12-LB: Subcutaneous Administration of the Novel Somatostatin Receptor 2 Antagonist ZT-01 Restores the Glucagon Response to Hypoglycemia in STZ-Diabetic Rats to Normal Levels

Restoration of the lost glucagon response to hypoglycemia may be an effective means to prevent the onset of hypoglycemia in patients with type 1 diabetes (T1D). Elevation of the inhibitory hormone somatostatin in T1D may act on alpha cells, via the somatostatin receptor 2 (SSTR2), to suppress glucagon release during hypoglycemia. We previously demonstrated that a novel SSTR2 antagonist, ZT-01, exhibited superior efficacy at restoring the glucagon response to hypoglycemia compared to an established SSTR2 antagonist, PRL-2903, when given intraperitoneally at a dose of 10 mg/kg. In this study, we first evaluated the pharmacokinetics of ZT-01 in healthy Sprague-Dawley rats. Within one hour after intraperitoneal administration of a 10 mg/kg dose, ZT-01 achieved 10-fold higher plasma Cmax compared to PRL-2903; however, pancreas concentration at 6 h post-dose was almost 4-fold higher for PRL-2903 compared to ZT-01 and plasma concentrations were similar for both 24 h post-dose. We subsequently conducted a dose de-escalation study to identify the lowest dose of ZT-01 that could improve glucagon secretion in poorly controlled insulin-treated streptozotocin (STZ)-diabetic Sprague Dawley rats, under hypoglycemic clamp conditions. ZT-01 was administered subcutaneously one hour prior to the induction of hypoglycemia (blood glucose