Origins of Skeletal Fragility in Type 1 Diabetes

1 型糖尿病骨骼脆弱的起源

基本信息

批准号：
10733855
负责人：
John L Fowlkes
金额：
$ 52.35万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-25 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733855
关键词：
Ablation Affect Architecture Bone Density Bone Matrix Characteristics Clinical Critical Pathways Development Diabetes Mellitus Effectiveness Event Evolution Exposure to FOXO1A gene Fracture Glucose Health Homologous Gene Hormones Human Hyperglycemia Impairment Insulin Insulin Signaling Pathway Insulin deficiency Insulin-Dependent Diabetes Mellitus Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Intervention Knockout Mice Laboratories Ligands Maps Molecular Mus Observational Study Osteoblasts Osteogenesis Osteoporosis PI3 gene Pathway interactions Personal Satisfaction Persons Predisposition Prevention Production Proto-Oncogene Proteins c-akt Resistance Risk Rodent Model Serum Signal Pathway Signal Transduction Therapeutic Tissues bone bone health bone strength diabetic diabetic bone disease experience fragility fracture improved inhibitor mechanical properties mouse model osteoprogenitor cell pharmacologic preclinical study prevent receptor response skeletal skeletal disorder therapeutic target transcriptomics

项目摘要

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.

患有 1 型糖尿病 (T1D) 的人会出现多种骨骼健康疾病，包括骨矿物质密度（BMD）降低，脆性骨折（即骨质疏松症）的风险增加。这些特征是糖尿病骨病（DBD）的主要临床特征。有证据表明 DBD 发生在 T1D 进展早期；涉及骨形成受损；微架构的结果异常和骨基质质量差；并且与高血糖和内源性下降同时发生胰岛素和胰岛素样生长因子-1 的产生。尽管许多人认为糖尿病患者的骨骼缺陷作为葡萄糖失调的直接结果而发生，我们在小鼠模型中进行的临床前研究得到了支持对人类的观察性研究表明，胰岛素和胰岛素样物质的产生和作用受损生长因子-1 (IGF-1) 可能是 DBD 的根本原因。具体来说，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情况下； 2) 近- 仅使血糖正常化不足以预防 DBD； 3) 胰岛素和IGF-1治疗改善抗骨折能力和新骨形成； 4) 胰岛素和 IGF-1 都利用相似的下游促进成骨细胞生成和骨形成的途径。阐明机制和信号胰岛素和/或 IGF-1 调节成骨的途径；了解缺陷或受损的情况每个信号都可能有助于 DBD；并描述每种方法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 缺乏如何导致 DBD 组织、细胞和分子水平，以及 2) 每种激素如何重叠和独立发挥作用通过特定下游信号通路产生的影响最终可能成为治疗靶点预防和/或逆转 DBD。