Li Xing, Tang Jie, Lin Sha, Liu Xuwei, Li Yifei
Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
Front Med (Lausanne). 2024 Feb 5;11:1332162. doi: 10.3389/fmed.2024.1332162. eCollection 2024.
Observational studies have consistently shown significant associations between the IGF family and metabolic diseases, including diabetes. However, these associations can be influenced by confounding factors and reverse causation. This study aimed to assess the causal relationship between the IGF family and diabetes using Mendelian randomization (MR).
We conducted a two-sample MR analysis to investigate the causal effects of the IGF family on diabetes. Instrumental variables for the IGF family and diabetes were derived from summary-level statistics obtained from genome-wide association studies. Horizontal pleiotropy was assessed using MR-Egger regression and the weighted median method. We applied the inverse-variance weighted method as part of the conventional MR analysis to evaluate the causal impact of the IGF family on diabetes risk. To test the robustness of the results, we also employed MR-Egger regression, the weighted median method, and a leave-one-out analysis.
Our study revealed that IGF-1 causally increases the risk of Type 2 Diabetes (T2D), while IGFBP-6, adiponectin and INSR decreases the risk (IGF-1, OR 1.02 [95% CI 1-1.03], = 0.01; IGFBP-6, OR 0.92 [95% CI 0.87-0.98], = 0.01; Adiponectin, OR 0.837 [95% CI 0.721-0.970], = 0.018; INSR, OR 0.910 [95% CI 0.872-0.950], = 1.52 × 10-5). Additionally, genetically lower levels of IGF-1 and IGFBP-5, along with higher levels of IGFBP-7, were associated with an increased risk of Type 1 Diabetes (T1D) (IGF-1, OR 0.981 [95% CI 0.963-0.999], = 0.037; IGFBP-5, OR 0.882 [95% CI 0.778-0.999], = 0.049; IGFBP-7, OR 1.103 [95% CI 1.008-1.206], = 0.033).
In summary, our investigation has unveiled causal relationships between specific IGF family members and T1D and T2D through MR analysis. Generally, the IGF family appears to reduce the risk of T1D, but it presents a more complex and controversial role in the context of T2D. These findings provide compelling evidence that T2D is intricately linked with developmental impairment. Our study results offer fresh insights into the pathogenesis and the significance of serum IGF family member concentrations in assessing diabetes risk.
观察性研究一直表明胰岛素样生长因子（IGF）家族与包括糖尿病在内的代谢性疾病之间存在显著关联。然而，这些关联可能受到混杂因素和反向因果关系的影响。本研究旨在利用孟德尔随机化（MR）评估IGF家族与糖尿病之间的因果关系。
我们进行了一项两样本MR分析，以研究IGF家族对糖尿病的因果效应。IGF家族和糖尿病的工具变量来自全基因组关联研究获得的汇总统计数据。使用MR-Egger回归和加权中位数方法评估水平多效性。我们应用逆方差加权方法作为传统MR分析的一部分，以评估IGF家族对糖尿病风险的因果影响。为了检验结果的稳健性，我们还采用了MR-Egger回归、加权中位数方法和留一法分析。
我们的研究表明，IGF-1因果性地增加2型糖尿病（T2D）风险，而IGFBP-6、脂联素和胰岛素受体底物（INSR）降低风险（IGF-1，比值比[OR]1.02[95%置信区间（CI）1 - 1.03]，P = 0.01；IGFBP-6，OR 0.92[95%CI 0.87 - 0.98]，P = 0.01；脂联素，OR 0.837[95%CI 0.721 - 0.970]，P = 0.018；INSR，OR 0.910[95%CI 0.872 - 0.950]，P = 1.52×10⁻⁵）。此外，基因水平较低的IGF-1和IGFBP-5，以及较高水平的IGFBP-7，与1型糖尿病（T1D）风险增加相关（IGF-1，OR 0.981[95%CI 0.963 - 0.999]，P = 0.037；IGFBP-5，OR 0.882[95%CI 0.778 - 0.999]，P = 0.049；IGFBP-7，OR 1.103[95%CI 1.008 - 1.206]，P = 0.033）。
总之，我们的研究通过MR分析揭示了特定IGF家族成员与T1D和T2D之间的因果关系。一般来说，IGF家族似乎降低T1D风险，但在T2D背景下其作用更为复杂且存在争议。这些发现提供了令人信服的证据，表明T2D与发育障碍密切相关。我们的研究结果为发病机制以及血清IGF家族成员浓度在评估糖尿病风险中的意义提供了新的见解。
