Pasireotide (SOM230) Prevents Sulfonylurea-induced Hypoglycemia in Rats

Abstract

Persistent hypoglycemia is a serious condition that is frequently reported in patients undergoing sulfonylurea treatment, often necessitating hospitalization in the event of overdose. Somatostatin is a regulatory hormone with a broad range of physiological actions that include the inhibition of insulin and glucagon secretion, predominantly via activation of the somatostatin receptor subtypes sstr₅ and sstr₂, respectively. Previous studies have demonstrated that octreotide, a potent somatostatin analogue with high affinity for sstr₂ and moderate affinity for sstr₅, significantly increases serum glucose levels and prevents recurrence of hypoglycemic episodes in patients with sulfonylurea-induced hypoglycemia. Pasireotide (SOM230) is a multireceptor-targeted somatostatin analogue with a 39-, 30- and 5-fold higher binding affinity for sstr₅, sstr₁ and sstr₃, respectively, and a slightly lower (0.4-fold) affinity for sstr₂ compared with octreotide. This study evaluated the effects of pasireotide and octreotide in rats with glyburide-induced hypoglycemia. In fasted rats, pasireotide (10 and 30 µg/kg) prevented glyburide-induced hypoglycemia in a dose-dependent manner for up to 6 h. Qualitatively similar results were observed in non-fasted rats. However, the antihypoglycemic effect of pasireotide was stronger in non-fasted rats, resulting in transient hyperglycemia. In contrast to pasireotide, octreotide 10 µg/kg did not prevent glyburide-induced hypoglycemia in fasted and non-fasted rats, while octreotide 30 µg/kg resulted in small but significant increases in blood glucose at 3 h post-dose only. These findings suggest that pasireotide could have a more potent effect than octreotide in the management of patients with severe hypoglycemia caused by hyperinsulinemia.

Key words

hypoglycemia - sulfonylurea - octreotide - pasireotide - hyperglycemia

• References

• 1 Dougherty PP, Klein-Schwartz W. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol 2010; 6: 199-206
• 2 Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ 2005; 172: 213-226
• 3 Fasano CJ, Rowden AK, O’Malley GF et al. Quantitative insulin and C-peptide levels among ED patients with sulfonylurea-induced hypoglycemia-a prospective case series. Am J Emerg Med 2010; 28: 952-955
• 4 Bronstein AC, Spyker DA, Cantilena Jr LR et al. 2010; Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28^th Annual Report. Clin Toxicol (Phila) 2011; 49: 910-941
• 5 Van Op den Bosch J, Adriaensen D, Van Nassauw L et al. The role(s) of somatostatin, structurally related peptides and somatostatin receptors in the gastrointestinal tract: A review. Regul Pept 2009; 156: 1-8
• 6 Hauge-Evans AC, King AJ, Carmignac D et al. Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 2009; 58: 403-411
• 7 Zambre Y, Ling Z, Chen MC et al. Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5. Biochem Pharmacol 1999; 57: 1159-1164
• 8 Rossowski WJ, Coy DH. Potent inhibitory effects of a type four receptor-selective somatostatin analog on rat insulin release. Biochem Biophys Res Commun 1993; 197: 366-371
• 9 Singh V, Brendel MD, Zacharias S et al. Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab 2007; 92: 673-680
• 10 Rossowski WJ, Coy DH. Specific inhibition of rat pancreatic insulin or glucagon release by receptor-selective somatostatin analogs. Biochem Biophys Res Commun 1994; 205: 341-346
• 11 Fasano CJ, O’Malley G, Dominici P et al. Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia. Ann Emerg Med 2008; 51: 400-406
• 12 Schmid HA, Schoeffter P. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology 2004; 80 (Suppl. 01) 47-50
• 13 Schmid HA, Brueggen J. Effects of somatostatin analogues on glucose homeostasis in rats. J Endocrinol 2012; 212: 49-60
• 14 Clark MA, Humphrey SJ, Smith MP et al. Unique natriuretic properties of the ATP-sensitive K(+)-channel blocker glyburide in conscious rats. J Pharmacol Exp Ther 1993; 265: 933-937
• 15 Mitra SW, Mezey E, Hunyady B et al. Colocalization of somatostatin receptor sst5 and insulin in rat pancreatic beta-cells. Endocrinology 1999; 140: 3790-3796
• 16 Rowden AK, Fasano CJ. Emergency management of oral hypoglycemic drug toxicity. Emerg Med Clin North Am 2007; 25: 347-356
• 17 Dougherty PP, Klein-Schwartz W. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol 2010; 6: 199-206
• 18 Henry RR, Ciaraldi TP, Armstrong D et al. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab 2013; 98: 3446-3453
• 19 Boscaro M, Ludlam WH, Atkinson B et al. Treatment of pituitary dependent Cushing’s disease with the multi-receptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009; 94: 115-122