Somatostatin Receptor 2 antagonists (SSTR2a) increase glucagon counter-regulation to hypoglycemia in various rodent models of type-1 diabetes mellitus. Here we investigated the efficacy of SSTR2a in improving glucagon counter-regulation in a rat model of type-2 diabetes mellitus (T2DM). For this, male Sprague Dawley rats (n=18) were given a high fat diet for 3 weeks, followed by low-dose streptozotocin exposure (35 mg/kg, IP) to induce T2DM. Rats were then divided into SSTR2a treatment (PRL-2903, 10 mg/kg) or vehicle (n=9 for each) 1-hour before insulin-induced hypoglycemia (3 IU/kg NovoRapid). This process was repeated 1 week later in a cross-over design, with the data pooled over SSTR2a and vehicle treatments. A group of normal-chow-fed rats (n=3) served as nondiabetic controls. Mean blood glucose levels were higher at 20, 30, 40, and 50 minutes post insulin administration in the T2DM rats treated with PRL-2903, as compared to vehicle (p ≤ 0.05). The number of T2DM rats that developed biochemical hypoglycemia (blood glucose ≤ 3.5 mmol/L) tended to be less with PRL-2903 (5/18) vs. vehicle (9/18). Compared with vehicle treatment, PRL-2903 promoted higher plasma glucagon counter-regulation, as indicated by area under curve (AUC) analysis (p < 0.05). Thus, SSTR2a treatment improves the attenuated glucagon response to hypoglycemia in T2DM rats.
M. Nejad-Mansouri: None. P. Zaree Bavani: None. J. Aiken: None. N.C. DSouza: None. E.G. Hoffman: None. R. Liggins: None. M. Riddell: Advisory Panel; Self; Xeris Pharmaceuticals, Inc. Research Support; Self; Dexcom, Inc. Speaker’s Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc. Stock/Shareholder; Self; Zucara Therapeutics Inc.
National Research Council Canada; Zucara Therapeutics