Introduction & Objective: Treatment of severe hypoglycemia (SH) with EG causes hyperglucagonemia, resulting in gastrointestinal distress that limits its real-world utility. Prophylactic dosing of SSTR2a augments glucagon counterregulation during insulin-induced hypoglycemia in diabetic rats. Here, we tested the use of SSTR2a as a rescue treatment for SH.
Methods: After 3 episodes of insulin-induced hypoglycemia to impair glucagon counterregulation, healthy male rats received an overdose of regular insulin before a SC injection of vehicle, EG (0.15 mg) or SSTR2a (10 mg/kg ZT-01) at the onset of level 2 hypoglycemia. Blood glucose (BG) and plasma glucagon were monitored for 2 h by saphenous venipuncture.
Results: BG continued to fall gradually with vehicle to a nadir of 1.7±0.6 mM at 110 min. Euglycemia was restored by EG in 6 of 8 rats from t=15-60 min (4.6±1.3 mM, n=8) and maintained in 1 of 8 rats from t=70-120 min (3.0±0.9 mM, n=8). SSTR2a raised BG to level 1 hypoglycemia in 5 of 8 rats (t=15-60 min: 3.4±1.0 mM, n=8) before restoring euglycemia in 4 of 8 rats (t=70-120 min: 5.0±2.3 mM, n=8). Compared to vehicle, BG was higher with SSTR2a from t=15-30 and 90-120 min and glucagon AUC (0-120 min) was 24- & 1.5-fold higher with EG and SSTR2a, respectively.
Conclusion: SSTR2a provided more gradual and sustained recovery from SH than EG without causing systemic hyperglucagonemia.
E.G. Hoffman: None. N. DSouza: None. N. Aleali: None. N. Nozariasbmarz: None. S. Fatehi: None. D. Shakeri: None. O. Chan: None. R. Liggins: Employee; Zucara Therapeutics. Stock/Shareholder; Zucara Therapeutics. M.C. Riddell: Consultant; Eli Lilly and Company. Speaker's Bureau; Novo Nordisk. Advisory Panel; Supersapiens. Consultant; Dexcom, Inc. Speaker's Bureau; Sanofi. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Stock/Shareholder; Zucara Therapeutics.
Zucara Therapeutics Inc.
