INCREASED ABUNDANCE OF INSULIN IGF-I HYBRID RECEPTORS IN ADIPOSE-TISSUE FRONT NIDDM PATIENTS/

Insulin/IGF-I hybrid receptors composed of an insulin receptor (IR) al pha beta-hemireceptor and a type 1 IGF receptor (IGF-IR) alpha beta-he mireceptor are formed in tissues expressing both molecules. To date th ere is a limited information about the proportion of hybrids in tissue s of normal or diabetic subjects. In this study, we determined the abu ndance of hybrids in fat from control and NIDDM subjects by using a mi crowell-based immunoassay. Microwells coated with MA-20 anti-IR or alp ha-IGF-IR-PA anti-IGF-IR antibody were incubated with tissue extracts. Immunoadsorbed receptors were incubated with I-125-insulin or I-125-I GF-I in the presence or absence of unlabeled ligands, and hybrids were quantitated as the fraction of I-125-IGF-I binding immunoadsorbed wit h MA-20. Abundance of hybrids was increased in NIDDM patients as compa red with controls (B/T = 1.29 +/- 0.18 and 0.52 +/- 0.06%; P < 0.008, respectively), and it was inversely correlated with both IR number (r = -0.65; P < 0.002), and in vivo insulin sensitivity measured by insul in tolerance test (r = -0.75; P < 0.005), whereas it was positively co rrelated with insulinemia (r = 0.63: P < 0.003). Insulin binding affin ity was lower in NIDDM subjects than in controls (ED50 = 1.87 +/- 0.32 and 0.54 +/- 0.20 nmol/l; P < 0.009, respectively), and was correlate d with the percentage of hybrids. Maximal IGF-I binding was significan tly greater in NIDDM patients than controls and was positively correla ted with the percentage of hybrids whereas IGF-I binding affinity did not differ between the two groups. Results show that expression of hyb rids is increased in fat of NIDDM patients compared to control subject s and is correlated with in vivo insulin sensitivity thus raising the possibility that alterations in expression of hybrids which bind IGF-I with higher affinity than insulin may contribute, at least in part, t o insulin resistance. (C) 1997 Elsevier Science Ireland Ltd.