Effect of AP102, a subtype 2 and 5 specific somatostatin analog, on glucose metabolism in rats.

Abstract

PURPOSE:

Somatostatin analogs are widely used to treat conditions associated with hormonal hypersecretion such as acromegaly and metastatic neuroendocrine tumors. First generation somatostatin analogs, such as octreotide and lanreotide, have high affinity for somatostatin receptor subtype 2 (SSTR2), but have incomplete efficacy in many patients. Pasireotide targets multiple SSTRs, having the highest affinity for SSTR5, but causes hyperglycemia and diabetes mellitus in preclinical and clinical studies. AP102 is a new somatostatin analogs with high affinity at both SSTR2 and SSTR5. We aimed to characterize the effects of AP102 vs. pasireotide on random and dynamic glucose levels, glucoregulatory hormone concentrations and growth axis measures in healthy Sprague-Dawley rats.

METHODS:

Three doses of each compound were evaluated under acute conditions (1, 10, and 30 µg/kg s.c.), and two doses during a chronic (4-week) infusion (3 and 10 µg/kg/h s.c.).

RESULTS:

Neither acute nor chronic AP102 administration altered blood glucose concentrations or dynamic responses following an intraperitoneal glucose tolerance test. In contrast, acute and chronic pasireotide dosing increased random and post-intraperitoneal glucose tolerance test blood glucose measures, compared to vehicle-treated controls. Both AP102 and pasireotide acutely suppressed growth hormone levels, although insulin-like growth factor-1 and somatic growth was suppressed to a greater extent with pasireotide.

CONCLUSIONS:

AP102 is a new dual SSTR2/SSTR5-specific somatostatin analog that acutely reduces growth hormone but does not cause hyperglycemia during acute or chronic administration in a healthy rat model. Further studies in diabetic animals and in humans are necessary to determine the potential utility of AP102 in the clinical setting.

• Authors: Erika Tarasco, Petra Seebeck, Svende Pfundstein, Adrian F Daly, Philippe J Eugster, Alan G Harris, Eric Grouzmann, Thomas A Lutz, Christina N Boyle
• Journal: Endocrine (Endocrine) Vol. 58 Issue 1 Pg. 124-133 (Oct 2017) ISSN: 1559-0100 [Electronic] United States
• PMID: 28822091 (Publication Type: Journal Article)

Chemical References

• Hormones
• Insulin
• Receptors, Somatostatin
• Sstr2 protein, rat
• Somatostatin
• somatostatin receptor 5
• Growth Hormone
• pasireotide
• Glucose

Topics

• Animals
• Glucose (metabolism)
• Glucose Tolerance Test
• Growth (drug effects)
• Growth Hormone (blood)
• Hormones (metabolism)
• Infusions, Subcutaneous
• Insulin (blood)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, Somatostatin (drug effects)
• Somatostatin (analogs & derivatives, pharmacology)