Positive association of glucagon with bone turnover markers in type 2 diabetes: A cross‐sectional study
Hui GuoChunhua SuiShaohong GeJian CaiDongping LinYuyu GuoNingjian WangYing ZhouRong YingKexi ZhaTao GuYan ZhaoYingli LuZengmei An
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Abstract Aims The osteo‐metabolic changes in type 2 diabetes (T2D) patients are intricate and have not been fully revealed. It is not clear whether glucagon is entirely harmful in the pathogenesis of diabetes or a possible endocrine counter‐regulation mechanism to reverse some abnormal bone metabolism. This study aimed to investigate the association between glucagon and bone turnover markers (BTMs) in T2D patients. Methods A total of 3984 T2D participants were involved in a cross‐sectional study in Shanghai, China. Serum glucagon was measured to elucidate its associations with intact N‐terminal propeptide of type I collagen (P1NP), osteocalcin (OC), and β ‐C‐terminal telopeptide ( β ‐CTX). Glucagon was detected with a radioimmunoassay. Propeptide of type I collagen, OC, and β ‐CTX were detected using chemiluminescence. The diagnosis of T2D was based on American Diabetes Association criteria. Results The concentration of glucagon was positively correlated with two BTMs [OC–β: 0.034, 95% CI: 0.004, 0.051, p = 0.024; CTX–β: 0.035, 95% CI: 0.004, 0.062, p = 0.024]. The result of P1NP was [P1NP–regression coefficient ( β ): 0.027, 95% CI: −0.003, 0.049, p = 0.083]. In the glucagon tertiles, P for trend of the BTMs is [P1NP: 0.031; OC: 0.038; CTX: 0.020], respectively. Conclusions Glucagon had a positive effect on bone metabolism. The concentrations of the three BTMs increased as glucagon concentrations rose. This implied that glucagon might speed up skeletal remodelling, accelerate osteogenesis, and promote the formation of mature bone tissue. At the same time, the osteoclastic process was also accelerated, providing raw materials for osteogenesis to preserve the dynamic balance. In view of the successful use of single‐molecule as well as dual/triple agonists, it would be feasible to develop a preparation that would reduce osteoporosis in diabetic patients.Keywords:
Bone remodeling
N-terminal telopeptide
Development of optimal bone mass during early adulthood is determined by the balance between bone formation and resorption. The utility of minimally invasive biomarkers for monitoring bone turnover balance in maturing non-human primates has received limited attention. This study evaluated the biological variation of osteocalcin (a marker of bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, a marker of bone resorption), and the ratio of osteocalcin to CTX (reflecting bone turnover balance), in 136 rhesus and cynomolgus macaques aged 3.8-11.6 years. In a subsample of the animals (n = 28), blood samples were collected at monthly intervals over 4 months. Between-subject analysis revealed that there were no sex or species differences for CTX. Osteocalcin and the ratio of osteocalcin to CTX were higher in males than in females, and in rhesus macaques than in cynomolgus macaques. There were no changes in osteocalcin, CTX, or the ratio of osteocalcin to CTX across 4 months for any of the groups. In contrast, there was considerable within-subject variation in osteocalcin and CTX concentrations. However, differences in values exhibited no discernible pattern, suggesting that within-subject variation can be reduced by averaging repeat measurements. In summary, the data provide reference values for male and female rhesus and cynomolgus macaques and support the utility of osteocalcin and CTX as biomarkers to monitor bone turnover at the population level.
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Osteocalcin (OC) is produced by osteoblasts during bone formation. OC is excreted into urine by glomerular filtration and can be found as fragments in urine. The presence of three vitamin K-dependent γ-carboxyglutamic acid residues is critical for osteocalcin's structure, which appears to regulate the maturation of bone mineral. Recent bone biology research have highlighted the importance of bone not only as a structural scaffold to support the human body, but also as a regulator of a metabolic processes that are independent of mineral metabolism. Circulating osteocalcin is present either as carboxylated or as undercarboxylated forms. Increased serum level of osteocalcin is linked with increased bone mineral density. The importance of the bone–kidney relation in physiologic regulation of mineral ion has also been extensively studied and documented. Several workers have uncovered the role of insulin as an additional factor involved in the skeletal remodelling process. Evidences are available which shows that osteoblastic insulin signalling is important for glucose metabolism. The measurement of OC in urine samples could be used as an index of bone turnover in monitoring bone metabolism. In this review, we have tried to explain different roles of OC, however further studies are required to elucidate the metabolic and hormonal role of OC in human body.
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Osteocalcin (OC) is non-collagenous bone matrix protein produced by osteoblasts. OC binds to hydroxyapatite and is deposited in the bone matrix. Concentration of OC in the blood seems to reflect both osteogenesis and increased bone metabolism and depends on age, sex, menopausal status. The aim of our study was to evaluate changes in the concentration of osteocalcin and selected biochemical parameters of bone turnover in different stages of life in healthy people. We found that the mean serum levels of OC were significantly greater in women than in men. The highest OC levels were found in men under the age of 30 with a decrease in the fourth decade of life. In the group of women of up to 40 years of age, OC concentrations were comparable with the equivalent group of men. The lowest concentration of OC was found in the age group 40-49, with the significant increase in the subsequent decades of life. In both men and women, we found a significant correlation of OC with the calcium concentrations and alkaline phosphatase activity. Osteocalcin determinationa, particulary in women, may be useful laboratory parameters of osteoporosis process.
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Pyridinoline
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The recent development of biochemical markers gives the opportunity to assess bone metabolism. Osteocalcin is a non collagenous protein of the bone matrix specifically synthesized by osteoblasts. The concentration of osteocalcin in serum reflects osteoblastic function and bone turnover. It has emerged as a more specific index of bone metabolism than serum alkaline phosphatase activity. Great care must be taken in blood sampling, processing and storage to avoid protein degradation. Inasmuch, we have shown in human clinical settings, the interest of this marker in patients with bone metabolic disorders characterized by increased bone turnover such as primary and secondary hyperparathyroidism or postmenopausal osteoporosis. Conversely, exogenous or endogenous high levels of corticosteroids rapidly induced a reversible decrease in osteocalcin levels.
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Studies of a glucagon radioimmunoassay using antiserum 30K suggest that when plasma samples from different individuals are assayed against a single standard curve, an inappropriately wide range of values for fasting human pancreatic glucagon levels is obtained. Evidence is presented that plasma from different subjects contains non-specific factors which interfere with the assay. These factors depress the binding of labeled glucagon but appear to be neither pancreatic glucagon nor an enteric factor with glucagon-like immunoreactivity.
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Objective To investigate the changes of bone metabolism markers in patients with hyperthyroidism before and after treatment and the characteristics of bone turnover rate.Methods Forty-six patients with hyperthyroidism and thirty healthy controls were included into this study.Electrochemical luminescence immunoassay(ECLIA) method was used to measure serum osteocalcin and β-cross laps levels in all the hyperthyroid patients before and after antithyroid (methimazole) therapy and thirty healthy volunteers.Results The mean concentrations of both osteocalcin and β-cross laps in hyperthyroid patients before and after treatment were significantly higher than those in the healthy subjects (P0.000),increased by 1.74 folds and 1.80 folds respectively before treatment and 2.26 folds and 2.16 folds respectively after treatment.The correlation analysis showed that the serum FT3 was positively correlated with osteocalcin(P0.05) and FT4 was positively correlated with osteocalcin and β-cross laps (P0.05) before methimazole treatment.The serum osteocalcin was positively correlated with β-cross laps (P0.01) as well.Compared with the untreated hyperthyroidism group,serum osteocalcin and β-cross laps were further increased after methimazole treatment for 2 months (P0.05).Conclusions High bone turnover rate characterizes the bone metabolism in the patients with hyperthyroidism.The activity of bone may dominant with osteoclast resulting in abnormal bone metabolism in the untreated hyperthyroidism patients.However,in the patients who under treatment,both bone resorption and bone formation were further increased and bone formation were more prominent,which suggested that the osteoblast activity dominant the whole progress in favor of bone remodeling.
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Interferon-α (IFN-α) is used in the treatment of many haematological diseases and it is known that IFN-α may affect bone turnover. The effect of IFN-α on bone metabolism was studied in 10 haematological patients. The mean duration of the treatment was 4 (range: 2.8–7.2) months. Besides the usual markers of bone metabolism, levels of the cross-linked C-terminal telopeptide of type I collagen (ICTP), the N-terminal propeptide of type I procollagen (PINP) and the bone-specific alkaline phosphatase were measured. The bone mineral density was measured by computed tomography. During IFN-α treatment, serum ICTP decreased from a mean of 5.4 (range: 1.8–12.4) to 3.6 (range: 1.4–8.8) μg/l (P= 0.017). All other variables reflecting bone metabolism remained unaltered during IFN-α treatment. The bone mineral density remained unchanged. It was concluded that the observed decrease in ICTP may be an indicator of a beneficial therapeutic effect of IFN-α on bone turnover, resulting in decreased bone resorption. However, it is possible that elevated pretreatment ICTP values reflected disease of the bone marrow.
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In this pancreatic-glucagon-specific radioimmunoassay we used C-terminal-region-specific antiserum. OAL-123, produced against a 19-29 C-terminal fragment of porcine glucagon. On measurement of pooled plasma the ranges for intra- and inter-assay coefficients of variation were 4.8-8.1% and 7.5-10.7%, respectively. The concentration of immunoreactive glucagon in plasma of healthy subjects, as measured with the OAL-123 assay system, was 87.9 (SD 23.8) ng/L. Measurement of the same plasma samples with the 30K assay system (30K being an antiserum highly specific for pancreatic glucagon) showed a comparable value, 86.2 (SD 26.3) ng/L. We followed changes in human and dog plasma immunoreactive glucagon concentrations on arginine infusion and after glucose load, using the OAL-123 and the 30K assay systems, with identical results. Combining other results of comparative immunochemical characterization of the OAL-123 and 30K assay systems, we confirmed that the antisera raised against the C-terminal fragment of glucagon can be used in radioimmunoassay of pancreatic glucagon.
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Physical activity is most probably an important factor to increase bone mass. The exact mechanisms by which this takes place are not completely understood. During the last years methods have become available making it possible to study the metabolism of type I collagen in bone in more detail. In this study seven male athletes were studied before and after a short-term maximal work (a modified Wingate test at a retardation of 7.5 % of body weight) during 30 seconds. Blood samples were drawn before the test and 5 and 60 minutes after. Serum concentrations of type I procollagen carboxyterminal propeptide (PICP) and car-boxyterminal telopeptide of type I collagen (ICTP) were measured, as were serum calcium, parathyroid hormone and osteocalcin. Serum PICP and ICTP reflect synthesis and degradation of type I collagen, respectively and mainly bone collagen metabolism. A significant increase of ionized calcium and lactate was noted while PTH and total serum calcium did not change. No significant alterations of either ICTP, PICP or osteocalcin were registered. We conclude from this study that the short-term maximal work performed by means of the modified Wingate test failed to show any significant changes in bone metabolism (osteocalcin and metabolites of type I collagen). A short experimental period and lactacidosis might contribute to the unaltered bone metabolism. The results mainly indicate that there is no pool of bone biochemical markers in young athletic males that is washed out by short bursts of intense exercise.
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