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Effect of the urotensin‐II receptor antagonist palosuran on secretion of and sensitivity to insulin in patients with Type 2 diabetes mellitus
Author(s) -
Sidharta Patricia N.,
Rave Klaus,
Heinemann Lutz,
Chiossi Eleonora,
Krähenbühl Stephan,
Dingemanse Jasper
Publication year - 2009
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2009.03480.x
Subject(s) - medicine , endocrinology , insulin resistance , diabetes mellitus , type 2 diabetes , type 2 diabetes mellitus , population , insulin , antagonist , receptor , environmental health
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Urotensin‐II (U‐II) is one of the most potent vasoconstrictors identified thus far. • Although differences in both U‐II blood levels and U‐II receptor (UT‐receptor) expression have been observed in patients with cardiovascular and cardiorenal disease, the precise function in humans has not been elucidated. • U‐II and its receptor have been reported to be involved in glucose metabolism and insulin resistance, which can lead to the development of Type 2 diabetes mellitus. • In rat models of diabetes, palosuran, a selective, potent antagonist of the human UT‐receptor, improved several disease markers. WHAT THIS STUDY ADDS • In this study in diabetic patients, the effects of palosuran on insulin secretion and sensitivity were investigated using a hyperglycaemic glucose clamp and a meal tolerance test and daily glucose levels were also studied. • Although no obvious beneficial effect of palosuran in this patient population was observed, the study contributes to providing more insight inro the human U‐II/UT‐receptor system. 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 µU 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 τ (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.