ZT-01, a Somatostatin Receptor 2 Antagonist, Enhances Glucagon Counterregulation in Diabetic Rats

Patients with insulin-treated type 2 diabetes (T2D) often experience impaired glucagon counterregulation, increasing their risk of severe hypoglycemia. Current treatments primarily focus on glycemic control, but addressing the blunted glucagon response remains a critical unmet need. Somatostatin, an inhibitory hormone, suppresses glucagon secretion via somatostatin receptor 2 (SSTR2). Antagonizing SSTR2 could therefore enhance glucagon release, potentially improving the body's natural defense against dangerously low blood sugar, but the long-term effects on overall glycemia and durability of this effect are not well understood.

Researchers induced T2D in male Sprague-Dawley rats using a high-fat diet and streptozotocin (35 mg/kg). After a 7-day insulin maintenance period, rats received a single dose of SSTR2a (ZT-01, 3 mg/kg) or vehicle (n = 7-8 per group) before an insulin overdose hypoglycemic challenge. Following a one-week washout, rats were administered ZT-01 (3 mg/kg) or vehicle daily for 8 days, with a second hypoglycaemic challenge performed on the last day to assess sustained effects. Primary endpoints included glucagon counterregulation and overall glycemic control.

Repeated administration of the SSTR2a ZT-01 significantly increased glucagon counterregulation in response to both acute and sustained hypoglycemic exposures in both T2D and control rats (all p < 0.05). This enhancement was observed after both single-dose and one-week daily dosing regimens. When administered without hypoglycemia, ZT-01 caused a transient rise in glucagon, c-peptide, and glucose levels in both healthy and T2D animals, indicating its mechanism of action. Importantly, despite these transient effects, daily ZT-01 administration did not worsen overall glycemia in T2D rats.

T2D rats receiving ZT-01 for 8 days (days 8-22) demonstrated reduced daily insulin needs without significantly affecting their blood glucose levels, suggesting improved insulin sensitivity or endogenous glucose regulation. Food intake and body weight remained unaffected by ZT-01 treatment.