Undercarboxylated osteocalcin, body fat, and diabetes in older adults

描述（由申请人提供）：在小鼠身上的新发现表明，骨骼影响糖尿病的发展。成骨细胞的产物，低羧化骨钙素（ucOC），作为一种调节胰岛素敏感性和胰岛素分泌的激素，这一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分泌降低。ESP敲除小鼠表现出ucOC水平升高，OC正常，表型与OC敲除小鼠的镜像。这只老鼠改善了胰岛素敏感性和胰岛素分泌，即使喂食高脂肪也不会肥胖。然而，尚不清楚这些机制是否适用于人类。如果在临床研究中被发现，这条连接骨骼和能量代谢的途径可能会为保持胰岛素敏感性和胰岛素产生带来新的方法，并对糖尿病的预防产生影响。迫切需要翻译研究来确定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。为了评估老年人群中ucOC与能量代谢和骨密度之间的关系，本研究项目将使用健康、衰老和身体组成（Health ABC）研究的数据和生物标本，该研究包括3075名男性和女性，白人和非裔美国人，基线年龄为70-79岁。骨钙素和ucOC将在突发糖尿病患者（N=162）和基线队列随机样本的基线血清中进行检测，分层为糖尿病患者（N=135），糖代谢受损（N=135）和血糖正常（N=135）。健康ABC研究有9年的纵向数据，加上基线ucOC测定，可以立即用于测试ucOC增加与糖尿病风险降低和葡萄糖和脂质代谢改善相关的假设。将采用病例队列设计，包括偶发糖尿病病例和基线亚队列中没有流行糖尿病的病例，来评估ucOC水平是否能预测糖尿病的发展。使用基线亚队列（包括糖尿病患者和非糖尿病患者），该研究还将确定基线ucOC水平是否预测空腹血糖、糖化血红蛋白和胰岛素抵抗的变化，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）的变化，以及双x线吸收仪（DXA）测量的总脂肪量和骨密度。肥胖和瘦素将作为ucOC与这些结果之间关联的潜在中介进行评估。这项研究有望通过评估骨产物（低羧化骨钙素）对人类胰岛素敏感性、体脂和糖尿病发展的影响的证据，开辟新的领域。一项新的、出乎意料的小鼠研究发现表明，骨细胞产生的一种激素，无羧化骨钙素（ucOC），可以改善脂肪细胞的胰岛素敏感性，增加胰腺的胰岛素分泌，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，该研究项目将使用来自已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水平是否预示着9年内糖尿病的发展或全身脂肪的增加。

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.