INCREASED EXPRESSION OF INSULIN INSULIN-LIKE GROWTH-FACTOR-I HYBRID RECEPTORS IN SKELETAL-MUSCLE OF NONINSULIN-DEPENDENT DIABETES-MELLITUS SUBJECTS/

Insulin receptors (IR) and IGF-I receptors (IGF-IR) have been shown to form hybrid receptors in tissues coexpressing both molecules. To date there is no information about the distribution of hybrids in tissues of normal or diabetic subjects. We developed a microwell-based immunoa ssay to quantitate hybrids in small human tissues samples. Micro-wells were coated with MA-20 anti-TR antibody or alpha-IGF-IR-PA antibody d irected against the IGF-IR alpha-subunit, and incubated with skeletal muscle extracts of patients with noninsulin-dependent diabetes mellitu s (NIDDM) and normal controls. Immobilized receptors were incubated wi th I-125-insulin or I-125-IGF-I in the presence or absence of the two unlabeled ligands. Hybrids were quantified as the fraction of I-125-IG F-I binding immunoadsorbed with MA-20 and expressed as percentage of t otal IGF-IR (type I+hybrids) immobilized with alpha-IGF-IR-PA. The imm unoassay was validated using Western blotting analysis. Relative abund ance of hybrids detected in NIDDM patients was higher than in controls . The percentage of hybrids was negatively correlated with IR number a nd in vivo insulin sensitivity measured by an insulin tolerance test, whereas the percentage was positively correlated with insulinemia Insu lin binding affinity was lower in NIDDM patients than in controls, and was correlated with the percentage of hybrids. Maximal IGF-I binding was significantly higher in muscle from NIDDM patients compared to con trols and was positively correlated with the percentage of hybrid rece ptors whereas IGF-I binding affinity did not differ between the two gr oups. These results raise the possibility that alterations in expressi on of hybrid receptors may contribute to decreased insulin sensitivity , and to increased sensitivity to IGF-I. Because IGF-I has been propos ed as a hypoglycemic agent in NIDDM, these results are relevant to the development of new approaches to the treatment of insulin resistance of NIDDM.