Effect of Somatostatin Receptor 2 Antagonism (SSTR2a) on Oral Glucose Tolerance (OGT) in a Rat Model of Type 2 Diabetes (T2D)

Background: Hypoglycemia remains a concern for insulin-treated individuals living with diabetes. SSTR2a increases the endogenous glucagon counterregulatory response during hypoglycemia in rodent models of diabetes, but its impact on OGT is unclear. We examined the impact of SSTR2a on OGT in a rodent model of T2D maintained on basal insulin therapy. Methods: High fat fed (HFF), low dose streptozotocin (35 mg/kg) T2D rats received SSTR2a treatment (ZT-01 3 mg/kg) or vehicle (N=8-9/group) immediately before a fasted OGT test (OGTT, 2 g/kg). Glycemia, glucagon and c-peptide levels were measured pre- and post-dose and monitored for 120 minutes. Results: The OGTT resulted in comparable rises in blood glucose levels in both groups, consistent with an animal model of T2D. Glucagon levels rose within 15 minutes of SSTR2a and glucose administration (120 ± 70 vs 4.8 ± 3, p=0.006) and remained higher than controls for the duration of the OGTT. C-peptide levels also increased from baseline by 116 ± 77% in SSTR2a-treated animals compared to 28.9 ± 70% in controls. Conclusion: SSTR2a treatment increases glucagon and c-peptide levels following oral glucose ingestion in this rat model of T2D. These preliminary findings suggest that the use of the SSTR2a should not adversely impact glucose control around meals if used as a preventive therapy against insulin-induced hypoglycemia. Disclosure N. C. D'souza: 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. N. Aleali: None. D. Shakeri: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. M. El-zahed: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None. Funding GlycoNet (CD-85)