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Within brown adipose tissue (BAT), the brain isoform of creatine kinase (CKB) has been proposed to regulate the regeneration of ADP and phosphocreatine in a futile creatine cycle (FCC) that stimulates energy expenditure. However, the presence of FCC, and the specific creatine kinase isoforms regulating this theoretical model within white adipose tissue (WAT), remains to be fully elucidated. In the present study, creatine did not stimulate respiration in cultured adipocytes, isolated mitochondria or mouse permeabilized WAT. Additionally, while creatine kinase ubiquitous-type, mitochondrial (CKMT1) mRNA and protein were detected in human WAT, shRNA-mediated reductions in Ckmt1 did not decrease submaximal respiration in cultured adipocytes, and ablation of CKMT1 in mice did not alter energy expenditure, mitochondrial responses to pharmacological β 3 -adrenergic activation (CL 316, 243) or exacerbate the detrimental metabolic effects of consuming a high-fat diet. Taken together, these findings solidify CKMT1 as dispensable in the regulation of energy expenditure, and unlike in BAT, they do not support the presence of FCC within WAT., Competing Interests: Drs. G.H. and M.W. are Editorial Board members for Function but were blinded from reviewing or making decisions regarding this manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Context: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures. No study has evaluated the correlation of bone histomorphometry (BH) parameters with glycemic control and presence of chronic complications (CCs) in premenopausal women with T2DM., Objectives: To evaluate BH and correlate them with the degree of glycemic control and presence of CCs., Design, Settings, and Patients: This was a cross-sectional study conducted at a tertiary medical center. Twenty-six premenopausal women with T2DM were divided into groups with glycated hemoglobin HbA1c < 7% (good control, GC; n = 10) and HbA1c > 7% (poor control, PC; n = 16), and further subdivided into groups with (n = 9) and without (n = 17) CCs. BH parameters (bone volume [bone volume per total volume, BV/TV], trabecular thickness [Tb.Th], trabecular number [Tb.N], trabecular separation [Tb.Sp], osteoid thickness [O.Th], osteoid surface [osteoid surface per bone surface, OS/BS]), mineralizing surface [MS/BS], bone formation rate [BFR]), mineral apposition rate [MAR]) as well as serum pentosidine (PEN) and insulin-like growth factor (IGF)-1 were measured. The BH data were compared among the groups and with a BH control group (control group, CG, n = 15) matched by age, sex, and race., Results: BV/TV was increased in GC (P < .001) and PC (P = .05) groups and O.th (P = .03) was smaller in the PC group than in the CG. A comparison of the groups with and without CCs with the CG showed in the group with CCs, O.Th was smaller(P = .01) and BV/TV similar to the CG (P = .11). HbA1c correlated negatively with O.Th (P = .02) and OS/BS (P = .01). There was no correlation of BH to PEN and IGF-1., Conclusion: BH in premenopausal patients with T2DM is affected by disease control and chronic complications., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Mineral bone disorder (MBD) is an early complication of chronic kidney disease (CKD), with complex interactions in the bone-kidney-energy axis. These events lead to impaired bone remodelling, which in turn is associated with cardiovascular disease. Recently, we reported on a positive effect of phosphate binder treatment on bone remodelling markers and a reduction in serum FGF-23 levels in predialysis-CKD patients. The goal of the present study of this trial was to examine the effects of phosphate binders on energy-regulating hormones and Wnt pathway., Methods: In this present post hoc analysis of the above randomized, open-label, 8-week trial, which compared the effects of increasing doses of sevelamer-HCl or calcium acetate on various CKD-MBD parameters in 40 normophosphatemic CKD Stage 3-4 patients, we measured serum sclerostin, Dickkopf-1, leptin, adiponectin and serotonin concentrations., Results: Serum sclerostin, Dickkopf-1 and leptin were elevated at baseline despite normal calcium, phosphorus levels and daily urinary phosphorus excretion. There were significant and positive correlations between sclerostin and FGF-23, as well between leptin and Dickkopf-1. Treatment with both phosphate binders led to a significant decrease in phosphate overload. However, sevelamer-HCl, but not with calcium acetate, led to a significant decrease in serum FGF-23, sclerostin and leptin, and to a significant increase in bone alkaline phosphatase levels., Conclusions: Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.

Background: Cardiac remodeling in uremia is characterized by left ventricular hypertrophy, interstitial fibrosis and microvascular disease. Cardiovascular disease is the leading cause of death in uremic patients, but coronary events alone are not the prevalent cause, sudden death and heart failure are. We studied the cardiac remodeling in experimental uremia, evaluating the isolated effect of parathyroid hormone (PTH) and phosphorus., Methods: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx); they also received vehicle (V) and PTH at normal (nPTH) or high (hPTH) doses. They were fed with a poor-phosphorus (pP) or rich-phosphorus (rP) diet and were divided into the following groups: 'Sham': G1 (V+normal-phosphorus diet (np)) and 'Nx+PTx': G2 (nPTH+pP), G3 (nPTH+rP), G4 (hPTH+pP) and G5 (hPTH+rP). After 8 weeks, biochemical analysis, myocardium morphometry and arteriolar morphological analysis were performed. In addition, using immunohistochemical analysis, we evaluated angiotensin II, α-actin, transforming growth factor-beta (TGF-β) and nitrotyrosine, as well as fibroblast growth factor-23 (FGF-23), fibroblast growth factor receptor-1 (FGFR-1) and runt-related transcription factor-2 (Runx-2) expression., Results: Nx animals presented higher serum creatinine levels as well as arterial hypertension. Higher PTH levels were associated with myocardial hypertrophy and fibrosis as well as a higher coronary lesion score. High PTH animals also presented a higher myocardial expression of TGF-β, angiotensin II, FGF-23 and nitrotyrosine and a lower expression of α-actin. Phosphorus overload was associated with higher serum FGF-23 levels and Runx-2, as well as myocardial hypertrophy. FGFR-1 was positive in the cardiomyocytes of all groups as well as in calcified coronaries of G4 and G5 whereas Runx-2 was positive in G3, G4 and G5., Conclusion: In uremia, PTH and phosphorus overload are both independently associated with major changes related to the cardiac remodeling process, emphasizing the need for a better control of these factors in chronic kidney disease.

Background: Vascular calcification (VC) is commonly seen in patients with chronic kidney disease (CKD). Elevated levels of phosphate and parathormone (PTH) are considered nontraditional risk factors for VC. It has been shown that, in vitro, phosphate transforms vascular smooth muscle cells (VSMCs) into calcifying cells, evidenced by upregulated expression of runt-related transcription factor 2 (Runx2), whereas PTH is protective against VC. In addition, Runx2 has been detected in calcified arteries of CKD patients. However, the in vivo effect of phosphate and PTH on Runx2 expression remains unknown., Methods: Wistar rats were submitted to parathyroidectomy, 5/6 nephrectomy (Nx) and continuous infusion of 1-34 rat PTH (at physiological or supraphysiological rates) or were sham-operated. Diets varied only in phosphate content, which was low (0.2%) or high (1.2%). Biochemical, histological, immunohistochemistry and immunofluorescence analyses were performed., Results: Nephrectomized animals receiving high-PTH infusion presented VC, regardless of the phosphate intake level. However, phosphate overload and normal PTH infusion induced phenotypic changes in VSMCs, as evidenced by upregulated aortic expression of Runx2. High-PTH infusion promoted histological changes in the expression of osteoprotegerin and type I collagen in calcified arteries., Conclusions: Phosphate, by itself is a potential pathogenic factor for VC. It is of note that phosphate overload, even without VC, was associated with overexpression of Runx2 in VSMCs. The mineral imbalance often seen in patients with CKD should be corrected.

Background: Although scintigraphy with (99m)Tc-sestamibi (MIBI) has been used to localize parathyroid glands prior to surgery for hyperparathyroidism, using it to evaluate parathyroid function remains controversial. The purpose of this study was to evaluate the possible association of MIBI uptake with gland weight, histological pattern and proliferative activity of parathyroid cells., Methods: We studied 18 patients with secondary hyperparathyroidism (SHP); mean age 38+/-3 years, 55% female, mean time on haemodialysis 7.7+/-0.9 years. All patients had parathyroidectomy (PTx). The weights of the removed glands were estimated, and parathyroid hyperplasia was classified as diffuse (n = 28) or nodular (n = 29). The expression of proliferative cell nuclear antigen (PCNA) was evaluated by immunohistochemistry. Before PTx, all patients underwent MIBI evaluation and were categorized using a 0-3 uptake scoring system. Low uptake (scores of 0 and 1) was seen in 39 glands and high uptake (scores of 2 and 3) in 18., Results: Estimated gland weights, percentage of nodular hyperplasia and PCNA expression were greater in glands with high MIBI scores than in those with low scores (P<0.01). In glands with nodular hyperplasia, PCNA expression was higher (318+/-66 cells/mm2) than in those with diffuse hyperplasia (104+/-16 cells/mm2; P<0.001)., Conclusions: High MIBI scores were associated with high estimated gland weight, degree of cell proliferation and presence of nodular hyperplasia. MIBI scintigraphy is useful in clinical practice for localizing parathyroid glands, and it could guide the management of SHP by indicating the degree of its severity.

Background: Secondary hyperparathyroidism (2HPT) develops in chronic renal failure due to disturbances of calcium, phosphorus and vitamin D metabolism. It is characterized by high turnover bone disease and an altered calcium-parathyroid hormone (PTH) relationship. Calcitriol has been widely used for the treatment of 2HPT. However, it remains controversial whether calcitriol is capable of inducing changes of the calcium-PTH curve. The aim of the present study was to examine this issue and to determine the effect of calcitriol on bone remodelling in patients with severe 2HPT., Methods: We evaluated 16 chronic haemodialysis patients with severe 2HPT (PTH 899+/-342 pg/ml). Each patient underwent a dynamic parathyroid function test (by infusion of calcium gluconate and sodium citrate) and a bone biopsy before and after a 6 month period of i.v. calcitriol therapy (CTx)., Results: After treatment, eight patients were identified as calcitriol responders and the other eight as non-responders, based on plasma PTH level (<300 pg/ml for responders and >300 pg/ml for non-responders). The first group had higher plasma 25OHD(3) levels (39+/-8 vs 24+/-7 ng/ml, P<0.005). As to the calcium-PTH curve, we found differences in slope (-12.7+/-5.2 vs -21.7+/-11.4, P=0.05), basal/maximum PTH ratio (48.8+/-14.9 vs 71.05+/-20.1%, P=0.01) and time to achieve hypocalcaemia (79.0+/-13.5 vs 94.3+/-13.7 min, P<0.001). Initial histomorphometric parameters did not allow identification of the different groups. After the 6-month CTx, alterations in the calcium-PTH curve were clearly seen in responders [a drop in maximum PTH (from 1651+/-616 to 938+/-744 pg/ml, P<0.05) and minimum PTH (from 163+/-75.4 to 102.2+/-56.7 pg/ml, P<0.005)], associated with an increase in minimum/basal PTH ratio (from 23.3+/-11.6 to 34.5+/-20.4%, P<0.05) and maximum calcium (from 0.99+/-0.07 to 1.1+/-0.09 mmol/l, P<0.05). Set point and slope were not altered after calcitriol treatment, in responders (set point=1.17+/-0.08 vs 1.15+/-0.1 mmol/l, ns; slope=-12.7+/-5.2 vs -12.9+/-9.3, ns) or non-responders (set point=1.21+/-0.05 vs 1.21+/-0.2 mmol/l, ns; slope=-21.7+/-11.4 vs -17.3+/-8.4, ns). Bone formation parameters were reduced in all patients [osteoid surface (OS/BS)=from 57.1+/-21.6 to 41.6+/-26%, P<0.05 for responders, and from 76.7+/-12 to 47.1+/-15%, P<0.001 in non-responders], but non-responders had increased bone resorption [eroded surface (ES/BS)=7.1+/-3.4 vs 16.6+/-4.9, P<0.05]., Conclusion: Calcitriol had non-uniform effects on parathyroid function and bone remodelling in uraemic patients. Non-responders exhibited a decoupled remodelling process that could further influence mineral balance or possibly also bone structure. To avoid such undesirable effects, early identification of non-responder patients is crucial when using calcitriol for the treatment of 2HPT.