Increasing levels of magnesium in blood are associated with reduced risk of cardiovascular disease in chronic kidney disease (CKD). Magnesium supplementation may reduce the progression of vascular ...calcification in CKD. The diurnal pattern and effect of fasting on magnesium in blood and urine in CKD is unknown, and knowledge of this may influence management of magnesium supplementation.
We included ten patients with CKD stage four without diabetes mellitus and ten healthy controls. Participants were admitted to our hospital ward for a 24-h study period. Blood and urine samples were collected in a non-fasting state at 8 o'clock in the morning and every third hour hereafter until the final samples in a fasting state at 8 o'clock the following morning.
We found no diurnal variation in plasma magnesium (p = 0.097) in either group, but a significant diurnal variation in urinary excretion of magnesium (p = 0.044) in both CKD and healthy controls with no significant interaction between the two groups, and thus no suggestion that CKD affects diurnal variation of plasma magnesium or urinary magnesium excretion. The levels of plasma magnesium were not significantly different in fasting and non-fasting conditions.
Magnesium in plasma does not display a significant diurnal variation and can be measured at any time of day and in both fasting and non-fasting conditions. Urinary magnesium excretion displays diurnal variation, which is likely related to increased uptake of magnesium during meals and helps maintain a stable concentration of magnesium in blood.
•Magnesium is an important mineral of clinical relevance in chronic kidney disease.•Plasma magnesium does not exhibit a diurnal rhythm in chronic kidney disease.•Plasma magnesium is not influenced by fasting in chronic kidney disease.•Urinary magnesium displays a diurnal rhythm which likely maintains steady plasma magnesium.
In healthy individuals, GIP enhances insulin secretion and reduces bone resorption As GIP has impaired insulinotropic effects in patients with type 2 diabetes (T2D), we investigated the effect of ...glucose and GIP on bone resorption in these patients.
In a randomized, double-blinded, cross-over study, 12 male patients with T2D underwent six study days with 90-minute GIP or matching placebo (saline) infusions on paired days with plasma glucose (PG) clamped at three levels: Fasting hyperglycemia (mean PG ∼8 mmol/l), aggravated hyperglycemia (mean PG ∼12 mmol/l), or insulin-induced hypoglycemia (mean PG 3-8 mmol/l). Primary outcome measure was CTX (a marker of bone resorption expressed as %-change from baseline ± SD).
On days with fasting hyperglycemia, CTX was suppressed by 36±15% during GIP compared to 0±9% during saline infusion (p<0.0001). On days with aggravated hyperglycemia, CTX was suppressed by 47±23% during GIP compared to 10±9% during saline infusion (p=0.0005). On days with insulin-induced hypoglycemia, CTX was suppressed by 40±15% during GIP compared to 12±11% during saline infusion (p<0.0001).
In conclusion, Short-term GIP infusions during hyperglycemia reduce bone resorption by more than a third suggesting that GIP has preserved effects on bone in patients with T2D.
Disclosure
M.B. Christensen: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. N.R. Jørgensen: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.
Objective
Neuronal‐specific enolase (NSE) and protein S100B have gained considerable interest as the markers of CNS injury, glial cell activation, and/or blood‐brain barrier (BBB) disruption. No ...studies have investigated NSE and S100B in cluster headache (CH), but these biomarkers could contribute to the understanding of CH.
Methods
Patients with episodic CH in bout (eCHa), in remission (eCHr), and chronic CH (cCH) were included in this randomized, double‐blind, placebo‐controlled, 2‐way cross‐over provocation study carried out at the Danish Headache Center. The primary endpoints included (1) differences of NSE and S100B in between groups (eCHa, eCHr, and cCH) at baseline; (2) differences over time in plasma concentrations of NSE and S100B between patient developing an attack and those who did not; (3) differences in plasma concentrations over time of NSE and S100B between active day and placebo day. Baseline findings were compared to the historical data on migraine patients and healthy controls and presented with means ± SD.
Results
Nine eCHa, 9 eCHr, and 13 cCH patients completed the study and blood samples from 11 CGRP‐induced CH attacks were obtained. There were no differences in NSE levels between CH groups at baseline, but CH patients in active disease phase had higher levels compared with 32 migraine patients (9.1 ± 2.2 µg/L vs 6.0 ± 2.2 µg/L, P < .0001) and 6 healthy controls (9.1 ± 2.2 µg/L vs 7.3 ± 2.0 µg/L, P = .007). CGRP‐infusion caused no NSE changes and, but a slight, non‐significant, increase in NSE was seen in patients who reported a CGRP‐induced CH attack (2.39 µg/L, 95% Cl −0.26, 3.85, P = .061). At baseline S100B levels in eCHa patients were higher compared to cCH patients (0.06 ± 0.02 µg/L vs 0.04 ± 0.02 µg/L, P = .018). Infusion of CGRP and CGRP‐induced attacks did not change S100B levels. Apart from induced CH‐attacks no other adverse events were noted.
Conclusions
At baseline eCHa patients had higher S100B plasma levels than cCH patients and there was a slight, however not significant, NSE increase in response to CGRP‐induced CH attack. Our findings suggest a possible role of an ictal activation of glial cells in CH pathophysiology, but further studies are warranted.
Escherichia coli is the dominant facultative bacterium in the normal intestinal flora. E. coli is, however, also responsible for the majority of serious extraintestinal infections. There are distinct ...serotypical differences between facultative and invasive E. coli strains. Invasive strains frequently produce virulence factors such as α-hemolysin (HlyA), which causes hemolysis by forming pores in the erythrocyte membrane. The present study reveals that this pore formation triggers purinergic receptor activation to mediate the full hemolytic action. Non-selective ATP-receptor (P2) antagonists (PPADS, suramin) and ATP scavengers (apyrase, hexokinase) concentration dependently inhibited HlyA-induced lysis of equine, murine, and human erythrocytes. The pattern of responsiveness to more selective P2-antagonists implies that both P2X₁ and P2X₇ receptors are involved in HlyA-induced hemolysis in all three species. In addition, our results also propose a role for the pore protein pannexin1 in HlyA-induced hemolysis, as non-selective inhibitors of this channel significantly reduced hemolysis in the three species. In conclusion, activation of P2X receptors and possibly also pannexins augment hemolysis induced by the bacterial toxin, HlyA. These findings potentially have clinical perspectives as P2 antagonists may ameliorate symptoms during sepsis with hemolytic bacteria.
Osteocytes reside as a cellular network throughout the mineralised matrix of bone and are considered the primary mechanosensors of this tissue. They sense mechanical stimulation such as fluid flow ...and are able to regulate osteoblast and osteoclast functions on the bone surface. Previously, we found that ATP is released load-dependently from osteocytes from the onset of mechanical stimulation. Therefore, the aim of the present study was to investigate whether and how ATP release can be evoked in osteocytes via purinergic receptor activation. ATP release was quantified by real-time determination using the luciferin-luciferase assay and the release pathway was investigated using pharmacological inhibition. The P2Y receptor profile was analysed using gene expression analysis by reverse transcription polymerase chain reaction, while functional testing was performed using measurements of intracellular calcium responses to P2 receptor agonists. These investigations demonstrated that MLO-Y4 osteocytes express functional P2Y
2
, P2Y
4
, P2Y
12
and P2Y
13
receptors in addition to the previously reported P2X receptors. Further, we found that osteocytes respond to nucleotides such as ATP, UTP and ADP by increasing the intracellular calcium concentration and that they release ATP dose-dependently upon stimulation with 1–10 μM UTP. In addition to this, osteocytes release large amounts of ATP upon cell rupture, which might also be a source for other nucleotides, such as UTP. These findings indicate that mechanically induced ATP signals may be propagated by P2 receptor activation and further ATP release in the osteocyte network and implicate purinergic signalling as a central signalling pathway in osteocyte mechanotransduction.
Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists ...are antidiabetic drugs, which may also affect bone turnover.
In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (
= 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (
= 23), or placebo (
= 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and
and
scores were calculated for BMD.
In women (
= 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (
= 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD
score < -2, and 23% of patients (17% of women and 29% of men) displayed -2.5 <
scores < -1 indicating osteopenia, but none had osteoporosis. After treatment, PINP decreased at trend level significance (
= 0.05), and body mass index BMD increased for L2-L4 (
= 0.016). No changes in bone markers were significant after correction for mean prolactin levels.
Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin.
Several cross-sectional studies have shown hair cortisol concentration to be associated with adiposity, but the relationship between hair cortisol concentration and longitudinal changes in measures ...of adiposity are largely unknown. We included 786 adults from the NoHoW trial, who had achieved a successful weight loss of ≥5% and had a body mass index of ≥25 kg/m
prior to losing weight. Hair cortisol concentration (pg/mg hair) was measured at baseline and after 12 months. Body weight and body fat percentage were measured at baseline, 6-month, 12-month and 18-month visits. Participants weighed themselves at home ≥2 weekly using a Wi-Fi scale for the 18-month study duration, from which body weight variability was estimated using linear and non-linear approaches. Regression models were conducted to examine log hair cortisol concentration and change in log hair cortisol concentration as predictors of changes in body weight, change in body fat percentage and body weight variability. After adjustment for lifestyle and demographic factors, no associations between baseline log hair cortisol concentration and outcome measures were observed. Similar results were seen when analysing the association between 12-month concurrent development in log hair cortisol concentration and outcomes. However, an initial 12-month increase in log hair cortisol concentration was associated with a higher subsequent body weight variability between month 12 and 18, based on deviations from a nonlinear trend (β: 0.02% per unit increase in log hair cortisol concentration 95% CI: 0.00, 0.04;
=0.016). Our data suggest that an association between hair cortisol concentration and subsequent change in body weight or body fat percentage is absent or marginal, but that an increase in hair cortisol concentration during a 12-month weight loss maintenance effort may predict a slightly higher subsequent 6-months body weight variability.
ISRCTN registry, identifier ISRCTN88405328.
Impaired muscle function has been coupled to vitamin D insufficiency in young women and in elderly men and women. Those living at Northern latitudes are at risk for vitamin D insufficiency due to low ...sun exposure which may be more pronounced among elite swimmers because of their indoor training schedules. We aimed to examine vitamin D status among young elite swimmers and evaluate the association between vitamin D status and muscle strength. Twenty-nine swimmers, 12 female and 17 male (16-24 years) residing at latitude 55-56°N were studied in March and April. Blood samples were analyzed for serum 25-hydroxyvitamin D (s-25(OH)D) and hand-grip strength was measured as marker of muscle strength. Subjects´ vitamin D and calcium intake were assessed by food frequency questionnaire and sun exposure and training status by questionnaires. Mean (± SD) s-25(OH)D was 52.6 ± 18.3nmol/L among all swimmers. In 45% of the swimmers s-25(OH)D was below 50 nmol/L. Female swimmers had higher s-25(OH)D concentration than male swimmers (61.7 ± 17,5 nmol/L vs. 46.2 ± 16,5 nmol/L, p = .026). Among male swimmers, those with sufficient vitamin D status had higher hand grip strength than those with insufficient vitamin D status (50.6 ± 6.4 kg vs. 41.1 ± 7.8 kg, p = .02). Among Danish elite swimmers 45% had an insufficient vitamin D status during the spring; the prevalence being higher among male swimmers. Muscle strength was significantly higher in male swimmers with sufficient vitamin D status.
A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, postmenopausal women, and in people with malnutrition. At present, ...no pharmacologic treatments are available. Thus, there is an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis and, intriguingly, a number of animal studies prove the ability of PTH to induce fracture healing. PTH may therefore be a potential novel treatment option in humans with impaired healing. However, more randomized clinical trials documenting the clinical efficacy of PTH as a promoter of fracture healing in the clinical setting are warranted. Also, strontium ranelate seems to have beneficial effects on fracture healing under conditions with impaired healing. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn. In contrast, bisphosphonates—which are the most widely used drug for treating osteoporosis—delay the healing process slightly, although apparently not clinically relevant. Finally, a number of newer antiresorptive agents are available, but very few studies have addressed their effects on bone healing.
Background and aim
In rodents, osteocalcin (OCN) stimulates insulin production and insulin sensitivity, both important factors during partial remission in humans with type 1 diabetes (T1D). However, ...decreased OCN has been reported in both adult and pediatric T1D. This study aims at investigating bone turnover and partial remission in children and adolescents with recent onset T1D.
Subjects and methods
Ninety‐nine individuals (33% girls) were recruited within 3 months of T1D onset and examined three times, 6 months apart. Outcome variables were bone formation markers OCN and procollagen type 1 amino‐terminal propeptide (P1NP) and the bone resorption marker C‐terminal crosslinked telopeptide of type 1 collagen (CTX). Dependent variables included IDAA1c (surrogate marker of partial remission), total body bone mineral density (BMD) and stimulated C‐peptide as representative of endogenous insulin production.
Results
OCN‐ and P1NP Z‐scores were significantly decreased throughout the study, whereas CTX Z‐scores were increased. None of the bone turnover markers changed significantly between visits. Total body BMD Z‐score did not change during the study but was significantly higher than the reference population at visit 2 (P = .035). There were no differences in the bone turnover markers for those in partial remission as defined by either C‐peptide or IDAA1c at any visit. The individual change in CTX Z‐score was negatively associated with the increase of IDAA1c (P = .030) independent of C‐peptide decline (P = .034).
Conclusion
Bone turnover markers indicate increased bone resorption and decreased bone formation during the first year of T1D. The negative association between bone resorption and IDAA1c might represent compensatory mechanisms affecting insulin sensitivity.
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