Effect of the urotensin-II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus

Abstract

Aims: To investigate the effects of palosuran, a nonpeptidic, potent and selective antagonist of the urotensin-II receptor, on insulin and glucose regulation in 20 diet-treated patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, randomized, crossover, proof-of-concept study.

Methods: After 4 weeks' oral treatment with 125 mg palosuran or placebo b.i.d.,effects on insulin secretion and sensitivity and blood glucose levels were assessed by means of a hyperglycaemic glucose clamp, meal tolerance test, homeostasis model assessment-insulin resistance score, and daily self-monitoring of blood glucose. Plasma concentrations of palosuran were determined for 12 h on the last day of intake.

Results: Palosuran did not affect second-phase insulin response (primary end-point) during the hyperglycaemic glucose clamp in comparison with placebo [paired difference of -1.8 microU ml(-1), 95% confidence interval (CI) -7.8, 4.2]. Likewise, no effects of palosuran were detected on the first-phase insulin response, or on insulin secretion and blood glucose levels during the meal tolerance test or on homeostasis model assessment-insulin resistance score. No clinically significant effects on daily blood glucose profiles were observed during the study. Geometric mean C(max) and AUC(tau) (95% CI) and median t(max) (range) in this patient population were 180 ng ml(-1) (125, 260), 581 ng.h ml(-1) (422, 800) and 3.0 h (0.67, 4.3), respectively.

Conclusions: The results of this study indicate that antagonism of the urotensin-II system does not influence insulin secretion or sensitivity or daily blood glucose levels in diet-treated patients with Type 2 diabetes.

Figure 1

Arithmetic mean (± SD) of glucose infusion rate per kilogram bodyweight (lower) and blood glucose (upper) vs. time during the hyperglycaemic glucose clamp test (n= 20). Palosuran (–□–); Placebo ()

Figure 2

Arithmetic mean (± SD) concentration–time course of insulin during the hyperglycaemic glucose-clamp test (n= 20). Palosuran (–□–); Placebo ()

Figure 3

Arithmetic mean (± SD) concentration–time courses of blood glucose (left) and insulin (right) during the meal tolerance test (n= 20). Palosuran (–□–); Placebo ()

Figure 4

Arithmetic mean plasma concentration (SD) vs. time profile (0–12 h) of palosuran in patients with diet-treated Type 2 diabetes mellitus (n= 20) after 4 weeks' treatment with palosuran 125 mg b.i.d.