Visual Abstract
Background: Defective glucagon counterregulation to hypoglycemia in T1D involves elevated somatostatin signalling on the α cell. In rats, SSTR2a treatment (ZT-01 <1 mg/kg) restores normal response in hypoglycemica and higher doses (≥3 mg/kg) transiently increase glucagon in euglycemia. In T2D, glucagon counterregulation to hypoglycemia may also be blunted, but SSTR2a has not been evaluated. We test the effect of high dose (3 mg/kg) ZT-01 in hyperglycemia in T2D and in euglycemia.
Methods: High fat fed, low dose streptozotocin (T2D) and healthy rats were treated with subcutaneous ZT-01 or vehicle (N=7-8/group). Glycemia, glucagon and C-peptide were measured for 4 h post-dose.
Results: SSTR2a treatment promoted a significant rise in basal glucagon in both T2D and control rats, up to 3 hours post-dose. Basal C-peptide was lower in T2D versus healthy rats (1.9 vs. 2.5 ng/ml) increasing in both groups 30 min after SSTR2a dosing (2.7 vs. 4.1 ng/mL). Both diabetes (p=0.03) and treatment (p=0.01) were significant effects (2-way ANOVA). Post-dose glucose was elevated from baseline in T2D but not in healthy rats.
Conclusion: High dose SSTR2a transiently increased glucagon. C-peptide was increased to a lesser extent in T2D. Consequently, glucose levels were affected in T2D but not healthy rats. Insulin production and sensitivity in T2D may play an important role in responses to SSTR2a in this model.
N. C. D'souza: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. M. Popkov: None. R. Liggins: Employee; Self; Zucara Therapeutics Inc. M. Riddell: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Lilly Diabetes, Research Support; Self; Dexcom, Inc., Insulet Corporation, Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi, Stock/Shareholder; Self; Zucara Therapeutics Inc.
GlycoNet
