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

该项目的目标是确定性腺功能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) 促进成年小鼠β细胞增殖、胰岛素分泌和胰岛素敏感性。它主要是由 成骨细胞是一种不活跃的羧化形式，它在血液中释放并被骨吸收激活 通过部分脱羧基作用。因此，生理学或药理学事件促进骨形成和/或 吸收应增加血液中活性OCN的水平，从而增强其对β-细胞团的积极作用 和葡萄糖代谢。 性腺功能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 生物学受到了深刻的影响。事实上，在性激素耗尽的情况下，就像伴随着 绝经后，骨吸收增加，而骨形成没有增加到同样的程度。这个 骨形成和骨吸收对OCN的调节因此增加了这种年龄依赖性的可能性 荷尔蒙紊乱可能会影响血液中活跃的OCN水平，从而影响β细胞的增殖和功能。在……里面 支持这一假设的是，大鼠去卵巢(OVX)后不久胰腺细胞增殖增强，并 我们自己的初步结果表明，卵巢切除(OVX)和切除(Orch)小鼠的血清水平较高 活跃的OCN水平，2)由于促进β细胞增殖而导致的β细胞质量增加，3)轻度 与假手术(Sham)相比，血清胰岛素水平和4)正常血糖水平升高 控制。然而，β细胞质量和胰岛素水平不受去势基因缺陷小鼠和正常小鼠的影响。 Gprc6aPdx1-/-小鼠和这些小鼠在手术后14天变得轻度高血糖。这些 观察表明，雌激素缺乏对骨骼的影响，以及对活性OCN的产生， 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油井- 描述了雌激素信号减少对β细胞存活的负面影响，并因此保存在 最不可能的是，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细胞的影响。 老鼠和人类的生物学和葡萄糖代谢。我们的具体目标(SA)是： SA1：确定雌激素耗竭如何影响活性骨钙素的产生。 目的：明确去卵巢对β细胞生物学和血糖稳态的影响。 SA3：确定雌激素缺乏对骨钙素生物学的积极影响及其对骨钙素的调节 β-细胞的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.