Insulin-Like Growth Factor Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25) Is Linked to Endothelial-Dependent Vasodilation in High-Ferritin Type 2 Diabetes

Abstract

Type 2 diabetes is characterized by variable degrees of vascular dysfunction (1,2). We have recently reported improved vasomotor responses in high-ferritin type 2 diabetic patients following bloodletting (3), an intervention that is believed to reduce the deleterious effects of circulating iron on vascular function (4,5). Insulin-like growth factor binding protein–related protein 1 (IGFBP-rP1) is a 30 kDa modular glycoprotein known to be secreted by vascular and nonvascular cells (6–8). Besides its involvement in developmental processes and tumor growth (9,10), IGFBP-rP1 may play a role in the vasculature, given its abundance as an endothelial marker (11–13), its stimulatory actions on prostacyclin synthesis (7), and its vasodilatory effects on the retina of diabetic rats (14). To our knowledge, no clinical studies have examined the role of serum IGFBP-rP1 as a vascular factor. We hypothesized that circulating IGFBP-rP1 is linked to the vasomotor responses that follow iron depletion in high-ferritin type 2 diabetes. The study subjects ( n = 24 male patients, mean ± SD age 55.5 ± 8.1 years, BMI 29.1 ± 3.6 kg/m2, and A1C 6.2 ± 0.9%), are part of a well-characterized sample of high-ferritin type 2 diabetic patients subjected to bloodletting as previously reported by us (3,15). In the original cohort, 28 diabetic patients with elevated serum ferritin concentrations were randomized to either iron depletion (intervention group; n = 13) or to observation ( n = 15) according to a randomization table that included age, BMI, and A1C. The two groups were also matched for pharmacological treatment and chronic diabetes complications. The iron depletion intervention …