This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bramnert, M. Articles by Groop, L. Search for Related Content PubMed PubMed Citation Articles by Bramnert, M. Articles by Groop, L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB GLUCOSE Medline Plus Health Information Hormone Replacement Therapy

Growth Hormone Replacement Therapy Induces Insulin Resistance by Activating the Glucose-Fatty Acid Cycle

Department of Endocrinology (M.B., M.S., E.L., P.M., L.G.), University Hospital, S-205 02 Malmö, Sweden; and Copenhagen Muscle Research Centre (J.R.D.), Department of Human Physiology, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Margareta Bramnert, Department of Endocrinology, University Hospital MAS, S-205 +2 Malmö, Sweden. E-mail: margareta.bramnert{at}skane.se.

The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 µg/kg body weight·d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[³H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects.

GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy.

In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy.

This work was supported by the Nordisk Insulin Foundation, Albert Påhlsson's Foundation, and Pharmacia \|[amp ]\| Upjohn, Inc. (Stockholm, Sweden).

Abbreviations: AUC, Area under the curve; B, blood; BIA, bioelectrical impedance; BMI, body mass index; BW, body weight; CV, coefficient(s) of variation; FFA, free fatty acid; FV, fractional velocity of GS activity; G-6-P, glucose-6-phosphate; GHD, GH-deficient or GH deficiency; GS, glycogen synthase; HGP, hepatic glucose production; NADH, nicotinamide adenine dinucleotide phosphate; OGTT, oral glucose tolerance test; S, serum; TBW, total body water; UDP, uridine diphosphate.

This article has been cited by other articles:

				L. Audi, A. Carrascosa, C. Esteban, M. Fernandez-Cancio, P. Andaluz, D. Yeste, R. Espadero, M. L. Granada, H. Wollmann, L. Fryklund, et al. The exon 3-deleted/full-length Growth Hormone Receptor Polymorphism Does Not Influence the Effect of Puberty or Growth Hormone Therapy on Glucose Homeostasis in Short Non-Growth Hormone-Deficient Small-for-Gestational-Age Children: Results from a Two-Year Controlled Prospective Study J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2709 - 2715. [Abstract] [Full Text] [PDF]

				J. Gibney, M.-L. Healy, and P. H. Sonksen The Growth Hormone/Insulin-Like Growth Factor-I Axis in Exercise and Sport Endocr. Rev., October 1, 2007; 28(6): 603 - 624. [Abstract] [Full Text] [PDF]

				H. Holmer, J. Svensson, L. Rylander, G. Johannsson, T. Rosen, B.-A. Bengtsson, M. Thoren, C. Hoybye, M. Degerblad, M. Bramnert, et al. Nonfatal Stroke, Cardiac Disease, and Diabetes Mellitus in Hypopituitary Patients on Hormone Replacement Including Growth Hormone J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3560 - 3567. [Abstract] [Full Text] [PDF]

				S. D'Amico, J. Shi, R. V Sekhar, F. Jahoor, K. J Ellis, K. Rehman, J. Willis, M. Maldonado, and A. Balasubramanyam Physiologic growth hormone replacement improves fasting lipid kinetics in patients with HIV lipodystrophy syndrome Am. J. Clinical Nutrition, July 1, 2006; 84(1): 204 - 211. [Abstract] [Full Text] [PDF]

				M.-H. Gannage-Yared, S. Khalife, M. Semaan, F. Fares, S. Jambart, and G. Halaby Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. Eur. J. Endocrinol., July 1, 2006; 155(1): 167 - 176. [Abstract] [Full Text] [PDF]

				J. L. J. van der Velden, R. C. J. Langen, M. C. J. M. Kelders, E. F. M. Wouters, Y. M. W. Janssen-Heininger, and A. M. W. J. Schols Inhibition of glycogen synthase kinase-3{beta} activity is sufficient to stimulate myogenic differentiation Am J Physiol Cell Physiol, February 1, 2006; 290(2): C453 - C462. [Abstract] [Full Text] [PDF]

				M. L. Healy, J. Gibney, C. Pentecost, P. Croos, D. L. Russell-Jones, P. H. Sonksen, and A. M. Umpleby Effects of High-Dose Growth Hormone on Glucose and Glycerol Metabolism at Rest and during Exercise in Endurance-Trained Athletes J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 320 - 327. [Abstract] [Full Text] [PDF]

				M. Hansen, R. Morthorst, B. Larsson, A. Flyvbjerg, M. H. Rasmussen, H. Orskov, A. Astrup, M. Kjaer, and K. H. W. Lange Effects of 2 wk of GH administration on 24-h indirect calorimetry in young, healthy, lean men Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1030 - E1038. [Abstract] [Full Text] [PDF]

				K. Yuen, J. Frystyk, M. Umpleby, L. Fryklund, and D. Dunger Changes in Free Rather Than Total Insulin-Like Growth Factor-I Enhance Insulin Sensitivity and Suppress Endogenous Peak Growth Hormone (GH) Release following Short-Term Low-Dose GH Administration in Young Healthy Adults J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3956 - 3964. [Abstract] [Full Text] [PDF]

				M. M. Buijs, J. A. Romijn, J. Burggraaf, M. L. de Kam, M. Frolich, M. T. Ackermans, H. P. Sauerwein, A. F. Cohen, A. E. Meinders, and H. Pijl Glucose homeostasis in abdominal obesity: hepatic hyperresponsiveness to growth hormone action Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E63 - E68. [Abstract] [Full Text] [PDF]

				R. C. C. Ryther, A. S. Flynt, B. D. Harris, J. A. Phillips III, and J. G. Patton GH1 Splicing Is Regulated by Multiple Enhancers Whose Mutation Produces a Dominant-Negative GH Isoform That Can Be Degraded by Allele-Specific Small Interfering RNA (siRNA) Endocrinology, June 1, 2004; 145(6): 2988 - 2996. [Abstract] [Full Text] [PDF]

				P. Maison, S. Griffin, M. Nicoue-Beglah, N. Haddad, B. Balkau, and P. Chanson Impact of Growth Hormone (GH) Treatment on Cardiovascular Risk Factors in GH-Deficient Adults: A Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2192 - 2199. [Abstract] [Full Text] [PDF]