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

Abstract

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 <60 mg/dL) at doses ranging from 0.1 µg/kg to 3 mg/kg. Administration of ZT-01 at 0.3 or 1 mg/kg improved the glucagon response by 5.3 or 6.3-fold, respectively (P<0.05), relative to the diabetic control group. The glucagon response in this dose range was comparable to that observed in nondiabetic rats administered vehicle. We therefore conclude that ZT-01 at doses ranging from 0.3 to 1 mg/kg normalized the glucagon response to hypoglycemia in STZ-diabetic rats and may be an effective compound for the prevention hypoglycemia in patients with T1D. Disclosure R. Farhat: None. E. Simonson: None. M. Riddell: Advisory Panel; Self; Zucara Therapeutics Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. R. Liggins: Advisory Panel; Self; Zucara Therapeutics Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc. O. Chan: None. Funding JDRF; The Leona M. and Harry B. Helmsley Charitable Trust