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: 7896451
• 负责人: ANN V SCHWARTZ
• 金额: $ 12.59万
• 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/7896451
• 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(由申请者提供)：在老鼠身上的新发现表明骨骼影响糖尿病的发展。成骨细胞的一种产物，低羧化骨钙素(UcOC)，作为一种激素调节胰岛素敏感性和分泌，这是一种意想不到的联系，有望为胰岛素抵抗、肥胖和糖尿病提供新的见解。Ucoc的作用特别值得注意，因为它同时增加了小鼠模型中胰岛素的产生和胰岛素敏感性。OC基因敲除的小鼠肥胖，糖尿病和甘油三酯水平增加，胰岛素敏感性和胰岛素产生减少。ESP基因敲除小鼠表现出高水平的ucOC，而OC正常，其表型与OC基因敲除小鼠的表型相似。这只小鼠的胰岛素敏感度和产量都得到了改善，即使在高脂肪喂养的情况下也不会肥胖。然而，目前还不知道这些机制是否在人类身上起作用。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带来保存胰岛素敏感性和产生胰岛素的新方法，这对预防糖尿病具有重要意义。迫切需要进行翻译研究，以确定ucoc是否可以预测人类糖脂代谢的变化。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与老年人能量代谢和骨密度之间的关系，这项研究项目将使用来自健康、老龄化和身体成分(Health ABC)研究的数据和生物标本，该研究以基线年龄为70-79岁，包括3,075名男性和女性，白人和非裔美国人。储存的糖尿病患者(N=162)的基线血清中的骨钙素和骨钙素将在基线队列中的随机抽样中进行检测，这些患者分为糖尿病流行患者(N=135)、糖代谢受损患者(N=135)和血糖正常患者(N=135)。Health ABC的研究有九年的纵向数据，加上基线ucoc分析，可以立即用来检验假设，即ucoc的增加将与糖尿病风险的降低以及糖和脂代谢的改善相关联。将使用病例队列设计，包括糖尿病发病病例和未流行糖尿病的基线亚群中的病例，以评估ucoC水平是否可以预测糖尿病的发展。使用包括糖尿病患者和非糖尿病患者在内的基线子队列，这项研究还将确定基准线上的ucoC水平是否可以预测空腹血糖、A1C和胰岛素抵抗、血脂(血清甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白、非高密度脂蛋白和氧化低密度脂蛋白)以及总脂肪量和双X射线骨密度(DXA)测量的骨密度的变化。脂联素和瘦素将被评估为在ucoc和这些结果之间的任何关联的潜在中介。这项研究承诺通过评估证据来开辟新的领域，这些证据表明骨产品--低羧化骨钙素--对人类的胰岛素敏感性、体脂和糖尿病的发展有影响。公共卫生相关性：项目简介在老鼠身上的一项新的、意想不到的发现表明，由骨骼细胞产生的一种荷尔蒙--未羧化骨钙素(UcOC)--可以改善脂肪细胞中的胰岛素敏感性，增加胰腺产生的胰岛素，并降低体重增加和发展为糖尿病的风险。为了确定ucoc是否在人类中起到类似的作用，这项研究项目将使用已经在老年人中进行的纵向研究的数据和血清样本。这项研究项目将确定，在九年内，较低的ucoc水平是否预示着糖尿病的发展或全身脂肪的增加。