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型糖尿病的人（T1D）经历了几种骨骼健康疾病，包括骨矿物质密度降低（BMD）和脆弱性骨折的风险增加（即骨质疏松症）。这些特征是糖尿病骨病（DBD）的主要临床特征。证据表明DBD 发生在T1D的早期；涉及骨形成受损；导致微体系结构异常和骨基质质量差；并与高血糖和内源性下降相吻合胰岛素和胰岛素样生长因子1产生。尽管许多人假设糖尿病中的骨骼缺陷是葡萄糖失调的直接结果，我们在小鼠模型中的临床前研究，由人类的观察性研究表明，胰岛素和胰岛素样的生产和作用损害生长因子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人证明了在T1D的啮齿动物模型中：1）骨形成的缺陷发生在胰岛素缺乏症的背景下； 2）接近 - 单独的血清葡萄糖的归一化不足以防止DBD。 3）胰岛素和IGF-1治疗改善断裂性和新骨形成； 4）胰岛素和IGF-1都使用类似的下游促进成骨细胞生成和骨形成的途径。澄清机制和信号胰岛素和/或IGF-1调节成骨的途径；了解缺陷或障碍每个信号传导可能有助于DBD；并描述每个人如何对治疗方法做出贡献为了防止或治疗DBD，我们建议1）确定胰岛素和IGF-1缺陷对DBD的贡献组织，细胞和分子水平，以及2）每种激素如何进行重叠和独立通过特定的下游信号通路的影响，最终可能成为治疗靶标的防止和/或反向DBD。