Impact of gonadal failure on the bone-mediated regulation of glucose metabolism

性腺衰竭对骨介导的葡萄糖代谢调节的影响

• 批准号: 10024565
• 负责人: Patricia Florence Ducy
• 金额: $ 56.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10024565
• 关键词: Address; Adult; Affect; Age; Aging; B Cell Proliferation; Beta Cell; Biology; Blood; Blood Glucose; Bone Resorption; Cell Proliferation; Cell Survival; Cell Transplantation; Cell physiology; Cells; Cellular biology; Decarboxylation; Endocrine; Estrogens; Event; Extracellular Matrix; Failure; GPRC6A gene; Gene Expression; Goals; Gonadal Steroid Hormones; Histology; Hormonal; Hormones; Human; Hyperglycemia; Immunohistochemistry; In Vitro; Insulin; Islets of Langerhans; Kidney; Light; Mediating; Menopause; Metabolic; Modification; Molecular; Monitor; Mus; Normalcy; Operative Surgical Procedures; Organ; Osteoblasts; Osteocalcin; Osteogenesis; Ovariectomy; Pancreas; Pharmacology; Physiological; Postmenopause; Process; Production; Rattus; Regulation; Serum; Signal Transduction; Stress; Structure of beta Cell of islet; Testing; Time; Wild Type Mouse; Woman; age effect; age related; blood glucose regulation; bone; capsule; carboxylate; carboxylation; glucose metabolism; insulin secretion; insulin sensitivity; islet; mutant mouse model; preservation; receptor; sensor; stressor

The goal of this project is to characterize how gonadal failure may affect the bone-derived hormone osteocalcin and its regulation of β-cell proliferation and function in mice and human. Osteocalcin (Ocn) enhances β-cell proliferation, insulin secretion and insulin sensitivity in adult mice. It is primarily secreted by osteoblasts as an inactive - carboxylated - form, which is released in blood and activated by bone resorption via partial decarboxylation. Hence, physiological or pharmacological events enhancing bone formation and/or resorption should increase blood levels of active Ocn and thereby enhance its positive effect on β-cell mass and glucose metabolism. Gonadal failure is a hallmark of aging that causes major stress to many organs in the body. In particular, bone biology is profoundly affected. Indeed, upon sex steroid hormone depletion like the one accompanying menopause, bone resorption is increased while bone formation does not increase to the same extent. The regulation of Ocn by both bone formation and bone resorption thus raised the prospect that this age-dependent hormonal disruption may affect blood levels of active Ocn and as a result β-cell proliferation and function. In support of this hypothesis, pancreatic cell proliferation in rats is enhanced shortly after ovariectomy (OVX) and our own preliminary results indicate that OVX and orchiectomized (ORCH) mice have 1) higher serum levels of active Ocn, 2) an increase in β-cell mass due to enhanced β-cell proliferation, 3) a mild increase in serum insulin levels and 4) normal blood glucose levels compared to sham-operated (sham) controls. However, β-cell mass and insulin levels are not affected by OVX in Ocn-deficient mice or in Gprc6aPdx1-/- mice and these mice become mildly hyperglycemic 14 days post-surgery. These observations suggest that the effect of estrogen depletion on bone, and on the production of active Ocn, positively impacts β-cell biology. We therefore hypothesize that this regulation could oppose the well- described negative effect of decreased estrogen signaling on β-cell survival and as such preserve, at least transiently, a normal control of glucose metabolism upon gonadal failure. To test this hypothesis we will assess the effect of sex steroid depletion on osteocalcin biology, β-cell biology and glucose metabolism in both mice and humans. Our Specific Aims (SA) are: SA1: To define how estrogen depletion affects the production of active osteocalcin. SA2: To define the Ocn-dependent effects of OVX on β-cell biology and glucose homeostasis. SA3: To determine whether the positive effect of estrogen depletion on osteocalcin biology and its regulation of β-cell proliferation and function is conserved in humans.

该项目的目标是描述性腺衰竭如何影响骨源性激素 骨钙素及其对小鼠和人类β细胞增殖和功能的调节。骨钙素 (Ocn) 增强成年小鼠的β细胞增殖、胰岛素分泌和胰岛素敏感性。它主要是由 成骨细胞为非活性羧化形式，在血液中释放并通过骨吸收激活 通过部分脱羧。因此，生理或药理学事件增强骨形成和/或 吸收会增加活性 Ocn 的血液水平，从而增强其对 β 细胞质量的积极作用 和葡萄糖代谢。 性腺衰竭是衰老的一个标志，会给身体的许多器官带来巨大的压力。尤其是骨 生物学受到深刻影响。事实上，当性类固醇激素耗尽时，就像伴随的那样 更年期，骨吸收增加，而骨形成没有同样程度的增加。这 Ocn 通过骨形成和骨吸收的调节因此提出了这种年龄依赖性的前景 荷尔蒙紊乱可能会影响血液中活性 Ocn 的水平，从而影响 β 细胞的增殖和功能。在 支持这一假设的是，大鼠的胰腺细胞增殖在卵巢切除术（OVX）后不久就增强了，并且 我们自己的初步结果表明，OVX 和睾丸切除 (ORCH) 小鼠具有 1) 更高的血清 活性 O​​cn 水平，2) 由于 β 细胞增殖增强而导致 β 细胞质量增加，3) 轻度 与假手术 (sham) 相比，血清胰岛素水平增加，4) 血糖水平正常 控制。然而，Ocn 缺陷小鼠或 Ocn 缺陷小鼠的 β 细胞质量和胰岛素水平不受 OVX 影响。 Gprc6aPdx1-/- 小鼠和这些小鼠在手术后 14 天出现轻度高血糖。这些 观察结果表明，雌激素消耗对骨骼以及活性 Ocn 产生的影响， 对 β 细胞生物学产生积极影响。因此，我们假设这项规定可能会反对良好的 描述了雌激素信号减少对 β 细胞存活的负面影响，并因此保持， 至少短暂地，性腺衰竭时葡萄糖代谢的正常控制。 为了检验这一假设，我们将评估性类固醇消耗对骨钙素生物学、β-细胞的影响 小鼠和人类的生物学和葡萄糖代谢。我们的具体目标 (SA) 是： SA1：定义雌激素消耗如何影响活性骨钙素的产生。 SA2：定义 OVX 对 β 细胞生物学和葡萄糖稳态的 Ocn 依赖性影响。 SA3：确定雌激素消耗是否对骨钙素生物学及其调节产生积极影响 β细胞的增殖和功能在人类中是保守的。