Serum Leptin and Ghrelin Levels in Active and Inactive Acromegalic Patients During an Oral Glucose Tolerance Test

Abstract

Objective: Elevated BMI, fat mass and food intake increases leptin whereas ghrelin is reduced. Ghrelin stimulates growth hormone (GH) secretion. This prospective cross-sectional study was performed to investigate the influence of GH excess on leptin and ghrelin levels at baseline and after glucose load in a large group of acromegalic patients.

Design/Methods: Leptin, ghrelin, GH, glucose and insulin concentrations were measured during a 3 h OGTT in 17 active, 25 inactive patients without medication (inact) and 8 inactive patients treated successfully with somatostatin analogues (inact-SA). Leptin concentration was measured using an in-house immunfluorometric assay, total serum ghrelin by a commercially available radioimmunoassay. Leptin was corrected for BMI.

Results: During OGTT, no significant difference of baseline, nadir or AUC of leptin/BMI was seen between the groups (baseline leptin/BMI: act: 0.26 μgm²/lkg (0.06–0.87); inact: 0.34 μgm²/lkg (0.03–1.79); inact-SA: 0.29 μgm²/lkg (0.03–1.47). A slight but significant reduction of leptin/BMI occurred in all groups during OGTT (active p<0.001, inact p<0.001, inact-SA p<0.05). Inact had higher ghrelin levels (130 ng/L (69–292) compared to active (102 ng/L (27–232); p=n.s.). Inact-SA had significantly lower ghrelin levels (88 ng/L (72–113)) than inact (p<0.001). There was a significant decline of ghrelin during OGTT in all groups (active p<0.001, inact p<0.001, inact-SA p<0.05).

Conclusions: GH only has a slight influence on leptin secretion. Ghrelin levels are lowered by GH and SA. Nevertheless, the physiological decreasing effect of glucose load on ghrelin secretion is preserved.

pituitary adenoma - hormones - leptin - obesity

References

• 1 Baldelli R, Bellone S. et al . Oral glucose load inhibits circulating ghrelin levels to the same extent in normal and obese children.  Clin Endocrinol (Oxf). 2006;  64 ((3)) 255-259
• 2 Baldelli R, Durante C. et al . Serum leptin levels in acromegalic patients before and during somatostatin analogs therapy.  J Endocrinol Invest. 2003;  26 ((12)) 1219-1224
• 3 Banks WA, Tschop M. et al . Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure.  J Pharmacol Exp Ther. 2002;  302 ((2)) 822-827
• 4 Barkan AL, Dimaraki EV. et al . Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels.  J Clin Endocrinol Metab. 2003;  88 ((5)) 2180-2184
• 5 Berneis K, Vosmeer S. et al . Effects of glucocorticoids and of growth hormone on serum leptin concentrations in man.  Eur J Endocrinol. 1996;  135 ((6)) 663-665
• 6 Bolanowski M, Milewicz A. et al . Serum leptin levels in acromegaly – a significant role for adipose tissue and fasting insulin/glucose ratio.  Med Sci Monit. 2002;  8 ((10)) CR685-689
• 7 Bougoulia M, Tzotzas T. et al . Leptin concentrations during oral glucose tolerance test (OGTT) in obese and normal weight women.  Int J Obes Relat Metab Disord. 1999;  23 ((6)) 625-628
• 8 Brabant G, zur Muhlen A von. et al . Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study.  Horm Res. 2003;  60 ((2)) 53-60
• 9 Broglio F, Benso A. et al . The endocrine response to ghrelin as a function of gender in humans in young and elderly subjects.  J Clin Endocrinol Metab. 2003;  88 ((4)) 1537-1542
• 10 Broglio F, Gottero C. et al . Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans.  Clin Endocrinol (Oxf). 2004;  61 ((4)) 503-509
• 11 Cappiello V, Ronchi C. et al . Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients.  Eur J Endocrinol. 2002;  147 ((2)) 189-194
• 12 Casanueva FF, Dieguez C. Interaction between body composition, leptin and growth hormone status.  Baillieres Clin Endocrinol Metab. 1998;  12 ((2)) 297-314
• 13 Corica F, Corsonello A. et al . Leptin and norepinephrine plasma concentrations during glucose loading in normotensive and hypertensive obese women.  Am J Hypertens. 2001;  14 ((7 Pt 1)) 619-626
• 14 Cummings DE, Foster-Schubert KE. et al . Ghrelin and energy balance: focus on current controversies.  Curr Drug Targets. 2005;  6 ((2)) 153-169
• 15 Cummings DE, Shannon MH. Roles for ghrelin in the regulation of appetite and body weight.  Arch Surg. 2003;  138 ((4)) 389-396
• 16 Damjanovic SS, Petakov MS. et al . Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by trans-sphenoidal surgery.  J Clin Endocrinol Metab. 2000;  85 ((1)) 147-154
• 17 Date Y, Kojima M. et al . Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans.  Endocrinology. 2000;  141 ((11)) 4255-4261
• 18 Farin HM, Abbasi F. et al . Body mass index and waist circumference both contribute to differences in insulin-mediated glucose disposal in nondiabetic adults.  Am J Clin Nutr. 2006;  83 ((1)) 47-51
• 19 Freda PU, Reyes CM. et al . Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy.  J Clin Endocrinol Metab. 2003;  88 ((5)) 2037-2044
• 20 Giavoli C, Cappiello V. et al . Different effects of short- and long-term recombinant hGH administration on ghrelin and adiponectin levels in GH-deficient adults.  Clin Endocrinol (Oxf). 2004;  61 ((1)) 81-87
• 21 Giusti M, Bocca L. et al . In vitro effect of human recombinant leptin and expression of leptin receptors on growth hormone-secreting human pituitary adenomas.  Clin Endocrinol (Oxf). 2002;  57 ((4)) 449-455
• 22 Hamann A, Matthaei S. Regulation of energy balance by leptin.  Exp Clin Endocrinol Diabetes. 1996;  104 ((4)) 293-300
• 23 Horvath TL, Diano S. et al . Minireview: ghrelin and the regulation of energy balance – a hypothalamic perspective.  Endocrinology. 2001;  142 ((10)) 4163-4169
• 24 Imbeault P, Doucet E. et al . Difference in leptin response to a high-fat meal between lean and obese men.  Clin Sci (Lond). 2001;  101 ((4)) 359-365
• 25 Isozaki O, Tsushima T. et al . Interaction between leptin and growth hormone (GH)/IGF-I axis.  Endocr J. 1999;  46 (Suppl) 17-24
• 26 Janssen JA, Toorn FM van der. et al . Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy.  Eur J Endocrinol. 2001;  145 ((6)) 711-716
• 27 Jarkovska Z, Rosicka M. et al . Plasma levels of total and active ghrelin in acromegaly and growth hormone deficiency.  Physiol Res. 2006;  55 ((2)) 175-181
• 28 Jenkins AB, Markovic TP. et al . Carbohydrate intake and short-term regulation of leptin in humans.  Diabetologia. 1997;  40 ((3)) 348-351
• 29 Kawamata T, Inui A. et al . Perioperative plasma active and total ghrelin levels are reduced in acromegaly when compared with in nonfunctioning pituitary tumours even after normalization of serum GH.  Clin Endocrinol (Oxf). 2007;  67 ((1)) 140-144
• 30 Kojima M, Hosoda H. et al . Ghrelin is a growth-hormone-releasing acylated peptide from stomach.  Nature. 1999;  402 ((6762)) 656-660
• 31 Korbonits M, Trainer PJ. et al . Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary-adrenal activity.  Clin Endocrinol (Oxf). 1997;  46 ((6)) 751-757
• 32 Kozakowski J, Rabijewski M. et al . Decrease in serum ghrelin levels in patients with acromegaly normalize after successful surgical treatment.  Endokrynol Pol. 2005;  56 ((6)) 862-870
• 33 Lloyd RV, Jin L. et al . Leptin and leptin receptor in anterior pituitary function.  Pituitary. 2001;  4 ((1–2)) 33-47
• 34 Malik IA, English PJ. et al . The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency.  Clin Endocrinol (Oxf). 2004;  60 ((1)) 137-141
• 35 Miyakawa M, Tsushima T. et al . Effect of growth hormone (GH) on serum concentrations of leptin: study in patients with acromegaly and GH deficiency.  J Clin Endocrinol Metab. 1998;  83 ((10)) 3476-3479
• 36 Norrelund H, Hansen TK. et al . Ghrelin immunoreactivity in human plasma is suppressed by somatostatin.  Clin Endocrinol (Oxf). 2002;  57 ((4)) 539-546
• 37 Otto B, Spranger J. et al . The many faces of ghrelin: new perspectives for nutrition research?.  Br J Nutr. 2005;  93 ((6)) 765-771
• 38 Parkinson C, Whatmore AJ. et al . The effect of pegvisomant-induced serum IGF-I normalization on serum leptin levels in patients with acromegaly.  Clin Endocrinol (Oxf). 2003;  59 ((2)) 168-174
• 39 Popovic V, Damjanovic S. et al . Leptin and the pituitary.  Pituitary. 2001;  4 ((1–2)) 7-14
• 40 Rindi G, Torsello A. et al . Ghrelin expression and actions: a novel peptide for an old cell type of the diffuse endocrine system.  Exp Biol Med (Maywood). 2004;  229 ((10)) 1007-1016
• 41 Romon M, Lebel P. et al . Postprandial leptin response to carbohydrate and fat meals in obese women.  J Am Coll Nutr. 2003;  22 ((3)) 247-251
• 42 Romon M, Lebel P. et al . Leptin response to carbohydrate or fat meal and association with subsequent satiety and energy intake.  Am J Physiol. 1999;  277 ((5 Pt 1)) E855-861
• 43 Saad MF, Damani S. et al . Sexual dimorphism in plasma leptin concentration.  J Clin Endocrinol Metab. 1997;  82 ((2)) 579-584
• 44 Takaya K, Ariyasu H. et al . Ghrelin strongly stimulates growth hormone release in humans.  J Clin Endocrinol Metab. 2000;  85 ((12)) 4908-4911
• 45 Tan KC, Tso AW. et al . Effect of Sandostatin LAR on serum leptin levels in patients with acromegaly.  Clin Endocrinol (Oxf). 2001;  54 ((1)) 31-35
• 46 Torsello A, Bresciani E. et al . Ghrelin and GH secretion.  Minerva Endocrinol. 2002;  27 ((4)) 257-264
• 47 Tschop M, Flora DB. et al . Hypophysectomy prevents ghrelin-induced adiposity and increases gastric ghrelin secretion in rats.  Obes Res. 2002;  10 ((10)) 991-999
• 48 Tschop M, Weyer C. et al . Circulating ghrelin levels are decreased in human obesity.  Diabetes. 2001;  50 ((4)) 707-709
• 49 Lely AJ van der, Tschop M. et al . Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.  Endocr Rev. 2004;  25 ((3)) 426-457
• 50 Toorn FM van der, Janssen JA. et al . Central ghrelin production does not substantially contribute to systemic ghrelin concentrations: a study in two subjects with active acromegaly.  Eur J Endocrinol. 2002;  147 ((2)) 195-199
• 51 Wasko R, Jaskula M. et al . Ghrelin concentrations in acromegalic patients in relation to the administered therapy.  Neuro Endocrinol Lett. 2006;  27 ((1–2)) 162-168
• 52 Woods SC, Schwartz MW. et al . Food intake and the regulation of body weight.  Annu Rev Psychol. 2000;  51 255-277
• 53 Wu Z, Bidlingmaier M. et al . Quantification of the soluble leptin receptor in human blood by ligand-mediated immunofunctional assay.  J Clin Endocrinol Metab. 2002;  87 ((6)) 2931-2939

Correspondence