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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2911-2915
Copyright © 1998 by The Endocrine Society

Original Studies

Increased Abundance of Insulin/Insulin-Like Growth Factor-I Hybrid Receptors in Skeletal Muscle of Obese Subjects Is Correlated with In Vivo Insulin Sensitivity1

Massimo Federici, Ottavia Porzio, Davide Lauro, Patrizia Borboni, Barbara Giovannone, Luigi Zucaro, Marta Letizia Hribal and Giorgio Sesti

Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome- "Tor Vergata," Rome 00173,Italy

Address all correspondence and requests for reprints to: Giorgio Sesti, M.D., Dipartimento di Medicina Interna, Università di Roma-"Tor Vergata", Via Orazio Raimondo, 00173 Roma, Italy. E-mail: sesti{at}uniroma2.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 ± 0.20 and 2.6 ± 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 ± 0.20 and 0.86 ± 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 ± 0.14 and 0.44 ± 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ONE OF the most prevalent endocrine abnormalities observed in obesity is increased secretion of insulin, considered to be mainly a compensatory response to peripheral insulin resistance. Insulin initiates its action on target tissues by binding to cell surface receptors, thus activating the intrinsic tyrosine kinase that leads to phosphorylation of endogenous substrates (1). The insulin receptor is a heterotetrameric glycoprotein that shares considerable homology of structure and function with the type 1 insulin-like growth factor (IGF) receptor (2, 3, 4). Both receptors are composed of two extracellular {alpha}-subunits that contain the ligand binding site(s) and two transmembrane ß-subunits that possess the tyrosine kinase activity in their cytoplasmic domain. Hybrid receptors composed of an insulin receptor {alpha}ß-hemireceptor and a type 1 IGF receptor {alpha}ß-hemireceptor are formed in tissues coexpressing both molecules, as a consequence of the close homology between the two receptors (5, 6, 7, 8, 9). Previous studies have demonstrated that hybrid receptors bind IGF-I, but not insulin, with high affinity (10, 11, 12). Moreover, hybrid receptors function as type 1 IGF receptors, rather than typical insulin receptors, with respect to receptor autophosphorylation as well as to hormone internalization and degradation (10, 13). We recently reported that, in noninsulin-dependent diabetes melitus (NIDDM) patients, abundance of hybrid receptors is increased in target tissues of insulin action compared with normal subjects and is correlated with a decrease in in vivo insulin sensitivity (14). The question of whether the observed alterations are a defect specifically associated with NIDDM or represent an abnormality associated with other states of insulin resistance such as obesity is still unsettled. To address this issue, we applied a previously validated microwell-based immunoassay to measure abundance of hybrid receptors in skeletal muscle from normal and obese subjects and correlated hybrid receptors abundance with in vivo insulin action.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Materials

Human 125I-A14-monoiodoinsulin (290–320 µCi/µg) and 125I-IGF-I (280–310 µCi/µg) were purchased from Amersham Life Science (Buckinghamshire, UK). Recombinant human insulin was purchased from Sigma Chemicals Co. (St. Louis, MO), and recombinant human IGF-I was purchased from Boehringer Mannheim (Mannheim, Germany). The following antibodies were employed to detect receptors in microwell immunoassay and immunoprecipitation: {alpha}-IGF-IR-PA, a rabbit polyclonal antibody against the type 1 IGF receptor {alpha}-subunit that does not cross-react with the insulin receptor (9, 14), PA-13, a rabbit polyclonal antibody against the insulin receptor {alpha}-subunit that does not cross-react with the type 1 IGF receptor (15), and MA-20, a mouse monoclonal antibody specific for the insulin receptor {alpha}-subunit (16).IGF-I levels were measured by means of IGF-I IRMA kit from Nichols Institute Diagnostics (San Juan Capistrano, CA). All other chemicals were from Sigma Chemicals Co. (St. Louis, MO).

Subjects

Samples of rectus abdominus skeletal muscle were obtained during elective abdominal surgery from eight normal and eight obese subjects admitted to the hospital for cholecystectomy or total hysterectomy. Tissue samples were cleaned of all connective tissue and blood, immediately frozen in liquid nitrogen, and stored at -70 C until use. Clinical and biochemical data of the subjects are shown in Table 1Go. The control subjects had normal blood pressure and no family history of diabetes. No subject had taken any medication known to alter insulin or glucose metabolism. Insulin sensitivity was determined in six of the eight normal subjects and in six of the eight obese subjects by iv insulin tolerance test (ITT) (14, 17). After an overnight fast, a single bolus of regular insulin (0.1 U/kg body weight) was injected iv into an antecubital vein. Blood samples were collected at 15 and 5 min before and at 3, 6, 9, 12, 15, 20, and 30 min after insulin injection. The constant rate for plasma glucose disappereance (Kitt) was calculated according to the formula 0.693/t1/2. The plasma glucose t1/2 was calculated from the slope of least square analysis of the plasma glucose concentrations from 3–15 min after iv insulin injection, when the plasma glucose concentration declined linearly. Consent was obtained from all subjects after the nature of the procedure was explained. The study was performed in accordance with the principles of the Declaration of Helsinki.


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  		Table 1. Clinical characteristics of study subjects

 
Tissue solubilization

Skeletal muscle samples were solubilized in 50 mM Hepes buffer, pH 7.6, containing 150 mM NaCl, 1% Triton X-100, 1 mg/mL bacitracin, 2 mM PMSF, 1000 units/mL aprotinin for 60 min at 4 C. Insoluble material was removed by centrifugation at 100.000 x g for 60 min at 4 C and soluble fractions were diluted to 0.2% Triton X-100 and immediately assayed. Protein content of tissue extracts was determined by the Bradford dye binding method.

Microwell immunoassay

Ninety-six-well microwells were coated with {alpha}-IGF-IR-PA or MA-20 antibody in 20 mM NaHCO3, pH 9.6, and incubated for 16 h at 4 C (9, 14). The wells were then washed with buffer A containing 50 mM Hepes buffer, pH 7.6, 150 mM NaCl, 0.1% Triton X-100, 1 mg/mL bacitracin, 2 mM PMSF, 1000 units/mL aprotinin, 0.1% BSA, and incubated with skeletal muscle extracts (500 µg) for 16 h at 4 C. The wells were washed three times with buffer A, and immunoadsorbed receptors were incubated with 125I-IGF-I (60 pM) or 125I-insulin (60 pM) for 16 h at 4 C in the presence or absence of multiple concentrations of unlabeled ligands. The wells were washed three times, and radioactivity bound to immunoadsorbed receptors was collected by adding 2% SDS for 30 min at 24 C to the wells and counted.

Western blotting

Equal amounts of tissue extract (500 µg) were incubated for 16 h at 4 C with 1 µg of either {alpha}-IGF-IR-PA or PA-13 antibody, each bound to Protein A-Sepharose. The immunoprecipitates were subjected to SDS-PAGE under reducing conditions. Proteins (500 µg/lane) resolved by SDS-PAGE were electrophoretically transferred to nitrocellulose filters. The filters were then incubated for 16 h at 4 C with anti-IGF-IR {alpha}-subunit (N-20) or anti-IR {alpha}-subunit antibodies (N-20) (Santa Cruz Laboratories). After extensive washings, the filters were blotted with a secondary horseradish peroxidase-conjugated goat anti-rabbit antibody, and bound antibodies were visualized by enhanced chemiluminescence (Amersham Life Science, Buckinghamshire, UK). The intensity of the bands was quantified by imaging densitometer Bio-Rad GS-670 (Hercules, CA).

Statistical analysis

Unpaired Student’s t-test was used to compare mean values. Linear correlations between variables were tested by calculating Pearson’s correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Insulin and IGF-I binding studies in skeletal muscle of obese and normal subjects

Maximal specific 125I-insulin binding to MA-20-immunoadsorbed receptors was significantly higher in muscle from normal subjects than obese subjects (B/T = 2.60 ± 0.30 and 1.80 ± 0.20; P < 0.03, respectively) (Fig. 1aGo). Receptor binding affinity, estimated as the concentration of unlabeled insulin for half-maximal inhibition of 125I-insulin binding to MA-20-immunoadsorbed receptors (ED50), did not differ in the two groups of subjects (ED50 = 0.55 ± 0.28 and 0.72 ± 0.16 nM insulin, for normal and obese subjects, respectively). Plasma insulin levels were higher in obese subjects than in normal subjects and were negatively correlated with maximal specific insulin binding (r = -0.60; P < 0.01).



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  		Figure 1. Quantitation of insulin and type 1 IGF receptors in skeletal muscle of control and obese subjects. Skeletal muscle extracts from control and obese subjects were added to microwell coated with MA-20 or {alpha}-IGF-IR-PA antibody, and immunoadsorbed receptors were then incubated with 125I-IGF-I (60 pM) or 125I-insulin (60 pM) for 16 h at 4 C in the presence or absence of unlabeled ligands. Insulin receptors were estimated as maximal specific 125I-insulin binding to MA-20-immunoadsorbed receptors and expressed as B/T (A); type 1 IGF receptors were estimated as maximal specific 125I-IGF-I to {alpha}-IGF-IR-PA-immunoadsorbed receptors and expressed as B/T (B). Results are expressed as mean ± SE for eight subjects in each group.

 
Maximal specific 125I-IGF-I binding to {alpha}-IGF-IR-PA-immunoadsorbed receptors was significantly higher in muscle from obese subjects compared with normal subjects (B/T = 1.9 ± 0.20 and 0.86 ± 0.10; P < 0.0001, respectively) (Fig. 1bGo). Receptor affinity for IGF-I binding was similar in the two groups of subjects (ED50 = 0.60 ± 0.23 and 0.61 ± 0.15 nM IGF-I, for normal and obese subjects, respectively). Plasma IGF-I levels of obese subjects were negatively correlated with maximal specific IGF-I binding (r = -0.69; P < 0.003).

Quantitation of insulin/IGF-I hybrid receptors in skeletal muscle of obese and normal subjects

Maximal specific 125I-IGF-I binding to immunoadsorbed hybrid receptors was significantly higher in muscle from obese subjects than normal subjects (B/T = 1.21 ± 0.14 and 0.44 ± 0.10; P < 0.0003, respectively) (Fig. 2Go). Hybrid receptor affinity for IGF-I binding was similar in the two groups of subjects (ED50 = 0.57 ± 0.19 and 0.50 ± 0.25 nM IGF-I, for normal and obese subjects, respectively). Abundance of hybrid receptors was negatively correlated with maximal specific insulin binding (r = -0.60; P < 0.01) and positively correlated with maximal IGF-I binding (r = 0.92; P < 0.0001). Quantitation of relative abundance of hybrid receptors was also determined by immunoblotting with anti-{alpha}-IGF-IR N-20 antibody, after precipitation with {alpha}-IGF-IR-PA or PA-13 antibody. Figure 3Go (top) is a representative Western blot showing that {alpha}-IGF-IR-PA and PA-13 antibody precipitate a single molecular species of approximately 130 kDa, corresponding to the {alpha} subunit of the IGF receptor. Both type 1 IGF receptors (lanes 1 and 3) and hybrid receptors (lanes 2 and 4) were significantly increased in skeletal muscle from obese subjects. The bar graph summarizes the densitometric data from all eight control and eight obese subjects (Fig. 3Go, bottom). Type 1 IGF receptor protein content was 1.3 higher in obese than normal subjects (P < 0.03), and hybrid receptor content was 1.9 higher in obese than normal subjects (P < 0.01). These results were consistent with those obtained with the micro-well-based immunoassay.



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  		Figure 2. Quantitation of insulin/IGF-I hybrid receptors in skeletal muscle of control and obese subjects. Muscle extracts from control and obese subjects were added to microwell coated with MA-20, and immunoadsorbed receptors were then incubated with 125I-IGF-I (60 pM) in the presence or absence of unlabeled IGF-I (100 nM). Hybrid receptors were estimated as maximal specific IGF-I binding to MA-20-immobilized receptors and expressed as B/T. Results are expressed as mean ± SE for eight subjects in each group.

 


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  		Figure 3. Quantitation of type 1 IGF receptor and hybrid receptor protein content by Western blotting. Equal amount of skeletal muscle extracts (500 µg) from control (lanes 1 and 2) and obese subjects (lanes 3 and 4) were immunoprecipitated with {alpha}-IGF-IR-PA or PA-13 antibody, resolved by SDS-PAGE, and Western immunoblotted with IGF-IR {alpha}-subunit antibody (N-20). The upper panel shows a representative experiment. The bar graph in the lower panel summarizes the densitometric data from eight control and eight obese subjects. Data are presented as mean ± SE.

 
The fraction of insulin receptors assembled as hybrids was determined by immunoblotting. A representative Western blot is shown in Fig. 4Go (top), in which {alpha}-IGF-IR-PA and PA-13 antibody precipitate a single molecular species of approximately 130 kDa, corresponding to the {alpha} subunit of the insulin receptor. Insulin receptors were decreased (lanes 1 and 3), whereas hybrid receptors (lanes 2 and 4) were increased in obese subjects as compared with control subjects. The bar graph summarizes the densitometric data from all eight control and eight obese subjects (Fig. 4Go, bottom). Insulin receptor protein content was 1.25 lower in obese than normal subjects (P < 0.04), and hybrid receptor content was 1.5-fold higher in obese than normal subjects (P < 0.02). The proportion of insulin receptors assembled as hybrids was also estimated as the ratio of insulin receptors precipitated by {alpha}-IGF-IR-PA vs. total insulin receptors precipitated by PA-13 antibody. The percentage of insulin receptors assembled as hybrid receptors was significantly higher in obese subjects than in control subjects (35 ± 4 vs. 17 ± 3%, respectively, P < 0.0001). Abundance of hybrid receptors was positively correlated with both fasting plasma insulin levels (r = 0.70; P < 0.002) (Fig. 5aGo) and body mass index (BMI) (r = 0.71; P < 0.0019) (Fig. 5bGo), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67, P < 0.016) (Fig. 5cGo).



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  		Figure 4. Quantitation of type 1 IGF receptor and hybrid receptor protein content by Western blotting. Equal amount of skeletal muscle extracts (500 µg) from control (lanes 1 and 2) and obese subjects (lanes 3 and 4) were immunoprecipitated with PA-13 or {alpha}-IGF-IR-PA antibody, resolved by SDS-PAGE, and Western immunoblotted with IR {alpha}-subunit antibody (N-20). The upper panel shows a representative experiment. The bar graph in the lower panel summarizes the densitometric data from eight control and eight obese subjects. Data are presented as mean ± SE.

 


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  		Figure 5. Abundance of hybrid receptors expressed as B/T in skeletal muscle from control ({circ}) and obese (•) subjects in relation to fasting insulin levels (A), BMI (B), and in vivo insulin sensitivity (Kitt) (C).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although it is well-known that insulin resistance is a salient feature of several conditions such as NIDDM and obesity, the molecular mechanisms underlying this abnormality remain unclear. Recently, we demonstrated that abundance of insulin/IGF-I hybrid receptors is increased in placenta of insulin resistant women with gestational hypertension (18) and in skeletal muscle of NIDDM subjects (14) as compared with that of control subjects and is negatively correlated with in vivo insulin action. These findings suggest that increased abundance of hybrid receptors may represent a molecular defect associated with states of insulin resistance. The present study was undertaken to determine whether hybrid receptors abundance is related to obesity, a common cause of acquired insulin resistance. Quantitation of hybrid receptors revealed that their abundance was significantly increased in skeletal muscle of obese subjects compared with that of control subjects. Interestingly, increased abundance of hybrid receptors was positively correlated with BMI and negatively correlated with in vivo insulin sensitivity measured by ITT. These results raise the possibility that changes in abundance of hybrid receptors are related to the insulin resistance of certain obese subjects.

Factors regulating hybrid receptor formation in vivo are unknown. Previous studies with transfected cells coexpressing both insulin and type 1 IGF receptors (12, 13) and with mammalian tissues (9) have suggested that hybrid receptors are formed by a process of random assembly in which hybrids and classical receptors are formed with equal efficiency and in proportions determined by the molar ratio of the insulin and type 1 IGF receptor content. In several hyperinsulinemic insulin resistant states, including obesity, insulin receptor content is decreased as a consequence of elevated circulating insulin levels. We found that plasma insulin levels were significantly increased in obese subjects compared with control subjects and correlated with decreased insulin receptor content and increased hybrid receptors abundance. These results suggest that downregulation of insulin receptors as a consequence of hyperinsulinemia may lead to the formation of an increased proportion of hybrid receptors.

There is evidence that in subjects with reduced serum IGF-I levels, such as patients with isolated GH deficiency or Laron-type dwarfism, expression of type 1 IGF receptor is increased as a consequence of increased promoter activity of the IGF receptor gene (19, 20). Several abnormalities in GH-IGF-I axis have been described in obesity, including low spontaneous 24-h GH secretion, decreased GH release after stimulation, and low plasma IGF-I levels (21, 22, 23). In the present study, we found that plasma IGF-I levels were reduced in obese subjects and correlated with both increased type 1 IGF receptor content and increased hybrid receptor abundance. These results indicate that upregulation of type 1 IGF receptors due to changes in plasma IGF-I levels may result in modifications in hybrid receptor abundance. Taken together, the data suggest that insulin and IGF-I may play a major role in hybrid receptor formation by regulating expression of their own receptors. However, it is not possible to rule out that other possibilities may account for the present results. For example, alterations in hybrid receptor expression may represent a primary defect rather than a secondary event due to changes in plasma insulin or IGF-I levels. Thus, hyperinsulinemia might be compensatory for the defect in hybrids assembly causing sequestration of insulin receptors in a less responsive form. Alternatively, increased abundance of hybrid receptors, which bind IGF-I with higher affinity than insulin, may represent an adapting mechanism by which insulin-sensitive tissues protect themselves from hyperinsulinemia, which has some other underlying causes.

Although we did not assess the in vivo sensitivity to IGF-I in obese subjects, there may be enhanced sensitivity to IGF-I because of upregulation of both type 1 IGF receptor and hybrid receptor. In this respect, it is interesting to note that short-term administration of recombinant human IGF-I to insulin resistant obese patients with NIDDM was able to overcome insulin resistance and improve metabolic control (24).

In conclusion, we found that hybrid receptor abundance is increased in skeletal muscle of obese subjects and is significantly related to BMI and in vivo insulin sensitivity. In view of these and previous results (15), we hypothesize that changes in expression of hybrid receptors, whose abundance is negatively correlated with in vivo insulin sensitivity, may represent a molecular defect common to insulin resistant states including obesity and NIDDM.


   Acknowledgments
 
We are grateful to Professor Renato Lauro (Rome, Italy) for helpful discussions.


   Footnotes
 
1 This work was supported in part by grants from BIOMED 2 EC-Programme (ERB BMH4-CT96–0751, G.S.) and Programma Nazionale di Ricerca sui Farmaci (seconda fase)-Ministero dell’Università e della Ricerca Scientifica e Tecnologica. Back

Received February 17, 1998.

Accepted May 13, 1998.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals