Undercarboxylated osteocalcin, body fat, and diabetes in older adults

老年人中羧基化骨钙素、体脂肪和糖尿病

• 批准号: 7738539
• 负责人: ANN V SCHWARTZ
• 金额: $ 22.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738539
• 关键词: Adipocytes; Affect; African American; Aging; Biological; Biological Assay; Body Composition; Body fat; Bone Density; C-reactive protein; Categories; Cholesterol; Clinical Data; Clinical Research; Data; Development; Diabetes Mellitus; Diabetes prevention; Elderly; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Glucose; Health; Hemoglobin; Hip region structure; Homeostasis; Hormones; Human; Image; Impaired fasting glycaemia; Infiltration; Insulin; Insulin Resistance; Interleukin-6; Knockout Mice; Lead; Leptin; Lipids; Longitudinal Studies; Measures; Mediating; Modeling; Mus; Muscle; Obesity; Observational Study; Osteoblasts; Osteocalcin; Outcome; Pancreas; Participant; Pathway interactions; Phenotype; Play; Population; Production; Research Project Grants; Risk; Rodent Model; Role; Sampling; Serum; Skeleton; Source; Specimen; Testing; Thigh structure; Triglycerides; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Visceral; Weight Gain; Woman; X-Ray Computed Tomography; adiponectin; aged; blood glucose regulation; bone; bone cell; bone metabolism; cohort; design; diabetes risk; fasting glucose; feeding; follow-up; glucose metabolism; impaired glucose tolerance; improved; inflammatory marker; insight; insulin sensitivity; lipid metabolism; low density lipoprotein inhibitor; men; mouse model; novel strategies; obesity prevention; oxidized low density lipoprotein; prospective; public health relevance; resistin; translational study

DESCRIPTION (provided by applicant): New findings in mice suggest that bone affects the development of diabetes. A product of osteoblasts, undercarboxylated osteocalcin (ucOC), functions as a hormone regulating insulin sensitivity and production, an unexpected connection that promises new insights into insulin resistance, obesity and diabetes. The effect of ucOC is particularly noteworthy because it increases both insulin production and insulin sensitivity in mouse models. OC knock-out mice were obese with increased rates of diabetes and triglyceride levels and reduced insulin sensitivity and insulin production. An ESP knock-out mouse exhibited increased levels of ucOC, with normal OC, and a phenotype that was a mirror image of the OC knock-out mice. This mouse had improved insulin sensitivity and production and was protected from obesity even with high fat feeding. However, it is not known if these mechanisms operate in humans. If found in clinical studies, this pathway connecting bone and energy metabolism could lead to new approaches for preserving insulin sensitivity and production with implications for prevention of diabetes. Translational studies are urgently needed to determine whether ucOC predicts changes in glucose and lipid metabolism in humans. Limited clinical data suggest that higher ucOC levels have negative effects on the skeleton. In order to assess the associations between ucOC and energy metabolism as well as bone density in a population of older adults, this research project will use data and biological specimens from the Health, Aging and Body Composition (Health ABC) study, a cohort of 3,075 men and women, white and African-American, aged 70-79 years at baseline. Osteocalcin and ucOC will be assayed in stored baseline serum among participants with incident diabetes (N=162) and in a random sample of the baseline cohort, stratified into those with prevalent diabetes (N=135), impaired glucose metabolism (N=135) and normoglycemia (N=135). The Health ABC study has nine years of longitudinal data that, with the addition of baseline ucOC assays, can be immediately used to test the hypotheses that increased ucOC will be associated prospectively with reduced risk of diabetes and with improvements in glucose and lipid metabolism. A case-cohort design, including the incident diabetes cases and those in the baseline sub-cohort without prevalent diabetes, will be used to assess whether ucOC levels predict diabetes development. Using the baseline sub-cohort that includes those with and without diabetes, the study will also determine whether ucOC levels at baseline predict changes in fasting glucose, A1C and insulin resistance, in lipids (serum triglycerides, total cholesterol, LDLc, HDLc, nonHDLc, and oxidized LDL), and in total fat mass and bone density measured by dual x-ray absorptiometry (DXA). Adiponection and leptin will be assessed as potential intermediaries in any associations between ucOC and these outcomes. This study promises to break new ground by assessing evidence that the bone product, undercarboxylated osteocalcin, has an effect on insulin sensitivity, body fat, and the development of diabetes in humans. PUBLIC HEALTH RELEVANCE: Project Narrative A new, and unexpected, finding in mice indicates that a hormone produced by bone cells, uncarboxylated osteocalcin (ucOC), improves insulin sensitivity in fat cells, increases insulin production by the pancreas, and reduces the risk of weight gain and development of diabetes. In order to determine if ucOC plays a similar role in humans, this research project will use data and serum specimens from an already established longitudinal study in older adults. This research project will determine if lower ucOC levels predict development of diabetes or increases in total body fat over nine years.

描述（由申请人提供）：小鼠的新发现表明骨骼影响糖尿病的发展。成骨细胞的产物，低羧基骨钙素（ucOC），作为一种激素调节胰岛素的敏感性和生产，一个意想不到的连接，承诺对胰岛素抵抗，肥胖和糖尿病的新见解。ucOC的作用特别值得注意，因为它增加了小鼠模型中的胰岛素产生和胰岛素敏感性。OC基因敲除小鼠肥胖，糖尿病发病率和甘油三酯水平增加，胰岛素敏感性和胰岛素分泌减少。ESP基因敲除小鼠表现出ucOC水平升高，OC正常，表型与OC基因敲除小鼠相同。这只小鼠的胰岛素敏感性和产量得到了改善，即使在高脂肪喂养的情况下也不会肥胖。然而，尚不清楚这些机制是否在人类中起作用。如果在临床研究中发现，这种连接骨骼和能量代谢的途径可能会导致保护胰岛素敏感性和生产的新方法，从而对预防糖尿病产生影响。迫切需要转化研究来确定ucOC是否能预测人类葡萄糖和脂质代谢的变化。有限的临床数据表明，较高的ucOC水平对骨骼有负面影响。为了评估ucOC与老年人人群中能量代谢以及骨密度之间的相关性，本研究项目将使用来自健康、衰老和身体组成（健康ABC）研究的数据和生物样本，该研究包括3，075名男性和女性，白色和非洲裔美国人，基线年龄为70-79岁。将在患有偶发糖尿病的参与者（N=162）中以及在基线队列的随机样本中测定储存的基线血清中的骨钙素和ucOC，所述基线队列被分层为患有普遍糖尿病（N=135）、葡萄糖代谢受损（N=135）和血糖正常（N=135）的那些。健康ABC研究有9年的纵向数据，加上基线ucOC测定，可以立即用于检验假设，即ucOC增加与糖尿病风险降低以及葡萄糖和脂质代谢改善相关。病例队列设计，包括新发糖尿病病例和基线子队列中无糖尿病的病例，将用于评估ucOC水平是否预测糖尿病发展。使用包括糖尿病患者和非糖尿病患者的基线子队列，该研究还将确定基线时的ucOC水平是否可预测空腹血糖、A1 C和胰岛素抵抗、血脂（血清甘油三酯、总胆固醇、LDLc、HDLc、非HDLc和氧化LDL）以及通过双能X射线吸收测定法（DXA）测量的总脂肪量和骨密度的变化。脂联素和瘦素将被评估为ucOC与这些结果之间任何关联的潜在中介。这项研究有望通过评估骨产品，低羧基骨钙素，对胰岛素敏感性，体脂和人类糖尿病的发展有影响的证据，开辟新的天地。公共卫生相关性：一个新的，意想不到的，在小鼠中的发现表明，由骨细胞产生的激素，非羧基骨钙素（ucOC），提高脂肪细胞中的胰岛素敏感性，增加胰腺的胰岛素分泌，并降低体重增加和糖尿病发展的风险。为了确定ucOC是否在人类中发挥类似的作用，该研究项目将使用已经建立的老年人纵向研究的数据和血清样本。该研究项目将确定较低的ucOC水平是否可以预测糖尿病的发展或九年内全身脂肪的增加。