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.


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.


JDRF; The Leona M. and Harry B. Helmsley Charitable Trust

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at