Division of Preventive Medicine Brigham and Women's Hospital Harvard Medical School Boston MA.
F. Hoffman-La Roche, Ltd Basel Switzerland.
J Am Heart Assoc. 2019 Aug 6;8(15):e012790. doi: 10.1161/JAHA.119.012790. Epub 2019 Jul 19.
Background Pathologic angiogenesis is a hallmark of type 2 diabetes mellitus (T2DM) microvascular complications and may modulate adipogenesis and precede the onset of clinical diabetes mellitus; however, longitudinal data are unavailable. Placental growth factor is a potent proangiogenic factor that stimulates the formation of mature and durable vessels but is understudied in human diseases. Methods and Results We conducted a prospective case-cohort study of baseline placental growth factor and incident T2DM within the WHS (Women's Health Study). A random sample of incident T2DM cases (n=491) occurring over a 15-year follow-up period was selected and compared with a reference subcohort (n=561). Case subjects were matched to the reference risk set on 5-year age groups and race. All subjects in this analysis were required to have a hemoglobin A <6.5% at WHS enrollment. Median baseline levels of placental growth factor were higher in case subjects compare to the reference subcohort (18.0 pg/mL versus 17.2 pg/mL) but were only weakly correlated with glycemic measures and not associated with obesity. The risk of diabetes mellitus increased across placental growth factor quartile in the base model (hazard ratios, 1.00, 1.14, 1.46, and 2.14; P-trend<0.001) and in multivariable-adjusted models accounting for clinical T2DM risk factors (hazard ratios, 1.00, 1.17, 1.45, and 2.61; P-trend<0.001). These findings were not substantially altered by further adjustment for high-sensitivity C-reactive protein, hemoglobin A, or fasting insulin and remained robust in sensitivity analyses excluding those diagnosed within 2 years of enrollment and those with baseline hemoglobin A ≥6.0%. Conclusions Elevated placental growth factor levels are associated with future T2DM independent of traditional risk factors, measures of glycemia, insulin resistance, and high-sensitivity C-reactive protein. These prospective data suggest that pathologic angiogenesis may occur well before the clinical onset of T2DM and thus may have relevance to vascular complications of this disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479.
病理性血管生成是 2 型糖尿病（T2DM）微血管并发症的标志，可能调节脂肪生成并先于临床糖尿病的发生；然而，目前尚无纵向数据。胎盘生长因子是一种强有力的促血管生成因子，可刺激成熟和持久血管的形成，但在人类疾病中研究较少。
我们在 WHS（妇女健康研究）中进行了一项前瞻性病例队列研究，研究基线胎盘生长因子与 15 年随访期间发生的 T2DM 之间的关系。选择了在 15 年随访期间发生的随机 T2DM 病例（n=491）的一个新病例，并与一个参考亚队列（n=561）进行比较。病例对象与参考风险集按 5 岁年龄组和种族进行匹配。本分析中的所有受试者均要求在 WHS 入组时血红蛋白 A <6.5%。与参考亚队列相比，病例组的胎盘生长因子基线中位数水平更高（18.0pg/ml 与 17.2pg/ml），但与血糖测量值仅呈弱相关，与肥胖无关。在基础模型中，胎盘生长因子 quartile 与糖尿病风险呈正相关（风险比，1.00、1.14、1.46 和 2.14；P-trend<0.001），在多变量调整模型中考虑了临床 T2DM 危险因素（风险比，1.00、1.17、1.45 和 2.61；P-trend<0.001）。进一步调整高敏 C 反应蛋白、血红蛋白 A 或空腹胰岛素后，这些发现没有明显改变，并且在排除入组后 2 年内诊断的病例和基线血红蛋白 A≥6.0%的病例的敏感性分析中仍然稳健。
升高的胎盘生长因子水平与传统危险因素、血糖测量值、胰岛素抵抗和高敏 C 反应蛋白无关，与未来的 T2DM 相关。这些前瞻性数据表明，病理性血管生成可能在临床 T2DM 发生之前就已经发生，因此可能与该疾病的血管并发症有关。
http://www.clinicaltrials.gov。
NCT00000479。
