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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:2783-2787, September 2003

Nutrient Metabolism

Insulin/Insulin-Like Growth Factor-I Hybrid Receptor Abundance Decreases with Development in Suckling Pigs1,2

Agus Suryawan, Hanh V. Nguyen, Renan A. Orellana, Jill A. Bush and Teresa A. Davis3

U.S. Department of Agriculture/Agriculture Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030

3To whom correspondence should be addressed. E-mail: tdavis{at}bcm.tmc.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
The activation of the insulin signaling pathway that leads to translation initiation is enhanced in skeletal muscle of neonates, and decreases with development in parallel with the developmental decline in muscle protein synthesis. Because the elevated expression of insulin receptor (IR)/insulin-like growth factor-I receptor (IGF-IR) hybrids has been associated with insulin resistance in some studies, we hypothesized that IR/IGF-IR hybrid abundance and binding affinity increase with development. To test this hypothesis, we determined the abundances and binding affinities of the IR, IGF-IR and hybrid receptor in skeletal muscle of 7- and 26-d-old pigs. We found that the abundances of IR, IGF-IR and hybrid receptor were higher in muscle of 7- than 26-d-old pigs. However, the relative proportions of hybrid receptor abundance compared with IR abundance and IGF-IR abundance were similar at both ages. The binding affinities of the IR, IGF-IR and hybrid receptor also were similar at both ages. Overall, the results suggest that insulin/IGF-I hybrid receptor abundance and binding affinity do not contribute to the developmental decline in the activation of the insulin signaling pathway.

KEY WORDS: • neonate • insulin signaling • protein synthesis • muscle • growth

The insulin signaling cascade is initiated by insulin on binding to its receptor (1). This leads to activation of the insulin receptor tyrosine kinase and subsequent phosphorylation of several cytosolic substrates, primarily the insulin receptor substrate (IRS)3 proteins (2,3). IRS proteins function as "docking proteins," transmitting insulin signals to several proteins that contain Src-homology 2 (SH2) domains (4), including phosphatidylinositol (PI) 3-kinase, which triggers the downstream signaling pathway to insulin-stimulated biological responses such as glucose and amino acid transport, glycogen synthesis and protein synthesis (5).

Several studies indicate that early steps of the insulin signaling pathway play an important role in the regulation of protein synthesis (6–8). Our in vivo studies in neonatal pigs suggest that the feeding-induced stimulation of skeletal muscle protein synthesis can be completely reproduced by the infusion of insulin, even when glucose and amino acids are maintained at fasting levels (9,10). This response to insulin decreases with development, in parallel with the developmental decline in the response to feeding (11). This suggests that the developmental decline in the response to feeding reflects a change in insulin-mediated signals that stimulate translation initiation (12–14).

Our recent studies in muscle of suckling pigs showed that there is a developmental decrease in insulin receptor (IR) activation, which is paralleled by the developmental decrease in muscle protein synthesis (13). The enhanced insulin receptor activation in skeletal muscle of 7- compared with 26-d-old pigs is due in part to a higher receptor number and to enhanced tyrosine phosphorylation of the insulin receptor. This developmental decline in insulin receptor activation is transduced to downstream signaling components including IRS-1, PI 3-kinase, protein kinase B, 70-kDa ribosomal protein S6 kinase and the eukaryotic initiation factor repressor protein, 4E-BPI (12,14). Furthermore, the higher IR activation in muscle of the neonate is associated with reduced activity of protein tyrosine phosphatase-1B (PTP-1B), which functions to dephosphorylate the activated IR (15). Nonetheless, the signaling components that regulate the enhanced activation of the insulin receptor in skeletal muscle of the neonate are not completely known.

In muscle and other tissues that express both IR and insulin-like growth factor-I receptor (IGF-IR), hybrid receptors, composed of an insulin receptor {alpha}ß-heterodimer and an IGF-I receptor {alpha}ß-heterodimer, can be formed (16,17). Although the molecular mechanism of hybrid receptor formation is not known, functional analysis indicates that insulin/IGF-I hybrid receptors function more like IGF-I receptors with respect to a higher affinity to IGF-I than to insulin and to receptor autophosphorylation (18,19). For that reason, an increased proportion of hybrid receptors will reduce insulin binding, resulting in compromised insulin sensitivity in tissues expressing both receptors (20). Indeed, enhanced hybrid receptor abundance has been reported in insulin-resistant states (20–22). In the current study, we tested the hypothesis that in muscle of suckling pigs, insulin/IGF-I hybrid receptor abundance and binding affinity increase with development, consistent with our previous report (13) on the developmental decline in the activation of the insulin signaling pathway.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
Animals.

Crossbred (Landrace x Yorkshire x Duroc x Hampshire) pregnant sows (Agriculture Headquarters, Texas Department of Criminal Justice, Huntsville, TX) were housed in lactation crates in individual, environmentally controlled rooms 2 wk before farrowing. Sows (n = 2) were fed a commercial diet (5084, PMI Feeds, Richmond, IN) and had free access to water. After farrowing, piglets remained with the sow and were not given supplemental creep feed. Piglets were studied at 7 and 26 d of age; body weight (2.62 ± 0.12 and 9.71 ± 0.77 kg, respectively) was similar to that of artificially raised piglets (23). Four piglets were used in each age group. Pigs were fed after overnight food deprivation via two gavage administrations of 30 mL/kg body weight of porcine mature milk (University of Nebraska, Lincoln, NE) at 60-min intervals. Pigs were killed 30 min after they were last fed; samples of longissimus dorsi muscle and liver were rinsed in ice-cold saline and rapidly frozen. The protocol was approved by the Animal Care and Use Committee of Baylor College of Medicine and was conducted in accordance with the NRC guidelines (24).

Materials.

BioMag goat anti-mouse IgG and goat anti-rabbit IgG magnetic beads were obtained from Polysciences (Warrington, PA), and the magnetic sample rack was from Promega (Madison, WI). Reagents for SDS-PAGE were from Bio-Rad Laboratories (Richmond, CA). The protein assay kit was purchased from Pierce (Rockford, IL). Anti-human insulin receptor antibody (SC-711) and anti-human IGF-I receptor antibody (SC-9038) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). The enhanced chemiluminescence Western blotting detection kit (ECL-Plus) was obtained from Amersham (Arlington Heights, IL). 125I-insulin and 125I-IGF-1 were purchased from Amersham Biosciences (Piscataway, NJ). Other chemicals and reagents were from Sigma Chemical (St. Louis, MO).

Preparation of tissue extracts.

Samples for immunoblotting were prepared by a previously described method (13). Briefly, samples of frozen muscle were pulverized in liquid nitrogen and homogenized in ice-cold homogenization buffer. The homogenate was incubated for 45 min at 4°C with gentle mixing and then centrifuged at 35,000 x g for 1 h at 4°C. The supernatant was collected and an aliquot was assayed for protein concentration using the bicinchoninic acid assay (Pierce).

Immunoprecipitation.

To determine IR, IGF-I and IR/IGF-I hybrid receptor abundance, protein samples from tissue extract preparations were immunoprecipitated with anti-IR or anti-IGF-IR antibody. The immunoprecipitation procedure was conducted according to Suryawan et al. (13). Briefly, equal amounts of protein (500 µg protein in 500 µL buffer) were incubated by gentle rocking overnight at 4°C with 20 µL of primary antibody (IR or IGF-IR antibody). The next day, 500 µL of secondary antibody (goat anti-rabbit IgG linked to magnetic beads) was added. After 1 h incubation at 4°C, the samples were washed three times in low salt buffer using a magnetic sample rack, and resuspended in 500 µL of low salt buffer containing 10 g/L dry skim milk. Each sample was added to 500 µL of resuspended beads and rocked for at least 1 h at 4°C. The beads were captured using the magnetic rack and washed twice in low salt buffer and once in high salt buffer. The captured beads were resuspended in 100 µL 1X sample buffer, boiled for 5 min and stored at -80°C until electrophoresis.

Western blot analysis.

To measure IR or IGF-IR abundance, equal amounts of IR and IGF-IR immunoprecipitant were subjected to SDS-PAGE (13). The proteins were then transferred to a polyvinylidene difluoride membrane using transfer buffer overnight. The membrane was incubated for 1 h at room temperature in a Tris-buffered saline-Tween 20 solution containing 50 g/L nonfat dried milk. After the blocking step, the membrane was incubated with anti-human IR or IGF-IR antibodies for 1 h followed by incubation with secondary antibody. After several washings, the membranes were developed with an enhanced chemiluminescence detection kit (ECL-Plus, Amersham Pharmacia) before exposure onto Kodak-X-Omat film. The blots were quantified by computerized densitometry (Molecular Dynamics). To measure the hybrid receptor abundance, an equal amount of IR immunoprecipitant was subjected to SDS-PAGE followed by immunoblotting as above, using IGF-I antibody as the primary antibody.

The ligand binding affinity assay.

The binding assay was used according to Federici et al. (20). Microwells (96-well) were coated with 50 µL of anti-IR or anti-IGF-I antibody (both 10 mg/L) by incubation for 16 h at 4°C, then washed three times with binding buffer A containing 50 mmol/L Hepes buffer, pH 7.6, 150 mmol/L NaCl, 1 mL/L Triton X-100, 1g/L bacitracin, 2 mmol/L phenylmethylsulfonyl fluoride, 106 U/L aprotinin and 1 g/L bovine serum albumin. For analysis of insulin binding affinity to its receptor, IGF-I binding affinity to its receptor and IGF-I binding affinity to hybrid receptor, 500-µg tissue samples were extracted and equal amounts of protein were incubated in anti-IR, anti- IGF-I or anti-IGF-I-coated wells in buffer A containing 125I-insulin (60 pmol/L) or 125I-IGF-1 (60 pmol/L) for 16 h at 4°C in the presence or absence of unlabeled insulin or unlabeled IGF-I, respectively. After washing with buffer A to remove the unbound ligand, radioactivity bound to immobilized receptors was collected by adding 20 g/L SDS for 30 min at 24°C and was counted in a gamma counter. Insulin and IGF-I binding data were analyzed by a sigmoidal dose-response model using the PRISM computer program (GraphPad Software, San Diego, CA).

Statistics.

ANOVA (general linear modeling) was used to assess the effect of development. Differences with P-values < 0.05 were considered significant. Animals were the experimental unit. Data are means ± SEM.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
IR abundance in muscle was higher (+73%, P < 0.05) in 7- than in 26-d-old pigs (Fig. 1A). Similarly, IGF-IR abundance was also higher (+56%, P < 0.05) in 7- than in 26-d-old pigs (Fig. 1B). Hybrid receptor abundance was higher (+92%; P < 0.05) in muscle of 7- than 26-d-old pigs (Fig. 1C). However, the two age groups did not differ in their relative proportions of both hybrid receptor to IR and hybrid receptor to IGF-IR (Fig. 2).



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  		FIGURE 1 Assessment of insulin (panel A), IGF-I (panel B) and hybrid (panel C) receptor abundance in skeletal muscle of 7- and 26-d-old pigs. The immunoblots shown are representative of those obtained in four similar experiments. Densitometry data are means ± SEM, n = 4. *Different from 7 d, P < 0.05.

 


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  		FIGURE 2 Assessment of the relative proportion of hybrid receptor to IR and hybrid receptor to IGF-I-R in skeletal muscle of 7- and 26-d-old pigs. Values are means ± SEM, n = 4.

 
Because we did not observe any age-related differences in the abundance of hybrid receptors relative to IR and IGF-IR abundance, we determined the insulin and IGF-I binding affinity to their respective receptors, and the binding affinity of IGF-I to the hybrid receptors, in skeletal muscle of suckling pigs. At concentrations ranging from 0.01 to 100 nmol/L, insulin inhibited saturable binding of 125I-insulin (Fig. 3A). The dose that half maximally displaced 125I-insulin from its receptor (ED50), a measure of binding affinity, was similar in both age groups (ED50 = 0.62 ± 0.07 and 0.55 ± 0.06 nmol/L, respectively, in 7- and 26-d-old pigs). Similarly, 125I-IGF-I binding to its receptor was inhibited by nonradioactive IGF-I (Fig. 3B). IGF-I receptor binding affinity was similar in both age groups (ED50 = 0.60 ± 0.07 and 0.67 ± 0.1 nmol/L, respectively, in 7- and 26-d-old pigs). Furthermore, IGF-I effectively inhibited saturable binding of 125I-IGF-I to hybrid receptors (Fig. 3C). The receptor binding affinity also did not differ in the two age groups (ED50 = 0.60 ± 0.06 and 0.64 ± 0.1 nmol/L in 7- and 26-d-old pigs, respectively).



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  		FIGURE 3 Assessment of insulin (panel A), IGF-I (panel B) and hybrid (panel C) receptor binding affinities in skeletal muscle of 7- and 26-d-old pigs. Percentages of maximum binding are means ± SEM, n = 4.

 
Because the two age groups did not differ in the binding affinities of insulin and IGF-I to three receptors, we wanted to verify the specific binding of ligands to their respective receptors. Increasing concentrations of competing nonradiolabeled IGF-I were used in an insulin binding competitive inhibition experiment, and increasing concentrations of competing nonradiolabeled insulin were used in an IGF-I binding competitive inhibition experiment (Fig. 4). IGF-I was ineffective in displacing insulin from its receptor, even at concentrations as high as 100 nmol/L (Fig. 4A). Similarly, insulin was not effective in inhibiting saturable 125I-IGF-I binding either to IGF-1R or to hybrid receptors (Fig. 4B, C).



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  		FIGURE 4 Assessment of ligand binding to the receptors in skeletal muscle of 7- d-old pigs. Specificity of 125I-insulin binding to immunoabsorbed insulin receptor (panel A), immunoabsorbed IGF-I receptor (panel B) and immunoabsorbed hybrid receptor (panel C). Percentages of maximum binding are means ± SEM, n = 4. *Significant difference between ligands, P < 0.05. #Significant difference between ligands, P < 0.001.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
The diverse biological effects of insulin are initiated by the binding of insulin to its cell surface tyrosine kinase receptors (25). This action induces autophosphorylation of the receptor on tyrosine residues and stimulates its tyrosine kinase activity toward downstream intracellular substrates, leading to stimulation of insulin-induced metabolism, including protein synthesis (8,25). The tyrosine kinase activity of the insulin receptor, which plays a crucial role in the transmission of the signal, is two-fold higher in muscle of 7- than in 26-d-old pigs (13). This developmental decline in insulin receptor activation parallels the developmental change in both the feeding and insulin-induced stimulation of muscle protein synthesis (9–11). To elucidate the molecular mechanism of the enhanced IR activation in muscle of suckling pigs, in the current study we examined the abundance of insulin/IGF-I hybrid receptors that have been shown to affect insulin sensitivity (21,22).

Because the insulin/IGF-I hybrid receptor abundance is tightly related to IR and IGF-IR abundance, we first determined IR and IGF-IR abundance. IR abundance and IGF-IR abundance were ~75 and >50% higher, respectively, in skeletal muscle of 7- than in 26-d-old pigs. The current studies are consistent with other studies showing that insulin receptor abundance in muscle is higher in suckling than in adult rats and dogs (26,27). However, in those studies, unlike the current study, age-related changes in IR abundance were compounded by changes in diet composition. Furthermore, in pig skeletal muscle, IGF-IR mRNA levels decrease with advancing age (28).

Accumulated evidence indicates that there are important differences in function between IR and IGF-IR, i.e., the IR appears to be a vital mediator of metabolic responses, whereas IGF-IR is involved primarily in the control of growth, development and differentiation (29). Moreover, despite genetic evidence showing that IGF-IR is generally a growth promoter, whereas IR is a metabolic regulator (30), recent in vivo studies indicate that IGF-I can function like insulin as well, i.e., IGF-I stimulates glucose transport in human skeletal muscle (31), and IGF-I infusion can reproduce the insulin-induced stimulation of skeletal muscle protein synthesis in suckling pigs (32). Hence, our results indicate that the enhanced IR and/or IGF-IR abundance in suckling muscle may contribute to the higher growth rate of skeletal muscle during early postnatal development.

To examine other factors that may influence insulin sensitivity in muscle of suckling pigs, we determined the abundance and proportion of insulin/IGF-I hybrid receptors. The results indicate that the insulin/IGF-I hybrid receptor abundance is nearly two-fold higher in muscle of 7- than in 26-d-old pigs. However, the relative proportion of hybrid receptors to both IR and IGF-IR was similar at both ages. To the best of our knowledge, this is the first study to examine the developmental changes in the abundance and relative proportion of insulin/IGF-I hybrid receptors. Accumulated evidence indicates that the hybrid receptor in muscle of obese and type 2 diabetic individuals is positively correlated with insulin resistance (22,33). Therefore, the lack of developmental changes in hybrid receptor abundance relative to IR and IGF-IR abundance in skeletal muscle of the neonate indicates that other mechanisms may be responsible for the insulin hypersensitivity of the neonate. Because the response of muscle protein synthesis to insulin decreases profoundly between 7 and 26 d of age (9), these results further suggest that insulin/IGF-I hybrid receptors do not play an important role in modulating the developmental changes in the insulin responsiveness of muscle protein synthesis in the neonate.

Because we did not observe differences between the age groups in the relative proportion of hybrid receptors to IR and IGF-IR and because insulin sensitivity is affected by insulin receptor binding affinity as well as receptor number (34), we determined insulin and IGF-I binding affinities to their receptors and IGF-I binding affinity to the hybrid receptor. Receptor binding affinity, estimated as the concentration of unlabeled insulin or IGF-I required to inhibit 50% of maximum 125I-insulin or 125I-IGF-I binding to immobilized insulin, IGF-I and insulin/IGF-I hybrid receptors (EC50), did not differ at the two ages. Similar findings, that insulin and IGF-I binding affinities to their receptors are unaffected by development, were reported in studies involving rats (26). However, to the best of our knowledge, this study was the first to examine the effect of development on IGF-I binding affinity to hybrid receptor. From these results, we conclude that the insulin receptor number, but not the insulin receptor or hybrid receptor binding affinities, likely contributes to the enhanced insulin sensitivity in muscle of suckling pigs.

We showed previously that insulin receptor activation, as measured by ß-IR phosphorylation per IR abundance, is higher in muscle of 7- than in 26-d-old pigs (13). Thus, the enhanced insulin sensitivity in muscle of 7-d-old pigs was not due solely to the elevated IR abundance, but to other regulators as well. Recently, we found that the activity of PTP-1B, a phosphotyrosine phosphatase that attenuates insulin signaling by catalyzing the dephosphorylation of the insulin receptor, increases with development (15). This suggests that the reduced PTP-1B activation in muscle of suckling pigs also contributes to the enhanced insulin sensitivity of skeletal muscle in young pigs.

In conclusion, the current study tested the hypothesis that insulin/IGF-I hybrid receptor abundance and binding affinity increase with development, consistent with the developmental decline in the activation of the insulin signaling pathway. However, the data do not support our hypothesis, but instead show that hybrid receptor abundance decreases with development. Moreover, when expressed in relative proportion to IR or IGF-I-R, hybrid receptor abundance does not change with development. Hybrid receptor binding affinity also does not change with development. This suggests that insulin/IGF-I hybrid receptors do not contribute to the enhanced insulin sensitivity of skeletal muscle in suckling pigs and implies that other factors play a crucial role in the regulation of insulin receptor activation. Because a better understanding of the molecular mechanisms that regulate the activation of signal transduction pathways that modulate insulin-stimulated muscle protein synthesis is important to the development of improved strategies to promote animal growth, further search for these unknown factors is warranted.


   ACKNOWLEDGMENTS
 
We thank M. Fiorotto and H. Mersmann for helpful discussion, W. Liu for laboratory assistance, J. Stubblefield for care of animals, L. Loddeke for editorial review and J. Croom for secretarial assistance.


   FOOTNOTES
 
1 This work is a publication of the United States Department of Agriculture/Agricultural Research Service (USDA/ARS) Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. Back

2 Funded in part by National Institute of Arthritis and Musculoskeletal and Skin Diseases Institute Grant R01-AR-44474 (T.A.D.) and USDA/ARS CRIS 6250–510000-033 (T.A.D.). Back

4 Abbreviations used: IGF-I, insulin-like growth factor-1; IGF-IR, insulin-like growth factor-1 receptor; IR, insulin receptor; IRS, insulin receptor substrate; PI 3-kinase, phosphatidylinositol 3-kinase; PTP-1B, protein tyrosine phosphatase-1B; SH2, Src-homology 2. Back

Manuscript received 22 January 2003. Initial review completed 16 April 2003. Revision accepted 20 June 2003.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

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