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| ID | Type | Description | Link |
|---|---|---|---|
| WI182140 | Other Grant/Funding Number | Pfizer |
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| Name | Class |
|---|---|
| Pfizer | INDUSTRY |
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Acromegaly is a rare hormonal disorder leading to increased morbidity and mortality. In the vast majority of cases, a pituitary somatotroph cell adenoma causes excess growth hormone (GH) secretion, leading to hepatic insulin-like-growth factor 1 (IGF-1) hypersecretion. Both the disease as well as its treatment with long-acting somatostatin analogs (LA-SMSA) and/or pegvisomant affect glucose and lipid metabolism, possibly contributing to increased cardiovascular risk.
In this pilot study, the investigators want to explore insulin sensitivity, postprandial gut hormone response, lipid handling and adipocytokine profile in the following 4 groups:
Furthermore, a longitudinal exploration will be performed in uncontrolled acromegalic patients (i.e. patients with serum IGF-1 levels above age-specific thresholds and/or symptoms due to active acromegaly (excessive sweating , arthralgia)) on LA-SMSA monotherapy (group 5). In this group, insulin sensitivity, postprandial gut hormone response, lipid handling and adipocytokine profile will be explored before introducing pegvisomant and three months after normalisation of IGF-1 levels.
The investigators hypothesize that lipid and glucose handling will be less efficient in the controlled acromegalic patients on LA-SMSA than in controlled patients on combination therapy or after surgery, and that there will be no difference in substrate metabolism between healthy controls and controlled acromegalic patients on combination treatment or after surgery. Further, they hypothesize that introducing pegvisomant in uncontrolled acromegalic patients will improve their postprandial lipid and glucose handling.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Controlled on LA-SMSA | Patients with controlled acromegaly on long-acting somatostatin analogs | ||
| Controlled on LA-SMSA and pegvisomant | Patients with controlled acromegaly on long-acting somatostatin analogs and pegvisomant | ||
| Controlled after surgery | Controlled acromegaly patients without need for medical therapy after surgery | ||
| Healhy controls | Healthy volunteers | ||
| Uncontrolled on LA-SMSA | Patients with uncontrolled acromegaly (i.e. with serum IGF-1 levels above age-specific thresholds and/or symptoms due to active acromegaly (e.g. excessive sweating, arthralgia)) on LA-SMSA monotherapy in maximal dosage |
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| Measure | Description | Time Frame |
|---|---|---|
| change in insulin sensitivity | Glucose disposal rate during last half hour of hyperinsulinemic-euglycemic clamp procedure, corrected for lean body mass (in µmol/min/kgLBM) | before start of pegvisomant and 3 months after normalisation of IGF-1 after start of pegvisomant in group 5 |
| insulin sensitivity | Glucose disposal rate during last half hour of hyperinsulinemic-euglycemic clamp procedure, corrected for lean body mass (in µmol/min/kgLBM) | At enrollment in groups 1-4 |
| Measure | Description | Time Frame |
|---|---|---|
| fasting and postprandial glucose | Serum glucose levels during mixed-meal test (before and 10, 30, 60, 120, 180, 240, 300 minutes after ingestion of standard mixed-meal (bread, margarine, cheese and milk) providing a caloric content of 1000 kCal whereby 45% of the energy comes from fat, 36% from carbohydrates and 19% from proteins) | At enrollment in groups 1-4 |
| Measure | Description | Time Frame |
|---|---|---|
| Resting energy expenditure | Resting energy expenditure determined using indirect calorimetry | At enrollment in group 1-4 |
| Weight | At enrollment in group 1-4 |
Inclusion Criteria:
Exclusion Criteria:
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Groups 1-3 and 5: outpatient clinic attendants Group 4: recruted from community (by placard)
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| Name | Affiliation | Role |
|---|---|---|
| Guy T'Sjoen, MD, PhD | University Hospital, Ghent | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ghent University Hospital, Department of Endocrinology, 9K12IE | Ghent | 9000 | Belgium |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 14510913 | Background | Baldelli R, Battista C, Leonetti F, Ghiggi MR, Ribaudo MC, Paoloni A, D'Amico E, Ferretti E, Baratta R, Liuzzi A, Trischitta V, Tamburrano G. Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clin Endocrinol (Oxf). 2003 Oct;59(4):492-9. doi: 10.1046/j.1365-2265.2003.01876.x. | |
| 16076947 |
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| ID | Term |
|---|---|
| D000172 | Acromegaly |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D001849 | Bone Diseases, Endocrine |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D006964 | Hyperpituitarism |
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Serum
| fasting and postprandial insulin | Insulin levels during standard mixed-meal test (cfr.supra) | At enrollment in groups 1-4 |
| fasting and postprandial gut hormone levels | Serum levels of gastric inhibitory polypeptide (GIP), ghrelin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin and cholecystokinin before start during standard mixed-meal test (cfr.supra) | At enrollment in groups 1-4 |
| fasting adipokine levels | Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6) | At enrollment in group 1-4 |
| fasting lipid levels | Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol | At enrollment in groups 1-4 |
| change in fasting and postprandial glucose | Serum glucose levels during mixed-meal test (before and 10, 30, 60, 120, 180, 240, 300 minutes after ingestion of standard mixed-meal (bread, margarine, cheese and milk) providing a caloric content of 1000 kCal whereby 45% of the energy comes from fat, 36% from carbohydrates and 19% from proteins) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| change in fasting and postprandial insulin levels | Insulin levels during standard mixed-meal test (cfr.supra) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| change in fasting and postprandial gut hormone levels | Serum levels of gastric inhibitory polypeptide (GIP), ghrelin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin and cholecystokinin before start during standard mixed-meal test (cfr.supra) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| change in fasting adipokine levels | Fasting serum levels of leptin, adiponectin and interleukin 6 (IL-6) | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| change in fasting lipid levels | Fasting serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| Standing height | At enrollment in group 1-4 |
| Waist and hip circumference | At enrollment in group 1-4 |
| Change in resting energy expenditure | Resting energy expenditure determined using indirect calorimetry | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| Weight change | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| Change in standing height | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| Change in waist and hip circumference | before start of pegvisomant and 3 months after normalisation of IGF-1 levels after start of pegvisomant in group 5 |
| Barkan AL, Burman P, Clemmons DR, Drake WM, Gagel RF, Harris PE, Trainer PJ, van der Lely AJ, Vance ML. Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant. J Clin Endocrinol Metab. 2005 Oct;90(10):5684-91. doi: 10.1210/jc.2005-0331. Epub 2005 Aug 2. |
| 20463098 | Background | Berg C, Petersenn S, Lahner H, Herrmann BL, Buchfelder M, Droste M, Stalla GK, Strasburger CJ, Roggenbuck U, Lehmann N, Moebus S, Jockel KH, Mohlenkamp S, Erbel R, Saller B, Mann K; Investigative Group of the Heinz Nixdorf Recall Study and the German Pegvisomant Observational Study Board and Investigators. Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control. J Clin Endocrinol Metab. 2010 Aug;95(8):3648-56. doi: 10.1210/jc.2009-2570. Epub 2010 May 12. |
| 16498061 | Background | Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, Tortora F, Burman P, Kourides IA, Strasburger CJ, Lombardi G. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance. Eur J Endocrinol. 2006 Mar;154(3):467-77. doi: 10.1530/eje.1.02112. |
| 17484056 | Background | De Marinis L, Bianchi A, Fusco A, Cimino V, Mormando M, Tilaro L, Mazziotti G, Pontecorvi A, Giustina A. Long-term effects of the combination of pegvisomant with somatostatin analogs (SSA) on glucose homeostasis in non-diabetic patients with active acromegaly partially resistant to SSA. Pituitary. 2007;10(3):227-32. doi: 10.1007/s11102-007-0037-7. |
| 12727951 | Background | Freda PU, Reyes CM, Conwell IM, Sundeen RE, Wardlaw SL. Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy. J Clin Endocrinol Metab. 2003 May;88(5):2037-44. doi: 10.1210/jc.2002-021683. |
| 22323865 | Background | Kim SK, Suh S, Lee JI, Hur KY, Chung JH, Lee MK, Min YK, Kim JH, Kim JH, Kim KW. The ability of beta-cells to compensate for insulin resistance is restored with a reduction in excess growth hormone in Korean acromegalic patients. J Korean Med Sci. 2012 Feb;27(2):177-83. doi: 10.3346/jkms.2012.27.2.177. Epub 2012 Jan 27. |
| 16821203 | Background | Kozakowski J, Rabijewski M, Zgliczynski W. [Lowered ghrelin levels in acromegaly-normalization after treatment]. Endokrynol Pol. 2005 Nov-Dec;56(6):862-70. Polish. |
| 19208728 | Background | Mazziotti G, Floriani I, Bonadonna S, Torri V, Chanson P, Giustina A. Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies. J Clin Endocrinol Metab. 2009 May;94(5):1500-8. doi: 10.1210/jc.2008-2332. Epub 2009 Feb 10. |
| 19240267 | Background | Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24. |
| 19820031 | Background | Moller L, Norrelund H, Jessen N, Flyvbjerg A, Pedersen SB, Gaylinn BD, Liu J, Thorner MO, Moller N, Lunde Jorgensen JO. Impact of growth hormone receptor blockade on substrate metabolism during fasting in healthy subjects. J Clin Endocrinol Metab. 2009 Nov;94(11):4524-32. doi: 10.1210/jc.2009-0381. Epub 2009 Oct 9. |
| 21045065 | Background | Neggers SJ, Kopchick JJ, Jorgensen JO, van der Lely AJ. Hypothesis: Extra-hepatic acromegaly: a new paradigm? Eur J Endocrinol. 2011 Jan;164(1):11-6. doi: 10.1530/EJE-10-0969. Epub 2010 Nov 2. |
| 11415859 | Background | Peracchi M, Porretti S, Gebbia C, Pagliari C, Bucciarelli P, Epaminonda P, Manenti S, Arosio M. Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly. Eur J Endocrinol. 2001 Jul;145(1):R1-4. doi: 10.1530/eje.0.145r001. |
| 9279024 | Background | Pierluissi J, de Pierluissi RM. Effect of glucose-dependent insulinotropic polypeptide (GIP) on insulin response to glucose in acromegalics. Acta Cient Venez. 1995;46(2):89-96. |
| 10377503 | Background | Plockinger U, Holst JJ, Messerschmidt D, Hopfenmuller W, Quabbe HJ. Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects. Eur J Endocrinol. 1999 Jun;140(6):538-44. doi: 10.1530/eje.0.1400538. |
| 14708034 | Background | Velasquez-Mieyer PA, Umpierrez GE, Lustig RH, Cashion AK, Cowan PA, Christensen M, Spencer KA, Burghen GA. Race affects insulin and GLP-1 secretion and response to a long-acting somatostatin analogue in obese adults. Int J Obes Relat Metab Disord. 2004 Feb;28(2):330-3. doi: 10.1038/sj.ijo.0802561. |
| D010900 |
| Pituitary Diseases |
| D007027 | Hypothalamic Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D004700 | Endocrine System Diseases |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |