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

Yun Ning, Alwin G P Schuller, Sheri Bradshaw, Peter Rotwein, Thomas Ludwig, Jan Frystyk, John E. Pintar

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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 (∼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 β-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.

Original languageEnglish (US)
Pages (from-to)2173-2186
Number of pages14
JournalMolecular Endocrinology
Volume20
Issue number9
DOIs
StatePublished - 2006

Fingerprint

Insulin-Like Growth Factor Binding Protein 4
Insulin-Like Growth Factor Binding Protein 3
Knockout Mice
Glucose
Mutation
Insulin-Like Growth Factor I
Growth
Insulin-Like Growth Factor Binding Proteins
Insulin-Like Growth Factor Binding Protein 5
Insulin
Insulin-Like Growth Factor II
Quadriceps Muscle
Growth and Development
Adipose Tissue
Cell Count
Parturition
Weights and Measures

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. / Ning, Yun; Schuller, Alwin G P; Bradshaw, Sheri; Rotwein, Peter; Ludwig, Thomas; Frystyk, Jan; Pintar, John E.

In: Molecular Endocrinology, Vol. 20, No. 9, 2006, p. 2173-2186.

Research output: Contribution to journalArticle

Ning, Yun ; Schuller, Alwin G P ; Bradshaw, Sheri ; Rotwein, Peter ; Ludwig, Thomas ; Frystyk, Jan ; Pintar, John E. / Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. In: Molecular Endocrinology. 2006 ; Vol. 20, No. 9. pp. 2173-2186.
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