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.

• Authors: Patricia N Sidharta, Klaus Rave, Lutz Heinemann, Eleonora Chiossi, Stephan Krähenbühl, Jasper Dingemanse
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 68 Issue 4 Pg. 502-10 (Oct 2009) ISSN: 1365-2125 [Electronic] England
• PMID: 19843053 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Blood Glucose
• Insulin
• Quinolines
• Receptors, G-Protein-Coupled
• UTS2R protein, human
• Urotensins
• Urea
• 1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea

Topics

• Adult
• Aged
• Blood Glucose (drug effects, metabolism)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Double-Blind Method
• Female
• Glucose Clamp Technique
• Glucose Tolerance Test
• Humans
• Insulin (blood, metabolism)
• Insulin Secretion
• Male
• Middle Aged
• Quinolines (blood, therapeutic use)
• Receptors, G-Protein-Coupled (blood)
• Treatment Outcome
• Urea (analogs & derivatives, blood, therapeutic use)
• Urotensins (blood)