Effects of a Combination of rhGH and Metformin on Adiponectin Levels in Patients with Metabolic Syndrome

Abstract

Adiponectin is a recently discovered adipocytokine that correlates negatively with body mass index and body fat. In patients with GH deficiency, treatment with recombinant human growth hormone (rhGH) reduces body fat mass and thus may also have a favorable effect in patients with metabolic syndrome, and would also be expected to increase adiponectin levels. However, due to its diabetogenic effect, rhGH treatment also bears an increased risk for the development of type 2 diabetes mellitus. We conducted a 18-month randomized, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (MGH) in 14 obese men (7 MGH; 7 Metformin+Placebo, 54 ± 2 years, BMI 33.0 ± 1.2 kg/m²) with mildly elevated fasting plasma glucose (FPG) at screening (6.1-8.0mmol/l). All patients received metformin (850 mg twice daily) for treatment of type 2 diabetes mellitus/impaired glucose tolerance, either alone or in combination with rhGH (daily dose 9.5 μg/kg body weight). Glucose disposal rate (GDR) was measured using the euglycemic hyperinsulinemic clamp technique, and body composition was measured by DEXA at 0 and 18 months. After 18 months, the mean adiponectin concentration increased by 32 ± 11 % (p = 0.018) in the MGH group and did not change in the MP group (- 10 ± 13 %; p = n. s.). The difference in relative changes in adiponectin levels between the two groups after 18 months was statistically significant (p = 0.026). Improvement in insulin sensitivity (GDR) correlated positively with adiponectin levels (r = 0.73; p = 0.004). In conclusion, the additional administration of rhGH increased adiponectin levels in patients with metabolic syndrome, indicating its potential role in adiponectin-associated insulin sensitivity alterations.

Key words

Adiponectin - Growth hormone - Metabolic syndrome

References

• 1 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
• 2 Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof K, Bjorntorp P, Sjostrom L, Bengtsson B A. 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
• 3 Johannsson G, Bengtsson B A. Growth hormone and the metabolic syndrome.  J Endocrinol Invest. 1999;  22 41-46
• 4 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
• 5  . 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
• 6 Knowler W C, Barrett-Connor E, Fowler S E, Hamman R F, Lachin J M, Walker E A, Nathan D M. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med. 2002;  346 393-403
• 7 Mohlig M, Wegewitz U, Osterhoff M, Isken F, Ristow M, Pfeiffer A F, Spranger J. Insulin decreases human adiponectin plasma levels.  Horm Metab Res. 2002;  34 655-658
• 8 Skurk T, Van Harmelen V, Lee Y M, Wirth A, Hauner H. Relationship between IL-6, Leptin and Adiponectin and Variables of Fibrinolysis in Overweight and Obese Hypertensive Patients.  Horm Metab Res. 2002;  34 659-663
• 9 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
• 10 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
• 11 Statnick M A, Beavers L S, Conner L J, Corominola H, Johnson D, Hammond C D, Rafaeloff-Phail R, Seng T, Suter T M, Sluka J P, Ravussin E, Gadski R A, Caro J F. Decreased expression of apM1 in omental and subcutaneous adipose tissue of humans with type 2 diabetes.  Int J Exp Diabetes Res. 2000;  1 81-88
• 12 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley R E, Tataranni P A. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
• 13 Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno N H, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.  Nature. 2003;  423 762-769
• 14 Fasshauer M, Klein J, Kralisch S, Klier M, Lossner U, Bluher M, Paschke R. Growth hormone is a positive regulator of adiponectin receptor 2 in 3T3-L1 adipocytes.  FEBS Lett. 2004;  558 27-32
• 15 Zimmet P Z, King H O, Bjorntorp S P. Obesity, hypertension, carbohydrate disorders and the risk of chronic diseases. Is there any epidemiological evidence for integrated prevention programmes?.  Med J Aust. 1986;  145 256-259, 262
• 16 Zimmet P, Bjorntorp P. Adipose tissue cellularity in obese nondiabetic men in an urbanized Pacific island (Polynesian) population.  Am J Clin Nutr. 1979;  32 1788-1791
• 17 Herrmann B L, Berg C, Vogel E, Nowak T, Renzing-Koehler K, Mann K, Saller B. Effects of a combination of recombinant human growth hormone with metformin on glucose metabolism and body composition in patients with metabolic syndrome.  Horm Metab Res. 2004;  36 54-61
• 18 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
• 19 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
• 20 Fruebis J, Tsao T S, Javorschi S, Ebbets-Reed D, Erickson M R, Yen F T, Bihain B E, Lodish H F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.  Proc Natl Acad Sci U S A. 2001;  98 2005-2010
• 21 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman M L, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.  Nat Med. 2001;  7 941-946
• 22 Kappes A, Loffler G. Influences of ionomycin, dibutyryl-cycloAMP and tumour necrosis factor- alpha on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes.  Horm Metab Res. 2000;  32 548-554
• 23 Arner P. The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.  Trends Endocrinol Metab. 2003;  14 137-145
• 24 Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.  Diabetes. 2001;  50 2094-2099
• 25 Bengtsson B A, Brummer R J, Bosaeus I. Growth hormone and body composition.  Horm Res. 1990;  33 19-24
• 26 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
• 27 Chu N V, Kong A P, Kim D D, Armstrong D, Baxi S, Deutsch R, Caulfield M, Mudaliar S R, Reitz R, Henry R R, Reaven P D. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes.  Diabetes Care. 2002;  25 542-549
• 28 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
• 29 Phillips S A, Ciaraldi T P, Kong A P, Bandukwala R, Aroda V, Carter L, Baxi S, Mudaliar S R, Henry R R. Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy.  Diabetes. 2003;  52 667-674