Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3,-4, and-5

IGF-I and IGF-II are essential regulators of mammalian growth, development and metabolism, whose actions are modified by six high-affinity IGF binding proteins ( IGFBPs). New lines of knockout ( KO) mice lacking either IGFBP-3, -4, or -5 had no apparent deficiencies in growth or metabolism beyond a modest growth impairment ( similar to 85 - 90% of wild type) when IGFBP-4 was eliminated. To continue to address the roles of these proteins in whole animal physiology, we generated combinational IGFBP KO mice. Mice homozygous for targeted defects in IGFBP-3, - 4, and - 5 remain viable and at birth were the same size as IGFBP-4 KO mice. Unlike IGFBP- 4 KO mice, however, the triple KO mice became significantly smaller by adulthood ( 78% wild type) and had significant reductions in fat pad accumulation ( P < 0.05), circulating levels of total IGF-I ( 45% of wild type; P < 0.05) and IGF-I bioactivity ( 37% of wild type; P < 0.05). Metabolically, triple KO mice showed normal insulin tolerance, but a 37% expansion ( P < 0.05) of beta-cell number and significantly increased insulin secretion after glucose challenge, which leads to enhanced glucose disposal. Finally, triple KO mice demonstrated a tissue-specific decline in activation of the Erk signaling pathway as well as weight of the quadriceps muscle. Taken together, these data provide direct evidence for combinatorial effects of IGFBP-3, -4, and -5 in both metabolism and at least some soft tissues and strongly suggest overlapping roles for IGFBP-3 and -5 in maintaining IGF-I- mediated postnatal growth in mice.