Plasma Placental Growth Factor Concentrations Are Elevated Well in Advance of Type 2 Diabetes Mellitus Onset: Prospective Data From the WHS

Edward K Duran, Nancy R Cook, Maria Bobadilla, Eunjung Kim, JoAnn E Manson, Julie E Buring, Paul M Ridker, Aruna D Pradhan, Edward K Duran, Nancy R Cook, Maria Bobadilla, Eunjung Kim, JoAnn E Manson, Julie E Buring, Paul M Ridker, Aruna D Pradhan

Abstract

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 A1c <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 A1c, or fasting insulin and remained robust in sensitivity analyses excluding those diagnosed within 2 years of enrollment and those with baseline hemoglobin A1c ≥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.

Keywords: angiogenesis; diabetes mellitus; placenta growth factor; vascular disease; vascular growth factor.

Figures

Figure 1
Figure 1
Spline analyses for risk associations between PlGF and incident type 2 diabetes mellitus. A, In the base model adjusting for WHS (Women's Health Study) treatment assignment and stratification factors, the risk of incident type 2 diabetes mellitus (T2DM) had a strongly linear association with increasing concentration of PlGF) (Pnon‐linearity=0.92; Plinearity<0.001). Knots for model 1 were identified at 13.1, 17.8, and 23.6 mg/dL, with the first knot set as reference. B, Adjustment for traditional clinical T2DM risk factors (model 2 covariates) did not significantly attenuate the linear association between PlGF and incident T2DM (Pnon‐linearity=0.97; Plinearity<0.001). C, Further adjustment for hsCRP, HbA1c, and fasting insulin had no meaningful impact the association observed in (B) (Pnon‐linearity=0.20; Plinearity<0.001). Knots for model 2 and model 5 were identified at 13.3, 17.8, and 23.6 mg/dL, with first knot set as reference. All models exclude top and bottom fifth percentiles of data to reduce the impact of extreme data points. HbA1c indicates hemoglobin A1c; hsCRP, high‐sensitivity C‐reactive protein; PlGF, placental growth factor.
Figure 2
Figure 2
Stratified analyses for risk associations between placental growth factor and incident T2DM. A, Hazard ratios for the association between median concentration of PlGF and incident T2DM according to 3 ranges of follow‐up time. As shown, time at which diabetes mellitus was diagnosis had no meaningful impact on the association with PlGF level. B and C, Joint effects of PlGF according to insulin level (B) and obesity status (C). Elevated PlGF appeared to augment the risk of incident diabetes mellitus in the presence of both high and low insulin and in those with or without obesity (Pinteraction>0.05 for both). High status indicates biomarker value greater than or equal to the median concentration in the subcohort. Subjects considered obese if BMI ≥30.0 kg/m2. BMI indicates body mass index; PlGF, placental growth factor; T2DM, type 2 diabetes mellitus.

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