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      Osteocalcin Is Not Associated with the Risk of Type 2 Diabetes: Findings from the EPIC-NL Study

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          To investigate whether total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC) and percentage of uncarboxylated osteocalcin (%ucOC) are associated with the risk of type 2 diabetes.


          This nested case control study included 1,635 participants, 833 incident diabetes cases and 802 non-diabetic control participants, aged 21–70 years from the EPIC-NL cohort. Baseline concentrations of tOC, ucOC and %ucOC were assessed. During 10 years of follow-up, diabetes cases were self-reported and verified against information from general practitioners or pharmacists. The association between the different forms of osteocalcin and diabetes risk was assessed with logistic regression adjusted for diabetes risk factors (waist circumference, age, sex, cohort, smoking status, family history of diabetes, hypertension, alcohol intake, physical activity and education) and dietary factors (total energy intake and energy adjusted intake of fat, fiber, protein and calcium).


          TOC concentration was not associated with diabetes risk, with an odds ratio (OR) of 0.97 (0.91–1.03) for each ng/ml increment after adjustment for diabetes risk factors and dietary factors. No association between ucOC and %ucOC and the risk of diabetes was observed either. In sex stratified analyses (P interaction = 0.07), higher %ucOC tended to be associated with an increased risk of type 2 diabetes in a multivariable model in women (OR 1.05 for each increment of 5% ucOC (1.00–1.11), P trend = 0.08), but not in men (OR 0.96 for each increment of 5% ucOC (0.88–1.04)). When waist circumference was replaced by body mass index, none of the osteocalcin forms were associated with the risk of type 2 diabetes in the final model among both women and men.


          Available evidence suggests that tOC, ucOC and %ucOC are each not associated with the risk of type 2 diabetes. However, more large-scale cohort studies are needed to clarify the presence of any association between the different forms of osteocalcin and the risk of type 2 diabetes.

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          Most cited references 20

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          Adjustment for total energy intake in epidemiologic studies.

          In epidemiologic studies, total energy intake is often related to disease risk because of associations between physical activity or body size and the probability of disease. In theory, differences in disease incidence may also be related to metabolic efficiency and therefore to total energy intake. Because intakes of most specific nutrients, particularly macronutrients, are correlated with total energy intake, they may be noncausally associated with disease as a result of confounding by total energy intake. In addition, extraneous variation in nutrient intake resulting from variation in total energy intake that is unrelated to disease risk may weaken associations. Furthermore, individuals or populations must alter their intake of specific nutrients primarily by altering the composition of their diets rather than by changing their total energy intake, unless physical activity or body weight are changed substantially. Thus, adjustment for total energy intake is usually appropriate in epidemiologic studies to control for confounding, reduce extraneous variation, and predict the effect of dietary interventions. Failure to account for total energy intake can obscure associations between nutrient intakes and disease risk or even reverse the direction of association. Several disease-risk models and formulations of these models are available to account for energy intake in epidemiologic analyses, including adjustment of nutrient intakes for total energy intake by regression analysis and addition of total energy to a model with the nutrient density (nutrient divided by energy).
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            Endocrine regulation of energy metabolism by the skeleton.

            The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.
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              Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

              To assess the validity and repeatability of a simple index designed to rank participants according to their energy expenditure estimated by self-report, by comparison with objectively measured energy expenditure assessed by heart-rate monitoring with individual calibration. Energy expenditure was assessed over one year by four separate episodes of 4-day heart-rate monitoring, a method previously validated against whole-body calorimetry and doubly labelled water. Cardio-respiratory fitness was assessed by four repeated measures of sub-maximum oxygen uptake. At the end of the 12-month period, participants completed a physical activity questionnaire that assessed past-year activity. A simple four-level physical activity index was derived by combining occupational physical activity together with time participating in cycling and other physical exercise (such as keep fit, aerobics, swimming and jogging). One hundred and seventy-three randomly selected men and women aged 40 to 65 years. The repeatability of the physical activity index was high (weighted kappa=0.6, ). There were positive associations between the physical activity index from the questionnaire and the objective measures of the ratio of daytime energy expenditure to resting metabolic rate and cardio-respiratory fitness As an indirect test of validity, there was a positive association between the physical activity index and the ratio of energy intake, assessed by 7-day food diaries, to predicted basal metabolic rate. The summary index of physical activity derived from the questions used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study suggest it is useful for ranking participants in terms of their physical activity in large epidemiological studies. The index is simple and easy to comprehend, which may make it suitable for situations that require a concise, global index of activity.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                29 September 2015
                : 10
                : 9
                [1 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
                [2 ]Department of Orthopaedics, Yale University School of Medicine, New Haven, Connecticut, United States of America
                [3 ]Center for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
                Baylor College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JWJB YTS. Performed the experiments: JWJB CMG YTS. Analyzed the data: SRZ. Contributed reagents/materials/analysis tools: SRZ JWJB. Wrote the paper: SRZ JWJB. Reviewed/edited the manuscript: SRZ JWJB CMG AMWS DLA YTS.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Figures: 0, Tables: 2, Pages: 10
                The EPIC-NL study was funded by “Europe against Cancer” program of the European Commission, the Dutch Ministry of Public Health, Welfare and Sports, the Dutch Cancer Society, ZonMW, the Netherlands Organization for Health Research and Development and the World Cancer Research Fund (WCRF). Analyses of the vitamin K biomarkers were funded by a European Foundation for the Study of Diabetes (EFSD)/ Janssen "Rising star" research fellowship (JWJ Beulens). J.W.J. Beulens and S.R. Zwakenberg are supported by the Senior Dr. Dekker grant (2013T120) from the Dutch Heart Foundation.
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                The informed consent that was signed by the study participants is not compliant with publishing individual data in an open access institutional repository or as supporting information files with the published paper. However, a data request can be sent to the principal Investigator of EPIC-NL, Prof. Petra H. Peeters, MD, PhD. The data request can be sent to professor Peeters via the EPIC-NL Steering Committee at info@ .



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