REVISTA ARGENTINA DE ENDOCRINOLOGÍA Y METABOLISMO
Domené, H. M. 1; Bengolea, V.S. 2; Jasper, H.G. 1
Los factores de crecimiento insulinosímiles (IGF-I y II), son polipéptidos que desempeñan un rol importante en el crecimiento y el metabolismo. Son producidos en múltiples tejidos y ejercen sus efectos en forma local (acción autocrina/paracrina) o a distancia (acción endocrina). Circulan formando complejos con proteínas transportadoras (IGFBPs). Éstas incrementan la vida media de los IGFs y modulan su biodisponibilidad. Alrededor del 80-90 % de los IGFs se encuentra en un complejo ternario de aproximadamente 150 kDa formado por IGF-I o II, IGFBP-3 ó -5 y una glicoproteína de aproximadamente 85 kDa conocida como subunidad ácidolabil (ALS). El desarrollo de un modelo animal con ausencia de ALS (ratón ALS-KO) y más recientemente la descripción del primer paciente con deficiencia completa de ALS, han contribuido a caracterizar las consecuencias hormonales y metabólicas de su deficiencia. En un paciente con retraso del crecimiento y la pubertad, se encontró una respuesta normal de GH a pruebas de estímulo (GH máxima 31.0 ng/ml) con niveles circulantes muy disminuidos de IGF-I (31 ng/ml; -5.3 DE) é IGFBP-3 (0.22 μg/ml; -9.7 DE). Los niveles de ALS fueron no detectables (< 1 mg/L) y no se observó la formación de complejos ternarios. Se caracterizó una mutación en homocigosis en el gen IGFALS (1338delG, E35fsX120) que predice la formación de una proteína truncada. A la edad de 20 años presentó un desarrollo puberal completo, con un empuje del crecimiento normal de 8.3 cm/año, alcanzando una talla final normal de 166.4 cm, (-0.94 DE). Se constató insulinorresistencia y osteopenia. La asociación de retraso del crecimiento con niveles normales o aumentados de GH y niveles extremadamente disminuidos de IGF-I e IGFBP-3, son característicos de la insensibilidad a la GH, o de la presencia de una GH biológicamente inactiva. Sin embargo, la inestabilidad del IGF-I circulante por deficiencia de ALS emerge como un diagnóstico alternativo. El hallazgo, en el paciente con deficiencia de ALS, de talla normal con niveles marcadamente disminuidos de IGF-I (total, libre y bioactivo) sugiere un rol preponderante del IGF-I producido localmente en el crecimiento lineal. El retardo puberal, la insulinorresistencia y la osteopenia, podrían ser indicadores del requerimiento del IGF-I circulante para el inicio de la pubertad a edad adecuada, la acción normal de la insulina y la adquisición de una masa ósea normal.
Insulin-like growth factor (IGF)-I and II are stimulators of cell growth and differentiation. They are synthesized by many tissues and cell types during fetal and postnatal life. They are capable of endocrine actions as shown by increasing plasma concentration after birth. Insulin-like growth factor (IGF)-I and II (IGFs) form complexes with specific binding proteins (IGFBP-1 to -6). These complexes are referred to as binary complexes consisting of IGF-I or IGF-II and one IGFBP, or as ternary complexes consisting of one molecule each of IGF-I or IGF-II, IGFBP-3 or -5, and an acid-labile subunit known as ALS. Binary and ternary complexes contain respectively 10-15% and 80-90% of total plasma IGFs, leaving 1% or less of plasma IGFs in free form. Free IGF-I has a half-life of approximately 10 minutes in plasma, which is extended to 30-90 min when in binary complexes, and to more than 12 hours when in ternary complexes. Ternary complex formation restricts the IGFs to the circulation and prolongs their half-life. ALS is mainly produced in the liver under the control of GH stimulation. Recently, the development of an animal model for ALS deficiency (the ALS-KO mouse) and the identification of a patient with an inactivating mutation in the IGFALS gene, have provided the opportunity to assess the physiological role of this protein, and to characterize the endocrine and metabolic consequences of its deficiency. In a patient with delay of growth and pubertal development (Height: 145.2 cm; 2.05 SDS below the mean; Tanner stage I for both sexual development and pubic hair) we have found normal GH-stimulated levels (maximal GH 31.0 ng/ml) with marked reduction of IGF-I (31 ng/ml; -5.3 SDS) and IGFBP-3 (0.22 μg/ml; -9.7 SDS) plasma concentrations. Normal or increased GH levels, associated to reduced levels of IGF-I, are characteristic of GH insensitivity or biological inactive GH. However, in these conditions the magnitude of the growth-factor deficiency usually correlates with the severity of growth impairment. After six month of treatment with GH (0.17 mg/ kg body weight), there was no effect on either the growth velocity or the serum levels of IGF-I and IGFBP-3. We hypothesized that the deficiency of IGF-I and IGFBP-3, observed in this patient, could be related to their instability in the circulation. The finding of undetectable levels of ALS steered the investigation to the IGFALS gene. The patient resulted homozygous for the frame-shift mutation 1338delG, E35fsX120 in the IGFALS gene, which encodes a truncated and probably inactive protein. The lack of immuno and functional ALS was assessed by means of Western immunoblot and ternary complex formation by size-exclusion chromatography. The follow up to the age of 20 years, has shown that the patient attained a complete pubertal development, a normal growth spurt of 8.3 cm/year, and a normal near final height of 166.4 cm (-0.94 SDS). The patient also presented insulin-resistance (glucose 100 mg/dl; insulin 32 μUI/ml; HOMA index 7.9), and osteopenia, even after he completed pubertal development (BMD at lumbar spine Z score -2.1 SDS at 19 years of age). The original somatomedin hypothesis proposed that the growth-promoting actions of GH are mediated through the circulating liver-generated IGF-I. Recently, the role of circulating IGF-I in growth has been challenged by the finding that specific disruption of the hepatic igf1 gene in mouse, the main source of circulating IGF-I, or the inactivation of the gene encoding the ALS (igfals) in mice, has a minor effect on growth, despite causing a profound reduction in serum IGF-I. The complete deficiency of the acid-labile subunit, caused by an inactivating mutation in the IGFALS gene, represents a unique condition in which the inability of ternary complex formacrecition, produces a marked reduction of circulating IGF-I, with presumably no effects on locally produced IGF-I. The finding that normal circulating IGF-I is not essential to attain a normal final height, suggest that normal growth could be sustained by local production of IGF-I. Pubertal delay, insulin-resistance, and osteopenia may all result as a consequence of the reduction of serum IGF-I levels, indicating that circulating IGF-I plays an important role in the timing of the onset of puberty, and is required for a normal insulin action, and for the acquisition of a normal bone mass.