Somatostatin Receptor II Antagonism Improves Glucagon Counterregulatory Responses to Recurrent Hypoglycemia in Male Sprague-Dawley Rats

Abstract

Glucagon (GCN) helps prevent hypoglycemia when blood glucose levels drop; however, recurrent hypoglycemia attenuates GCN counterregulation to subsequent bouts of hypoglycemia. As somatostatin normally inhibits GCN secretion, we tested the hypothesis that a somatostatin receptor type 2 antagonist (SSTR2a), PRL-2903, improves GCN responses attenuated by recurrent hypoglycemia in healthy rats. Healthy male Sprague-Dawley rats (n=22) were made hypoglycemic on three consecutive days (days 1-3, blood glucose 1.7-2.2 mmol/L for ∼2 h) via exogenous insulin administration (10-, 8- and 5- U/kg of Humulin-R on days 1-3, respectively). GCN levels during hypoglycemia on day 3 were significantly lower than on day 1 (117±47 pg/mL vs. 184±77 [mean±SD] pg/mL; P=0.001), highlighting the role of recurrent hypoglycemia in counterregulatory failure. On day 4, rats were treated with either PRL-2903 (10 mg/kg IP; n=13) or vehicle (n=9) 1 h prior to the induction of hypoglycemia with 5 U/kg of R-insulin. GCN levels during hypoglycemia (i.e., glucose ≤3.5 mmol/L) were 2.5-fold higher (109±55 vs. 44±26 pg/mL; P=0.004) compared to vehicle, and time to reach hypoglycemia was 3.2-fold longer (64±45 vs. 20±10 min; P =0.001), with PRL-2903 pre-treatment. Interestingly, C-peptide levels were also lower (P=0.001) with PRL-2903 (0.35±0.22 ng/mL), compared to vehicle (0.63±0.21 ng/mL), inferring a lower insulin secretion during hypoglycemia with PRL-2903 treatment. In conclusion, our data suggests that SSTR2a improves GCN responses following recurrent hypoglycemia, and that this improvement may be associated with a reduction in insulin secretion in healthy rats. Therefore, SSTR2a treatment may be a useful therapeutic approach to improve GCN counterregulatory responses to hypoglycemia. Disclosure M. Riddell: Speaker's Bureau; Self; Medtronic. Consultant; Self; Eli Lilly and Company, JAEB Center For Health Research, Xeris Pharmaceuticals, Inc.. Research Support; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; Zucara Theraputics. Other Relationship; Self; JDRF. M. Jahangiriesmaili: None. E.R. Mandel: None. C.A. Greenberg: None. A.M. Pasieka: None. T. Teich: None. O. Chan: None. R.T. Liggins: Employee; Self; Zucara Therapeuytics, Inc..