Prolonged Somatostatin Receptor 2 Antagonism Enhances Glucagon Response to Hypoglycemia in Male Diabetic Rats

In diabetes, glucagon is typically oversecreted during hyperglycemia but undersecreted during hypoglycemia. Administration of a somatostatin receptor antagonist (SSTR2a) increases glucagon counterregulation during hypoglycemia in rodent models of type 1 diabetes (T1D) but less is known about its effect on glucagon in type 2 diabetes (T2D). Using a rodent model of insulin-requiring diabetes, we evaluated the effects of daily SSTR2a administration with insulin dosing (study A: 8 days) and repeated exposures to hypoglycemia (study B: 4× over 11 days) on glucagon and glycemia. In study A, 8 days of SSTR2a treatment at 3.0 mg/kg transiently increased glucagon levels after dosing but did not significantly affect the glycemic response to basal or bolus insulin. In study B, with daily low-dose SSTR2a treatment (0.3 mg/kg/d), the glucagon counterregulatory response to insulin-induced hypoglycemia increased while time to hypoglycemic onset was delayed on challenge days 1 and 2. SSTR2a treatment did not affect food intake, body mass, or C-peptide levels, but was associated with a lower glycated hemoglobin A1c level at the end of the study relative to controls (4.3 ± 0.9 vs 5.3 ± 0.8%; P < .05). In summary, in a rat model of insulin-treated T2D, daily SSTR2a administration increased glucagon counterregulation to hypoglycemia without worsening overall insulin sensitivity or glycemic control.