One Week Exposure to a Somatostatin Receptor 2 Antagonist ( <scp>SSTR2a</scp> ) Enhances Glucagon Counterregulation to Insulin‐Induced Hypoglycaemia and Does Not Worsen Glycemia in a Male Rat Model of Insulin‐Requiring Type 2 Diabetes

ABSTRACT Introduction Administration of a somatostatin receptor 2 antagonist (SSTR2a) increases glucagon responsiveness to hypoglycaemia in insulin‐treated type 2 diabetes (T2D), but the durability of this effect and the impact of repeated SSTR2a dosing on overall glycaemia in T2D are unclear. This study evaluated the effects of daily SSTR2a administration on glucagon counterregulation and overall glycaemia in a male rat model of T2D. Methods T2D was induced in male Sprague–Dawley rats using high‐fat feeding and streptozotocin (35 mg/kg) (day 0). After a 7‐day insulin maintenance period, T2D and control rats were administered a single dose of SSTR2a (ZT‐01, 3 mg/kg) or vehicle ( n = 7–8 per group) prior to a hypoglycaemic challenge with an insulin overdose (day 8). After a one‐week washout period, T2D and control rats were administered drug or vehicle for 8 days, with a second hypoglycaemic challenge performed on the last day. Results Glucagon counterregulation to both hypoglycaemic exposures increased with SSTR2a in T2D and controls (all p &lt; 0.05). Dosed without hypoglycaemia, SSTR2a induced a transient rise in glucagon, c‐peptide, and glucose levels in both healthy and T2D rats, but food intake and body weight were unaffected. T2D rats on SSTR2a (days 8–22) had reduced daily insulin needs without significantly affecting blood glucose levels. Conclusion In this male rat model of T2D, repeat dosing of SSTR2a increases glucagon counterregulation without worsening glycemia.