Growth Hormone Replacement Therapy and Insulin Sensitivity

Johan Svensson and Bengt-Åke Bengtsson

Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Göteborg, Sweden

Address all correspondence and requests for reprints to: Johan Svensson, M.D., Ph.D., Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Gröna Stråket 8, SE-413 45 Göteborg, Sweden. E-mail: Johan.Svensson{at}medic.gu.se.

In adults with hypopituitarism, several studies show that untreated GH deficiency is associated with insulin resistance (1, 2). Short-term (<6 months) GH replacement further decreases insulin sensitivity (3, 4). After this initial deterioration of insulin sensitivity, however, an improvement of insulin sensitivity is observed and insulin sensitivity returns toward baseline values. In studies by O’Neal et al. (3) and Fowelin et al. (4), insulin sensitivity returned toward baseline values after 3 and 6 months of GH replacement, respectively. In the study presented in this issue of JCEM by Bramnert et al., insulin sensitivity was measured after 1 wk and 6 months of GH replacement therapy using the hyperinsulinemic, euglycemic clamp technique (5). In this study, insulin sensitivity was still decreased after 6 months of GH replacement therapy as compared with baseline (5). There was, however, a tendency to an improvement in insulin sensitivity between 1 wk and 6 months of treatment. At 1 wk, mean insulin sensitivity was -52% of that at baseline, and at 6 months, mean sensitivity was -39% of that at baseline.

A generally accepted hypothesis for the return of insulin sensitivity toward baseline values after 3–12 months of GH replacement therapy is the beneficial effects by GH on body composition. GH replacement therapy has been shown to induce a sustained increase in lean mass and a sustained reduction in body fat (6). In addition, GH replacement therapy increases well-being and physical activity level (7). When these beneficial effects exceed the negative effects, insulin sensitivity returns toward baseline values. In the study by Bramnert et al. (5), the GH replacement therapy did not increase lean mass. This absence of an increase in lean mass provides one explanation why insulin sensitivity was still decreased after 6 months of treatment.

There are now several studies that have determined the long-term (>=1 yr) effect of GH replacement therapy on insulin sensitivity. Some studies report that insulin sensitivity is still lower than at baseline (8, 9), whereas other studies report unchanged insulin sensitivity as compared with baseline during long-term GH replacement therapy (10, 11). The results of one study, using the hyperinsulinemic, euglycemic clamp technique, suggest that the decreased baseline insulin sensitivity persists at least up to 2 yr of GH treatment (12). However, in a study by Hwu et al. (13), 1 yr of GH treatment normalized insulin sensitivity as measured by a modified insulin suppression test. In a study by Jørgensen et al. (14), insulin sensitivity (M-value) was similar in GH-deficient patients as in controls after 5 yr of GH replacement therapy. In a 5-yr GH treatment trial, the circulating hemoglobin A1c level was reduced after 5 yr of GH replacement in adults with adult onset GH deficiency (6). In a study by Svensson et al. (15), insulin sensitivity was unchanged during 7-yr GH replacement therapy (15). In this study, there was even a tendency that the GH replacement therapy provided protection from the age-related decline in insulin sensitivity that was observed in the matched control subjects (15).

There are few data regarding the incidence of diabetes mellitus type 2 in GH-deficient adults. Preliminary analyses based on data from KIMS (Pharmacia Metabolic Database) suggest that the incidence of diabetes mellitus type 2 in GH-treated hypopituitary patients with normal body mass index is similar to that in the background population (16). Long-term (>=1 yr) GH replacement therapy, therefore, seems to be a safe procedure in terms of insulin sensitivity and diabetes mellitus type 2. The problem is mainly how to avoid the transient decrease in insulin sensitivity during the first months of GH replacement therapy.

GH replacement therapy increases lipolysis, thereby increasing circulating free fatty acid (FFA) concentrations (3, 4). According to the glucose-FFA cycle postulated by Randle et al. (17), these increased FFA concentrations may decrease the uptake of glucose in skeletal muscle. Later studies using acipimox, a blocker of FFA release, have confirmed the inverse relationship between circulating FFA concentrations and insulin sensitivity in GH-deficient adults (18, 19, 20). In the study by Bramnert et al. (5), there was a close correlation between lipid oxidation and circulating FFA concentration, suggesting that the increased rate of lipid oxidation was a consequence of the lipolytic action of GH. Therefore, the increased lipolysis induced by GH replacement therapy seems to be a sword with two edges in terms of insulin sensitivity. The short-term effect, with increased lipid oxidation and increased circulating FFA levels, deteriorates insulin sensitivity. The long-term effect, with a reduction in body fat, is beneficial for insulin sensitivity.

The study by Bramnert et al. (5) showed an increase in the relative distribution of insulin resistant type IIB fibers in skeletal muscle after 6 months of GH replacement therapy (5). It is unclear whether this is a primary effect by GH or merely a consequence of the decreased insulin sensitivity. In a study by Christopher et al. (12), decreased glycogen synthase activity was found in skeletal muscle in GH-deficient adults after 2 yr of GH replacement therapy (12). It was hypothesized that increased FFA availability could be important for the decreased glycogen synthase activity (12).

The initial studies with GH replacement therapy in adults used high doses of GH (21, 22). The high doses of GH induced profound changes in body composition and were also accompanied by fluid-related side effects. Later studies have shown that if GH replacement therapy is started at a low dose that is gradually increased based on the clinical response (body composition, well-being, and serum IGF concentration), a similar efficacy is achieved with a minimum of side effects (23). Individualized GH replacement therapy will result in a more gradual reduction in body fat than treatment with a high, fixed dose of GH. A slow, gradual reduction in body fat will result in lower increases in lipid oxidation and circulating FFA levels, thereby minimizing the transient decrease in insulin sensitivity the first months of GH treatment. In the study by Bramnert et al. (5), a fixed dose of GH was given. Although this was not a high dose of GH, it could be hypothesized that the response in insulin sensitivity could have been more beneficial if the dose of GH had been gradually increased based on the clinical response.

In normal subjects, obesity (especially abdominal obesity), high age, and decreased insulin sensitivity of other causes, are risk factors for the development of diabetes mellitus type 2. There is no reason to believe otherwise than that these are major risk factors also in hypopituitary adults. This is also our clinical experience (15), which finds support in the preliminary data from KIMS (16). In hypopituitary patients with high risk of developing diabetes mellitus type 2, it is essential to avoid a further decrease in insulin sensitivity during the first months of GH replacement therapy. Therefore, hypopituitary patients with high risk to developing diabetes type 2 should be given a very low dose of GH at initiation of therapy, and the dose of GH should be slowly increased based on the clinical response. In this way, we believe that the initial decrease in insulin sensitivity during GH replacement therapy can be minimized in these patients.

In conclusion, during the first months of GH replacement therapy there is a transient decrease in insulin sensitivity. Increased lipid oxidation and increased FFA availability can at least partly explain this transient decrease in insulin sensitivity. Long-term (>=1 yr) GH replacement is a safe procedure in terms of insulin sensitivity, and in some studies an improvement of insulin sensitivity has even been observed. Individualized GH replacement therapy, starting with a low dose of GH that is gradually increased based on the clinical response, can probably minimize the transient decrease in insulin sensitivity during the first months of treatment.

Acknowledgments

This study was supported by Grant 11621 from the Swedish Medical Research Council.

Footnotes

Abbreviation: FFA, Free fatty acid.

Received February 10, 2003.

Accepted February 10, 2003.

References

  1. Johansson J-O, Fowelin J, Landin K, Lager I, Bengtsson B-Å 1995 Growth hormone-deficient adults are insulin-resistant. Metabolism 44:1126–1129[Medline]
  2. Hew F, Koschmann M, Christopher M, Rantzau C, Vaag A, Ward G, Beck-Nielsen H, Alford F 1996 Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity. J Clin Endocrinol Metab 81:555–564[Abstract]
  3. O’Neal D, Kalfas A, Dunning P, Christopher MJ, Sawyer SD, Ward GM, Alford FA 1994 The effects of 3 months treatment of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults. A minimal model analysis. J Clin Endocrinol Metab 79:975–983[Abstract]
  4. Fowelin J, Attvall S, Lager I, Bengtsson B-Å 1993 Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 42:1443–1447[Medline]
  5. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L 2003 Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. J Clin Endocrinol Metab 88:000–0000
  6. Götherström G, Svensson J, Koranyi J, Alpsten M, Bosæus I, Bengtsson B-Å, Johannsson G 2001 A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. J Clin Endocrinol Metab 86:4657–4665[Abstract/Free Full Text]
  7. Hernberg-Ståhl E, Luger A, Abs R, Bengtsson B-Å, Feldt-Rasmussen U, Wilton P, Westberg B, Monson JP 2001 Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency. J Clin Endocrinol Metab 86:5277–5281[Abstract/Free Full Text]
  8. Weaver J, Monson J, Noonan K, John WG, Edwards A, Evans KA, Cunningham J 1995 The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. J Clin Endocrinol Metab 80:153–159[Abstract]
  9. Rosenfalck A, Maghsoudi S, Fisker S, Jørgensen JOL, Christiansen JS, Hilsted J, Vølund AA, Madsbad S 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[Abstract/Free Full Text]
  10. Al-Shoumer K, Gray R, Anyaoku V, Hughes C, Beshyah S, Richmond W, Johnston DG 1998 Effects of four years’ treatment with biosynthetic human growth hormone (GH) on glucose homeostasis, insulin secretion and lipid metabolism in GH-deficient adults. Clin Endocrinol (Oxf) 48:795–802[CrossRef][Medline]
  11. Bûlow B, Erfurth E 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[CrossRef][Medline]
  12. Christopher M, Hew F, Oakley M, Rantzau C, Alford F 1998 Defects of insulin action and skeletal muscle glucose metabolism in growth hormone-deficient adults persist after 24 months of recombinant human growth hormone therapy. J Clin Endocrinol Metab 83:1668–1681[Abstract/Free Full Text]
  13. Hwu C-M, Kwok C, Lai T-Y, Lee T-S, Hsiao L-C, Lee S-H, Fang VS, Ho L-T 1997 Growth hormone (GH) replacement reduces total body fat and normalizes insulin sensitivity in GH-deficient adults: a report of one-year clinical experience. J Clin Endocrinol Metab 82:3285–3292[Abstract/Free Full Text]
  14. Jørgensen JO, Vahl N, Nyholm B, Juul A, Müller J, Møller N, Schmitz O, Skakkebæk NE, Christiansen JS 1996 Substrate metabolism and insulin sensitivity following long-term growth hormone (GH) replacement therapy in GH-deficient adults. Endocrinol Metab 3:281–286
  15. Svensson J, Fowelin J, Landin K, Bengtsson B-Å, Johansson J-O 2002 Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab 87:2121–2127[Abstract/Free Full Text]
  16. Bengtsson B-Å, Abs R, Feldt-Rasmussen U, Goth M, Monson J, Thunander M, Koltowska-Häggström M, Mattsson A, Wilton P 2002 The risk of diabetes mellitus in hypopituitary patients on growth hormone substitution. Growth Horm IGF Res 12:302–303 (Abstract 233)
  17. Randle P, Garland P, Hales C, Newsholme E 1963 The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789[Medline]
  18. Nielsen S, Møller N, Christiansen JS, Jørgensen JO 2001 Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure. Diabetes 50:2301–2308[Abstract/Free Full Text]
  19. Segerlantz M, Bramnert M, Manhem P, Laurila E, Groop L 2001 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[Abstract/Free Full Text]
  20. Nielsen S, Møller N, Pedersen S, Christiansen JS, Jørgensen JO 2002 The effect of long-term pharmacological antilipolysis on substrate metabolism in growth hormone (GH)-substituted GH-deficient adults. J Clin Endocrinol Metab 87:3274–3278[Abstract/Free Full Text]
  21. Jørgensen JOL, Pedersen SA, Thuesen L, Jørgensen, Møller J, Skakkebæk NE, Christiansen JS 1989 Beneficial effect of growth hormone treatment in GH-deficient adults. Lancet i:1221–1225
  22. Salomon F, Cuneo R, Hesp R, Sönksen P 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797–1803[Abstract]
  23. Johannsson G, Rosén T, Bengtsson B-Å 1997 Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults. Clin Endocrinol (Oxf) 47571–581