THU0039 Insulin-like growth factor 1 receptor regulates the phenotype and function of cd21+ b cells

ABSTRACT Cardiovascular disease is the leading cause of death in people with type 2 diabetes and is linked to insulin resistance even in the absence of diabetes. Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. By contrast, mice lacking the IGF-1 receptor or the IGF-1 receptor plus one Ir allele appear normal. Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function.

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INSULIN-LIKE GROWTH FACTOR-I IMPROVES MUCOSAL STRUCTURE AND FUNCTION IN TRANSPLANTED RAT SMALL INTESTINE

Transplantation Journal ◽

10.1097/00007890-199503150-00020 ◽

1995 ◽

Vol 59 (5) ◽

pp. 755-761 ◽

Cited By ~ 42

Author(s):

Wei Zhang ◽

Wendy L. Frankel ◽

William T. Adamson ◽

Jonathan A. Roth ◽

Mark P. Mantell ◽

...

Keyword(s):

Small Intestine ◽

Growth Factor ◽

Structure And Function ◽

Insulin Like Growth Factor ◽

Rat Small Intestine ◽

Factor I ◽

Growth Factor I ◽

And Function

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Growth hormone and insulin-like growth factor I induce immunoglobulin (Ig)E and IgG4 production by human B cells.

Journal of Experimental Medicine ◽

10.1084/jem.180.2.727 ◽

1994 ◽

Vol 180 (2) ◽

pp. 727-732 ◽

Cited By ~ 38

Author(s):

H Kimata ◽

M Fujimoto

Keyword(s):

Growth Hormone ◽

B Cells ◽

Growth Factor ◽

Mononuclear Cells ◽

Immunoglobulin E ◽

Interleukin 4 ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Growth Factor I

We studied the effects of growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-II, and insulin on human immunoglobulin E (IgE) and IgG4 production. GH and IGF-I induced IgE and IgG4 production by normal donors' mononuclear cells (MNC) depleted of sIgE+ and sIgG4+ B cells without affecting IgM, IgG1, IgG2, IgG3, IgA1, or IgA2 production, whereas IGF-II and insulin failed to do so. GH-induced IgE and IgG4 production was specific, and was not mediated by IGF-I, interleukin 4 (IL-4), or IL-13, since it was blocked by anti-GH antibody (Ab), but not by anti-IGF-I Ab, anti-IL-4 Ab, or anti-IL-13 Ab. Conversely, IGF-I-induced IgE and IgG4 production was blocked by anti-IGF-I Ab, but not by anti-GH Ab, anti-IL-4 Ab, or anti-IL-13 Ab. Moreover, interferon alpha (IFN-alpha) or IFN-gamma, which counteracted IL-4-and IL-13-induced IgE and IgG4 production, had no effect on induction by GH or IGF-I. In contrast to MNC, GH or IGF-I failed to induce IgE and IgG4 production by purified sIgE-, sIgG4- B cells. However, in the presence of anti-CD40 monoclonal antibody (mAb), GH or IGF-I induced IgE and IgG4 production by these cells. Purified sIgE+, but not sIgE-, B cells from atopic patients spontaneously produced IgE. GH or IGF-I with anti-CD40 mAb failed to enhance IgE production by sIgE+ B cells, whereas they induced IgE production by sIgE- B cells. Similarly, whereas GH or IGF-I with anti-CD40 mAb failed to enhance IgG4 production by sIgG4+ B cells from atopic patients, they induced IgG4 production by sIgG4- B cells. Again, neither IgE nor IgG4 induction was blocked by anti-IL-4 Ab or anti-IL-13 Ab. These results indicate that GH and IGF-I induce IgE and IgG4 production by class switching in an IL-4- and IL-13-independent mechanism.

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Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function.

Endocrinology ◽

10.1210/endo.136.1.7828521 ◽

1995 ◽

Vol 136 (1) ◽

pp. 124-131 ◽

Cited By ~ 69

Author(s):

P A Hill ◽

J J Reynolds ◽

M C Meikle

Keyword(s):

Growth Factor ◽

Osteoclast Formation ◽

Insulin Like Growth Factor ◽

Factor I ◽

Growth Factor I ◽

And Function ◽

Stimulation Of

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Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.80.12.3447 ◽

1995 ◽

Vol 80 (12) ◽

pp. 3447-3457 ◽

Cited By ~ 13

Author(s):

T. Siebler

Keyword(s):

Growth Factor ◽

Receptor Expression ◽

Chromosome 15 ◽

Insulin Like Growth Factor ◽

Factor I ◽

Growth Factor I ◽

And Function

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Structural, gene expression, and functional analysis of the fugu (Takifugu rubripes) insulin-like growth factor binding protein-4 gene

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90439.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. R558-R566 ◽

Cited By ~ 22

Author(s):

Mingyu Li ◽

Yun Li ◽

Ling Lu ◽

Xianlei Wang ◽

Qingli Gong ◽

...

Keyword(s):

Growth Factor ◽

Expression Patterns ◽

Biological Action ◽

Takifugu Rubripes ◽

Insulin Like Growth Factor ◽

Igf Binding Proteins ◽

Physiological Regulation ◽

Functional Conservation ◽

Igf Receptors ◽

And Function

The insulin-like growth factor (IGF) signaling pathway is a conserved pathway that regulates animal development, growth, metabolism, reproduction, and aging. The biological actions of IGFs are modulated by IGF-binding proteins (IGFBPs). Although the structure and function of fish IGFBP-1, -2, -3, and -5 have been elucidated, there is currently no report on the full-length structure of a fish IGFBP-4 nor its biological action. In this study, we cloned and characterized the IGFBP-4 gene from fugu. Sequence comparison, phylogenetic, and synteny analyses indicate that its chromosomal location, gene, and protein structure are similar to its mammalian orthologs. Fugu IGFBP-4 mRNA was easily detectable in all adult tissues examined with the exception of spleen. Older animals tended to have higher levels of IGFBP-4 mRNA in the muscle and eyes compared with younger animals. Starvation resulted in significant increases in IGFBP-4 mRNA abundance in the muscle, liver, gallbladder, and brain. Overexpression of fugu and human IGFBP-4 in zebrafish embryos caused a significant decrease in body size and somite number, suggesting that fugu IGFBP-4 inhibits growth and development, possibly by binding to IGFs and inhibiting their binding to the IGF receptors. These results provide new information about the structural and functional conservation, expression patterns, and physiological regulation of the IGFBP-4 gene in a teleost fish.

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