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会影响糖尿病的发育。成骨细胞（UCOC）的成骨细胞（UCOC）的产物，可作为调节胰岛素敏感性和产生的激素，这是一种意外的连接，有望提供新的见解，以对胰岛素抵抗，肥胖和糖尿病。 UCOC的效果特别值得注意，因为它在小鼠模型中增加了胰岛素的产生和胰岛素敏感性。 OC敲除小鼠肥胖，糖尿病和甘油三酸酯水平增加，胰岛素敏感性和胰岛素产生降低。 ESP敲除小鼠表现出增加的UCOC水平，具有正常的OC，并且表型是OC敲除小鼠的镜像。该小鼠的胰岛素敏感性和产生提高了，即使摄入高脂肪，也可以保护肥胖。但是，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持胰岛素敏感性和产生的新方法，并影响预防糖尿病。迫切需要翻译研究以确定UCOC是否可以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水平对骨架具有负面影响。为了评估UCOC与能量代谢之间的关联以及老年人人群中的骨密度，该研究项目将使用健康，衰老和身体组成（健康ABC）研究中的数据和生物标本，这是3,075名男性和女性，男性和女性，白人和非裔美国人，年龄为70至79岁，年龄为70-79岁，年龄为基础。骨钙蛋白和UCOC将在患有糖尿病的参与者（n = 162）的参与者中和基线队列的随机样本中分析，分为患有糖尿病的患者（n = 135），葡萄糖代谢（n = 135）和正常糖（Normoglycemia）（n = 135）（n = 135）（n = 135）（n = 135）（N = 135）。 Health ABC研究具有九年的纵向数据，随着基线UCOC分析，可以立即用于测试假设UCOC的假设，即UCOC增加将与糖尿病风险降低以及葡萄糖和脂质代谢的改善有关。病例 - 霍特设计，包括入射糖尿病病例和没有普遍糖尿病的基线亚船体的病例，将用于评估UCOC水平是否预测糖尿病的发育。 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吸收法（DXA）。在UCOC与这些结果之间的任何关联中，脂肪异构和瘦素将被评估为潜在的中介。这项研究有望通过评估证据表明骨产物（羧化骨钙素）对胰岛素敏感性，体内脂肪和人类糖尿病的发展有影响。公共卫生相关性：项目叙事在小鼠中的一种新的和意外的发现表明，骨细胞产生的激素，未羧化的骨钙素（UCOC）改善了脂肪细胞中胰岛素敏感性，可通过胰腺产生胰岛素，并减少糖尿病的体重增加和发育的风险。为了确定UCOC是否在人类中起着相似的作用，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标本。该研究项目将确定较低的UCOC水平是预测糖尿病的发展还是在九年中总体脂肪的增加。