Abstract
Insulin-like growth factor I (IGF-I) has important anabolic and homeostatic functions in tissues like skeletal muscle, and a decline in circulating levels is linked with catabolic conditions. Whereas IGF-I therapies for musculoskeletal disorders have been postulated, dosing issues and disruptions of the homeostasis have so far precluded clinical application. We have developed a novel IGF-I variant by site-specific addition of polyethylene glycol (PEG) to lysine 68 (PEG-IGF-I). In vitro, this modification decreased the affinity for the IGF-I and insulin receptors, presumably through decreased association rates, and slowed down the association to IGF-I-binding proteins, selectively limiting fast but maintaining sustained anabolic activity. Desirable in vivo effects of PEG-IGF-I included increased half-life and recruitment of IGF-binding proteins, thereby reducing risk of hypoglycemia. PEG-IGF-I was equipotent to IGF-I in ameliorating contraction-induced muscle injury in vivo without affecting muscle metabolism as IGF-I did. The data provide an important step in understanding the differences of IGF-I and insulin receptor contribution to the in vivo activity of IGF-I. In addition, PEG-IGF-I presents an innovative concept for IGF-I therapy in diseases with indicated muscle dysfunction.
Highlights
Insulin-like growth factor (IGF-I)2 is a circulating anabolic hormone that unlike insulin is complexed to high affinity binding proteins (IGFBP) that exert homeostatic effects by regulating availability to most cells in the body [1, 2]
polyethylene glycol (PEG)-Insulin-like growth factor I (IGF-I) showed ϳ10-fold lower KD values because of lower on-rates and unchanged off-rates. This resulted in extended PEG-IGF-I availability for 15 min IGF-IR activation in the presence of serum IGFBP compared with recombinant human IGF-I (rhIGF-I)
In Vivo Pharmacokinetic and Pharmacodynamic Properties— To assess acute side effects in mice, we investigated hypoglycemia elicited by PEG-IGF-I and rhIGF-I in relation to their pharmacokinetic and pharmacodynamic properties
Summary
Insulin-like growth factor (IGF-I)2 is a circulating anabolic hormone that unlike insulin is complexed to high affinity binding proteins (IGFBP) that exert homeostatic effects by regulating availability to most cells in the body [1, 2]. Competition experiments were performed with 1.1 ϫ 106 (L6(WT)), 1.6 ϫ 105 (L6(InsR-A)), or 9.0 ϫ 105 (CHO(InsR-B)) cells/ml, incubated for 3, 5, and 2.5 h at 15 °C with iodinated ligand (20,000 cpm), respectively, with or without cold rhInsulin (Novo Nordisk), rhIGF-I (PeProTech), or PEG-IGF-I. IGF-IR- or InsR-transfected 3T3 cells were stimulated with rhIGF-I, PEG-IGF-I, or rhInsulin for 15 min at 37 °C and analyzed for receptor phosphorylation.
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