Effects of Somatostatin Receptor 2 Inhibition on Glucagon Counterregulation and C-Peptide Levels in Hypoglycemia Conditioned Male Sprague-Dawley Rats

The counterregulatory hormone glucagon prevents hypoglycemia; however, recurrent hypoglycemia attenuates glucagon counterregulation to subsequent hypoglycemia. This may explain why patients with diabetes are at increased risk for severe hypoglycemic events with time. As somatostatin inhibits glucagon secretion, we hypothesize that a somatostatin receptor type II antagonist (SSTR2a), PRL-2903, improves glucagon responses attenuated by recurrent hypoglycemia. Healthy male Sprague-Dawley rats were made hypoglycemic on three consecutive days (blood glucose 1.7-2.2 mmol/L) via insulin administration (10-, 8- and 5-U/kg of Humulin-R on days 1-3, respectively). On day 4, rats were treated with either SSTR2a or vehicle 1 h prior to the induction of hypoglycemia with 5 U/kg of R-insulin. Glucagon levels during hypoglycemia were 2.5-fold higher compared to vehicle, and time to reach hypoglycemia was 3.2-fold longer with SSTR2a pre-treatment. Also, C-peptide levels were lower with SSTR2a compared to vehicle. Hepatic glycogen levels were also lower with SSTR2a pre-treatment compared to vehicle.