The Insulin/IGF-I Axis in Diabetic Osteopathy

糖尿病骨病中的胰岛素/IGF-I 轴

• 批准号: 8998113
• 负责人: John L Fowlkes
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-23 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998113
• 关键词: Affect; Animal Model; Animals; Biology; Bone Density; Bone Diseases; Clinical; Data; Development; Diabetes Mellitus; Event; Financial compensation; Fracture; Fracture Healing; Gene Expression; Gene Targeting; Growth and Development function; Health; Homeostasis; Homologous Gene; Human; Impairment; Insulin; Insulin Receptor; Insulin Signaling Pathway; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Knock-out; Knockout Mice; Laboratories; Ligands; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Osteoblasts; Osteogenesis; Osteopathic Medicine; Osteoporosis; Pathogenesis; Pathway interactions; Personal Satisfaction; Phenotype; Play; Process; Production; Receptor Signaling; Relative (related person); Risk; Role; Signal Transduction; Skeletal Development; Stream; Streptozocin; Therapeutic; Time; To specify; blood glucose regulation; bone; bone quality; diabetic; improved; in utero; mouse model; osteogenic; postnatal; pre-clinical; prevent; receptor; skeletal; skeletal abnormality; skeletal disorder; therapy development; transcription factor

DESCRIPTION (provided by applicant): Type 1 diabetes mellitus (T1D) is associated with several disorders of skeletal health, including decreased bone mineral density (BMD) and an increased risk for osteoporosis and fragility fracture. Moreover, clinical evidence suggests that skeletal abnormalities in T1D result from the detrimental effects of T1D on bone formation. While BMD is typically not diminished in Type 2 diabetes mellitus (T2D), bone quality is impaired and fracture risk is increased. The shared as well as distinct features underlying diabetic osteopathy in T1D and T2D are not well understood at this time; however, studies have suggested that impaired insulin production, insulin action, insulin-like growth factor-I (IGF-I) action, as well as indirect effects of insulin to promote insulin-like growth factor-I (IGF-I) production, may be central events in promoting diabetic bone disease. Recent data from our laboratory examining animal models of diabetes have demonstrated that: 1) severe deficits in bone formation occur in the context of insulin-deficiency in mouse models of T1D; 2) normalization of systemic insulin levels stimulates new bone formation through RUNX2 and RUNX2 target genes in diabetic animals; and 3) insulin and IGF-I may signal via similar down-stream pathways to promote osteoblastogenesis. To clarify mechanisms by which insulin and/or IGF-I modulate osteogenesis, and how deficiencies or impaired signaling of each may contribute to diabetic osteopathy, we will examine through which signaling pathway(s) insulin regulates RUNX2 and RUNX2 target genes. We also will study mice generated in our laboratory with conditional knock-out of the insulin receptor (IR) in osteoblasts (OIRKO mice) in regards to in utero skeletal development, postnatal affects on skeletal growth and development, and de novo bone formation. Furthermore, we will dissect the specific roles of insulin and IGF-I and their cognate receptors in the osteoblastogenic process by comparing control osteoblasts to osteoblasts lacking the IR, the IGF-1 receptor (IGFR), or both the IR and IGFR in regards to insulin, IGF-I or insulin and IGF-I stimulated proliferation, differentiation, and osteogenic gene expression. To specify the roles that insulin and IGF-I may play in the pathogenesis and treatment of diabetic osteopathy, we will investigate the effects of diabetes on bone homeostasis and integrity in the osteoblast-specific insulin receptor knock-out (OIRKO) mouse, the IGFR knock-out (OIGFRKO) mouse, or the IR/IGFR double-knock out (DKO) mouse. We then will evaluate the impact of insulin or IGF-I therapy to affect bone integrity in the diabetic OIRKO, OIGFRKO, and DKO mouse. Finally, we will determine if FoxO transcription factors, major down-stream targets of insulin and IGF-I signaling, are integral to the diabetic bone phenotype. We will study the effects of osteoblast-specific deficiencies in FoxO1, FoxO3 and FoxO4 in STZ- induced diabetes as a way to preserve skeletal integrity in T1D. Together, these studies will provide critical mechanistic and pre-clinical information needed to better understand how corrections in insulin and/or IGF-I in diabetes may be beneficial in preventing and treating diabetic osteopathy.

描述（由申请人提供）：1 型糖尿病 (T1D) 与多种骨骼健康疾病相关，包括骨矿物质密度 (BMD) 降低以及骨质疏松和脆性骨折风险增加。此外，临床证据表明，1 型糖尿病的骨骼异常是由于 1 型糖尿病对骨形成的有害影响造成的。虽然 2 型糖尿病 (T2D) 患者的骨密度通常不会降低，但骨质量会受损，骨折风险会增加。 T1D 和 T2D 糖尿病骨病的共同特征和独特特征目前尚不清楚；然而，研究表明，胰岛素产生、胰岛素作用、胰岛素样生长因子-I (IGF-I) 作用受损，以及胰岛素促进胰岛素样生长因子-I (IGF-I) 产生的间接作用，可能是促进糖尿病骨病的核心事件。我们实验室检查糖尿病动物模型的最新数据表明：1) T1D 小鼠模型在胰岛素缺乏的情况下会出现严重的骨形成缺陷； 2) 糖尿病动物全身胰岛素水平正常化通过RUNX2和RUNX2靶基因刺激新骨形成； 3) 胰岛素和 IGF-I 可能通过类似的下游途径发出信号以促进成骨细胞生成。为了阐明胰岛素和/或 IGF-I 调节成骨的机制，以及每种信号传导的缺陷或受损如何导致糖尿病骨病，我们将检查胰岛素通过哪些信号传导途径调节 RUNX2 和 RUNX2 靶基因。我们还将研究在我们实验室中条件性敲除成骨细胞中胰岛素受体 (IR) 的小鼠（OIRKO 小鼠）的子宫内骨骼发育、出生后对骨骼生长和发育的影响以及从头骨形成。此外，我们将通过将对照成骨细胞与缺乏 IR、IGF-1 受体 (IGFR) 或同时缺乏 IR 和 IGFR 的成骨细胞进行比较，剖析胰岛素和 IGF-I 及其同源受体在成骨细胞生成过程中的具体作用。胰岛素、IGF-I或胰岛素和IGF-I刺激增殖、分化和成骨基因表达。为了明确胰岛素和 IGF-I 在糖尿病骨病的发病机制和治疗中可能发挥的作用，我们将研究糖尿病对成骨细胞特异性胰岛素受体敲除 (OIRKO) 小鼠 (IGFR) 骨稳态和完整性的影响敲除 (OIGFRKO) 小鼠或 IR/IGFR 双敲除 (DKO) 小鼠。然后，我们将评估胰岛素或 IGF-I 治疗对糖尿病 OIRKO、OIGFRKO 和 DKO 小鼠骨完整性的影响。最后，我们将确定 FoxO 转录因子（胰岛素和 IGF-I 信号传导的主要下游靶标）是否是糖尿病骨表型的组成部分。我们将研究成骨细胞特异性缺陷 FoxO1、FoxO3 和 FoxO4 对 STZ 诱导的糖尿病的影响，以此作为保持 1 型糖尿病骨骼完整性的一种方法。总之，这些研究将提供关键的机制和临床前信息，以更好地了解糖尿病中胰岛素和/或 IGF-I 的校正如何有益于预防和治疗糖尿病骨病。

项目成果

Postnatal loss of the insulin receptor in osteoprogenitor cells does not impart a metabolic phenotype.

出生后骨祖细胞中胰岛素受体的丧失不会赋予代谢表型。

• DOI: 10.1038/s41598-020-65717-3
• 发表时间: 2020
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Fowlkes,JohnL;ClayBunn,R;Kalaitzoglou,Evangelia;Ray,Phil;Popescu,Iuliana;Thrailkill,KathrynM
• 通讯作者: Thrailkill,KathrynM