Diabetes, obesity & metabolism · 2026
One Week Exposure to a Somatostatin Receptor 2 Antagonist (SSTR2a) Enhances Glucagon Counterregulation to Insulin-Induced Hypoglycaemia and Does Not Worsen Glycemia in a Male Rat Model of Insulin-Requiring Type 2 Diabetes.
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D'Souza Ninoschka C, Hoffman Emily G, Atherley Sara C, Champsi Sabrina, Aleali Nadia, Liggins Richard T, Chan Owen, Riddell Michael C
Аннотация
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 < 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.
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 < 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.