Maintenance of a healthy skeleton is highly dependent on an intricate regulation of bone metabolism, as changes in the balance between bone formation and bone resorption leads to bone loss, bone ...fragility and ultimately bone fractures. During the last three decades it has become increasingly evident that physiological release of purines in the extracellular space is imperative for bone homeostasis and is orchestrated via the network of purinoceptors. Adenosine derivatives are released locally in the skeleton either by the bone forming osteoblasts or the bone degrading osteoclasts actioned directly by processes like mechanical loading and indirectly by systemic hormones. Adenosine derivatives directly affect the bone cells by their action on the membranal receptors or have co-stimulatory actions with bone active hormones such as parathyroid hormone or the gut hormones. Any deviations leading to increased levels of extracellular adenosine derivatives in the bone tissue such as in pathologic situations, trigger complex pathways with opposing effects on tissue health as presented by studies involving a range of model organisms. Pathological conditions where skeletal purinergic signaling is affected are following tissue injury like microdamage and macroscopic fractures; and during inflammatory processes where nucleotides and nucleosides play an important part in the pathophysiological skeletal response. Moreover, adenosine derivatives also play an important role in the interaction between malignant cells and bone cells in several types of cancers involving the skeleton, such as but not limited to multiple myeloma and bone osteolysis. Much knowledge has been gained over the last decades. The net- resulting phenotype of adenosine derivatives in bone (including the ratio of ATP to Adenosine) is highly dependent on CD39 and CD73 enzymes together with the expression and activity of the specific receptors. Thus, each component is important in the physiological and pathophysiological processes in bone. Promising perspectives await in the future in treating skeletal disorders with medications targeting the individual components of the purinergic signaling pathway.
The gut hormone glucose-dependent insulinotropic polypeptide (GIP) causes postprandial insulin release and inhibits bone resorption assessed by carboxy-terminal collagen crosslinks (CTX).
To study if ...GIP affects bone homeostasis biomarkers independently of insulin release and glycemic level.
Randomized, double-blinded, crossover study with 5 study days.
Ten male C-peptide-negative patients with type 1 diabetes.
On 3 matched days with "low glycemia" (plasma glucose in the interval 3 to 7 mmol/L for 120 minutes), we administered intravenous (IV) GIP (4 pmol × kg-1 × min-1), glucagon-like peptide 1 (1 pmol × kg-1 × min-1), or placebo (saline), and on 2 matched days with "high glycemia" (plasma glucose 12 mmol/L for 90 minutes), we administered either GIP or saline.
CTX, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone (PTH).
During low glycemia: GIP progressively suppressed CTX from baseline by up to 59 ± 18% compared with 24 ± 10% during saline infusion (P < 0.0001). Absolute values of P1NP and PTH did not differ between days. During high glycemia: GIP suppressed CTX from baseline by up to 59 ± 19% compared with 7 ± 9% during saline infusion (P < 0.0001). P1NP did not differ between days. GIP suppressed PTH after 60 minutes compared with saline (P < 0.01), but this difference disappeared after 90 minutes.
Short-term GIP infusions robustly reduce bone resorption independently of endogenous insulin secretion and during both elevated and low plasma glucose, but have no effect on P1NP or PTH after 90 minutes.
Aims/hypothesis
Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by ...medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment.
Methods
Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18–35 years, BMI between 18.5 kg/m
2
and 27.5 kg/m
2
, HbA
1c
< 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit.
Results
Data from participants who completed visit 1 (
n
=23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of
Intestinibacter
spp. and
Clostridium
spp., as well as an increased abundance of
Escherichia/Shigella
spp. and
Bilophila wadsworthia
. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects.
Conclusions/interpretation
Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies.
Trial registration
Clinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050
Funding
This project was funded by Danish Diabetes Association and The Novo Nordisk Foundation
Purpose
The present study examined the effects of 15 weeks of soccer training and two different swimming training protocols on bone turnover in sedentary middle-aged women.
Methods
Eighty-three ...premenopausal mildly hypertensive women age: 45 ± 6 (±SD) years, height: 165 ± 6 cm, weight: 80.0 ± 14.1 kg, body fat: 42.6 ± 5.7 %, systolic blood pressure/diastolic blood pressure: 138 ± 6/85 ± 3 mmHg were randomized into soccer training (SOC,
n
= 21), high-intensity intermittent swimming (HS,
n
= 21), moderate-intensity swimming (MS,
n
= 21) intervention groups, and a control group (C,
n
= 20). The training groups completed three sessions per week for 15 weeks. DXA scans were performed and resting blood samples were drawn pre- and post-intervention.
Results
In SOC, plasma osteocalcin, procollagen type I N propeptide and C-terminal telopeptide increased (
P
< 0.05) by 37 ± 15, 52 ± 23 and 42 ± 18 %, respectively, with no changes in MS, HS and C. The intervention-induced increase in SOC was larger (
P
< 0.05) than in MS, HS and C. In SOC, leg BMC increased (
P
< 0.05) by 3.1 ± 4.5 %, with a larger increase in SOC than in C. Femoral shaft and trochanter bone mineral density (BMD) increased (
P
< 0.05) by 1.7 ± 1.9 and 2.4 ± 2.9 %, respectively, in SOC, with a greater (
P
< 0.05) change in SOC than in MS and C, whereas total body and total leg BMD did not change in any of the groups.
Conclusion
In conclusion, 15 weeks of soccer training with sedentary middle-aged women caused marked increases in bone turnover markers, with concomitant increases in leg bone mass. No changes in bone formation and resorption markers were seen after prolonged submaximal or high-intensity intermittent swimming training. Thus, soccer training appears to provide a powerful osteogenic stimulus in middle-aged women.
Aims
Schizophrenia is associated with cardiovascular co‐morbidity and a reduced life‐expectancy of up to 20 years. Antipsychotics are dopamine D2
receptor antagonists and are the standard of medical ...care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP‐1RA, exenatide once‐weekly, in non‐diabetic, antipsychotic‐treated, obese patients with schizophrenia.
Material and methods
Antipsychotic‐treated, obese, non‐diabetic, schizophrenia spectrum patients were randomized to double‐blinded adjunctive treatment with once‐weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis.
Results
Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences (
P
= .23). The exenatide and placebo groups experienced significant (
P
= .004), however similar (
P
= .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment.
Conclusions
Treatment with exenatide once‐weekly did not promote weight loss in obese, antipsychotic‐treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight‐lowering effect of GLP‐1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti‐obesity regimens effective in the general population may not be readily implemented in antipsychotic‐treated patients with schizophrenia.
Aims/hypothesis
Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased ...risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality.
Methods
In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA
1c
concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses.
Results
Higher fasting and non-fasting glucose and HbA
1c
concentrations were associated with higher risk of any fragility fracture (
p
<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 1.11, 1.79,
p
=0.004), with similar results for fasting glucose and HbA
1c
in two-sample MR analyses (ORs 1.50 1.03, 2.18,
p
=0.03; and 2.79 1.12, 6.93,
p
=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41),
p
=0.06; 1.36 (0.89, 2.09),
p
=0.15; and 2.47 (0.95, 6.43),
p
=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither.
Conclusions/interpretation
Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.
Graphical Abstract
The class II transactivator (CIITA), encoded by the CIITA gene, controls expression of immune response regulators, which affect bone homeostasis. Previously, we investigated a functional CIITA ...polymorphism in elderly women. Women carrying the allele associated with lower CIITA levels displayed higher bone mineral density (BMD), but also higher bone loss. The present exploratory study in a rat model sought to investigate effects of differential expression of Ciita on bone structural integrity and strength. Two strains DA (normal-to-high expression) and DA.VRA4 (lower expression) underwent ovariectomy (OVX) or sham-surgery at ~ 14-weeks of age (DA OVX n = 8, sham n = 4; DA.VRA4 OVX n = 10, sham n = 2). After 16-weeks, femoral BMD and bone mineral content (BMC) were measured and morphometry and biomechanical testing performed.
In DA.VRA4 rats, BMD/BMC, cross-sectional area and biomechanical properties were lower. Ciita expression was accompanied by OVX-induced changes to cross-sectional area and femoral shaft strength; DA rats had lower maximum load-to-fracture. Thus, while lower Ciita expression associated with lower bone mass, OVX induced changes to structural and mechanical bone properties were less pronounced.
The data tentatively suggests association between Ciita expression and structural and mechanical bone properties, and a possible role in bone changes resulting from estrogen deficiency.
A vegan diet has been associated with increased bone fracture risk, but the physiology linking nutritional exposure to bone metabolism has only been partially elucidated. This study investigated ...whether a vegan diet is associated with increased bone turnover and altered calcium homeostasis due to insufficient intake of calcium and vitamin D.
Fractionated and total 25-hydroxyvitamin D (25(OH)-D), parathyroid hormone (PTH), calcium, and four bone turnover markers (osteocalcin, N-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP), and C-terminal telopeptide of type I collagen (CTX)) were measured in serum from 78 vegans and 77 omnivores.
When adjusting for seasonality and constitutional covariates (age, sex, and body fat percentage) vegans had higher concentrations of PINP (32 95% CI: 7, 64%, P = 0.01) and BAP (58 95% CI: 27, 97%, P < 0.001) compared to omnivores, whereas CTX (30 95% CI: -1, 72%, P = 0.06) and osteocalcin (21.8 95% CI: -9.3, 63.7%, P = 0.2) concentrations did not differ between the two groups. Vegans had higher serum PTH concentration (38 95% CI: 19, 60%; P < 0.001) and lower 25(OH)-D serum concentration (-33 95% CI: -45, -19%; P < 0.001), but similar serum calcium concentration (-1 95% CI: -3, 1%, P = 0.18 compared to omnivores.
Vegans have higher levels of circulating bone turnover markers compared to omnivores, which may in the long-term lead to poorer bone health. Differences in dietary habits including intake of vitamin D and calcium may, at least partly, explain the observed differences.
Understanding the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of rosacea might provide new therapeutic avenues for individuals with this disease.
To compare plasma levels of ...CGRP between individuals with rosacea and healthy controls.
In this cross-sectional case-control study conducted in Copenhagen, Denmark, we collected blood samples from the antecubital vein from adults with rosacea and from healthy controls.
We enrolled 123 individuals with rosacea and 68 healthy controls. After adjusting for age and sex, plasma levels of CGRP were significantly higher in individuals with rosacea (mean, 95% confidence interval: 140.21 pmol/L, 128.50-151.92 pmol/L), compared with controls (110.77 pmol/L, 99.91-120.14 pmol/L, p = 0.002). Plasma levels of CGRP were not affected by age, sex, BMI, concomitant migraine, rosacea sub- or phenotype, concomitant disease or current treatment.
Participants were not age-, sex- and BMI-matched.
Elevated plasma levels of CGRP in individuals with rosacea suggest a role of CGRP in the pathogenesis of rosacea. Targeting CGRP signalling might hold therapeutic promise in people affected by this disease.
NCT03872050.
The purinergic P2X7 receptor (P2X7R) plays an important role in the crosstalk between pancreatic stellate cells (PSCs) and cancer cells, thus promoting progression of pancreatic ductal adenocarcinoma ...(PDAC). Single nucleotide polymorphisms (SNPs) in the P2X7R have been reported for several cancers, but have not been explored in PDAC.
Blood samples from PDAC patients and controls were genotyped for 11 non-synonymous SNPs in P2X7R and a risk analysis was performed. Relevant P2X7R-SNP GFP variants were expressed in PSCs and cancer cells and their function was assayed in the following tests. Responses in Ca
were studied with Fura-2 and dye uptake with YO-PRO-1. Cell migration was monitored by fluorescence microscopy. Released cytokines were measured with MSD assay.
Risk analysis showed that two SNPs 474G>A and 853G>A (rs28360447, rs7958316), that lead to the Gly150Arg and Arg276His variants, had a significant but opposite risk association with PDAC development, protecting against and predisposing to the disease, respectively. In vitro experiments performed on cancer cells and PSCs expressing the Gly150Arg variant showed reduced intracellular Ca
response, fluorescent dye uptake, and cell migration, while the Arg276His variant reduced dye uptake but displayed WT-like Ca
responses. As predicted, P2X7R was involved in cytokine release (IL-6, IL-1β, IL-8, TNF-α), but the P2X7R inhibitors displayed varied effects.
In conclusion, we provide evidence for the P2X7R SNPs association with PDAC and propose that they could be considered as potential biomarkers.
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