Novel Somatostatin Receptor 2 Antagonist Zt-01 Prevents Hypoglycemia Onset In Stz-Diabetic Rats By Improving Glucagon Secretion

Iatrogenic hypoglycemia remains one of the most serious risks for people with type 1 diabetes (T1D) undergoing intensive insulin therapy. Development of counterregulatory failure, occurring in the early stages of diabetes, highlighted by loss of the ability to secrete glucagon in response to hypoglycemia, is one of the main contributing factors. While the reason for this loss is still uncertain, it has been suggested that enhanced secretion of the pancreatic hormone, somatostatin, in T1D may play a role. Previously, it was reported that antagonism of somatostatin receptor 2 (SSTR2) with the peptide PRL-2903 successfully improved the glucagon response to insulin-induced hypoglycemia in streptozotocin (STZ)-diabetic rats. In the current study, we assessed the effectiveness of a new SSTR2 antagonist, ZT-01, to prevent hypoglycemia during an insulin bolus challenge and evaluated the effect of both ZT-01 and PRL-2903 under stepped hyperinsulinemic-euglycemic-hypoglycemic clamp conditions. In both studies, STZ-diabetic rats maintained with daily insulin were administered either vehicle, PRL-2903 (10 mg/kg) or ZT-01 (10 mg/kg) intraperitoneally, one hour prior to the induction of hypoglycemia. ZT-01 was more effective than PRL-2903 in preventing the onset of hypoglycemia in response to the insulin bolus challenge. Median time of hypoglycemia onset (BG ≤54 mg/dL) was 60 min in controls, 70 min with PRL-2903 administration, and 125 min with ZT-01 administration. Furthermore, all control and PRL-2903 dosed rats experienced, while 28% of rats receiving ZT-01, avoided hypoglycemia. During the hypoglycemic clamp, ZT-01 was more effective than PRL-2903 at improving glucagon responses in hypoglycemia. ZT-01 administration increased glucagon peak by 4-fold over the response to PRL-2903 (P Disclosure J. Aiken: None. N.C. D’Souza: None. E. Simonson: None. R. Farhat: None. O. Chan: None. R. Liggins: Advisory Panel; Self; Zucara Therapeutics Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc. 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. Funding JDRF; The Leona M. and Harry B. Helmsley Charitable Trust