Effects of Long-acting Release Octreotide on Glucose Homeostasis in Acromegaly Patients after Trans-Sphenoidal Surgery

Abstract

The present study was aimed to investigate glucose homeostasis and insulin secretion in acromegalic patients during octreotide-long acting release (LAR) therapy and designed as an observational prospective study. 18 acromegalic patients who had undergone trans-sphenoidal surgery with active disease were included. All patients were treated with octreotide-LAR injection for 1 year. These patients received oral glucose tolerance test (OGTT) before, 21 days after, and 1 year after octreotide-LAR treatment. Primary outcomes were changes in glucose levels and insulin secretion during an OGTT. We also determined the differences between subjects with normalized and uncontrolled IGF-1 levels. Of the 18 patients treated with octreotide-LAR for 1 year, 89% achieved fasting GH levels <2.5 μg/l, 85% reached the nadir GH concentration <1 μg/l, and 61% achieved normal age- and sex-matched IGF-1 values. 21 days after one dose of octreotide-LAR injection, insulin response during OGTT significantly decreased, and the Matsuda index increased significantly. One year after octreotide-LAR therapy, most parameters of glucose homeostasis returned to baseline levels. However, insulin response during OGTT at 30 and 60 min, and the insulinogenic index were still significantly decreased. Compared with the IGF-1-normalized group, the IGF-1 uncontrolled group had the same fasting GH and nadir GH levels and a higher insulin AUC and total insulin secretion. During octreotide-LAR treatment, the early-phase insulin response to OGTT is reduced and plasma glucose levels remained normal in most patients. The IGF-1 uncontrolled group had the same fasting GH and nadir GH levels during OGTT, but had better glucose homeostasis.

Key words

acromegaly - diabetes - octreotide - oral glucose tolerance test

References

• 1 Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly.  J Clin Endocrinol Metab. 1998;  83 2646-2652
• 2 Harris AG. Acromegaly: epidemiology, etiology, and classification. In:, Daly AF, (ed). Acromegaly and its management. Philadelphia: Lippincott-Raven; 1996: 17-19
• 3 Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S. Criteria for cure of acromegaly: a consensus statement.  J Clin Endocrinol Metab. 2000;  85 526-529
• 4 Jap TS, Ho LT. Insulin secretion and sensitivity in acromegaly.  Clin Physiol Biochem. 1990;  8 64-69
• 5 Clemmons DR. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity.  J Clin Invest. 2004;  113 25-27
• 6 Barrande G, Pittino-Lungo M, Coste J, Ponvert D, Bertagna X, Luton JP, Bertherat J. Hormonal and metabolic effects of radiotherapy in acromegaly: long-term results in 128 patients followed in a single center.  J Clin Endocrinol Metab. 2000;  85 3779-3785
• 7 Kasayama S, Otsuki M, Takagi M, Saito H, Sumitani S, Kouhara H, Koga M, Saitoh Y, Ohnishi T, Arita N. Impaired beta-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients.  Clin Endocrinol (Oxf). 2000;  52 549-555
• 8 Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, Gomez JM, Halperin I, Lucas-Morante T, Moreno B, Obiols G, de Pablos P, Paramo C, Pico A, Torres E, Varela C, Vazquez JA, Zamora J, Albareda M, Gilabert M. On behalf of the REA participants: Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry.  Eur J Endocrinol. 2004;  151 439-446
• 9 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;  90 5684-5691
• 10 Jørgensen JOL, Feldt-Rasmussen U, Frystyk J, Chen J-W, Kristensen LO, Hagen C, ØrskovH. Cotreatment of acromegaly with a somatostatin analog and a growth hormone receptor antagonist.  J Clin Endocrinol Metab. 2005;  90 5627-5631
• 11 Ronchi CL, Varca V, Beck-Peccoz P, Orsi E, Donadio F, Baccarelli A, Giavoli C, Ferrante E, Lania A, Spada A, Arosio M. Comparison between six-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors.  J Clin Endocrinol Metab. 2006;  91 121-128
• 12 Colao A, Pivonello R, Galderisi M, Cappabianca P, Auriemma RS, Galdiero M, Cavallo LM, Esposito F, Lombardi G. Impact of treating acromegaly first with surgery or somatostatin analogs on cardiomyopathy.  J Clin Endocrinol Metab. 2008;  93 2639-2646
• 13 Brazeau P, Vale W, Burnus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone.  Science. 1973;  179 77-79
• 14 Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide.  N Engl J Med. 1996;  334 246-254
• 15 Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Opportunities in somatostatin research: biological, chemical and therapeutic aspects.  Nat Rev Drug Discov. 2003;  2 999-1017
• 16 Freda PU, Katznelson L, van der Lely AJ, Reyes CM, Zhao S, Rabinowitz D. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis.  J Clin Endocrinol Metab. 2005;  90 4465-4473
• 17 Colao A, Pivonello R, Auriemma RS, Briganti F, Galdiero M, Tortora F, Caranci F, Cirillo S, Lombardi G. Predictors of tumor shrinkage after primary therapy with somatostatin analogues in acromegaly: a prospective study in 99 patients.  J Clin Endocrinol Metab. 2006;  91 2112-2118
• 18 Ronchi C, Epaminonda P, Cappiello V, Beck-Peccoz P, Arosio M. Effects of two different somatostatin analogs on glucose tolerance in acromegaly.  J Endocrinol Invest. 2002;  25 502-507
• 19 Parkinson C, Drake WM, Roberts ME, Meeran K, Besser GM, Trainer PJ. A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal.  J Clin Endocrinol Metab. 2002;  87 1797-1804
• 20 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;  59 492-499
• 21 Ben-Shlomo A, Melmed S. Somatostatin agonists for treatment of acromegaly.  Mol Cell Endocrinol. 2008;  286 192-198
• 22 Giustina A, Girelli A, Buffoli MG, Cimino A, Legati F, Valentini U, Giustina G. Low-dose octreotide is able to cause a maximal inhibition of the glycemic responses to a mixed meal in obese type 2 diabetic patients treated with insulin.  Diabetes Res Clin Pract. 1991;  14 47-54
• 23 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;  94 1500-1508
• 24 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic glucose clamp.  Diabetes Care. 1999;  22 1462-1470
• 25 Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 26 Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management.  Endocr Rev. 2004;  25 102-152
• 27 Colao A, Auriemma RS, Savastano S, Galdiero M, Grasso LF, Lombardi G, Pivonello R. Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-month study.  J Clin Endocrinol Metab. 2009;  94 2907-2914
• 28 Carmichael JD, Bonert VS, Mirocha JM, Melmed S. The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly.  J Clin Endocrinol Metab. 2009;  94 523-527
• 29 Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Järvinen H, Van Haeften T, Renn W, Gerich J. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.  Diabetes Care. 2000;  23 295-301

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