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

这个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 成骨细胞是一种无活性的羧化形式，它在血液中释放，并通过骨吸收激活 通过部分脱羧作用。因此，增强骨形成和/或骨形成的生理或药理学事件是可能的。 吸收应增加血液中活性Ocn水平，从而增强其对β细胞群的积极作用 和葡萄糖代谢。 性腺衰竭是衰老的一个标志，会对身体的许多器官造成重大压力。尤其是骨头 生物学受到深刻影响。事实上，当性类固醇激素耗尽时， 绝经后，骨吸收增加，而骨形成没有增加到相同的程度。的 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骨形成和骨吸收的前景。 激素中断可影响活性OCN的血液水平，并因此影响β-细胞增殖和功能。在 为了支持这一假设，大鼠的胰腺细胞增殖在卵巢切除术（OVX）后不久增强， 我们自己的初步结果表明，OVX和睾丸切除（ORCH）小鼠1）血清中 活性Ocn水平，2）由于增强的β细胞增殖导致的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和4）血糖水平正常 对照然而，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的影响。 Gprc 6aPdx 1-/-小鼠，并且这些小鼠在手术后14天变得轻度高血糖。这些 观察表明雌激素消耗对骨，和对活性OCN的产生， 对β细胞生物学有积极影响。因此，我们假设这一规定可能会反对- 描述了雌激素信号传导减少对β细胞存活的负面影响， 至少是短暂的，在性腺衰竭时葡萄糖代谢的正常控制。 为了验证这一假设，我们将评估性类固醇耗竭对骨钙素生物学、β-细胞生物学和骨形成的影响。 生物学和葡萄糖代谢在小鼠和人类。我们的具体目标（SA）是： SA 1：确定雌激素耗竭如何影响活性骨钙素的产生。 SA 2：确定OVX对β细胞生物学和葡萄糖稳态的Ocn依赖性影响。 SA 3：确定雌激素耗竭对骨钙素生物学的积极影响及其对骨钙素生物学的调节作用。 β细胞增殖和功能在人类中是保守的。

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.