Acute Hyperinsulinemia is Associated with Increased Plasma Adrenomedullin Concentrations in Uncomplicated Obesity

Abstract

Objective: Adrenomedullin (AM) is a potent hypotensive peptide which may be implicated in the insulin regulatory system. Acute hyperinsulinemia exerts no influence on plasma AM in normal subjects while no data on obese subjects has been reported.

Purpose: The aim of the study was to investigate the effect of acute hyperinsulinemia on the plasma AM concentration in patients with uncomplicated obesity.

Research Methods: We measured the plasma AM levels in 23 obese subjects (BMI 41.9 ± 9.8 kg/m²), 21 females and 2 males (mean age 31 ± 7.2 years), before and during a euglycemic hyperinsulinemic clamp. The control group consisted of 43 healthy subjects (HS) (22 males and 21 females; mean age 38 ± 12 years; BMI 23.3 ± 3.2 kg/m²).

Results: Baseline plasma AM was found to be higher in obese subjects (20.4 ± 8.4 pg/ml) than in normal subjects (11.3 ± 0.8 pg/ml) (p < 0.001). A significant increase in the plasma AM levels was observed in obese subjects during acute hyperinsulinemia (from 20.4 ± 8.4 pg/ml at 0 min to 26 ± 8.9 pg/ml at 120 min, p < 0.02). Plasma AM concentrations were significantly correlated with insulin levels at 30 min (r = 0.44; p = 0.04) and 120 min (r = 0.40, p = 0.05) during the clamp.

Discussion: In conclusion, acute hyperinsulinemia induced a significant increase in the plasma levels of AM in uncomplicated obese subjects. Hyperinsulinemia may, at least in part, regulate levels of AM in obesity, explaining the high levels of the peptide in these subjects.

Key words

Adrenomedullin - euglycemic hyperinsulinemic clamp

References

• 1 Bonadonna R C, Groop L, Kramer N, Ferrannini E, Del Prato S, De Fronzo R A. Obesity and insulin resistance in humans: a dose-response study.  Metabolism. 1990;  39 452-459
• 2 Charles C J, Rademaker M T, Richards A M, Coeper G J, Coy D H, Jing N Y, Nicholls M G. Hemodynamic, hormonal and renal effects of adrenomedullin in conscious sheep.  Am J Physiol. 1997;  272 (6 Pt 2) R2040-2047
• 3 DeFronzo R A, Tobin J D, Andres R. Glucose clamp tecnique: a method for quantifying insulin secretion resistance.  Am J Physiol. 1979;  237 E214-E222
• 4 Di Iorio R, Marinoni E, Scavo D, Letizia C, Cosmi E V. Adrenomedullin in pregnancy.  Lancet. 1997;  349 328-(letter)
• 5 Ebara T, Miura K, Okumura M, Matsuura T, Kimi S, Yukimura T, Iwao H. Effect of adrenomedullin on renal hemodynamics and functions in dogs.  Eur J Pharmacol. 1994;  263 69-73
• 6 Eto T, Kitamura K, Kato J. Biological and clinical roles of adrenomedullin in circulation control and cardiovascular diseases.  Clinical Exp Pharmacol Physiol. 1999;  26 371-380
• 7 Fukuhara M, Tsuchiohashi T, Abe I, Fujishima M. Cardiovascular and neurohormonal effects of intravenous adrenomedullin in conscious rabbits.  Am J Physiol. 1995;  269 R1289-1293
• 8 Grey N, Kipnis D M. Effect of diet composition on the hyperinsulinemia of obesity.  N Engl J Med. 1971;  285 827-831
• 9 Iacobellis G, Ribaudo M C, Leto G, Zappaterreno A, Vecci E, Di Mario U. Influence of excess fat on cardiac morphology and function: study in uncomplicated obesity.  Obes Res. 2002;  10 767-773
• 10 Ichiki Y, Kitamura K, Kangawa K, Kawamoto M, Matsuo H, Eto T. Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma.  FEBS Lett. 1994;  338 6-10
• 11 Katsuki A, Sumida Y, Gabazza E C, Murashima S, Urakawa H, Morioka K, Kitagawa N, Tanaka T, Araki-Sasaki R, Hori Y, Nakatani K, Yano Y, Adachi Y. Acute hyperinsulinemia is associated with increased circulating levels of adrenomedullin in patients with type 2 diabetes mellitus.  Eur J Endocrinol. 2002;  147 71-75
• 12 Kitamura K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma.  Biochem Biophys Res Commun. 1993;  192 553-560
• 13 Letizia C, Cerci S, Centanni M, De Toma G, Subioli S, Scuro L. Circulating levels of adrenomedullin in patients with Addison's disease before and after corticosteroid treatment.  Clin Endocrinol (Oxf). 1998;  48 145-148
• 14 Letizia C, Tamburrano G, Alò P, Paoloni A, Caliumi C, Marinoni E. Adrenomedullin, a new peptide, in patients with insulinoma.  Eur J Endocrinol. 2001;  144 517-520
• 15 Lainchbury J G, Troughton R W, Lewis L K, Yandle T G, Richards A M, Nicholls M G. Hemodynamic, hormonal and renal effects of short-term adrenomedullin infusion in healthy volunteers.  J Clin Endocrinol Metab. 2000;  85 1016-1020
• 16 Majid D S, Kadowitz P J, Coy D H, Navar L G. Renal responses to intra-arterial administration of adrenomedullin in dogs.  Am J Physiol. 1996;  270 F200-F205
• 17 Marinoni E, Di Iorio R, Letizia C, Villaccio B, Scucchi L, Cosmi E V. Immunoreactive adrenomedullin in human fetoplacental tissues.  Am J Obstet Gynecol. 1998;  178 784-787
• 18 Martinez A, Weaver C, Lopez J, Bhathena S J, Elsasser T H, Miller M J, Moody T W, Unworth E J, Cutitta F. Regulation of insulin secretion and blood glucose metabolism by adrenomedullin.  Endocrinology. 1996;  137 2626-2632
• 19 Martinez A, Cutitta F, Teitelman G. Expression pattern for adrenomedullin during pancreatic development in the rat reveals a common precursor with other endocrine cell types.  Cell Tissue Res. 1998;  293 95-100
• 20 Messerli F H, Ventura H O, Reisin E, Dreslinski G R, Dunn F G, MacPhee A A, Frohlich E D. Borderline hypertension and obesity: two prehypertensive states with elevated cardiac output.  Circulation. 1982;  66 55-60
• 21 Minami J, Nishikimi T, Ishimitsu T, Makino Y, Kawano Y, Takaishita S, Kangawa K, Matsuoka H. Effect of an hypocaloric diet on adrenomedullin and natriuretic peptides in obese patients with essential hypertension.  J Cardiovasc Pharmacol. 2000;  36 (Suppl 2) 583-586
• 22 Nagai Y, Yamashita H, Takamura T, Kobayashi K I. Does acute hyperinsulinemia change plasma adrenomedullin concentration in healthy men?.  Diab Med. 2000;  17 249-250
• 23 Nagaya N, Nishikimi T, Horio T, Yoshihara F, Kanazawa A, Matsuo H, Kangawa K. Cardiovascular and renal effects of adrenomedullin in rats with heart failure.  Am J Physiol. 1999;  276 R213-218
• 24 Nakamura M, Yoshida H, Makita S, Arakawa N, Niinuma H, Hiramori K. Potent and long-lasting vasodilatory effects of adrenomedullin in humans. Comparison between normal subjects and patients with chronic heart failure.  Circulation. 1997;  95 1214-1221
• 25 Parkes D G. Cardiovascular actions of adrenomedullin in conscious sheep.  Am J Physiol. 1995;  268 H2574-H2578
• 26 Rademaker M T, Charles C J, Lewis L K, Yandle T G, Cooper G J, Coy D H, Richards A M, Nicholls M G. Benefical hemodynamic and renal effects of adrenomedullin in an ovine model of heart failure.  Circulation. 1997;  96 1983-1990
• 27 Raison J, Achimastos A, Asmar R, Simon A, Safar M. Extracellular and interstitial fluid volume in obesity with and without associated systemic hypertension.  Am J Cardiol. 1986;  57 223-226
• 28 Richards A M, Nicholls M G, Lewis L, Lainchbury J G. Adrenomedullin.  Clin Sci. 1996;  91 3-16
• 29 Salans L, Knittle J, Hirsch J. The role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity.  J Clin Invest. 1968;  47 153-165
• 30 Sato K, Hirata J, Irai T, Iwashina M, Marmo E. Characterization of immunoreactive adrenomedullin in human plasma and urine.  Life Sci. 1995;  57 189-194
• 31 Sowers J R, Whitfield L A, Catania R A, Stern N, Tuck M L, Dornfeld L, Maxwell M. Role of sympathetic nervous system in blood pressure maintenance in obesity.  J Clin Endocrinol Metab. 1982;  54 1181-1186
• 32 Stern J, Batchelor B R, Hollander N, Cohn C K, Hirsch J. Adipose-cell size and immunoreactive insulin levels in obese and in normal-weight adults.  Lancet. 1972;  2 (7784) 948-951