. 10.1016/j.kint.2018.03.006
    Physiological Actions of Fibroblast Growth Factor-23. Erben Reinhold G Frontiers in endocrinology Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate reabsorption and vitamin D hormone synthesis in the kidney. At physiological concentrations of the hormone, the endocrine actions of FGF23 in the kidney are αKlotho-dependent, because high-affinity binding of FGF23 to FGF receptors requires the presence of the co-receptor αKlotho on target cells. It is well established that excessive concentrations of intact FGF23 in the blood lead to phosphate wasting in patients with normal kidney function. Based on the importance of diseases associated with gain of FGF23 function such as phosphate-wasting diseases and chronic kidney disease, a large body of literature has focused on the pathophysiological consequences of FGF23 excess. Less emphasis has been put on the role of FGF23 in normal physiology. Nevertheless, during recent years, lessons we have learned from loss-of-function models have shown that besides the paramount physiological roles of FGF23 in the control of 1α-hydroxylase expression and of apical membrane expression of sodium-phosphate co-transporters in proximal renal tubules, FGF23 also is an important stimulator of calcium and sodium reabsorption in distal renal tubules. In addition, there is an emerging role of FGF23 as an auto-/paracrine regulator of alkaline phosphatase expression and mineralization in bone. In contrast to the renal actions of FGF23, the FGF23-mediated suppression of alkaline phosphatase in bone is αKlotho-independent. Moreover, FGF23 may be a physiological suppressor of differentiation of hematopoietic stem cells into the erythroid lineage in the bone microenvironment. At present, there is little evidence for a physiological role of FGF23 in organs other than kidney and bone. The purpose of this mini-review is to highlight the current knowledge about the complex physiological functions of FGF23. 10.3389/fendo.2018.00267
    Lower soluble Klotho and higher fibroblast growth factor 23 serum levels are associated with episodes of atrial fibrillation. Mizia-Stec Katarzyna,Wieczorek Joanna,Polak Mateusz,Wybraniec Maciej T,Woźniak-Skowerska Iwona,Hoffmann Andrzej,Nowak Seweryn,Wikarek Maria,Wnuk-Wojnar Anna,Chudek Jerzy,Więcek Andrzej Cytokine AIMS:The proarrhythmic effect of fibroblast growth factor 23 (FGF23) was observed in patients with end stage kidney disease (ESKD). However, there is no data on the role of FGF23 and soluble Klotho (sKlotho) in the pathogenesis of atrial fibrillation (AF) beyond ESKD. The aim of the study was to assess the peripheral vein and left atrial (LA) serum levels of FGF23 and sKlotho along with calcium-phosphates parameters in patients with AF undergoing percutaneous radiofrequency pulmonary vein isolation (PVI). METHODS AND RESULTS:Sixty-nine consecutive patients (mean age: 55.8 ± 9.7 years, F/M: 26/43, CHA2DS2-Vasc: 1.7 ± 1.1) with paroxysmal/persistent AF undergoing PVI were included into the study. Blood samples were taken during PVI - baseline from the peripheral vein, then from the LA immediately after a septal puncture. RESULTS:There were significant differences in the concentrations of peripheral and LA serum sKlotho, intact FGF23 (iFGF23), calcium and phosphates; peripheral FGF23, calcium and phosphates levels were significantly higher, and sKlotho levels were significantly lower than the LA concentrations. Serum sKlotho levels correlated with the CHADS2-VASc score (r = 0.254, p = 0.034) and glucose level (r = 0.300, p = 0.005). Serum sKlotho gradient (LA - peripheral vein) correlated with the baseline AF burden in the Holter monitoring (r = -0.389, p = 0.003). PVI efficacy was confirmed in 52 (75%) patients. There was a significant difference in the iFGF23 gradient between patients with AF and without AF (80.3 vs. -47.6 pg/ml, p = 0.009) in the six-month follow-up. A receiver operating characteristic (ROC) analysis revealed that an iFGF23 gradient >28.7 pg/ml (AUC = 0.742, p = 0.002) was a predictor for AF recurrence. CONCLUSIONS:There is a gradient between the LA and peripheral vein in the markers of calcium-phosphate metabolism in patients undergoing PVI. Lower sKlotho and higher iFGF23 serum levels are associated with episodes of AF. Serum iFGF23 gradient is a potent predictor for the recurrence of AF. 10.1016/j.cyto.2018.08.005
    Regulation of α-Klotho Expression by Dietary Phosphate During Growth Periods. Fukuda-Tatano Shiori,Yamamoto Hironori,Nakahashi Otoki,Yoshikawa Ryouhei,Hayashi Mayu,Kishimoto Maki,Imi Yukiko,Yamanaka-Okumura Hisami,Ohnishi Kohta,Masuda Masashi,Taketani Yutaka Calcified tissue international Inorganic phosphate (Pi) is an essential nutrient for maintaining various biological functions, particularly during growth periods. Excess intake of dietary Pi increases the secretion of fibroblast growth factor 23 (FGF23) and parathyroid hormone to maintain plasma Pi levels. FGF23 is a potent phosphaturic factor that binds to the α-klotho/FGFR complex in the kidney to promote excretion of Pi into the urine. In addition, excess intake of dietary Pi decreases renal α-klotho expression. Down-regulation or lack of α-klotho induces a premature aging-like phenotype, resulting from hyperphosphatemia, and leading to conditions such as ectopic calcification and osteoporosis. However, it remains unclear what effects dietary Pi has on α-klotho expression at different life stages, especially during growth periods. To investigate this, we used C57BL/6J mice in two life stages during growing period. Weaned (3 weeks old) and periadolescent (7 weeks old) were randomly divided into seven experimental groups and fed with 0.02, 0.3, 0.6, 0.9, 1.2, 1.5, or 1.8% Pi diets for 7 days. As a result, elevated plasma Pi and FGF23 levels and decreased renal α-klotho expression were observed in weaned mice fed with a high Pi diet. In addition, a high Pi diet clearly induced renal calcification in the weaned mice. However, in the periadolescent group, renal calcification was not observed, even in the 1.8% Pi diet group. The present study indicates that a high Pi diet in weaned mice has much greater adverse effects on renal α-klotho expression and pathogenesis of renal calcification compared with periadolescent mice. 10.1007/s00223-019-00525-0
    Relationship between cFGF23/Klotho ratio and phosphate levels in patients with chronic kidney disease. Liu Zhongyan,Zhou Hao,Chen Xiaoying,Chen Hong,Wang Yi,Wang Ting,Cai Luyan,Hong Yanyan,Ke Hailun,Zheng Jing International urology and nephrology PURPOSE:To characterize the relationship between the cFGF23/Klotho ratio and phosphate level in patients with chronic kidney disease (CKD). METHODS:A total of 152 patients with CKD stage 3-5 (CKD stage 3: n = 74; CKD stage 4: n = 60; CKD stage 5: n = 18) were included in the study. Thirty healthy volunteers served as controls. Intact-FGF23, cFGF23, Klotho, serum calcium, serum phosphate, and serum creatinine were measured, and estimated glomerular filtration rate (eGFR) was calculated. The Kruskal-Wallis H test was used for comparison between groups, and the Spearman test was used for correlation analysis. RESULTS:In CKD stage 3-5, creatinine and iFGF23 levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), phosphate levels were higher (P < 0.05), and Klotho levels were lower (P < 0.01), compared with controls. C-terminal-FGF23 levels were higher in CKD phase 4-5 (P < 0.05). In CKD stage 4-5, creatinine, iFGF23, and phosphate levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), cFGF23 levels were higher (P < 0.05), and Klotho levels were lower (P < 0.05), compared with CKD stage 3. In CKD stage 5, creatinine and cFGF23 levels, as well as the cFGF23/Klotho ratio, were higher (P < 0.01), phosphate and iFGF23 levels were higher (P < 0.05), and Klotho levels were lower (P < 0.01), compared with CKD stage 4. Phosphate was positively correlated with the cFGF23/Klotho ratio (r = 0.235, P < 0.01). CONCLUSIONS:EGFR reduction was associated with an increased cFGF23/Klotho ratio, and the cFGF23/Klotho ratio was positively correlated with phosphate. This suggests that the phosphate level can be controlled by modifying the cFGF23/Klotho ratio. 10.1007/s11255-019-02079-4
    Clinical significance of fibroblast growth factor-23 and soluble alpha klotho in different stages of chronic kidney disease. Khodeir Samy A,Okda Hanaa I,Abdalal Heba M Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia Most chronic kidney disease (CKD) biomarkers in the current clinical use are not sensitive enough and cannot be used to identify the early stage of the disease. Klotho is a transmembrane protein predominantly expressed in the renal tubules and implicated in managing phosphate homeostasis, together with fibroblast growth factor-23 (FGF-23); a bone-derived protein that increases urinary phosphate excretion. The present study was carried out on 50 patients CKD with different etiologies referred to the Internal Medicine Department and Out Patient Clinic of Tanta University Hospitals and 30 apparently healthy individuals of matched age and sex as a control group. They were subjected to the following assessment: detailed history taking, careful clinical examination, and laboratory investigations, including urea, creatinine, estimated glomerular filtration rate (eGFR), serum electrolytes, urinary albumin, urinary phosphorus (U-Ph), and specific laboratory tests for: Alpha Klotho (α-klotho) and FGF-23 by using ELISA technique. The present study shows that the mean value of serum creatinine, urea, phosphorus, urinary albumin, and FGF-23 were significantly increased, whereas there was a significant decrease in the mean value of eGFR, calcium, and U-Ph in the patients with CKD when compared with control group. Plasma level of serum α-klotho is significantly decreased in all patients with CKD when compared to the control group and there was a significant positive correlation between serum α-klotho level and eGFR, serum calcium level and U-Ph level. Plasma level of serum α-klotho is significantly decreased in all patients with CKD and serum α-klotho can be used as a good marker for early diagnosis and staging of CKD.
    Administration of alpha klotho reduces liver and adipose lipid accumulation in obese mice. Rao Zhijian,Landry Taylor,Li Peixin,Bunner Wyatt,Laing Brenton Thomas,Yuan Yuan,Huang Hu Heliyon α-Klotho, a known anti-aging protein, exerts diverse physiological effects including: maintenance of phosphate and calcium homeostasis, modulation of cell proliferation, and enhanced buffering of reactive oxygen species. However, the role of α-Klotho in the regulation of energy metabolism is complex and poorly understood. Here we investigated the effects of 5 weeks peripheral administration of α-Klotho in high fat diet induced obese mice. Food intake, blood glucose, and body weight were measured daily. Energy expenditure was determined with indirect calorimetry and body composition with magnetic resonance imaging. Liver and adipose tissue were collected for lipid content measurements and gene expression analysis. α-Klotho-treated mice experienced reduced adiposity, increased lean mass, and elevated energy expenditure, despite no changes in food intake, body weight, or fed blood glucose levels. Lipid accumulation in liver and adipose tissue was also reduced compared to controls. Furthermore, Real-time quantitative PCR showed reduced expression of key lipogenic genes in α-Klotho treated mice in these organs. Taken together, these data suggest encouraging therapeutic potential of α-Klotho and highlight a need for further research into the specific mechanisms explaining improved body composition, elevated energy expenditure, and reduced lipid content in both liver and adipose tissue in α-Klotho-treated mice. 10.1016/j.heliyon.2019.e01494
    Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy. Jiang Wei,Xiao Tangli,Han Wenhao,Xiong Jiachuan,He Ting,Liu Yong,Huang Yinghui,Yang Ke,Bi Xianjin,Xu Xinli,Yu Yanlin,Li Yan,Gu Jun,Zhang Jingbo,Huang Yunjian,Zhang Bo,Zhao Jinghong Molecular and cellular endocrinology Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury. As a calcium-dependent serine/threonine protein kinase involved in podocyte injury, protein kinase C isoform α (PKCα) was reported to regulate the phosphorylation of p66SHC. However, the role of PKCα/p66SHC in DN remains unknown. Klotho, an anti-aging protein with critical roles in protecting kidney, is expressed predominantly in the kidney and secreted in the blood. Nonetheless, the mechanism underlying amelioration of podocyte injury by Klotho in DN remains unclear. Our data showed that Klotho was decreased in STZ-treated mice and was further declined in diabetic KL ± mice. As expected, Klotho deficiency aggravated diabetes-induced proteinuria and podocyte injury, accompanied by the activation of PKCα and p66SHC. In contrast, overexpression of Klotho partially ameliorated PKCα/p66SHC-mediated podocyte injury and proteinuria. In addition, in vitro experiments showed that activation of PKCα and subsequently increased intracellular reactive oxygen species (ROS) was involved in podocytic apoptosis induced by high glucose (HG), which could be partially reversed by Klotho. Hence, we conclude that Klotho might inhibit PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy. 10.1016/j.mce.2019.110490
    The effect of high-dose vitamin D supplementation on bone mineral density in subjects with prediabetes. Larsen A U,Grimnes G,Jorde R Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA The rationale of this study was to determine the effect of high-dose vitamin D supplementation on bone mineral density (BMD). Prediabetic males given vitamin D had significantly less reduction in BMD at the femoral neck compared to the controls. The clinical implications of our findings require further investigation. INTRODUCTION:Type 2 diabetes mellitus is associated with increased fracture risk, and recent studies show crosstalk between bone and glucose metabolism. Few studies have investigated the effect of vitamin D supplementation on the bone without additional calcium. In the present study, we aimed to determine whether a high dose of vitamin D could improve bone mass density (BMD) in prediabetic subjects. METHODS:The current study was conducted as a secondary research on a previously performed trial, in which 511 subjects with prediabetes were randomized to vitamin D (20,000 IU per week) versus placebo for 5 years. BMD was measured using dual-energy X-ray absorptiometry (DEXA). RESULTS:Two hundred and fifty-six subjects were randomized to vitamin D and 255 to placebo. Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/L. Two hundred and two and 214 in the vitamin D and placebo groups, respectively, completed BMD measurements, whereas one in each group was excluded due to use of bisphosphonates. Males given vitamin D had significantly less reduction in BMD at the femoral neck measurement site compared to the controls (0.000 versus - 0.010 g/cm, p = 0.008). No significant differences between intervention groups were seen at the total hip measurement site, regarding both males and females. CONCLUSIONS:Vitamin D supplementation alone may be beneficial in males with prediabetes, but confirmatory studies are needed. 10.1007/s00198-017-4222-x
    Plasma 25-hydroxyvitamin D concentration and risk of type 2 diabetes and pre-diabetes: 12-year cohort study. Park Sue K,Garland Cedric F,Gorham Edward D,BuDoff Luke,Barrett-Connor Elizabeth PloS one BACKGROUND:It has been reported that higher plasma 25-hydroxyvitamin D is associated with lower risk of type 2 diabetes. However the results to date have been mixed and no adequate data based on a cohort are available for the high end of the normal range, above approximately 32 ng/ml or 80 nmol/L. METHODS:We performed a cohort study of 903 adults who were known to be free of diabetes or pre-diabetes during a 1997-1999 visit to a NIH Lipid Research Centers clinic. Plasma 25(OH)D was measured at Visit 8 in 1977-1979. The mean age was 74 years. The visit also included fasting plasma glucose and oral glucose tolerance testing. Follow-up continued through 2009. RESULTS:There were 47 cases of diabetes and 337 cases of pre-diabetes. Higher 25(OH)D concentrations (> 30 ng/ml) were associated with lower hazard ratios (HR) for diabetes: 30-39 ng/ml or 75-98 nmol/L: HR = 0.31, 95% CI = 0.14-0.70; for 40-49 ng/ml or 100-122 nmol/L: HR = 0.29, CI = 0.12-0.68; for > 50 ng/ml or 125 nmol/L: HR = 0.19, CI = 0.06-0.56. All HRs are compared to < 30 ng/ml or 75 nmol/L. There was an inverse dose-response gradient between 25(OH)D concentration and risk of diabetes with a p for trend of 0.005. Each 10 ng/mL or 25 nmol/L higher 25(OH)D concentration was associated with a HR of 0.64, CI = 0.48-0.86. 25(OH)D concentrations were more weakly inversely associated with pre-diabetes risk, and the trend was not significant. CONCLUSION:Further research is needed on whether high 25(OH)D might prevent type 2 diabetes or transition of prediabetes to diabetes. 10.1371/journal.pone.0193070
    Changes in beta cell function occur in prediabetes and early disease in the Lepr (db) mouse model of diabetes. Do Oanh H,Gunton Jenny E,Gaisano Herbert Y,Thorn Peter Diabetologia AIMS/HYPOTHESIS:Type 2 diabetes is a progressive disease that increases morbidity and the risk of premature death. Glucose dysregulation, such as elevated fasting blood glucose, is observed prior to diabetes onset. A decline in beta cell insulin secretion contributes to the later stages of diabetes, but it is not known what, if any, functional beta cell changes occur in prediabetes and early disease. METHODS:The Lepr (db) mouse (age 13-18 weeks) was used as a model of type 2 diabetes and a two-photon granule fusion assay was used to characterise the secretory response of pancreatic beta cells. RESULTS:We identified a prediabetic state in db/db mice where the animals responded normally to a glucose challenge but have elevated fasting blood glucose. Isolated islets from prediabetic animals secreted more and were bigger. Insulin secretion, normalised to insulin content, was similar to wild type but basal insulin secretion was elevated. There was increased glucose-induced granule fusion with a high prevalence of granule-granule fusion. The glucose-induced calcium response was not changed but there was altered expression of the exocytic machinery. db/db animals at the next stage of disease had overt glucose intolerance. Isolated islets from these animals had reduced insulin secretion, reduced glucose-induced granule fusion events and decreased calcium responses to glucose. CONCLUSIONS/INTERPRETATION:Beta cell function is altered in prediabetes and there are further changes in the progression to early disease. 10.1007/s00125-016-3942-3
    Mineral Nutrition and the Risk of Chronic Diseases: A Mendelian Randomization Study. Cheng Wen-Wen,Zhu Qiang,Zhang Hong-Yu Nutrients We applied Mendelian randomization analyses to investigate the potential causality between blood minerals (calcium, magnesium, iron, copper, and zinc) and osteoporosis (OP), gout, rheumatoid arthritis (RA), type 2 diabetes (T2D), Alzheimer's disease (AD), bipolar disorder (BD), schizophrenia , Parkinson's disease and major depressive disorder. Single nucleotide polymorphisms (SNPs) that are independent (² < 0.01) and are strongly related to minerals ( < 5 × 10) are selected as instrumental variables. Each standard deviation increase in magnesium (0.16 mmol/L) is associated with an 8.94-fold increase in the risk of RA ( = 0.044) and an 8.78-fold increase in BD ( = 0.040) but a 0.10 g/cm² increase in bone density related to OP ( = 0.014). Each per-unit increase in copper is associated with a 0.87-fold increase in the risk of AD ( = 0.050) and BD ( = 0.010). In addition, there is suggestive evidence that calcium is positively correlated (OR = 1.36, = 0.030) and iron is negatively correlated with T2D risk (OR = 0.89, = 0.010); both magnesium (OR = 0.26, = 0.013) and iron (OR = 0.71, = 0.047) are negatively correlated with gout risk. In the sensitivity analysis, causal estimation is not affected by pleiotropy. This study supports the long-standing hypothesis that magnesium supplementation can increase RA and BD risks and decrease OP risk and that copper intake can reduce AD and BD risks. This study will be helpful to address some controversial debates on the relationships between minerals and chronic diseases. 10.3390/nu11020378
    FGF23 Concentration and Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes. Chan Gary C,Divers Jasmin,Russell Gregory B,Langefeld Carl D,Wagenknecht Lynne E,Hsu Fang-Chi,Xu Jianzhao,Smith S Carrie,Palmer Nicholette D,Hicks Pamela J,Bowden Donald W,Register Thomas C,Ma Lijun,Carr J Jeffrey,Freedman Barry I Diabetes care OBJECTIVE:Cardiovascular and renal complications contribute to higher mortality in patients with diabetes. We assessed novel and conventional predictors of mortality in African American-Diabetes Heart Study (AA-DHS) participants. RESEARCH DESIGN AND METHODS:Associations between mortality and subclinical atherosclerosis, urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), plasma fibroblast growth factor 23 (FGF23) concentration, African ancestry proportion, and apolipoprotein L1 genotypes () were assessed in 513 African Americans with type 2 diabetes; analyses were performed using Cox proportional hazards models. RESULTS:At baseline, participants were 55.6% female with median (25th, 75th percentile) age 55 years (49.0, 62.0), diabetes duration 8 years (5.0, 13.0), glycosylated hemoglobin 60.7 mmol/mol (48.6, 76.0), eGFR 91.3 mL/min/1.73 m (76.4, 111.3), UACR 12.5 mg/mmol (4.2, 51.2), and coronary artery calcium 28.5 mg Ca (1.0, 348.6); 11.5% had two renal-risk variants. After 6.6-year follow-up (5.8, 7.5), 54 deaths were recorded. Higher levels of coronary artery calcified plaque, carotid artery calcified plaque, albuminuria, and FGF23 were associated with higher mortality after adjustment for age, sex, and African ancestry proportion. A penalized Cox regression that included all covariates and predictors associated with mortality identified male sex (hazard ratio [HR] 4.17 [95% CI 1.96-9.09]), higher FGF23 (HR 2.10 [95% CI 1.59-2.78]), and absence of renal-risk genotypes (HR 0.07 [95% CI 0.01-0.69]) as the strongest predictors of mortality. CONCLUSIONS:Accounting for conventional risk factors, higher FGF23 concentrations and non-renal-risk genotypes associated with higher mortality in African Americans with diabetes. These data add to growing evidence supporting FGF23 association with mortality; mechanisms whereby these novel predictors impact survival remain to be determined. 10.2337/dc17-0820
    Reduced Levels of Anti-Ageing Hormone Klotho Predict Renal Function Decline in Type 2 Diabetes. Fountoulakis Nikolaos,Maltese Giuseppe,Gnudi Luigi,Karalliedde Janaka The Journal of clinical endocrinology and metabolism Context and Objective:Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) with relatively preserved renal function is unknown. Design, Setting, Participants, and Measurements:Single-center observational follow-up study of 101 patients with T2DM and eGFR >45 mL/min [91% on renin angiotensin system (RAS) blockade] followed for a median of 9 years (range, 2 to 13 years). Main Outcome:Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, and fibroblast growth factor-23 levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements. Results:Patients with residual microalbuminuria (MA) despite RAS blockade (n = 53) had significantly lower levels of sKlotho [median, 184.7 pg/mL; interquartile range (IQR), 130.5 to 271.8 pg/mL) compared with patients without MA (n = 39; median, 235.2 pg/mL; IQR, 172.0 to 289.4 pg/mL; P = 0.03). Of the cohort, 21% reached the primary outcome. In a competing risk analysis, a 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.52; P < 0.001] independent of traditional risk factors. Patients with sKlotho below the median of 204.4 pg/mL had nearly a fourfold higher cumulative incidence of the primary outcome compared with those above the median (24% vs 6.2%; P = 0.01). Conclusions:In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM. 10.1210/jc.2018-00004
    Calcium Signaling in ß-cell Physiology and Pathology: A Revisit. Klec Christiane,Ziomek Gabriela,Pichler Martin,Malli Roland,Graier Wolfgang F International journal of molecular sciences Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium (Ca) signaling has been found to be vital for the proper insulin-releasing function of β-cells. Calcium dysregulation events can have a dramatic effect on the proper functioning of the pancreatic β-cells. The current review discusses the role of calcium signaling in health and disease in pancreatic β-cells and provides an in-depth look into the potential role of alterations in β-cell Ca homeostasis and signaling in the development of diabetes and highlights recent work that introduced the current theories on the connection between calcium and the onset of diabetes. 10.3390/ijms20246110
    High calcium intake from fat-free milk, body composition and glycaemic control in adults with type 2 diabetes: a randomised crossover clinical trial. Gomes Júnia Maria Geraldo,de Assis Costa Jorge,Ribeiro Priscila Vaz de Melo,Alfenas Rita de Cássia Gonçalves The British journal of nutrition We evaluated the effects of high-Ca fat-free milk v. low-Ca control diet on adiposity and on glycaemic control. Fourteen subjects with type 2 diabetes (aged 49·5 (sd 8·6) years, BMI 29·4 (sd 4·5) kg/m2, low habitual Ca consumption (<600 mg/d)) were included in this randomised, crossover clinical trial. Subjects participated in two 12-week experimental sessions (high-Ca fat-free milk (HC) or low-Ca control (LC)) separated by 8-week washout. Subjects daily consumed in the laboratory a breakfast shake containing 700 mg (HC) or 6·4 mg (LC) of Ca. Energy-restricted diets containing 800 mg of dietary Ca/d were prescribed. Dietary records data indicated the consumption of 1200 mg of Ca/d during HC and of 525 mg of Ca/d during LC. There was a greater reduction in body weight, body fat mass, waist circumference and waist:hip ratio after HC. Serum 25-hydoxyvitamin D and homeostatic model assessment-2 β-cell function (HOMA2-%B) increased, and serum uric acid, parathormone (PTH) and glycated Hb (HbA1c) concentrations reduced after HC. In addition, changes from baseline in terms of serum uric acid, glucose, HbA1c and PTH concentrations were lower, and those of HOMA2-%B, serum Ca and 25-hydoxyvitamin D were higher after the HC than after LC. The consumption of approximately three servings of fat-free milk and 1200 mg of dietary Ca/d enhanced weight loss, improved body composition and promoted glycaemic control in subjects with type 2 diabetes and low habitual Ca consumption (<600 mg/d). 10.1017/S0007114519001259
    Serum calcium and its complex association with incident type 2 diabetes. Chatterjee Ranee,Lin Pao-Hwa The American journal of clinical nutrition 10.3945/ajcn.116.143321
    Youth and Long-Term Dietary Calcium Intake With Risk of Impaired Glucose Metabolism and Type 2 Diabetes in Adulthood. Wu Feitong,Juonala Markus,Pahkala Katja,Buscot Marie-Jeanne,Sabin Matthew A,Pitkänen Niina,Rönnemaa Tapani,Jula Antti,Lehtimäki Terho,Hutri-Kähönen Nina,Kähönen Mika,Laitinen Tomi,Viikari Jorma S A,Raitakari Olli T,Magnussen Costan G The Journal of clinical endocrinology and metabolism CONTEXT:To the best of our knowledge, no previous studies have examined the role of youth calcium intake in the development of impaired glucose metabolism, especially those with long-term high calcium intake. OBJECTIVES:To examine whether youth and long-term (between youth and adulthood) dietary calcium intake is associated with adult impaired glucose metabolism and type 2 diabetes (T2D). DESIGN, SETTING, AND PARTICIPANTS:The Cardiovascular Risk in Young Finns Study is a 31-year prospective cohort study (n = 1134; age, 3 to 18 years at baseline). EXPOSURES:Dietary calcium intake was assessed at baseline (1980) and adult follow-up visits (2001, 2007, and 2011). Long-term (mean between youth and adulthood) dietary calcium intake was calculated. MAIN OUTCOME MEASURES:Adult impaired fasting glucose (IFG) and T2D. RESULTS:We found no evidence for nonlinear associations between calcium intake and IFG or T2D among females and males (all P for nonlinearity > 0.05). Higher youth and long-term dietary calcium intake was not associated with the risk of IFG or T2D among females or males after adjustment for confounders, including youth and adult body mass index. CONCLUSIONS:Youth or long-term dietary calcium intake is not associated with adult risk of developing impaired glucose metabolism or T2D. 10.1210/jc.2018-02321
    Genetic Prediction of Serum 25-Hydroxyvitamin D, Calcium, and Parathyroid Hormone Levels in Relation to Development of Type 2 Diabetes: A Mendelian Randomization Study. Yuan Shuai,Jiang Xia,Michaëlsson Karl,Larsson Susanna C Diabetes care OBJECTIVE:We conducted a Mendelian randomization study to investigate the associations of genetically predicted serum 25-hydroxyvitamin D (S-25OHD), calcium (S-Ca), and parathyroid hormone (S-PTH) levels with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS:Seven, six, and five single nucleotide polymorphisms (SNPs) associated with S-25OHD, S-Ca, and S-PTH levels, respectively, were used as instrumental variables. Data on T2DM were available for 74,124 case subjects with T2DM and 824,006 control subjects. The inverse variance-weighted method was used for the primary analyses, and the weighted median and Mendelian randomization (MR)-Egger methods were used for supplementary analyses. RESULTS:Genetically predicted S-25OHD but not S-Ca and S-PTH levels were associated with T2DM in the primary analyses. For 1 SD increment of S-25OHD levels, the odds ratio (OR) of T2DM was 0.94 (95% CI 0.88-0.99; = 0.029) in an analysis based on all seven SNPs and 0.90 (95% CI 0.83-0.98; = 0.011) in an analysis based on three SNPs within or near genes involved in vitamin D synthesis. Only the association based on the SNPs involved in vitamin D synthesis remained in the weighted median analysis, and no pleiotropy was detected ( = 0.153). Pleiotropy was detected in the analysis of S-Ca ( = 0.013). After correcting for this bias using MR-Egger regression, the OR of T2DM per 1 SD increment of S-Ca levels was 1.41 (95% CI 1.12-1.77; = 0.003). CONCLUSIONS:Modest lifelong higher S-25OHD levels were associated with reduced odds of T2DM, but the association was only robust for SNPs in the vitamin D synthesis pathway. The possible role of S-Ca levels for T2DM development requires further research. 10.2337/dc19-1247
    Circulating calcium levels and the risk of type 2 diabetes: a systematic review and meta-analysis. Zhu J,Xun P,Bae J C,Kim J H,Kim D J,Yang K,He K The British journal of nutrition Abnormal Ca homeostasis has been associated with impaired glucose metabolism. However, the epidemiological evidence is controversial. We aimed to assess the association between circulating Ca levels and the risk of type 2 diabetes mellitus (T2DM) or abnormal glucose homeostasis through conducting a systematic review and meta-analysis. Eligible studies were identified by searching electronic database (PubMed, Embase and Google Scholar) and related references with de novo results from primary studies up to December 2018. A random-effects meta-analysis was performed to estimate the weighted relative risks (RR) and 95 % CI for the associations. The search yielded twenty eligible publications with eight cohort studies identified for the meta-analysis, which included a total of 89 165 participants. Comparing the highest with the lowest category of albumin-adjusted serum Ca, the pooled RR was 1·14 (95 % CI 1·05, 1·24) for T2DM (n 51 489). Similarly, serum total Ca was associated with incident T2DM (RR 1·25; 95 % CI 1·10, 1·42) (n 64 502). Additionally, the adjusted RR for 1 mg/dl increments in albumin-adjusted serum Ca or serum total Ca levels was 1·16 (95 % CI 1·07, 1·27) and 1·19 (95 % CI 1·11, 1·28), respectively. The observed associations remained with the inclusion of a cohort study with ionised Ca as the exposure. However, data pooled from neither case-control (n 4) nor cross-sectional (n 8) studies manifested a significant correlation between circulating Ca and glucose homeostasis. In conclusion, accumulated data from the cohort studies suggest that higher circulating Ca levels are associated with an augmented risk of T2DM. 10.1017/S0007114519001430
    Proinflammatory cytokine MIF plays a role in the pathogenesis of type-2 diabetes mellitus, but does not affect hepatic mitochondrial function. Rodriguez-Sosa Miriam,Cabellos-Avelar Tecilli,Sanchez-Zamora Yuriko,Juárez-Avelar Imelda,García-Reyes Esperanza,Lira-León Alejandra,Benítez-Flores José Del Carmen,Pacheco-Fernández Thalia,Hiriart Marcia,Gutiérrez-Cirlos Emma Berta Cytokine BACKGROUND:Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although the effect of high glucose on liver function has been described, the role of MIF in hepatic mitochondrial function during T2DM has not been studied. OBJECTIVE:We examine the influence of MIF to hepatic mitochondrial function in T2DM mouse model. METHODS:WT and Mif BALB/c mice were treated with a single dose of streptozotocin (STZ). After an 8-week follow-up, serum glucose, proinflammatory cytokines, C-reactive protein (CRP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme quantification, and liver histological analyses were performed. Liver mitochondria were extracted, and mitochondrial function was evaluated by oximetry, swelling and peroxide production. RESULTS:Following treatment with STZ, WT mice (WT/STZ) developed significant hyperglycemia and high serum levels of MIF, tumor necrosis factor (TNF)-α, interleukin-β (IL-β), and CRP. Liver damage enzymes ALT and AST were found at high levels. In contrast, MifSTZ lacked serum MIF levels and showed smaller increases in blood glucose, less TNF-α, IL-1β, CPR, ALT and AST, and failure to develop clinical signs of disease compared to the WT/STZ group. Mitochondria extracted from the MifSTZ liver showed similar respiratory control (RC) to WT/STZ or healthy mice with glutamate/malate or succinate as substrates. The four respiratory chain complexes also had comparable activities. WT/STZ-isolated mitochondria showed low swelling with calcium compared to mitochondria from MifSTZ or healthy mice. Peroxide production was comparable in all groups. CONCLUSION:These results show although high systemic levels of MIF contribute to the development of T2DM pathology, the liver mitochondria remain unaltered. Importantly, the absence of MIF reduced the pathology of T2DM, also without altering liver mitochondrial function. These support MIF as a therapeutic target for the treatment of this disease in humans. 10.1016/j.cyto.2017.07.012
    Vitamin D Status, Calcium Intake and Risk of Developing Type 2 Diabetes: An Unresolved Issue. Muñoz-Garach Araceli,García-Fontana Beatriz,Muñoz-Torres Manuel Nutrients The relationship between vitamin D status, calcium intake and the risk of developing type 2 diabetes (T2D) is a topic of growing interest. One of the most interesting non-skeletal functions of vitamin D is its potential role in glucose homeostasis. This possible association is related to the secretion of insulin by pancreatic beta cells, insulin resistance in different tissues and its influence on systemic inflammation. However, despite multiple observational studies and several meta-analyses that have shown a positive association between circulating 25-hydroxyvitamin D concentrations and the risk of T2D, no randomized clinical trials supplementing with different doses of vitamin D have confirmed this hypothesis definitively. An important question is the identification of what 25-hydroxyvitamin D levels are necessary to influence glycemic homeostasis and the risk of developing T2D. These values of vitamin D can be significantly higher than vitamin D levels required for bone health, but the currently available data do not allow us to answer this question adequately. Furthermore, a large number of observational studies show that dairy consumption is linked to a lower risk of T2D, but the components responsible for this relationship are not well established. Therefore, the importance of calcium intake in the risk of developing T2D has not yet been established. Although there is a biological plausibility linking the status of vitamin D and calcium intake with the risk of T2D, well-designed randomized clinical trials are necessary to answer this important question. 10.3390/nu11030642
    Dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: The Korean Multi-Rural Communities Cohort (MRCohort). Oh J M,Woo H W,Kim M K,Lee Y-H,Shin D H,Shin M-H,Choi B Y Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:Although a possible mechanism for developing type 2 diabetes in relation to calcium intake has been suggested, there is currently little epidemiological evidence on the association between dietary calcium and type 2 diabetes (T2D). This study aimed to evaluate the prospective association between dietary calcium and T2D incidence among adults 40 years of age or over, from the Multi-rural Communities Cohort (MRCohort), South Korea. METHODS AND RESULTS:In total, 8313 participants (3033 men and 5280 women) who did not have diabetes at baseline were recruited between 2005 and 2013. The incidence rate ratio (IRR) was estimated using a modified Poisson regression model with a robust error estimator. During follow-up (31,570 person-years), 322 T2D cases were newly diagnosed. Dietary calcium (total and vegetable calcium) were inversely associated with the risk of T2D incidence among women (IRR = 0.61, 95% CI = 0.43-0.86, P for trend = 0.007 in third tertile of baseline total calcium intake comparing to the first tertile; IRR = 0.57, 95% CI = 0.39-0.84, P for trend = 0.006 for baseline vegetable calcium intake), not for men. The tendency of those inverse associations remained in both the normal fasting blood glucose group and the impaired fasting blood glucose group and were independent of obesity, smoking, and magnesium intake. CONCLUSIONS:Total and vegetable calcium may be inversely associated with T2D incidence among women, regardless of impaired fasting blood glucose group or normal group. The associations may be potentially dose-responsive. Moderate dietary calcium may be related to lower risk of T2D incidence comparing to low intake group among women. 10.1016/j.numecd.2017.10.005
    Intakes of Zinc, Potassium, Calcium, and Magnesium of Individuals with Type 2 Diabetes Mellitus and the Relationship with Glycemic Control. Brandão-Lima Paula Nascimento,Carvalho Gabrielli Barbosa de,Santos Ramara Kadija Fonseca,Santos Beatriz da Cruz,Dias-Vasconcelos Natalia Lohayne,Rocha Vivianne de Sousa,Barbosa Kiriaque Barra Ferreira,Pires Liliane Viana Nutrients The role of the concomitant intake of zinc, potassium, calcium, and magnesium in the glycemic control of individuals with type 2 diabetes mellitus (T2DM) has not been extensively discussed. We evaluated the relationship between the dietary intake of these micronutrients and glycemic markers in 95 individuals with T2DM (mean age 48.6 ± 8.4 years). Hierarchical grouping analysis was used to divide the individuals into two clusters according to their micronutrient intake, and differences between clusters were statistically assessed. Effects of individual and combination intake of micronutrients on glycated hemoglobin percentage (%HbA1c) were assessed using multiple linear regression and binary logistic regression analysis. We observed a high likelihood of inadequate intake of the four micronutrients. The group with lower micronutrient intake (cluster 1) displayed higher %HbA1c ( = 0.006) and triglyceride ( = 0.010) levels. High %HbA1c showed an association with cluster 1 (odds ratio (OR) = 3.041, 95% confidence interval (CI) = 1.131; 8.175) and time of T2DM diagnosis (OR = 1.155, 95% CI = 1.043; 1.278). Potassium (β = -0.001, = 0.017) and magnesium (β = -0.007, = 0.015) intakes were inversely associated with %HbA1c. Reduced concomitant intake of the four micronutrients studied proved to be associated with risk of increased %HbA1c in individuals with T2DM, which was particularly predicted by magnesium and potassium intakes. 10.3390/nu10121948
    Association between plasma strontium, a bone-seeking element, and type 2 diabetes mellitus. Chen Liangkai,Guo Qianqian,Wang Qiang,Luo Cheng,Chen Sijing,Wen Sheng,Tan Aijun,Yang Wei,Bao Wei,Hu Frank B,Liu Liegang Clinical nutrition (Edinburgh, Scotland) BACKGROUND & AIMS:Drinking water and food are the major sources of strontium in human. Strontium is essential for bone metabolism, while its role in glucose and lipid metabolism is largely unknown. We aimed to investigate the association of strontium, a bone-seeking element, with type 2 diabetes mellitus (T2DM) and impaired glucose regulation (IGR) and to further explore the potential mechanisms. METHODS:The case-control study included 1448 newly diagnosed T2DM patients, 782 IGR patients, and 2230 matched controls with normal glucose tolerance. Plasma strontium and other plasma minerals were quantified via inductively coupled plasma mass spectrometry. Multivariable logistic regression analysis was used to evaluate the independent associations between plasma strontium and T2DM and IGR. RESULTS:Plasma strontium was inversely associated with T2DM and IGR. After adjustment for sociodemographic, lifestyle factors, and multiple plasma metals, the odds ratios (95% confidence intervals) of T2DM and IGR were 0.45 (0.35-0.57) and 0.55 (0.43-0.71), respectively, comparing the highest to the lowest quartile of plasma strontium levels. In spline analysis, the odds of T2DM and IGR decreased remarkably with increasing strontium concentration and followed by a plateau. Additionally, plasma strontium was negatively associated with total cholesterol, low density lipoprotein cholesterol, and lipid peroxidation (plasma malondialdehyde level). CONCLUSIONS:The current study indicated that higher plasma strontium concentration was associated with lower odds of T2DM and IGR. Further studies are warranted to confirm these findings and to clarify the underlying mechanisms. 10.1016/j.clnu.2019.08.033
    Serum calcium changes and risk of type 2 diabetes mellitus in Asian population. Suh Sunghwan,Bae Ji Cheol,Jin Sang-Man,Jee Jae Hwan,Park Mi Kyoung,Kim Duk Kyu,Kim Jae Hyeon Diabetes research and clinical practice AIMS:We examined the association between changes in serum calcium levels with the incidence of type 2 diabetes mellitus (T2DM) in apparently healthy South Korean subjects. METHODS:A retrospective longitudinal analysis was conducted with subjects who had participated in comprehensive health check-ups at least four times over a 7-year period (between 2006 and 2012). In total, 23,121 subjects were categorized into tertiles based on changes in their albumin-adjusted serum calcium levels. Multivariate Cox regression models were fitted to assess the association between changes in serum calcium levels during follow-up and the relative risk of diabetes incidence. RESULTS:After a median follow-up of 57.4months, 1,929 (8.3%) new cases of T2DM occurred. Simple linear regression analysis showed serum calcium level changes correlated positively with changes in HbA1c and fasting plasma glucose (FPG) levels (B=5.72, p<0.001 for FPG; B=0.13, p<0.001 for HbA1c). An increase in albumin-adjusted serum calcium levels during follow-up was related to an increased risk of T2DM. After adjustment for potential confounders, the risk of T2DM was 1.6 times greater for subjects whose albumin-adjusted serum calcium levels were in the highest change tertile during follow-up than for subjects whose levels were in the lowest tertile (HR 1.65, 95% CI 1.44-1.88, P<0.001). CONCLUSIONS:The elevation of albumin-adjusted serum calcium levels was associated with an increased risk of T2DM, independent of baseline glycemic status. 10.1016/j.diabres.2017.08.022