Origins of Skeletal Fragility in Type 1 Diabetes

患有1型糖尿病(T1D)的人经历了几种骨骼健康障碍，包括 降低骨密度(BMD)并增加脆性骨折(即骨质疏松症)的风险。这些 特征性是糖尿病骨病的主要临床特征。有证据表明，DBD 发生在T1D进展的早期；涉及骨形成障碍；导致微结构 异常和骨基质质量差；同时伴有高血糖和内源性激素下降 胰岛素和胰岛素样生长因子-1的产生。虽然许多人认为糖尿病患者的骨骼缺陷 发生的直接原因是血糖失调，我们在小鼠模型上的临床前研究，支持 在人类中的观察性研究表明，胰岛素和胰岛素样物质的产生和作用的障碍 生长因子-1(IGF-1)可能是DBD的根本原因。具体地说，我们的实验室和其他实验室已经证明 在T1D啮齿动物模型中：1)骨形成缺陷发生在胰岛素缺乏的背景下；2)接近- 仅靠血糖正常化不足以预防糖尿病；3)胰岛素和胰岛素样生长因子-1疗法的改善 骨折抵抗和新骨形成；4)胰岛素和IGF-1都利用相似的下游 促进成骨细胞形成和骨形成的途径。阐明机制和信号转导 胰岛素和/或IGF-1调节成骨的途径；了解缺乏或损害 每一种信号都可能有助于DBD；并描述每种信号如何对治疗方法做出贡献 为了预防或治疗DBD，我们建议1)确定胰岛素和IGF-1缺乏对DBD的影响 组织、细胞和分子水平，以及2)每种激素如何相互重叠和相互独立 通过特定的下游信号通路的影响，最终可能成为治疗的靶点 预防和/或逆转DBD。

Humans with type 1 diabetes mellitus (T1D) experience several disorders of skeletal health, including decreased bone mineral density (BMD) and increased risk for fragility fractures (i.e., osteoporosis). These features are the primary clinical characteristics of diabetic bone disease (DBD). Evidence suggests that DBD occurs early in the progression of T1D; involves impaired bone formation; results in micro-architectural abnormalities and poor bone matrix quality; and coincides with hyperglycemia and a decline in endogenous insulin and insulin-like growth factor-1 production. While many have postulated that skeletal deficits in diabetes occur as a direct result of glucose dysregulation, our pre-clinical studies in mouse models, supported by observational studies in humans, show that impairment in the production and action of insulin and insulin-like growth factor-1 (IGF-1) may be root causes of DBD. Specifically, our laboratory and others have demonstrated that in rodent models of T1D: 1) deficits in bone formation occur in the context of insulin-deficiency; 2) near- normalization of serum glucose alone is not sufficient to prevent DBD; 3) insulin and IGF-1 therapy improve fracture resistance and new bone formation; and 4) both insulin and IGF-1 utilize similar down-stream pathways to promote osteoblastogenesis and bone formation. To clarify the mechanisms and signaling pathways by which insulin and/or IGF-1 modulate osteogenesis; to understand how deficiencies or impaired signaling of each may contribute to DBD; and to delineate how each may contribute to therapeutic approaches to prevent or treat DBD, we propose to 1) determine how insulin and IGF-1 deficiencies contribute to DBD at the tissue, cellular, and molecular level, and 2) how each hormone may perform overlapping and independent effects through specific downstream signaling pathways that may ultimately become therapeutic targets for preventing and/or reversing DBD.