The effects of the insulin-like growth factor-I aptamer, NBI-31772, on glucose homeostasis in the mouse.
The majority of insulin-like growth factor-I (IGF-I) in the adult rodent circulation is bound to high affinity IGF binding proteins. We investigated the changes in IGF-I clearance, blood glucose and plasma insulin levels, and tissue 2-deoxyglucose uptake after intravenous administration of the IGF aptamer, NBI-31772, which selectively competes with IGF-I for binding to the IGFBPs, but has no effect at the IGF-I receptor. Clearance of 125I-IGF-I was significantly increased in NBI-31772-treated mice compared with vehicle-treated mice (t1/2 = 45.0 +/- 1.9 vs. 56.3 +/- 3.9 min, respectively; p = 0.021). However, NBI-31772 had no significant effect on glucose levels, and no insulin sparing effect was apparent neither under basal conditions nor during an intravenous glucose challenge. The decline in the specific activity after 3H-2-deoxyglucose administration was significantly less rapid in NBI-31772-treated mice compared with controls, suggesting that the IGF-I aptamer had an inhibitory effect on hepatic gluconeogenesis. In contrast, no insulin-like effect was apparent in other tissues examined. 3H-2-deoxyglucose accumulation was similar in all tissues analyzed, including skeletal muscle, which is thought to be particularly sensitive to IGF-I. These data suggest that the IGF-I aptamer affects clearance of radiolabeled IGF-I from the circulation, but has no marked effects on glucose nor insulin homeostasis. The search for hydrophilic IGF aptamers with longer duration of action that could be used in the treatment of diabetes may be rewarding.
Silha
Josef V
JV
Department of Physiology, University of Manitoba, Winnipeg, MB R3E 0W3, Canada.
Murphy
Liam J
LJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007202:Indicators and Reagents; D007328:Insulin / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice
D001786:Blood Glucose; D002396:Catechols; D007202:Indicators and Reagents; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D007546:Isoquinolines; C436731:NBI 31772; D007334:Insulin-Like Growth Factor I; D003847:Deoxyglucose; D005947:Glucose