Effects of a Combination of Recombinant Human Growth Hormone with Metformin on Glucose Metabolism and Body Composition in Patients with Metabolic Syndrome

Abstract

Abdominal obesity and insulin resistance are central findings in metabolic syndrome. Since treatment with recombinant human growth hormone (rhGH) can reduce body fat mass in patients with organic GH deficiency, rhGH therapy may also have favourable effects on patients with metabolic syndrome. However, due to the highly increased risk for type 2 diabetes in these patients, strategies are needed to reduce the antagonistic effect of rhGH against insulin. We conducted a 18-month randomised, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (Met) in patients with metabolic syndrome. 25 obese men (55 ± 6 years, BMI 33.4 ± 2.9 kg/m²) with mildly elevated fasting plasma glucose (FPG) levels at screening (6.1 - 8.0 mmol/l) were included. All patients received metformin (850 mg twice daily) either alone or in combination with rhGH (daily dose 9.5 μg/kg body weight). An oGTT was performed at baseline, after 6 weeks, and after 3, 6, 12, and 18 months of therapy. Glucose disposal rate (GDR) was measured by euglycemic hyperinsulinemic clamp at 0 and 18 months and body composition was measured by DEXA every 6 months. In the Met + GH group, IGF-I increased from 146 ± 56 μg/l to 373 ± 111 μg/l (mean ± SD) after 3 months and remained stable after that. BMI did not change significantly in either group during the study. Total body fat decreased by -4.3 ± 5.4 kg in the Met + GH group and by -2.7 ± 2.9 kg in the Met + Placebo group (differences between the two groups: p = n. s.). Waist circumference decreased in both groups (Met + GH: 118 ± 8 cm at baseline, 112 ± 10 cm after 18 months; Met + Placebo: 114 ± 7 cm vs. 109 ± 8 cm; differences between the two groups: p = 0.096). In the Met + GH group, FPG increased significantly after 6 months (5.9 ± 0.7 vs. 6.7 ± 0.4 mmol/l; p = 0.005), but subsequently decreased to baseline levels (18 months: 5.8 ± 0.2 mmol/l). FPG remained stable in the Met + Placebo group until 12 months had elapsed, and then slightly decreased (baseline: 6.2 ± 0.3, 18 months: 5.5 ± 0.6 mmol/l, p = 0.02). No significant changes were seen in either group regarding glucose and insulin AUC during oGTT or HbA_1c levels. GDR at 18 months increased by 20 ± 39 % in Met + GH-group and decreased by -11 ± 25 % in the Met + Placebo group (differences between the two groups: p = 0.07). In conclusion, treatment of patients with metabolic syndrome and elevated FPG levels did not cause sustained negative effects on glucose metabolism or insulin sensitivity if given in combination with metformin. However, since our data did not show significant differences between the two treatment groups with respect to body composition or lipid metabolism, future studies including larger numbers of patients will have to clarify whether the positive effects of rhGH on cardiovascular risk factors that have been shown in patients with GH deficiency are also present in patients with metabolic syndrome, and are additive to the effects of metformin.

Key words

Growth hormone - Metformin - Metabolic syndrome

References

• 1 Reaven G M. Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
• 2 Rosen T, Eden S, Larson G, Wilhelmsen L, Bengtsson B A. Cardiovascular risk factors in adult patients with growth hormone deficiency.  Acta Endocrinol (Copenh). 1993;  129 195-200
• 3 Johannsson G, Marin P, Lonn L. et al . Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure.  J Clin Endocrinol Metab. 1997;  82 727-734
• 4 Johannsson G, Bengtsson B A. Growth hormone and metabolic syndrome.  J Endocrinol Invest. 1999;  22 41-46
• 5 Franco C, Bengtsson B A, Johannsson G. Visceral obesity and the role of the somatotropic axis in the development of metabolic complications.  Growth Horm IGF Res. 2001;  11 Suppl A S97-S102
• 6 Bjorntorp P, Rosmond R. Neuroendocrine abnormalities in visceral obesity.  Int J Obes Relat Metab Disord. 2000;  24 Suppl 2 S80-S85
• 7 Bjorntorp P. Neuroendocrine abnormalities in human obesity.  Metabolism. 1995;  44 (2 Suppl 2) 38-41
• 8 Veldhuis J D, Liem A Y, South S. et al . Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay.  J Clin Endocrinol Metab. 1995;  80 3209-3222
• 9 Veldhuis J D, Iranmanesh A, Weltman A. Elements in the pathophysiology of diminished growth hormone (GH) secretion in aging humans.  Endocrine. 1997;  7 41-48
• 10 Weltman A, Weltman J Y, Veldhuis J D, Hartman M L. Body composition, physical exercise, growth hormone and obesity.  Eat Weight Disord. 2001;  6 (3 Suppl) 28-37
• 11 Pijl H, Langendonk J G, Burggraaf J. et al . Altered neuroregulation of GH secretion in viscerally obese premenopausal women.  J Clin Endocrinol Metab. 2001;  86 5509-5515
• 12 Marin P, Kvist H, Lindstedt G, Sjostrom L, Bjorntorp P. Low concentrations of insulin-like growth factor-I in abdominal obesity.  Int J Obes Relat Metab Disord. 1993;  17 83-89
• 13 Amato G, Mazziotti G, Di Somma C. et al . Recombinant growth hormone (GH) therapy in GH-deficient adults: a long- term controlled study on daily versus thrice weekly injections.  J Clin Endocrinol Metab. 2000;  85 3720-3725
• 14 Feldt-Rasmussen U, Abs R, Bengtsson B A. et al . Growth hormone deficiency and replacement in hypopituitary patients previously treated for acromegaly or Cushing’s disease.  Eur J Endocrinol. 2002;  146 67-74
• 15 Fowelin J, Attvall S, von Schenck H, Smith U, Lager I. Characterization of the insulin-antagonistic effect of growth hormone in insulin-dependent diabetes mellitus.  Diabet Med. 1995;  12 990-996
• 16 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 1998;  352 854-865
• 17 Knowler W C, Barrett-Connor E, Fowler S E. et al . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med. 2002;  346 393-403
• 18 National Institutes of Health. Third report of the National Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Executive Summary. Bethesda MD,. National Institutes of Health, National Heart, Lung and Blood Institute 2001: No 01-3670
• 19 Alberti K G, Zimmet P Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1. Diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation.  Diabet Med. 1998;  15 539-553
• 20 DeFronzo R A, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.  J Clin Invest. 1985;  76 149-155
• 21 DeFronzo R A, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.  Diabetes Care. 1991;  14 173-194
• 22 Sugimoto M, Takeda N, Hattori J. et al . Pharmacological treatments for GH-induced insulin resistance.  Endocr J. 1999;  46 Suppl S51-S53
• 23 Richelsen B. Effect of growth hormone on adipose tissue and skeletal muscle lipoprotein lipase activity in humans.  J Endocrinol Invest. 1999;  22 10-15
• 24 Johannsson G, Karlsson C, Lonn L. et al . Serum leptin concentration and insulin sensitivity in men with abdominal obesity.  Obes Res. 1998;  6 416-421
• 25 Kay J P, Alemzadeh R, Langley G, D’Angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycemic morbidly obese adolescents.  Metabolism. 2001;  50 1457-1461
• 26 Chu N V, Kong A P, Kim D D. et al . Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.  Diabetes Care. 2002;  25 542-549
• 27 Wulffele M G, Kooy A, De Zeeuw D, Stehouwer C D, Gansevoort R T. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus; a systematic review.  Br J Clin Pharmacol. 2002;  53 549P-550P
• 28 Bengtsson B A, Brummer R J, Bosaeus I. Growth hormone and body composition.  Horm Res. 1990;  33 (Suppl 4) 19-24
• 29 Bengtsson B A. The consequences of growth hormone deficiency in adults.  Acta Endocrinol (Copenh). 1993;  128 Suppl 2 2-5
• 30 Beshyah S A, Freemantle C, Shahi M. et al . Replacement treatment with biosynthetic human growth hormone in growth hormone-deficient hypopituitary adults.  Clin Endocrinol (Oxf). 1995;  42 73-84
• 31 Johnston D G, Al-Shoumer K A, Chrisoulidou A, Kousta E, Beshyah S, Robinson S. Long-term effects of growth hormone therapy on intermediary metabolism and insulin sensitivity in hypopituitary adults.  J Endocrinol Invest. 1999;  22 37-40
• 32 Johannsson G, Oscarsson J, Rosen T. et al . Effects of 1 year of growth hormone therapy on serum lipoprotein levels in growth hormone-deficient adults. Influence of gender and Apo(a) and ApoE phenotypes.  Arterioscler Thromb Vasc Biol. 1995;  15 2142-2150
• 33 Binnerts A, Swart G R, Wilson J H. et al . The effect of growth hormone administration in growth hormone deficient adults on bone, protein, carbohydrate and lipid homeostasis, as well as on body composition.  Clin Endocrinol (Oxf). 1992;  37 79-87
• 34 Eden S, Wiklund O, Oscarsson J, Rosen T, Bengtsson B A. Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations.  Arterioscler Thromb. 1993;  13 296-301
• 35 Vermeulen A, Goemaere S, Kaufman J M. Testosterone, body composition and aging.  J Endocrinol Invest. 1999;  22 110-116
• 36 Marin P, Arver S. Androgens and abdominal obesity.  Baillieres Clin Endocrinol Metab. 1998;  12 441-451
• 37 Lamberts S W, van den Beld A W, van der Lely A J. The endocrinology of aging.  Science. 1997;  278 419-424
• 38 Ozata M, Oktenli C, Bingol N, Ozdemir I C. The effects of metformin and diet on plasma testosterone and leptin levels in obese men.  Obes Res. 2001;  9 662-667
• 39 Oleandri S E, Maccario M, Rossetto R. et al . Three-month treatment with metformin or dexfenfluramine does not modify the effects of diet on anthropometric and endocrine-metabolic parameters in abdominal obesity.  J Endocrinol Invest. 1999;  22 134-140
• 40 Juul A, Andersson A M, Pedersen S A. et al . Effects of growth hormone replacement therapy on IGF-related parameters and on the pituitary-gonadal axis in GH-deficient males. A double- blind, placebo-controlled crossover study.  Horm Res. 1998;  49 269-278