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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 542-549
Copyright © 1998 by The Endocrine Society

Original Studies

Long-Term Effect of Recombinant Human Insulin-Like Growth Factor I on Metabolic and Growth Control in a Patient with Leprechaunism

Jun Nakae, Mikiko Kato, Mari Murashita, Nozomi Shinohara, Toshihiro Tajima and Kenji Fujieda

Department of Pediatrics, Hokkaido University School of Medicine, Sapporo 060, Japan

Address all correspondence and requests for reprints to: Dr. Kenji Fujieda, Department of Pediatrics, Hokkaido University School of Medicine, Sapporo 060, Japan. E-mail: Ken-fuji{at}med.hokudai.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient’s fibroblasts showed normal binding of IGF-I, normal phosphorylation of the ß-subunit of the IGF-I receptor, and normal [3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increase the serum total IGF-I level, we administered rhIGF-I with combination therapy of intermittent and continuous sc injection. This sustained the serum total IGF-I level, but not the serum IGFBP-3 level, within the normal range. The patient was treated with combination therapy of rhIGF-I by both sc injection and continuous sc infusion for 6 yr and 10 months. Administration of rhIGF-I at total daily dose of 1.6 mg/kg maintained her growth rate and hemoglobin A1c level nearly within the normal range. These findings suggest 1) that this leprechaun patient has an IGF-Ideficient state and partial GH resistance, as reflected by impaired production of IGF-I and IGFBP-3; 2) that rhIGF-I treatment works effectively for preventing postnatal growth retardation and normalizing glucose metabolism in patients with extreme insulin resistance; 3) that this treatment requires relatively higher dose of rhIGF-I; and 4) that treatment appears to be safe and devoid of adverse effects.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INSULIN binds the {alpha}-subunit of the insulin receptor (IR), phosphorylates the ß-subunit and intracellular substrates, and triggers biological actions. Insulin exerts both metabolic effect and mitogenic effect on its target cells (1, 2, 3, 4). Thus, defects of insulin action in vivo are associated with retarded intrauterine growth and metabolic derangement in humans (5, 6). Indeed, leprechaunism, being the most severe form of insulin resistance, manifests abnormal glucose metabolism and retarded intrauterine and postnatal growth (7).

After the cloning of human IR complementary DNA (1, 2), identification of several mutations of the human IR gene in patients with the genetic form of insulin resistance has provided insight into the structure and function of IR (4). However, an effective therapeutic regimen in patients with severe insulin resistance has not yet been established.

Insulin-like growth factor I (IGF-I), a 70-amino acid polypeptide with extensive structural homology to insulin (48%), exerts its biological effects by binding to IGF-I receptor (IGF-IR), IR, or IGF-IR/IR hybrid receptor on the surface of target cells (8). IGF-I has major insulin-like effects on glucose uptake, glycolysis, and glycogen synthesis in vitro and in vivo (9, 10). Furthermore, it is supposed that IGF-I inhibits insulin secretion from the ß-cells through an IGF-I receptor-mediated pathway (11). Recently, it has been reported that short term treatment with recombinant human IGF-I (rhIGF-I) improved glucose metabolism in patients with the genetic syndrome of insulin resistance (12, 13, 14), and that IGF-I can mimic insulin’s effects on glucose metabolism by acting through its own receptor in mice genetically deficient of IRs (10). However, conflicting results for this therapy have been also reported (15, 16). Furthermore, there are few reports on the long term effects of rhIGF-I on glucose metabolism and growth in a patient with genetic form of severe insulin resistance (17).

In the present study, we have investigated the biological actions of IGF-I in fibroblasts of a leprechaun patient. We have also investigated short- and long-term effects of rhIGF-I administration on glucose metabolism and growth in a leprechaun patient with two mutations of the IR gene (18).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Case history

The patient is a 7-yr- and 4-month-old Japanese girl, the second child of healthy unrelated parents. She was born after a 39-week 1-day gestation as a small for gestational age infant with a birth weight and length of 1552 g and 44 cm, respectively. She had multiple phenotypic anomalies, including low set ears, prominent eyes, decreased sc fat, hirsutism, and clitoromegaly. Since birth she often manifested fasting hypoglycemia with remarkably high immunoreactive insulin levels (IRI; 121.2–488.4 µU/mL). At the age of 6 months, she was admitted to our hospital for evaluation of her abnormal glucose metabolism. On admission, her body length and weight were 61.8 cm (-2.5 SD) and 4595 g (-4.1 SD), respectively. Oral glucose tolerance test and insulin tolerance test proved her to have severe insulin resistance (Table 1GoGo, A and B). Phenotypic and laboratory features were consistent with a diagnosis of leprechaunism. The molecular analysis revealed a 1.3-kilobase deletion between exons 4 and 6 in the maternal allele, which skipped out exon 5 and induced a frame shift and premature stop codon (TAA) after amino acid 360 in exon 6, and a missense mutation that substituted Pro for Leu at amino acid 87 in the paternal allele, which reduced the insulin binding affinity (18).


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  		Table 1A. Oral glucose tolerance test

 

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  		Table 1B. Insulin tolerance test (0.1 U/kg insulin)

 
From 6–18 months of age, she was treated with only sc injection (SI) of rhIGF-I (Fujisawa Pharmaceutical Co., Tokyo, Japan) twice a day at a dose of 0.8 mg/kg·day. Thereafter, she was treated with rhIGF-I in a total daily dose of 1.0–1.6 mg/kg by both SI before each meal and continuous sc infusion (CSI). At the age of 7 yr and 4 months, she was readmitted to Hokkaido University Hospital to assess the effect of the long term treatment with rhIGF-I. On admission, her height and weight were 107.2 cm (-2.7SD) and 16.9 kg, respectively. Bone age was 5.6 yr, as estimated by the Tanner-Whitehouse method (19). The administration of arginine (0.5 g/kg) increased serum GH from 3.3 to 10.4 ng/mL. Nocturnal urinary GH excretion was high (93.0–152.2 ng/g creatinine; age-matched normal female, 3.70–53.84 ng/g creatinine).

Informed consent was obtained from the patient’s parents. This study was approved by the regional committee for medical research ethics. The patient visited our hospital every 3 months, and her height, weight, and serum biochemistries were evaluated. At that time, her drug compliance was determined.

Biological actions of IGF-I in the patient’s fibroblasts

Human forearm skin fibroblasts were obtained from the patient and a female control at 10 months of age. Fibroblasts were maintained in Ham’s F-12 medium (Life Technologies, Grand Island, NY) in a humidified atmosphere containing 5% CO2. To standardize the studies, cells were subcultured by splitting 1:3 every 7–10 days and then used for experiments 2–3 days after reaching confluence.

IGF-I binding assay

Assay was performed as described previously (20, 21). Various concentrations of unlabeled IGF-I (0–10 µg/mL) plus 0.2 ng/mL [125I]IGF-I (11.3 MGq/mg; DuPont-New England Nuclear, Boston, MA) were then added in a final volume of 0.5 mL HEPES binding buffer (22) plus 0.5% BSA. Incubations were performed at 15 C for 2.5 h. Thereafter, cells were solubilized, and radioactivity was estimated with a {gamma}-counter.

IGF-I-stimulated autophosphorylation of the ß-subunit of IGF-IR in fibroblasts

Confluent monolayers of fibroblasts in 10-cm plates were stimulated with or without IGF-I (10-8 nmol/L) for 1 min at 37 C after serum starvation for 16 h and solubilized in lysis buffer (50 mmol/L HEPES, pH 7.4, containing 1% Triton X-100, 4 mmol/L ethylenediamine tetraacetate, 2 mmol/L sodium orthovanadate, 10 mmol/L sodium pyrophosphate, and 100 mmol/L NaF). After clarifying the lysate by centrifugation, the supernatant was immunoprecipitated with anti-IGF-IR monoclonal antibody (Ab-1, Oncogene Science, NY) and protein A-agarose (Life Technologies) overnight at 4 C. The immune complexes were washed and resuspended in Laemmli’s sample buffer (23) containing 80 mmol/L dithiothreitol. The samples were electrophoresed on 7.5% SDS-PAGE and electroblotted to nitrocellulose filter. The filter was immunoblotted with antiphosphotyrosine antibody (Upstate Biotechnology, Lake Placid, NY) followed by chemiluminescence detection with horseradish peroxidase-conjugated antimouse IgG (ECL, Amersham, Arlington Heights, IL).

[3H]Thymidine incorporation in the patient’s fibroblasts

Assays were performed as described previously with minor modifications (24, 25). Confluent monolayers in 24-well plates were maintained for 18 h in Ham’s F-12 medium containing 0.1% FCS. Various concentrations of insulin or IGF-I were then added to the wells for 15 h. [Methyl-3H]thymidine (1.8 µCi/well; 740.0 gigabecquerels/mmol; DuPont-New England Nuclear, Boston, MA) was then added for 2 h at 37 C. The cells were washed with phosphate-buffered saline three times, and cold 5% trichloroacetic acid was added. After 30 min on ice, the cells were washed with phosphate-buffered saline twice, solubilized with 0.2 N NaOH, and counted for radioactivity.

Short-term effects of rhIGF-I on glucose metabolism and IGF and IGF-binding proteins (IGFBPs)

The short-term effect of rhIGF-I was examined after an overnight fast. After basal sampling at 0730 h, the patient received rhIGF-I at a dose of 0.4 mg/kg at 0 min, and blood sampling continued at 15, 30, 60, 90, 120, and 150 min and 3, 4, 6, 12, and 24 h. Serum total IGF-I, IGFBP-3, IRI, and blood glucose levels were measured. Furthermore, we investigated the effects of rhIGF-I at a total daily dose of 1.6 mg/kg by both SC and CSI on the IGF-IGFBP system. Venous blood was drawn before and 2 h after each meal. The total daily dietary calorie intake was 1760 cal. Serum total IGF-I, total IGFBP-1, IGFBP-3, IRI, and blood glucose levels were measured. Serum total IGF-I was measured by immunoradiometric assay, with a lower limit of sensitivity of 0.25 ng/mL and an average intraassay coefficiency of variation of 1.1–3.4% (Daiichi Radioisotope Laboratories, Tokyo, Japan). IRI was measured by RIA, with a lower limit of sensitivity of 2.5 µU/mL and an average intraassay coefficiency of variation of 6% (Pharmacia). IGFBP-3 was measured by RIA, with a lower limit of sensitivity of 0.925 ng/mL and an average intraassay coefficiency of variation of 1.4–4.0% (Daiichi Radioisotope Laboratories). Blood glucose was measured by standard glucose oxidase techniques.

IGF-I generation test

Production of IGF-I in vivo in this patient was investigated as follows. After an overnight fast, rhGH (Sumitomo Pharmaceutical Co., Tokyo, Japan) at a dose of 2.0 IU/kg·day 30 min before breakfast was administered for 3 consecutive days. Venous blood was drawn before each injection every day. As a control, two children with constitutional short stature (6 and 7 yr old, respectively) received rhGH at a dose of 0.2 IU/kg·day for 2 consecutive days. Serum total IGF-I, IGFBP-3, IRI, and blood glucose levels were measured.

Long-term effect of rhIGF-I treatment

We treated the patient with rhIGF-I for 6 yr and 10 months. To evaluate the long-term metabolic effect of rhIGF-I, we assessed hemoglobin A1c (HbA1c), total cholesterol, triglyceride, and free fatty acid levels. Furthermore, to evaluate the effect on physical growth, we assessed the relationship between the annual growth rate and the dosage of rhIGF-I. We also measured IGFBP-3 levels to evaluate the effect on IGFBP-3 production in vivo.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Biological actions of IGF-I in the patient’s fibroblasts

We performed [125I]IGF-I binding assay in the patient’s and normal control fibroblasts. Scatchard analysis revealed that the patient’s fibroblasts had a normal number of IGF-IR with normal binding affinity (Fig 1Go). Because this Scatchard plot was linear, there might be one population of receptor in the patient’s fibroblasts, and these data might exclude the presence of an IGF-IR/IR hybrid receptor. To rule out a dominant negative effect of this mutant IR that substituted Pro for Leu at amino acid 87 (Pro87IR) on endogenous IGF-IR, we assessed IGF-I-stimulated autophosphorylation of the ß-subunit of endogenous IGF-IR in the patient’s fibroblasts. In both the patient’s and normal control fibroblasts, IGF-I induced autophosphorylation of the ß-subunit of endogenous IGF-IR (Fig. 2Go). IGF-I could stimulate thymidine incorporation in the patient’s fibroblasts. Half-maximal stimulation in the patient’s or normal control fibroblasts occurred at 0.8 or 1.1 nmol/L, respectively (data not shown).



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  		Figure 1. Scatchard plot analysis of IGF-I binding to each fibroblast. IGF-I binding to the patient’s (closed circle) or normal female control (open circle) fibroblasts at 10 months of age was measured as described in Materials and Methods.

 


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  		Figure 2. Autophosphorylation of human IGF-I receptor in intact cells. Control or patient’s fibroblasts were incubated in the absence (lanes 1 and 3) or presence (lanes 2 and 4) of IGF-I (10-8 mol/L) at 37 C for 1 min, then solubilized, as described in Materials and Methods. Lanes 1 and 2 indicate the control fibroblasts, and lanes 3 and 4 indicate the patient’s fibroblasts.

 
Short-term effects of rhIGF-I administration on metabolic control and IGF-IGFBPs

The serum total IGF-I level increased to greater than 400 ng/mL 15 min after injection of a single dose of 0.4 mg/kg rhIGF-I. However, the serum IGF-I level rapidly declined to below 100 ng/mL in 3 h. The half-life of total serum IGF-I is estimated to be 90 min (Fig. 3Go). Although blood glucose and IRI were suppressed below 100 mg/dL and 100 µU/mL, respectively, until 150 min, the feeding 150 min after the injection increased both blood glucose and IRI above 200 mg/dL and 1000 µU/mL, respectively (data not shown). The IGFBP-3 level also increased slightly from 0.06 to 0.33 µg/mL, but was below the normal range (Fig. 3Go).



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  		Figure 3. Short-term effect of single dose rhIGF-I administration on IGF-I and IGFBP-3. After basal sampling, the patient received rhIGF-I at the dose of 0.4 mg/kg at 0 min, and blood sampling continued at 15, 30, 60, 90, 120, and 150 min and 3, 4, 6, 12, and 24 h. Serum total IGF-I (closed circle) and IGFBP-3 (open square) levels were measured. Open circles indicate the mean plasma IGF-I level after 0.12 mg/kg IGF-I sc administration in five normal human subjects (53).

 
Furthermore, the administration of rhIGF-I at a dose of 1.6 mg/kg·day raised the serum total IGF-I level to 157.5–585.9 ng/mL (age-matched normal females, 95–437 ng/mL; n = 40). However, this regimen failed to increase the IGFBP-3 level to the normal range, leading to a rise of 0.06–0.36 µg/mL (age-matched normal females, 2.00–4.16 µg/mL; n = 40; Fig. 4aGo). The blood glucose level was still high, but was suppressed below 300 mg/dL (Fig. 4bGo). Furthermore, the IRI level was not suppressed within the normal range, but was suppressed below 1000 µU/mL (Fig. 4bGo). However, the regimen of only SI at a dose of 0.4 mg/kg before each meal could not suppress the blood glucose level below 300 mg/dL and the IRI below 1000 µU/mL 2 h after each meal (data not shown). The serum total IGFBP-1 level was decreased from 224.51 ng/mL before breakfast to 98.45–127.02 ng/mL (Fig. 4bGo). During this regimen, the patient had no hypoglycemic symptoms.



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  		Figure 4. Short-term effect of rhIGF-I administration on IGF-IGFBPs. The patient received rhIGF-I at a total daily dose of 1.6 mg/kg with a combination of both SI and CSI. Venous blood was drawn before and 2 h after each meal. Serum total IGF-I, total IGFBP-1, IGFBP-3, IRI, and blood glucose levels were measured. A, Responses of total serum IGF-I (closed circle) and IGFBP-3 (closed square). B, Responses of blood glucose (open circle), IRI (closed triangle), and total IGFBP-1 (open triangle). Arrows indicate the SI of rhIGF-I (0.4 mg/kg) before each meal.

 
IGF-I generation test

No significant increment in serum total IGF-I in response to the administration of rhGH at a dose of 2.0 IU/kg·day for three consecutive days was observed in this patient. The total serum IGF-I increased from 13.4 on day 0 to 29.4 ng/mL on day 3 (Fig. 5aGo). In contrast, two children with constitutional short stature showed better responses of total serum IGF-I to rhGH even at the smaller dose of 0.2 IU/kg·day for 2 days, from 134.4 to 268.8 ng/mL and from 168.0 to 464.1 ng/mL, respectively (Fig. 5aGo). However, the patient’s fasting blood glucose and IRI increased from 74 to 112 mg/dL and from 316.3 to 582.2 µU/mL, respectively (Fig. 5bGo). The response of serum IGFBP-3 was blunted (Fig. 5aGo). These findings are consistent with partial GH insensitivity in the patient.



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  		Figure 5. IGF-I generation test. A, Responses of total serum IGF-I levels of the patient (open circle) and a constitutional short boy and girl (closed circle and square) to rhGH at doses of 2.0 and 0.2 IU/kg, respectively. The open triangle indicates the serum IGFBP-3 level of the patient. B, Responses of fasting blood glucose (open square) and IRI (closed circle) of the patient to rhGH at the dose of 2.0 IU/kg.

 
Long-term effect of rhIGF-I treatment on growth and glucose metabolism (Fig. 6Go)

Between 6–18 months of age, the patient was treated with rhIGF-I by SI twice a day at a dose of 0.8 mg/kg·day. During this period, her growth rate was 13.6 cm/yr. Between 18–30 months, she was treated by both CSI and SI before each meal at a dose of 1.6 mg/kg·day. During this period, her growth rate and HbA1c level were 7.7 cm/yr and 6.3–6.6% (normal range, 4.3–5.8%), respectively. Between 2 yr, 6 months and 4 yr, 6 months, the patient suffered from eating difficulty due to swallowing dysphagia resulting from tonsillar hyperplasia. Thus, during this time, the total daily dose of rhIGF-I was reduced to 1.0 mg/kg. Her growth rate declined to 4.5 and 2.4 cm/yr, and her HbA1c levels gradually increased to 9.3–10.5%. At age 3 yr, 6 months, she underwent tonsillectomy. Since 4 yr, 6 months of age, her total daily dose of rhIGF-I was increased to 1.6 mg/kg. At age 5 yr, 6 months, her serum IGFBP-3 level was extremely low (0.06 µg/mL). Her current height is 107.2 cm (-2.7 SD), and her body weight is 16.9 kg. Her growth rate is 6.5 cm/yr (within the normal range for age-matched Japanese females), and HbA1c levels are 8.3–8.8%. Her total cholesterol, triglyceride, and free fatty acid levels were not significantly different from those of age-matched controls (data not shown). Her serum testosterone level was within the range for normal prepubertal females (<5 ng/dL). The lack of signs of hyperandrogenism was remarkable. She had no retinopathy. Abdominal computed tomography and magnetic resonance imaging revealed no organomegaly of liver, spleen, ovary, or kidneys. Her motor and mental developments were normal. Her intelligence quotient at the age of 7 yr and 4 months was 89. Ultrasound cardiogram and electrocardiogram demonstrated her cardiac function to be normal.



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  		Figure 6. The growth curve of the patient. Closed circles indicate the height of the patient, and open circles indicate the weight of the patient. In addition, open circles linked by dotted lines with closed circles indicate the bone age of the patient.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
rhIGF-I treatment has been reported to be effective for maintaining blood glucose within the normal range in patients with the genetic form of insulin resistance (12, 13, 14). However, different study designs and underlying IR mutations have yielded conflicting results. The failure of IGF-I treatment to improve metabolic control in patients with extreme insulin resistance has been ascribed to the poor metabolic state of the patient, IGF-I resistance of target cells at a receptor or postreceptor level, an inhibitory action of the mutant IRs on IGF-IR signaling, the deficiency of serum binding proteins for IGF-I, and an increased clearance of IGF-I (15, 16). It is, therefore, of importance to exclude these variables at the start of treatment. Our patient showed a normal binding capacity for [125I]IGF-I, normal [3H]thymidine incorporation, and normal autophosphorylation of the ß-subunit of IGF-IR in response to IGF-I. These results excluded a dominant negative effect of the IR mutations on endogenous IGF-IRs and on IGF-I resistance.

However, our patient had extremely low serum total IGF-I and IGFBP-3 levels. The IGF-I generation test suggests partial GH insensitivity in this patient. Children with poorly controlled insulin-dependent diabetes mellitus also have low levels of serum IGF-I. They do not show a significant rise in circulating IGF-I in response to exogenous GH (26, 27, 28, 29). Several studies in diabetic animal models and cultured hepatocytes have also suggested that the GH resistance was due to a postreceptor defect (30, 31, 32). Furthermore, GH binding to rat liver is reduced in diabetes and restored by insulin treatment (33). This suggests that insulin may enhance hepatic responsiveness to GH by positively regulating GH receptors in the liver. These studies support a role for insulin in the production of IGF-I. However, the administration of rhGH to our patient increased fasting blood glucose and IRI. Thus, GH resistance is present, but does not occur at the GH receptor level; rather, it appears to be a postreceptor event. The results of our patient’s IGF-I generation tests resemble a malnutritional state. However, the patient’s growth curve suggests that she is the appropriate weight for height and exclude the possibility of malnutrition.

The short half-life of IGF-I indicates an accelerated clearance of serum IGF-I. Most serum IGF-I is bound to specific IGFBPs (34, 35). IGFBP-3 is the predominant IGFBP, and the majority of serum IGFs are bound to IGFBP-3 in a high molecular mass (150-kDa) ternary complex (35, 36). IGFBP-3 is GH dependent and low in patients with GH deficiency (37, 38, 39, 40). Our patient has a very low level of serum IGFBP-3 in the absence of GH deficiency and no IGFBP-3 response to exogenous administration of rhGH. Insulin has been suggested to increase hepatic IGFBP-3 production. In spontaneously diabetic BB/W rats, insulinopenia was associated with reduced serum IGFBP-3 and decreased hepatic IGFBP-3 messenger ribonucleic acid (41). Insulin stimulates IGFBP-3 gene transcription in cocultures of parenchymal and nonparenchymal cells from the livers of normal rats (42). Probably, defects in insulin action may result in reduced production of IGFBP-3 in this patient. The low level of serum IGFBP-3 may accelerate the urinary excretion of free IGF-I. Indeed, even during the administration of rhIGF-I at a total daily dose of 1.6 mg/kg, the patient’s blood glucose and IRI levels were high. These data indicate that the patient may have an IGF-I-resistant state in vivo. Thus, treatment with a high dose of rhIGF-I by both CSI and SI is required to maintain the serum concentration of total IGF-I within the normal range.

The administration of IGF-I has been reported to increase the IGFBP-3 level. In studies of protein-deprived, diabetic, and hypophysectomized rats, the infusion of IGF-I increases the serum IGFBP-3 level (43, 44, 45). IGF-I alters IGFBP-3 expression by decreasing IGFBP-3 messenger ribonucleic acid degradation in cocultures of parenchymal and nonparenchymal cells from the livers of normal rats (42). Indeed, in this study, the short term administration of rhIGF-I slightly increased the serum IGFBP-3 level. Furthermore, serum IGFBP-3 levels increased from 0.06 µg/mL at the age of 5 yr and 6 months to 0.41 µg/mL at the age of 7 yr and 4 months during the long term administration. The administration of rhIGF-I may increase the production of IGFBP-3 and decrease the excretion of IGF-I. IGF-I and its receptor are known to play an important role in fetal and postnatal growth (46, 47). Thus, both defects of insulin action and impaired production of IGF-I and IGFBP-3 in vivo may cause growth retardation in our patient.

In this study, the total serum IGFBP-1 level was decreased in the presence of increased IRI levels. Insulin is considered to be an important regulator of IGFBP-1 (48). Because of the patient’s insulin resistance, which is due to mutations decreasing the affinity of the IR to bind insulin (18), it is somewhat surprising that IGFBP-1 levels decreased. We speculate that the extreme hyperinsulinemia present in the patient or treatment with rhIGF-I is able to decrease IGFBP-1 levels, by acting either on the IR itself or on the IGF-I receptor in the same way as fasting hypoglycemia.

In other cases reported, the rhIGF-I treatment was not effective as metabolic and growth controls. In these cases, a total daily dose of rhIGF-I was low despite the impaired production of IGF-I in vivo (15, 16). It is important for the treatment with rhIGF-I in patients with severe insulin resistance to maintain IGF-I level within the normal range. Thus, the combination therapy with SI and CSI may be effective.

Concerns have been reviewed about the safety of long term IGF-I treatment. It has been reported that the administration of rhIGF-I in humans and hypophysectomized rats causes organomegaly and affects renal function (49, 50, 51). In our patient, computed tomography, magnetic resonance imaging, and renograms excluded these complications. However, our patient developed tonsillar hypertrophy at the age of 3 yr and 6 months. Most patients with Laron’s syndrome treated with rhIGF-I have been reported to have an apparent increase in the size of their nasopharyngeal lymphoid tissue (52). Thus, tonsillar hypertrophy may be considered a complication of this IGF-I treatment.

In conclusion, IGF-I deficiency in a patient with severe insulin resistance may be due to both impaired production and accelerated excretion of IGF-I. Thus, higher doses of rhIGF-I are required to maintain an adequate serum IGF-I concentration. Treatment with high doses of rhIGF-I by both SI and CSI prevented postnatal growth retardation and normalized glucose metabolism. This treatment has to date been free of complications. In addition, our patient shows partial GH resistance, with impaired production of IGF-I and IGFBP-3. This may contribute to growth retardation in our patient.


   Acknowledgments
 
We thank Dr. Domenico Accili (Developmental Endocrinology Branch, NICHHD, NIH) for his critical reading of the manuscript.

Received September 4, 1997.

Revised October 23, 1997.

Accepted November 11, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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