1774-LB: The Glucagon Stimulating Effect in Hypoglycemia of Somatostatin Receptor 2 Antagonist (SSTR2a) Is Maintained with Repeat Dosing

Introduction: A single dose of SSTR2a, ZT-01, reduces hypoglycemia exposure in diabetic rat models. However, the pharmacology of daily dosing in type 2 diabetes (T2D) rats has not been reported. The purpose of this study was to determine the effects of repeat ZT-01 dosing in a rat model of T2D with recurrent hypoglycemia.

Methods: In a high-fat-fed (HFF) low dose streptozotocin (35mg/kg) T2D rat model, ZT-01 was dosed daily (0.3 mg/kg/d) for 14 days (n=10-11/group). Rats underwent 4 insulin-induced (6-12 U/kg insulin aspart) hypoglycemic challenges 2-3 days apart, beginning on dosing day 8, with blood glucose and plasma glucagon and c-peptide measured over 2 hours post-insulin dose.

Results: ZT-01-treated rats showed improved glycemia with lower HbA1c vs controls (4.3 ± 0.9 vs 5.3 ± 0.8%, p<0.05) after 2-weeks of treatment. Glucagon response to hypoglycemia across all challenges was 9.7 ± 3.1 vs 22.6 ± 4.8-fold over baseline, with vehicle and ZT-01, respectively. ZT-01 reduced hypoglycemia exposure only in challenges 1 and 2, perhaps due to conditioning from antecedent hypoglycemia and a lower baseline blood glucose in challenge 4, particularly in the ZT-01-treated group (21.95 ± 5.4 vs 16.2 ± 6.3 mmol/L, p<0.05).

Conclusion: Daily dosing of SSTR2a resulted in a consistent increase in glucagon during repeated hypoglycemic challenges, and reduced hypoglycemia exposure in initial challenges. It may also improve overall glycemia in this T2D rat model of recurrent hypoglycemia.