Abstract
Abdominal obesity is connoted by hyperinsulinism and insulin insensitivity, a trend toward glucose intolerance, hypoactivity of GH/IGF-I axis and alterations of hypothalamo-pituitary-adrenal (HPA) axis. It has been hypothesized that treatment with metformin (MET) and dexfenfluramine (DEX) could counteract those endocrine- metabolic alterations. Thus, we studied the effects of 3-month treatment with MET or DEX on anthropometric (BMI, WHR, FM and FFM), metabolic (basal and OGTT-induced glucose) and hormonal variables (IGF-I, DHEA-S, androstendione, testosterone, fT3, fT4, TSH, basal and OGTT-induced insulin) as well as on blood pressure in 28 normotensive patients with abdominal obesity (OB, 3 M, 25 F; 47.5±1.5 yr [mean±SE], BMI 35.4±1.1 kg/m2, WHR 0.98±0.04 and 0.86±0.07, in M and F, respectively). All patients were on balanced hypocaloric diet (1400 Kcal/day). Patients were randomly assigned to treatment with MET (no.=10, 500 mg twice daily po) or DEX (no.=10, 15 mg thrice daily po) or placebo (no.=8). Before treatment all groups had similar anthropometric, metabolic and hormonal values. After 3-month treatment with MET, DEX or placebo, weight, BMI and WHR reductions were similar in all groups (p<0.05 vs baseline in either group). In each group FFM/FM ratio showed non significant trend toward increase. No significant variations in metabolic and endocrine variables were recorded in each group after 1 and 3-month treatment. However, glucose tolerance, OGTT-induced insulin response, glucose/ insulin ratio showed a similar trend toward improvement in all groups, while IGF-I, 24 h urinary cortisol, DHEA-S, androstendione, testosterone, thyroid hormone and TSH levels did not show any variation. Significant (p<0.02) and similar reductions of DBP, but not of SBP, levels were found in all groups. In conclusion, our findings demonstrate that, at least after 3-month treatment, metformin and dexfenfluramine do not modify the effects of diet on anthropometric, metabolic and hormonal parameters as well as on blood pressure in patients with abdominal obesity.
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References
National Institute of Health Consensus Development Panel on the health implications of obesity. Consensus Conference Statement. Ann. Int. Med. 103: 1073, 1985.
Caro J.F. Insulin resistance in obese and nonobese man. J. Clin. Endocrinol. Metab. 73: 691, 1991.
De Fronzo R.A., Ferranini E. Insulin Resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14: 3, 1991.
Letiexhe M.R., Scheen A.J., Gérard P.L., Desaive C., Lefebvre P.J. Postgastroplasty recovery of ideal body weight normalizes glucose and insulin metabolism in obese women. J. Clin. Endocrinol. Metab. 80: 364, 1995.
Guy-Grand B., Crepaldi G., Lefebvre P., Apfelbaum M., Gries A., Turner P. International trial of long-term dexfenfluramine in obesity. Lancet ii: 1142, 1989.
Scheen A.J., Letiexhe M.R., Lefèbvre P.J. Effects of metformin in obese patients with impaired glucose tolerance. Diabetes Metab. Rev. 11: S70, 1995.
Reaven G.M. Effect of metformin on various aspects of glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus with varying degrees of hyperglycemia. Diabetes Metab. Rev. 11: 97, 1995.
Blundell J.E. Serotonin and the biology of feeding. Am. J. Clin. Nutr. 55: 155S, 1992.
Pijl H., Koppeschaar H.P.F., Willekens L.A., Frolich F., Meinders E. The influence of serotonergic neurotransmission on pituitary hormone release in obese and non-obese females. Acta Endocrinol. (Copenh.) 128: 319, 1993.
Muller E.E., Nisticò G. Brain messengers and the pituitary. Academic Press, New York, 1989, p. 98.
Lee A.J. Metformin in non insulin-dependent diabetes mellitus. Pharmacotherapy 16, 31: 327, 1996.
Bailey C.J. Biguanides and NIDDM. Diabetes Care 45: 755, 1992.
De Fronzo R., Barzilai S., Simonson D.L. Mechanism of metformin action in obese and lean non insulin-dependent diabetic subjects. J. Clin. Endocrinol. Metab. 73: 1294, 1991.
Bailey C.J. Metformin and intestinal glucose handling. Diabetes Metab. Rev. 11: S23, 1995.
Del Prato S., Marchetto S., Pipitone A., Zanon M., de Kreutzenberg S.V., Tiengo A. Metformin and free fatty acid metabolism. Diabetes Metab. Rev. 11: 533, 1995.
Rouru J., Pesonen U., Koulu M., Huupponem R., Santti E., Virtanen K., Jhanwar-Uniyal M. Anorectic effect of metformin in obese zucher rats. Lack of evidence for the involment of neuropeptide Y. Eur. J. Pharm. 273: 99, 1995.
Giugliano D., De Rosa N., Di Mario G., Marfella R., Acampera R., Buoninconti R., D’Onofrio F. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 16: 1378, 1993.
Landin K., Teng Born L., Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J. Intern. Med. 229: 181, 1991.
Guy-Grand B. Clinical studies with d-fenfluramine. Am. J. Clin. Nutr. 55: 173S, 1992.
Garattini S., Bizzi A., Codegoni A.M., Caccia S., Mennini T. Progress report on the anorexia induced by drugs believed to mimic some of the effects of serotonin on the central nervous system. Am. J. Clin. Nutr. 55: 160, 1992.
McCann U.D., Seiden L.S., Rubin L.J., Ricaurte G.A. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. JAMA 278: 666, 1997.
Bremer J.M., Scott R.S., Lintott C. Dexfenfluramine reduces cardiovascular risk factors. Int. J. Ob. 18: 199, 1994.
Scheen A.J., Paolisso G., Salvatore T., Lefébvre P.J. Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine. Diabetes Care 14: 325, 1991.
Verdy M., Charbonneau L., Verdy I., Belanger R., Bolte E., Chiasson J.L. Fenfluramine in the treatment of non-insulin-dependent diabetics: hypoglycemic versus anorectic effect. Int. J. Obes. 7: 289, 1983
Bernini G.P., Argenio G.F., Vivaldi M.S., Del Corso C., Birindelli R., Luisi M., Franchi F. Impaired growth hormone response to insulin-induced hypoglycaemia in obese patients: restoration blocked by ritanserin after fenfluramine administration. Clin. Endocrinol. (Oxf.) 32: 453, 1990.
Medeiros-Neto G., Lima N., Perozim L., Pedrinola F., Wajchenberg L. The effect of hypocaloric diet with and without dfenfluramine treatment on growth hormone release after growth hormone-releasing factor stimulation in patients with android obesity. Metabolism 43: 969, 1994.
Schurmeyer T.H., Brademann G., von zur Muhlen A. Effect of fenfluramine on episodic ACTH and cortisol secretion. Clin. Endocrinol. (Oxf.) 45: 39, 1996.
Veldhuis J.D., Iranmanesh A., Ho K.K.Y., Waters M.J., Johnson M.L., Lizarralde G. Dual effects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J. Clin. Endocrinol. Metab. 72: 51, 1991.
Smith S.R. The endocrinology of obesity. Endocrinol. Metab. Clin. North Am. 25: 921, 1996.
Pasquali R., Cantobelli S., Casimirri F., Capelli M., Bortoluzzi F., Flamia R., Morselli-Labate A.M., Barbara L. The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution. J. Clin. Endocrinol. Metab. 77: 341, 1993.
Crepaldi G., Belfiore F., Bosello O., Caviezel F., Contaldo F., Enzi G., Melchionda G. Consensus Conference Italiana: sovrappeso, obesità e salute. (CCI S.O.S ′91). Ann. Ital. Med. Int. 6: 349, 1991.
Nestler J.E., Beer N.A., Jakubowicz D.J., Beer R.M. Effects of a reduction in circulating insulin by metformin on serum dehydroepiandrosterone sulfate in nondiabetic men. J. Clin. Endocrinol. Metab. 78: 549, 1994.
Fendri S., Debussche X., Puy H., Vincent O., Marcelli J.M., Debreuil A., Lalau J.D. Metformin effects on peripheral sensitivity to insulin in non diabetic obese subjects. Diabet. Metab. 19: 245, 1993.
Gudbjornsdottir S., Friberg P., Elam M., Atvall S., Lonnroth P., Wallin B.G. The effect of metformin and insulin on sympathetic nerve activity, norepinephrine spillover and blood pressure in obese, insulin resistant, normoglycemic, hypertensive men. Blood Pressure 3: 394, 1994.
Ditschueit H.H., Flechtner-Mors M., Dolderer M., Fulda U., Ditscuneit H. Endocrine and metabolic effects of dexfenfluramine in patients with android obesity. Horm. Metab. Res. 25: 573, 1993.
Pestell R.G., Crock P.A., Ward G.M., Alford F.P., Best J.D. Fenfluramine increases insulin action in patients with NIDDM. Diabetes Care 12: 252, 1989.
Tchernof A., Despres J.P., Belanger A., Dupont A., Prud’Homme D., Moorjani S., Lupien P.J., Labrie F. Reduced testosterone and adrenal C19 steroid levels in obese men. Metabolism 44: 513, 1995.
Copeland K.C., Colletti R.B., Devlin J.T., McAuliffe T.L. The relationship between insulin-like growth factor- I, adiposity, and aging. Metabolism 39: 584, 1990.
Phillips G.B. Relationship between serum sex hormones and glucose- insulin-lipid defect in men with obesity. Metabolism 42: 116, 1993.
Caufriez A., Golstein J., Lebrun P., Herchuelz A., Furlanetto R., Copinschi G. Relations between immunoreactive somatomedin C, insulin and T3 patterns during fasting in obese subjects. Clin. Endocrinol. (Oxf.) 20: 65, 1984.
Azziz R., Zacur H.A., Parker C.R. Jr., Bradley E.L. Jr., Boots L.R. Effect of obesity on the response to acute adrenocorticotropin stimulation in eumenorrhoic women. Fertil. Steril. 56: 427, 1991.
Barrett-Connor E., Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study. J. Clin. Endocrinol. Metab. 81: 59, 1996.
Hochberg Z., Hertz P., Colin V., Ish-shalom S., Yeshurun D., Youdim M.B.H., Amit T. The distal axis of growth hormone (GH) in nutritional disorder: GH-binding protein, insulin-like growth factor- I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa. Metabolism 41: 106, 1992.
Tchernof A., Labrie F., Bélanger A., Després J.P. Obesity and metabolic complications: contribution of dehydroepiandrosterone and other steroid hormones. Endocrinology 150: S155, 1996.
Nestler J.E., Clore J.N., Strauss J.F., Blackard W.G. The effect of hyperinsulinemia on serum testosterone, progesterone, dehyepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. J. Clin. Endocrinol. Metab. 64: 180, 1987.
Houston B., O’Neil I.E. Insulin and growth hormone act synergistically to stimulate insulin-like growth factor-I production by cultered chicken hepatocytes. J. Endocrinol. 128: 389, 1991.
Nestler J.E., McClanahan, Clore J.N., Blackard W.G. Insulin inhibits adrenal 17, 20-lyase activity in man. J. Clin. Endocrinol. Metab. 74: 362, 1992.
Clemmons D.R., Van Wyk J.J. Factors controlling blood concentrations of somatomedin C. J. Clin. Endocrinol. Metab. 13: 113, 1984.
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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 22, 134–140 (1999). https://doi.org/10.1007/BF03350893
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DOI: https://doi.org/10.1007/BF03350893