Effects of somatostatin receptor type 2 antagonism during insulin‐induced hypoglycaemia in male rats with prediabetes

Abstract

AbstractAimsTo examine if glucagon counterregulatory defects exist in a rat model of prediabetes (pre‐T2D) and to assess if a selective somatostatin receptor 2 antagonist (SSTR2a), ZT‐01, enhances the glucagon response to insulin‐induced hypoglycaemia.Materials and methodsHyperglycaemia was induced in 8‐ to 9‐week‐old male, Sprague‐Dawley rats via 7 weeks of high‐fat diet followed by a single, low‐dose intraperitoneal injection of streptozotocin (30 mg/kg). After 2 weeks of basal insulin therapy (0‐4 U/d insulin glargine, administered subcutaneously [SC]) to facilitate partial glycaemic recovery and a pre‐T2D phenotype, n = 17 pre‐T2D and n = 10 normal chow‐fed control rats underwent the first of two hypoglycaemic treatment‐crossover experiments, separated by a 1‐week washout period. On each experimental day, SSTR2a (3 mg/kg ZT‐01, SC) or vehicle was administered 1 hour prior to insulin‐induced hypoglycaemia (insulin aspart, 6 U/kg, SC).ResultsGlucagon counterregulation was marginally reduced with the induction of pre‐T2D. Treatment with SSTR2a raised peak plasma glucagon levels and glucagon area under the curve before and after insulin overdose in both and pre‐T2D rats. Blood glucose concentration was elevated by 30 minutes after SSTR2a treatment in pre‐T2D rats, and hypoglycaemia onset (≤3.9 mmol/L) was delayed by 15 ± 12 minutes compared with vehicle (P < 0.001), despite similar glucose nadirs in the two treatment groups (1.4 ± 0.3 mmol/L). SSTR2a treatment had no effect on blood glucose levels in the control group or on the hypoglycaemia‐induced decline in plasma C‐peptide levels in either group.ConclusionsTreatment with an SSTR2a increases glucagon responsiveness and delays the onset of insulin‐induced hypoglycaemia in this rat model of pre‐T2D where only a modest deficiency in glucagon counterregulation exists.