1-LB: Evaluating the Effectiveness of the Novel Somatostatin Receptor Antagonist (SSTR2a) ZT-01 for Hypoglycemia Prevention in a Rodent Model of Type 2 Diabetes

Abstract

Background: Few pharmacological strategies exist to prevent hypoglycemia in diabetes, other than reducing the intensity of glucose-lowering therapy. SSTR2a treatment increases glucagon counterregulation and reduces the time spent in hypoglycemia in rodent models of type 1 diabetes (T1D), but the utility of this approach in type 2 diabetes (T2D) is unclear. The purpose of this study was to test the effect of acute SSTR2a treatment in a rodent model of hypoglycemia in T2D. Methods: High fat fed (HFF), low dose streptozotocin (35 mg/kg) T2D rats received SSTR2a treatment (subcutaneous ZT-01 3 mg/kg) or vehicle (N=9-11/group) 60 min before the induction of hypoglycemia using rapid-acting insulin (12 U/kg). Glycemia, glucagon and c-peptide levels were measured intermittently pre- and post-dosing. Results: T2D in the rats was characterized by significantly higher baseline glucose (21.8 ± 4.7 vs 6.5 ± 0.7 mmol/L, p<0.05) and HbA1c (8.6 ± 0.6% vs 5.5 ± 0.5%; p<0.0001) levels relative to HFF controls (n=3). T2D rats also displayed reduced c-peptide levels relative to controls (3.1 ± 1.3 vs 6.1 ± 1.2 ng/ml, p<0.05). During hypoglycemic challenge (T2D rats only), SSTR2a elevated glucagon levels relative to vehicle treatment (glucagon Cmax: 156 ± 50 vs 77 ± 46 pg/ml, p<0.01) and reduced the incidence of hypoglycemia by ~40% (5/8 SSTR2a treated vs 9/9 vehicle treated rats). In those that developed hypoglycemia, the average time to hypoglycemia onset was delayed (103.1± 24.6 vs 66.1 ± 23.6 min, p<0.05) with SSTR2a compared to vehicle. Conclusion: SSTR2a treatment increases glucagon levels in this rodent model of T2D, which appears to reduce the risk for hypoglycemia following bolus insulin dosing. Disclosure N. C. D'souza: None. M. Nejad-mansouri: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. P. Zaree bavani: None. J. Aiken: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. N. Aleali: None. D. Shakeri: None. M. El-zahed: None. N. Akbarian: None. Funding GlycoNet (CD-85)