The long term therapeutic potential of recombinant human (rh)
IGF-I administration in
insulin-dependent diabetes mellitus (
IDDM) may be determined by changes in the
IGF binding proteins (IGFBPs) and thus the bioavailability of
IGF-I. We have therefore studied the effects of a single subcutaneous dose of rhIGF-I (40 micrograms/kg at 1800 h), when compared with an untreated control night, in 17 subjects with
IDDM, on serum concentrations of
IGF-I,
IGF-II,
IGFBP-3,
acid labile subunit (ALS), and
IGFBP-3 proteolysis. Mean (+/- S.E.M.)
IGF-I levels increased from 242 +/- 30 ng/ml to 399 +/- 26 ng/ml (P = 0.01) after rhIGF-I whereas
IGF-II levels declined from 600 +/- 45 ng/ml to 533 +/- 30 ng/ml. There was a small overnight reduction in baseline ALS levels from 48 +/- 2.8 to 44.5 +/- 3.2 micrograms/ml (P = 0.04) after rhIGF-I administration. An early fall in
IGFBP-3 concentrations on the control night was not seen after rhIGF-I and overall mean levels were increased (5.2 +/- 0.2 micrograms/ml vs 4.9 +/- 0.2 micrograms/ml, P = 0.04, on the control night). On the baseline night,
IGFBP-3 levels correlated with the sum of
IGF-I and
IGF-II (r = 0.73, P = 0.02) and with levels of the ALS (r = 0.7, P = 0.002). However after rhIGF-I, the sum of
IGF-I and
IGF-II no longer correlated with
IGFBP-3, whereas the relationship with ALS was maintained. Immunoblot studies in six subjects indicated that 60%-70% of the
IGFBP-3 was detected as a low molecular weight fragment at 1900 h on both study nights, but the amount of fragment declined to approximately 50% at 0100 h and 45% at 0700 h. In conclusion, despite a slight but significant fall in ALS,
IGFBP-3 levels rise after rhIGF-I administration in
IDDM. This cannot be explained by alterations in
IGFBP-3 proteolysis, and may relate to the relative stability of ALS/
IGFBP-3 when complexed principally with
IGF-I rather than
IGF-II.