Search

Aim: To evaluate the pharmacokinetics and efficacy of a novel somatostatin receptor 2 antagonist, ZT‐01, to stimulate glucagon release in rats with type 1 diabetes (T1D). Methods: The pharmacokinetics of ZT‐01 and PRL‐2903 were assessed following intraperitoneal or subcutaneous dosing at 10 mg/kg. We compared the efficacy of ZT‐01 with PRL‐2903 to prevent hypoglycaemia during an insulin bolus challenge and under hypoglycaemic clamp conditions. Results: Within 1 hour after intraperitoneal administration, ZT‐01 achieved more than 10‐fold higher plasma Cmax compared with PRL‐2903. Twenty‐four hour exposure was 4.7× and 11.3× higher with ZT‐01 by the intraperitoneal and subcutaneous routes, respectively. The median time to reach hypoglycaemia of more than 3.0 mmol/L was 60, 70, and 125 minutes following vehicle, PRL‐2903, or ZT‐01 administration, respectively. Furthermore, rats receiving ZT‐01 had significantly higher glucose nadirs following insulin administration compared with PRL‐2903– and vehicle–treated rats. During the hypoglycaemic clamp, ZT‐01 increased peak glucagon responses by ~4‐fold over PRL‐2903. Conclusions: We conclude that ZT‐01 may be effective in restoring glucagon responses and preventing the onset of hypoglycaemia in patients with T1D. [ABSTRACT FROM AUTHOR]

Aim: It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycaemia contributes to the development of counterregulatory failure. We previously reported that treatment with carvedilol, a non‐specific β‐blocker, prevented the development of counterregulatory failure and improved hypoglycaemia awareness in recurrently hypoglycaemic non‐diabetic rats. The current study investigated whether carvedilol has similar benefits in diabetic rats. Methods: Recurrently hypoglycaemic streptozotocin‐diabetic rats (STZ+RH) were treated with carvedilol for one week prior to undergoing a hypoglycaemic clamp. Hypoglycaemia awareness was evaluated in streptozotocin‐diabetic rats made hypoglycaemia unaware using repeated injections of 2‐deoxyglucose. Results: Compared to hypoglycaemia‐naïve STZ‐diabetic controls, exogenous glucose requirements were more than doubled in the STZ+RH animals and this was associated with a 49% reduction in the epinephrine response to hypoglycaemia. Treating STZ+RH animals with carvedilol improved the epinephrine response to hypoglycaemia. Of note, neither recurrent hypoglycaemia nor carvedilol treatment affected the glucagon response in diabetic animals. Additionally, carvedilol treatment improved the feeding response to insulin‐induced hypoglycaemia in diabetic animals made 'hypoglycaemia unaware' using repeated injections of 2‐deoxyglucose, suggesting the treatment improved awareness of hypoglycaemia as well. Conclusion: Our data suggest that carvedilol may be useful in preventing impairments of the sympathoadrenal response and the development of hypoglycaemia unawareness during recurring episodes of hypoglycaemia in diabetic animals. [ABSTRACT FROM AUTHOR]