Background: The increased risk for development of type 2 diabetes mellitus (T2DM) in adults with growth hormone deficiency (GHD) has been attributed to insulin resistance arising from increased visceral fat accumulation and the putative effects of low insulin-like growth factor I (IGF-I) levels on pancreatic β-cell mass and insulin secretion. Failure of GH replacement to reverse these abnormalities may reflect nonphysiological GH replacement or inability of the β-cell to recover. Methods and Results: We have demonstrated in normal subjects and in those with GHD that very low doses of GH can improve postabsorptive insulin sensitivity in direct relation to increased free IGF-I, reduce fasting glucose levels and potentially improve β-cell secretory capacity. Conclusions: These low doses of GH should prevent the development of T2DM in adult subjects, but this needs to be confirmed by long-term studies.

1.
Isaksson OG, Lindahl A, Nilsson A, Isgaard J: Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr Rev 1987;8:426–438.
2.
Davidson MB: Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 1987;8:115–131.
3.
Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L: Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. J Clin Endocrinol Metab 2003;88:1455–1463.
4.
Giavoli C, Porretti S, Ronchi CL, Cappiello V, Ferrante E, Orsi E, Arosio M, Beck-Peccoz P: Long-term monitoring of insulin sensitivity in growth hormone-deficient adults on substitutive recombinant human growth hormone therapy. Metabolism 2004;53:740–743.
5.
Caprio S, Boulware SD, Press M, Sherwin RS, Rubin K, Carpenter TO, Plewe G, Tamborlane WV: Effect of growth hormone treatment on hyperinsulinemia associated with Turner syndrome. J Pediatr 1992;120:238–243.
6.
Sas T, de Muinck Keizer-Schrama S, Aanstoot HJ, Stijnen T, Drop S: Carbohydrate metabolism during growth hormone treatment and after discontinuation of growth hormone treatment in girls with Turner syndrome treated with once or twice daily growth hormone injections. Clin Endocrinol (Oxf) 2000;52:741–747.
7.
Rosenfeld RG, Wilson DM, Dollar LA, Bennett A, Hintz RL: Both human pituitary growth hormone and recombinant DNA-derived human growth hormone cause insulin resistance at a postreceptor site. J Clin Endocrinol Metab 1982;54:1033–1038.
8.
Piatti PM, Monti LD, Caumo A, Conti M, Magni F, Galli-Kienle M, Fochesato E, Pizzini A, Baldi L, Valsecchi G, Pontiroli AE: Mediation of the hepatic effects of growth hormone by its lipolytic activity. J Clin Endocrinol Metab 1999;84:1658–1663.
9.
Woods KA, van Helvoirt M, Ong KK, Mohn A, Levy J, de Zegher F, Dunger DB: The somatotropic axis in short children born small for gestational age: relation to insulin resistance. Pediatr Res 2002;51:76–80.
10.
Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R: Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. Am J Physiol 1986;250:E269–E273.
11.
Wasada T, Aoki K, Sato A, Katsumori K, Muto K, Tomonaga O, Yokoyama H, Iwasaki N, Babazono T, Takahashi C, Iwamoto Y, Omori Y, Hizuka N: Assessment of insulin resistance in acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy. Endocr J 1997;44:617–620.
12.
Simpson H, Savine R, Sonksen P, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Cohen P, Hintz R, Ho K, Mullis P, Robinson I, Strasburger C, Tanaka T, Thorner M: Growth hormone replacement therapy for adults: into the new millennium. Growth Horm IGF Res 2002;12:1–33.
13.
Sesti G, Sciacqua A, Cardellini M, Marini MA, Maio R, Vatrano M, Succurro E, Lauro R, Federici M, Perticone F: Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance. Diabetes Care 2005;28:120–125.
14.
Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ: Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet 2002;359:1740–1745.
15.
Hart ‘t LM, Fritsche A, Rietveld I, Dekker JM, Nijpels G, Machicao F, Stumvoll M, van Duijn CM, Haring HU, Heine RJ, Maassen JA, van Haeften TW: Genetic factors and insulin secretion: gene variants in the IGF genes. Diabetes 2004;53(suppl 1):S26–S30.
16.
van Haeften TW, Twickler TB: Insulin-like growth factors and pancreas beta cells. Eur J Clin Invest 2004;34:249–255.
17.
Ueki K, Okada T, Hu J, Liew CW, Assmann A, Dahlgren GM, Peters JL, Shackman JG, Zhang M, Artner I, Satin LS, Stein R, Holzenberger M, Kennedy RT, Kahn CR, Kulkarni RN: Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 2006;38:583–588.
18.
Spina LD, Soares DV, Brasil RR, da Silva EM, Lobo PM, Conceicao FL, Vaisman M: Glucose metabolism and visceral fat in GH deficient adults: 1 year of GH replacement. Growth Horm IGF Res 2004;14:45–51.
19.
Spina LD, Soares DV, Brasil RR, Lobo PM, Lucia Conceicao F, Vaisman M: Glucose metabolism and visceral fat in GH deficient adults: two years of GH-replacement. Pituitary 2004;7:123–129.
20.
Boguszewski CL, Meister LH, Zaninelli DC, Radominski RB: One year of GH replacement therapy with a fixed low-dose regimen improves body composition, bone mineral density and lipid profile of GH-deficient adults. Eur J Endocrinol 2005;152:67–75.
21.
Ong KK, Emmett PM, Noble S, Ness A, Dunger DB, ALSPAC Study Team: Dietary energy intake at the age of 4 months predicts postnatal weight gain and childhood body mass index. Pediatrics 2006;117:E503–E508.
22.
Ogilvy-Stuart AL, Hands SJ, Adcock CJ, Holly JM, Matthews DR, Mohamed-Ali V, Yudkin JS, Wilkinson AR, Dunger DB: Insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-1, growth hormone, and feeding in the newborn. J Clin Endocrinol Metab 1998;83:3550–3557.
23.
Silbergeld A, Lazar L, Erster B, Keret R, Tepper R, Laron Z: Serum growth hormone binding protein activity in healthy neonates, children and young adults: correlation with age, height and weight. Clin Endocrinol (Oxf) 1989;31:295–303.
24.
Low LC, Tam SY, Kwan EY, Tsang AM, Karlberg J: Onset of significant GH dependence of serum IGF-I and IGF-binding protein 3 concentrations in early life. Pediatr Res 2001;50:737–742.
25.
Mauras N, Blizzard RM, Link K, Johnson ML, Rogol AD, Veldhuis JD: Augmentation of growth hormone secretion during puberty: evidence for a pulse amplitude-modulated phenomenon. J Clin Endocrinol Metab 1987;64:596–601.
26.
Mauras N, Rogol AD, Veldhuis JD: Increased hGH production rate after low-dose estrogen therapy in prepubertal girls with Turner’s syndrome. Pediatr Res 1990;28:626–630.
27.
Smith CP, Dunger DB, Williams AJ, Taylor AM, Perry LA, Gale EA, Preece MA, Savage MO: Relationship between insulin, insulin-like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life. J Clin Endocrinol Metab 1989;68:932–937.
28.
Martha PM Jr, Goorman KM, Blizzard RM, RogoI AD, Veldhuis JD: Endogenous growth hormone secretion and clearance rates in normal boys as determined by deconvolution analysis: relationship to age, pubertal status and body mass. J Clin Endocrinol Metab 1992;74:336–344.
29.
Arslanian SA, Kalhan SC: Correlations between fatty acid and glucose metabolism. Potential explanation of insulin resistance of puberty. Diabetes 1994;43:908–914.
30.
Caprio S, Plewe G, Diamond MP, Simonson SC, Boulware SD, Sherwin SS, Tamborlane WV: Increased insulin secretion during puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr 1989;114:963–967.
31.
Arslanian SA, Kalhan SC: Protein turnover during puberty in normal children. Am J Physiol 1996;270:E79–E84.
32.
Holly JM, Smith CP, Dunger DB, Edge JA, Biddlecombe RA, Williams AJ, Howell R, Chard T, Savage MO, Rees LH, et al.: Levels of the small insulin-like growth factor-binding protein are strongly related to those of insulin in prepubertal and pubertal children but only weakly so after puberty. J Endocrinol 1989;121:383–387.
33.
Holly JM, Smith CP, Dunger DB, Howell RJ, Chard T, Perry LA, Savage MO, Cianfarani S, Rees LH, Wass JA: Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-I. A synchronised approach to pubertal development? Clin Endocrinol (Oxf) 1989;31:277–284.
34.
He Q, Karlberg J: BMI in childhood and its association with height gain, timing of puberty, and final height. Pediatr Res 2001;49:244–251.
35.
Taylor AM, Dunger DB, Preece MA, Holly JM, Smith CP, Wass JA, Patel S, Tate VE: The growth hormone independent insulin-like growth factor-I binding protein BP-28 is associated with serum insulin-like growth factor-I inhibitory bioactivity in adolescent insulin-dependent diabetics. Clin Endocrinol (Oxf) 1990;32:229–239.
36.
Massa G, Dooms L, Bouillon R, Vanderschueren-Lodeweyckx M: Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1993;36:239–243.
37.
Katz LE, DeLeon DD, Zhao H, Jawad AF: Free and total insulin-like growth factor (IGF)-I levels decline during fasting: relationships with insulin and IGF-binding protein-1. J Clin Endocrinol Metab 2002;87:2978–2983.
38.
Lee PDK, Conover CA, Powell DR: Regulation and function of insulin like growth factor-binding protein-1. Proc Soc Exp Biol Med 1993;204:4–29.
39.
Ho KY, Veldhuis JD, Johnson ML, Furlanetto R, Evans WS, Alberti KGMM, Thorner MO: Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988;81:968–975.
40.
Conover CA, Lee PDK, Kanaley JA, Clarkson JT, Jensen MD: Insulin regulation of insulin-like growth factor binding protein-1 in obese and nonobese humans. J Clin Endocrinol Metab 1992;74:1355–1360.
41.
Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE, Orskov H: Free insulin-like growth factors in human obesity. Metabolism 1995;44:37–44.
42.
Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML, Lizarralde G: Dual defects in pulsatile growth hormone secretion and clearances subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab 1991;72:51–59.
43.
Scacchi M, Pincelli AI, Cavagnini F: Growth hormone in obesity. Int J Obes Relat Metab Disord 1999;23:260–271.
44.
Frystyk J, Grofte T, Skjaerbaek C, Orskov H: The effect of oral glucose on serum free insulin-like growth factor-I and -II in health adults. J Clin Endocrinol Metab 1997;82:3124–3127.
45.
Simpson HL, Jackson NC, Shojaee-Moradie F, Jones RH, Russell-Jones DL, Sonksen PH, Dunger DB, Umpleby AM: Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetes. J Clin Endocrinol Metab 2004;89:425–432.
46.
DeVol DL, Rotwein P, Sadow JL, Novakofski J, Bechtel PJ: Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth. Am J Physiol Endocrinol Metab 1990;259:E89–E95.
47.
Yarasheski KE: Growth hormone effects on metabolism, body composition, muscle mass, and strength. Exerc Sport Sci Rev 1994;22:285–312.
48.
Adams GR, Haddad F: The relationships between IGF-I, DNA content, and protein accumulation during skeletal muscle hypertrophy. J Appl Physiol 1996;81:2509–2516.
49.
Butler AA, LeRoith D: Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu Rev Physiol 2001;63:161–164.
50.
Yuen K, Ong K, Husbands S, Chatelain P, Fryklund L, Gluckman P, Ranke M, Cook D, Rosenfeld R, Wass J, Dunger D: The effects of short-term administration of two low doses versus the standard GH replacement dose on insulin sensitivity and fasting glucose levels in young healthy adults. J Clin Endocrinol Metab 2002;87:1989–1995.
51.
van den Berg G, Veldhuis JD, Frolich M, Roelfsema F: An amplitude-specific divergence in the pulsatile mode of growth hormone (GH) secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. J Clin Endocrinol Metab 1996;81:2460–2467.
52.
Yuen K, Frystyk J, Umpleby M, Fryklund L, Dunger D: 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 2004;89:3956–3964.
53.
Moller N, Jorgensen JO, Schmitz O, Moller J, Christiansen J, Alberti KG, Orskov H: Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. Am J Physiol 1990;258:E86–E91.
54.
Fowelin J, Attvall S, von Schenck H, Smith U, Lager I: Characterization of the insulin-antagonistic effect of growth hormone in man. Diabetologia 1991;34:500–506.
55.
GHRS: Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society (GHRS) workshop on adult growth hormone deficiency. J Clin Endocrinol Metab 1998;83:379–381.
56.
Bulow B, Link K, Ahren B, Nilsson AS, Erfurth EM: Survivors of childhood acute lymphoblastic leukaemia, with radiation- induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment. Clin Endocrinol (Oxf) 2004;61:683–691.
57.
Yuen KCJ, Frystyk J, White DK, Twickler TB, Koppeschaar HP, Harris PE, Fryklund L, Murgatroyd PR, Dunger DB: Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone dose in adults with severe growth hormone deficiency. Clin Endocrinol (Oxf) 2005;63:428–436.
58.
Yuen K, Dunger D: Persisting effects on fasting glucose levels and insulin sensitivity after 6 months of discontinuation of a very low dose GH therapy in adults with severe GH deficiency. Clin Endocrinol (Oxf) 2006;64:549–555.
59.
Yuen K, Wareham N, Frystyk J, Hennings S, Mitchell J, Fryklund L, Dunger D: Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on beta-cell function and post-load glucose tolerance. Eur J Endocrinol 2004;151:39–45.
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