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

Abstract

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.