Effects of growth hormone (GH) therapy withdrawal on glucose metabolism in not confirmed GH deficient adolescents at final height

Flavia Prodam, Silvia Savastio, Giulia Genoni, Deepak Babu, Mara Giordano, Roberta Ricotti, Gianluca Aimaretti, Gianni Bona, Simonetta Bellone, Flavia Prodam, Silvia Savastio, Giulia Genoni, Deepak Babu, Mara Giordano, Roberta Ricotti, Gianluca Aimaretti, Gianni Bona, Simonetta Bellone

Abstract

Context objective: Growth hormone deficiency (GHD) is associated with insulin resistance and diabetes, in particular after treatment in children and adults with pre-existing metabolic risk factors. Our aims were. i) to evaluate the effect on glucose metabolism of rhGH treatment and withdrawal in not confirmed GHD adolescents at the achievement of adult height; ii) to investigate the impact of GH receptor gene genomic deletion of exon 3 (d3GHR).

Design setting: We performed a longitudinal study (1 year) in a tertiary care center.

Methods: 23 GHD adolescent were followed in the last year of rhGH treatment (T0), 6 (T6) and 12 (T12) months after rhGH withdrawal with fasting and post-OGTT evaluations. 40 healthy adolescents were used as controls. HOMA-IR, HOMA%β, insulinogenic (INS) and disposition (DI) indexes were calculated. GHR genotypes were determined by multiplex PCR.

Results: In the group as a whole, fasting insulin (p<0.05), HOMA-IR (p<0.05), insulin and glucose levels during OGTT (p<0.01) progressively decreased from T0 to T12 becoming similar to controls. During rhGH, a compensatory insulin secretion with a stable DI was recorded, and, then, HOMAβ and INS decreased at T6 and T12 (p<0.05). By evaluating the GHR genotype, nDel GHD showed a decrease from T0 to T12 in HOMA-IR, HOMAβ, INS (p<0.05) and DI. Del GHD showed a gradual increase in DI (p<0.05) and INS with a stable HOMA-IR and higher HDL-cholesterol (p<0.01).

Conclusions: In not confirmed GHD adolescents the fasting deterioration in glucose homeostasis during rhGH is efficaciously coupled with a compensatory insulin secretion and activity at OGTT. The presence of at least one d3GHR allele is associated with lower glucose levels and higher HOMA-β and DI after rhGH withdrawal. Screening for the d3GHR in the pediatric age may help physicians to follow and phenotype GHD patients also by a metabolic point of view.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. HOMA-IR, Insulinogenic (INS) and disposition…
Figure 1. HOMA-IR, Insulinogenic (INS) and disposition (DI) index in GH deficient (GHD, group 1) and healthy (CS, group 2) adolescents with (Del, 27 subjects) and without (nDel, 31 subjects) the GH receptor (GHR) exon 3 deletion (d3GHR).
GHD adolescents are evaluated in the last year of therapy (T0) and after six (T6) and twelve (T12) rhGH withdrawal. Data are expressed as mean±SEM. The significance among the three measures (T0, T6 and T12) was calculated by Friedman test. The significance between GHD and CS was calculated by Mann-Whitney U test. *p

References

    1. Møller N, Jørgensen JO (2009) Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev 30: 152–177.
    1. LeRoith D, Yakar S (2007) Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 3: 302–310.
    1. Oliveira CR, Meneguz-Moreno RA, Aguiar-Oliveira MH, Barreto-Filho JA (2011) Emerging role of the GH/IGF-I on cardiometabolic control. Arq Bras Cardiol 97: 434–439.
    1. Segerlantz M, Bramnert M, Manhem P, Laurila E, Groop LC (2011) Inhibition of the rise in FFA by Acipimox partially prevents GH-induced insulin resistance in GH-deficient adults. J Clin Endocrinol Metab 86: 5813–5818.
    1. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, et al. (2003) Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. J Clin Endocrinol Metab 88: 1455–1463.
    1. Møller N, Butler PC, Antsiferov MA, Alberti KG (1989) Effects of growth hormone on insulin sensitivity and forearm metabolism in normal man. Diabetologia 32: 105–110.
    1. Smith TR, Elmendorf JS, David TS, Turinsky J (1997) Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1 and GLUT-4. Am J Physiol 272: 1071–1079.
    1. Dominici FP, Turyn D (2002) Growth hormone-induced alterations in the insulin-signaling system. Exp Biol Med (Maywood) 227: 149–157.
    1. Giavoli C, Ferrante E, Profka E, Olgiati L, Bergamaschi S, et al. (2010) Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy. Eur J Endocrinol 163: 361–368.
    1. Strawbridge RJ, Kärvestedt L, Li C, Efendic S, Ostenson CG, et al. (2007) GHR exon 3 polymorphism: association with type 2 diabetes mellitus and metabolic disorder. Growth Horm IGF Res 17: 392–398.
    1. Sørensen K, Aksglaede L, Munch-Andersen T, Aachmann-Andersen NJ, Leffers H, et al. (2009) Impact of the growth hormone receptor exon 3 deletion gene polymorphism on glucose metabolism, lipids, and insulin-like growth factor-I levels during puberty. J Clin Endocrinol Metab 94: 2966–2969.
    1. Rosenfalck AM, Maghsoudi S, Fisker S, Jørgensen JO, Christiansen JS, et al. (2000) The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults. J Clin Endocrinol Metab 85: 4173–4181.
    1. Hoffman AR, Kuntze JE, Baptista J, Baum HB, Baumann GP, et al. (2004) Growth hormone (GH) replacement therapy in adult-onset GH deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 89: 2048–2056.
    1. Svensson J, Fowelin J, Landin K, Bengtsson BA, Johansson JO (2002) Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab 87: 2121–2127.
    1. Bülow B, Erfurth EM (1999) A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-I without significant deterioration in glucose tolerance. Clin Endocrinol (Oxf) 50: 45–55.
    1. Appelman-Dijkstra NM, Claessen KM, Roelfsema F, Pereira AM, Biermasz NR (2013) Therapy of Endocrine disease: Long-term effects of recombinant human GH replacement in adults with GH deficiency: a systematic review. Eur J Endocrinol 169: R1–R14.
    1. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, et al. (2000) Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet 355: 610–613.
    1. Child CJ, Zimmermann AG, Scott RS, Cutler GB Jr, Battelino T, et al. (2011) Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab 96: E1025–E1033.
    1. Nørrelund H, Vahl N, Juul A, Møller N, Alberti KG, et al. (2000) Continuation of growth hormone (GH) therapy in GH-deficient patients during transition from childhood to adulthood: impact on insulin sensitivity and substrate metabolism. J Clin Endocrinol Metab 85: 1912–1917.
    1. Carroll PV, Drake WM, Maher KT, Metcalfe K, Shaw NJ, et al. (2004) Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth. J Clin Endocrinol Metab 89: 3890–3895.
    1. Heptulla RA, Boulware SD, Caprio S, Silver D, Sherwin RS, et al. (1997) Decreased insulin sensitivity and compensatory hyperinsulinemia after hormone treatment in children with short stature. J Clin Endocrinol Metab 82: 3234–3238.
    1. Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27: 1467–1495.
    1. Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46: 3–19.
    1. Utzschneider KM, Prigeon RL, Faulenbach MV, Tong J, Carr DB, et al. (2009) Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care 32: 335–41.
    1. Abdul-Ghani MA, Williams K, DeFronzo RA, Stern M (2007) What is the best predictor of future type 2 diabetes? Diabetes Care 2007 30: 1544–1548.
    1. Corneli G, Di Somma C, Prodam F, Bellone J, Bellone S, et al. (2007) Cut-off limits of the GH response to GHRH plus arginine test and IGF-I levels for the diagnosis of GH deficiency in late adolescents and young adults. Eur J Endocrinol 157: 701–708.
    1. American Diabetes Association (2013) Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 36(Suppl ()) 67–74.
    1. Matsuda M, DeFronzo R (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22: 1462–1470.
    1. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, et al. (1993) Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42: 1663–1672.
    1. Giannini C, Weiss R, Cali A, Bonadonna R, Santoro N, et al. (2012) Evidence for early defects in insulin sensitivity and secretion before the onset of glucose dysregulation in obese youths: a longitudinal study. Diabetes 61: 606–614.
    1. Cacciari E, Milani S, Balsamo A, Spada E, Bona G, et al. (2006) Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 29: 581–593.
    1. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114: 555–576.
    1. Pantel J, Machinis K, Sobrier ML, Duquesnoy P, Goossens M, et al. (2000) Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retro elements during primate evolution. J Biol Chem 23 275: 18664–18669.
    1. Seminara S, Merello G, Masi S, Filpo A, La Cauza F, et al. (1998) Effect of long-term growth hormone treatment on carbohydrate metabolism in children with growth hormone deficiency. Clin Endocrinol (Oxf) 49: 125–130.
    1. Radetti G, Pasquino B, Gottardi E, Contadin IB, Rigon F, et al. (2004) Insulin sensitivity in growth hormone-deficient children: influence of replacement treatment. Clin Endocrinol (Oxf) 61: 473–477.
    1. Jørgensen JO, Møller J, Alberti KG, Schmitz O, Christiansen JS, et al. (1993) Marked effects of sustained low growth hormone (GH) levels on day-to-day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects. J Clin Endocrinol Metab 77: 1589–1596.
    1. Van der Kaay D, Bakker B, van der Hulst F, Mul D, Mulder J, et al. (2010) Randomized GH trial with two different dosages in combination with a GnRH analogue in short small for gestational age children: effects on metabolic profile and serum GH, IGF1, and IGFBP3 levels. Eur J Endocrinol 162: 887–895.
    1. Filopanti M, Giavoli C, Grottoli S, Bianchi A, De Marinis L, et al. (2011) The exon 3-deleted growth hormone receptor: molecular and functional characterization and impact on GH/IGF-I axis in physiological and pathological conditions. J Endocrinol Invest 34: 861–868.
    1. Gao L, Zheng Z, Cao L, Shen S, Yang Y, et al. (2011) The growth hormone receptor (GHR) exon 3 polymorphism and its correlation with metabolic profiles in obese Chinese children. Pediatr Diabetes 12: 429–434.
    1. Arafat AM, Möhlig M, Weickert MO, Schöfl C, Spranger J, et al. (2010) Improved insulin sensitivity, preserved beta cell function and improved whole-body glucose metabolism after low-dose growth hormone replacement therapy in adults with severe growth hormone deficiency: a pilot study. Diabetologia 53: 1304–1313.
    1. Horan M, Newsway V, Yasmin, Lewis MD, Easter TE, et al. (2006) Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke. Hum Genet 119: 527–540.
    1. Takada D, Ezura Y, Ono S, Iino Y, Katayama Y, et al. (2003) Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred. Am J Med Genet A 121A: 136–140.
    1. Schneider HJ, Friedrich N, Klotsche J, Schipf S, Nauck M, et al. (2011) Prediction of incident diabetes mellitus by baseline IGF1 levels. Eur J Endocrinol 64: 223–229.
    1. Gungor N, Arslanian S (2004) Progressive beta cell failure in type 2 diabetes mellitus of youth. J Pediatr 144: 656–659.
    1. Lee S, Bacha F, Gungor N, Arslanian S (2008) Comparison of different definitions of pediatric metabolic syndrome: relation to abdominal adiposity, insulin resistance, adiponectin, and inflammatory biomarkers. J Pediatr 152: 177–184.
    1. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, et al. (2004) A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 36: 720–724.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere