Undercarboxylated osteocalcin (ucOC) may play a role in glucose homeostasis and cardiometabolic health. This review examines the epidemiological and interventional evidence associating osteocalcin ...(OC) and ucOC with metabolic risk and cardiovascular disease. The complexity in assessing such correlations, due to the observational nature of human studies, is discussed. Several studies have reported that higher levels of ucOC and OC are correlated with lower fat mass and HbA1c. In addition, improved measures of glycaemic control via pharmacological and non-pharmacological (e.g. exercise or diet) interventions are often associated with increased circulating levels of OC and/or ucOC. There is also a relationship between lower circulating OC and ucOC and increased measures of vascular calcification and cardiovascular disease. However, not all studies have reported such relationship, some with contradictory findings. Equivocal findings may arise because of the observational nature of the studies and the inability to directly assess the relationship between OC and ucOC on glycaemic control and cardiovascular health in humans. Studying OC and ucOC in humans is further complicated due to numerous confounding factors such as sex differences, menopausal status, vitamin K status, physical activity level, body mass index, insulin sensitivity (normal/insulin resistance/T2DM), tissue-specific effects and renal function among others. Current observational and indirect interventional evidence appears to support a relationship between ucOC with metabolic and cardiovascular disease. There is also emerging evidence to suggest a direct role of ucOC in human metabolism. Further mechanistic studies are required to (a) clarify causality, (b) explore mechanisms involved and (c) define the magnitude of this effect and its clinical importance.
Aim
The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with ...a simulated day shift schedule.
Methods
Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively.
Results
Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L−1; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II‐V) or insulin‐stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2).
Conclusion
Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.
Acute exercise increases osteocalcin (OC), a marker of bone turnover, and in particular the undercarboxylated form (ucOC). Males and females differ in baseline levels of total OC and it is thought ...the hormonal milieu may be driving these differences. Males and females adapt differently to the same exercise intervention, however it is unclear whether the exercise effects on OC are also sex-specific. We tested whether the responses of OC and its forms to acute High Intensity Interval Exercise (HIIE) and High Intensity Interval Training (HIIT) differed between males and females. Secondly, we examined whether sex hormones vary with OC forms within sexes to understand if these are driving factor in any potential sex differences.
Total OC (tOC), undercarboxylated OC (ucOC), and carboxylated OC (cOC) were measured in serum of 96 healthy participants from the Gene SMART cohort (74 males and 22 females) at rest, immediately after, and 3 h after a single bout of HIIE, and at rest, 48 h after completing a four week HIIT intervention. Baseline testosterone and estradiol were also measured for a subset of the cohort (Males = 38, Females = 20). Linear mixed models were used to a) uncover the sex-specific effects of acute exercise and short-term training on OC forms and b) to examine whether the sex hormones were associated with OC levels.
At baseline, males had higher levels of tOC, cOC, and ucOC than females (q < 0.01). In both sexes tOC, and ucOC increased to the same extent after acute HIIE. At baseline, in males only, higher testosterone was associated with higher ucOC (β = 3.37; q < 0.046). Finally, tOC and ucOC did not change following 4 weeks of HIIT.
While there were no long-term changes in OC and its forms. tOC and ucOC were transiently enhanced after a bout of HIIE similarly in both sexes. This may be important in metabolic signalling in skeletal muscle and bone suggesting that regular exercise is needed to maintain these benefits. Overall, these data suggest that the sex differences in exercise adaptations do not extend to the bone turnover marker, OC.
•No long-term changes in Osteocalcin after 4 week low-impact exercise intervention.•Osteocalcin is transiently enhanced after an acute bout of exercise in both sexes.•Sex differences in exercise adaptations are not evident in bone turnover marker, OC
Summary
We tested whether GPRC6A, the putative receptor of undercarboxylated osteocalcin (ucOC), is present in mouse muscle and whether ucOC increases insulin sensitivity following ex vivo muscle ...contraction. GPPRC6A is expressed in mouse muscle and in the mouse myotubes from a cell line. ucOC potentiated the effect of ex vivo contraction on insulin sensitivity.
Introduction
Acute exercise increases skeletal muscle insulin sensitivity. In humans, exercise increases circulating ucOC, a hormone that increases insulin sensitivity in rodents. We tested whether GPRC6A, the putative receptor of ucOC, is present in mouse muscle and whether recombinant ucOC increases insulin sensitivity in both C2C12 myotubes and whole mouse muscle following ex vivo muscle contraction.
Methods
Glucose uptake was examined in C2C12 myotubes that express GPRC6A following treatment with insulin alone or with insulin and increasing ucOC concentrations (0.3, 3, 10 and 30 ng/ml). In addition, glucose uptake, phosphorylated (p-)AKT and p-AS160 were examined ex vivo in extensor digitorum longus (EDL) dissected from C57BL/6J wild-type mice, at rest, following insulin alone, after muscle contraction followed by insulin and after muscle contraction followed by recombinant ucOC then insulin exposure.
Results
We observed protein expression of the likely receptor for ucOC, GPRC6A, in whole muscle sections and differentiated mouse myotubes. We observed reduced GPRC6A expression following siRNA transfection. ucOC significantly increased insulin-stimulated glucose uptake dose-dependently up to 10 ng/ml, in differentiated mouse C2C12 myotubes. Insulin increased EDL glucose uptake (∼30 %,
p
< 0.05) and p-AKT and p-AKT/AKT compared with rest (all
p
< 0.05). Contraction prior to insulin increased muscle glucose uptake (∼25 %,
p
< 0.05), p-AKT, p-AKT/AKT, p-AS160 and p-AS160/AS160 compared with contraction alone (all
p
< 0.05). ucOC after contraction increased insulin-stimulated muscle glucose uptake (∼12 %
p
< 0.05) and p-AS160 (<0.05) more than contraction plus insulin alone but without effect on p-AKT. In the absence of insulin and/or of contraction, ucOC had no significant effect on muscle glucose uptake.
Conclusions
GPRC6A, the likely receptor of osteocalcin (OC), is expressed in mouse muscle. ucOC treatment augments insulin-stimulated skeletal muscle glucose uptake in C2C12 myotubes and following ex vivo muscle contraction. ucOC may partly account for the insulin sensitizing effect of exercise.
Osteoporosis and sarcopenia are two conditions associated with aging and characterized by a simultaneous decline in bone and muscle mass, respectively. These conditions share common risk factors ...(genetic, endocrine, nutritional and lifestyle factors) and biological pathways that often co-exist in a syndrome known as osteosarcopenia. Among the endocrine causes, estrogens play a critical role, especially in women. Estrogens have been demonstrated to exert a positive effect on bone and muscle development and maintenance. For this reason, menopause is characterized by a loss in bone mineral density and skeletal muscle quality and quantity. To date, studies indicate a positive effect of hormonal therapy on the prevention and management of osteoporosis, to the point that estrogen is prescribed as a first-line treatment for osteoporosis by the major international authorities. While results on sarcopenia are still disputable, such that estrogens are not recommended to prevent muscle loss in postmenopausal women, increased response to anabolic stimuli with estrogen therapy suggests similar beneficial effects on muscle as seen with bone, particularly when combined with resistance exercise.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Time spent waiting for access to orthopaedic specialist health services has been suggested to result in increased pain in individuals with osteoarthritis (OA). We assessed whether time spent on an ...orthopaedic waiting list resulted in a detrimental effect on pain levels in patients with knee or hip OA.
We searched Ovid MEDLINE, EMBASE and EBSCOhost databases from inception until September 2021. Eligible articles included individuals with OA on an orthopaedic waitlist and not receiving active treatment, and reported pain measures at two or more time points. Random-effects meta-analysis was used to estimate the pooled effect of waiting time on pain levels. Meta-regression was used to determine predictors of effect size.
Thirty-three articles were included (n = 2,490 participants, 67 ± 3 years and 62% female). The range of waiting time was 2 weeks to 2 years (20.8 ± 18.8 weeks). There was no significant change in pain over time (effect size = 0.082, 95% CI = −0.009, 0.172), nor was the length of time associated with longitudinal changes in pain over time (β = 0.004, 95% CI = −0.005, 0.012). Body mass index was a significant predictor of pain (β = −0.043, 95% CI = −0.079, 0.006), whereas age and sex were not.
Pain remained stable for up to 1 year in patients with OA on an orthopaedic waitlist. Future research is required to understand whether pain increases in patients waiting longer than 1 year.
For many decades, fundamental cancer research has relied on two-dimensional in vitro cell culture models. However, these provide a poor representation of the complex three-dimensional (3D) ...architecture of living tissues. The more recent 3D culture systems, which range from ridged scaffolds to semiliquid gels, resemble their natural counterparts more closely. The arrangement of the cells in 3D systems allows better cell-cell interaction and facilitates extracellular matrix secretion, with concomitant effects on gene and protein expression and cellular behavior. Many studies have reported differences between 3D and 2D systems as regards responses to therapeutic agents and pivotal cellular processes such as cell differentiation, morphology, and signaling pathways, demonstrating the importance of 3D culturing for various cancer cell lines.
Summary
Bone remodeling markers (BRMs) are suppressed following the consumption of a meal. Our findings indicate that a single session of continuous moderate-intensity exercise, but not low-volume ...high-intensity interval exercise, performed 1 h after a meal attenuates the postprandial suppression of BRMs.
Introduction
Acute exercise transiently increases BRMs including osteocalcin (tOC) and the undercarboxylated form of osteocalcin (ucOC), a hormone that is implicated in glucose regulation. The effects of acute exercise and exercise-intensity on postprandial levels of tOC and ucOC are unknown.
Methods
Twenty-seven adults that were overweight or obese (age 30 ± 1 years; BMI 30 ± 1 kg∙m
−2
; mean ± SEM) were randomly allocated to perform a single session of low-volume high-intensity interval exercise (LV-HIIE; nine females, five males) or continuous moderate-intensity exercise (CMIE; eightfemales, five males) 1 h after consumption of a standard breakfast. Serum tOC, ucOC, and ucOC/tOC were measured at baseline, 1 h, and 3 h after breakfast consumption on a rest day (no exercise) and the exercise day (exercise 1 h after breakfast).
Results
Compared to baseline, serum tOC and ucOC were suppressed 3 h after breakfast on the rest day (− 10 ± 1% and − 6 ± 2%, respectively;
p
< 0.05), whereas ucOC/tOC was elevated (2.5 ± 1%;
p
= 0.08). Compared to the rest day, CMIE attenuated the postprandial-induced suppression of tOC (rest day − 10 ± 2% versus CMIE − 5 ± 2%,
p
< 0.05) and ucOC (rest day − 6 ± 4% versus CMIE 11 ± 2%,
p
< 0.05), and increased postprandial ucOC/tOC (rest day 3 ± 2% versus CMIE 15 ± 1%,
p
< 0.05). In contrast, LV-HIIE did not alter postprandial tOC, ucOC, or ucOC/tOC (all
p
> 0.1).
Conclusions
Acute CMIE, but not LV-HIIE, attenuates the postprandial-induced suppression of tOC and ucOC. CMIE may be an effective tool to control the circulating levels of BRMs following meal consumption in overweight/obese adults.
Summary
One year of calcium supplementation in older women led to modest reductions in total osteocalcin and undercarboxylated osteocalcin (ucOC), with no changes in muscle or fat mass, or glycated ...haemoglobin. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.
Introduction
Total osteocalcin (TOC) is a marker of bone turnover, while its undercarboxylated form has beneficial effects on glucose metabolism in mice. This post hoc analysis of a randomised double-blind, placebo-controlled trial examined whether 1 year of calcium supplementation affected circulating TOC, undercarboxylated osteocalcin (ucOC) or glycated haemoglobin (HbA1c) in 1368 older community-dwelling women (mean age 75.2 ± 2.7 years).
Methods
Women enrolled in the Calcium Intake Fracture Outcome Study trial (1998–2003) were supplemented with 1.2 g/d of elemental calcium (in the form of calcium carbonate) or placebo. Circulating TOC, ucOC and HbA1c was measured at 1 year (1999).
Results
After 1 year of calcium supplementation, TOC and ucOC levels were 17% and 22% lower compared with placebo (mean 22.7 ± 9.1 vs. 27.3 ± 10.9 μg/L and 11.1 ± 4.9 vs. 13.0 ± 5.7 μg/L, both
P
< 0.001). Carboxylated osteocalcin/ucOC was 6% lower after calcium supplementation (
P
< 0.05). Despite this, no differences in HbA1c were observed (calcium, 5.2 ± 0.6 vs. placebo, 5.3 ± 0.8%;
P
= 0.08). Calcium supplementation did not affect BMI, whole body lean or fat mass. In exploratory analyses, total calcium (dietary and supplemental) was inversely related to TOC and ucOC, indicating calcium intake is an important dietary determinant of osteocalcin levels.
Conclusion
One year of calcium supplementation in older women led to modest reductions in TOC and ucOC, with no changes in muscle or fat mass, or HbA1c. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.
Patients with type 2 diabetes mellitus (T2DM) experience a higher risk of fractures despite paradoxically exhibiting normal to high bone mineral density (BMD). This has drawn into question the ...applicability to T2DM of conventional fracture reduction treatments that aim to retain BMD. In a primary human osteoblast culture system, high glucose levels (25 mM) impaired cell proliferation and matrix mineralization compared to physiological glucose levels (5 mM). Treatment with parathyroid hormone (PTH, 10 nM), a bone anabolic agent, and cinacalcet (CN, 1 µM), a calcimimetic able to target the Ca
2+
-sensing receptor (CaSR), were tested for their effects on proliferation and differentiation. Strikingly, CN+PTH co-treatment was shown to promote cell growth and matrix mineralization under both physiological and high glucose conditions. CN+PTH reduced apoptosis by 0.9-fold/0.4-fold as measured by Caspase-3 activity assay, increased alkaline phosphatase (ALP) expression by 1.5-fold/twofold, increased the ratio of nuclear factor κ-B ligand (RANKL) to osteoprotegerin (OPG) by 2.1-fold/1.6-fold, and increased CaSR expression by 1.7-fold/4.6-fold (physiological glucose/high glucose). Collectively, these findings indicate a potential for CN+PTH combination therapy as a method to ameliorate the negative impact of chronic high blood glucose on bone remodeling.
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