Increased expression of low-affinity insulin receptor isoform and insulin/insulin-like growth factor-I hybrid receptors in term placenta from insulin-resistant women with gestational hypertension

Summary Gestational hypertension is associated with insulin-resistance; insulin and insulin-like growth factor-1 (IGF-1), acting through their receptors, play a role in the growth of the feto-placental unit. Since both receptors are exposed to the maternal circulation, it has been suggested that maternal metabolic abnormalities might affect placental insulin (HIR) and IGF-1 (IGF-1R) receptors. To clarify this issue, we characterized HIR and IGF-1R in placenta at term from normal women, normoinsulinaemic women with gestational hypertension (NGH), and hyperinsulinaemic women with gestational hypertension (HGH). Insulin binding was decreased in HGH women (B/T 0.12±0.03) compared to control and NGH women (B/T 0.18±0.07, p<0.036; and 0.22±0.5, p<0.009 respectively). Receptor affinity was lower in HGH women (ED₅₀ 0.95±0.32 nmol/l) than control and NGH women (ED₅₀ 0.42±0.19 nmol/l, p<0.01; and 0.40±0.1 nmol/l, p<0.007, respectively), whereas low-affinity Ex11⁺ isoform was higher in HGH women (Ex11⁺ 50±7,%) than in control and NGH women (Ex11⁺ 34±9%, p<0.001; and 39±4%, p<0.01, respectively). Increased expression of Ex11⁺ isoform was correlated with ED₅₀ (r=0.71; p<0.002) and insulinaemia (r=0.70, p<0.002). IGF-I binding was increased in HGH women (B/T 0.17±0.03) compared to control and NGH women (B/T 0.09±0.05, p<0.002; and 0.11±0.03, p<0.002, respectively). IGF-IR affinity was similar in the three groups. The percentage of insulin/IGF-I hybrid receptors was increased in HGH women (85±3%) compared to control and NGH women (68±7%, p<0.001; and 63±9%, p<0.001, respectively), and was positively correlated with insulinaemia (r=0.62, p<0.018), ED₅₀ of insulin binding (r=0.62, p<0.05), and maximal IGF-I binding (r=0.69, p<0.004); whereas it was inversely correlated with maximal insulin binding (r=–0.69, p<0.004). Results provide the first evidence for altered expression of insulin/IGF-I hybrids found in insulin-resistance states.Abbreviations IGF-1 Insulin-like growth factor-1 - IGF-1R IGF-1 receptor - HIR human insulin receptor - OGTT oral glucose tolerance test - HGH hyperinsulinaemia with gestational hypertension - NGH normoinsulinaemia with gestational hypertension - PA-C polyclonal antibody CDrs. H. Valensise, Y. Y. Liu, M. Federici have contributed equally to this work