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

Abstract

BackgroundPathologic 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 ResultsWe 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%.ConclusionsElevated 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.

­PlGF Regulates Angiopoietin-1 and Tie-2 Expression in Human Retinal Endothelial Cell-Pericyte Cocultures and iPSC-Derived Vascular Organoids through VEGFR1

“…51 In type 2 diabetic mellitus (T2DM), plasma PlGF concentrations are elevated before pathologic angiogenesis occurrence, suggesting that PlGF may serve as a potential biomarker for diagnosis of microvascular complication in T2DM patients. 52 Vitreous levels of PlGF signi cantly (p < 0.05) correlated with pathological angiogenesis and VEGF levels in diabetic patients with active PDR, and its receptor VEGFR1 (or FLT1) were detected in the ECs of proliferative neovasculature. 53 Another study also reported that vitreous PlGF levels are signi cantly higher in diabetic patients with DR than without DR. 54 These studies with clinical samples indicated that PlGF/VEGFR1 signaling is involved in the retinal microvascular complications both NPDR and PDR.…”

Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

“…PlGF expression is modulated by hyperglycaemia in endothelial cells. Elevated circulating PlGF has recently been identified in insulin resistance, metabolic syndrome, vascular inflammation and is an independent marker of the future development of type-II diabetes [19][20][21][22] . To determine whether hyperglycaemia upregulates the expression of PlGF, we incubated confluent primary human endothelial cells in medium containing 30 mM d-glucose for 24 h and measured the level of PlGF released into the medium by ELISA.…”

“…PlGF mRNA is expressed in white adipose tissue 53 , and PlGF (−/−) knock-out mice have a lower body weight and fat content than wild-type mice and a lower fat content when maintained on a high-fat diet 54 . Whether this is due to endothelial or adipocyte PlGF production was not fully established, but it suggests that in addition to increased risk of type II diabetes 21 and CVD 19,[23][24][25] , up-regulation of PlGF in insulin resistance/hyperglycaemia and the metabolic syndrome may also accelerate the development of obesity.…”

Effect of Flexible GnRH antagonist and long GnRH agonist protocols on follicular fluid levels of PlGF, AMH, oocyte’s morphology, and other IVF/ICSI outcomes in polycystic ovary syndrome women

“…rheumatoid arthritis [18], systemic lupus erythematosus [19], metabolic syndrome [20], type II diabetes [21], coronary artery disease [22], and neovascular age-related macular degeneration [23]. In addition, growing evidence has shown an important role of PlGF in regulating the reproduction process, starting from ovulation [24] to placentation, implantation, and embryo development [25][26][27][28].…”