Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus

摘要

Background: The cardiometabolic effects of SRT2104,uda novel SIRT1 activator, were investigated in people withudtype 2 diabetes mellitus (T2DM).udMethods: Fifteen adults with T2DM underwent audrandomised, double-blind, placebo-controlled cross-overudtrial and received 28 days of oral SRT2104 (2.0 g/day)udor placebo. Forearm vasodilatation (measured duringudintrabrachial bradykinin, acetylcholine and sodiumudnitroprusside infusions) as well as markers of glycaemicudcontrol, lipid profile, plasma fibrinolytic factors, andudmarkers of platelet-monocyte activation, were measuredudat baseline and at the end of each treatment period.udResults: Lipid profile and platelet-monocyteudactivation were similar in both treatment armsud(p>0.05 for all). Forearm vasodilatation wasudsimilar on exposure to acetylcholine and sodiumudnitroprusside (p>0.05,respectively). Bradykinin-inducedudvasodilatation was less during treatment with SRT2104udversus placebo (7.753vs9.044, respectively, meanuddifference=−1.291,(95% CI −2.296 to −0.285, p=0.012)).udEstimated net plasminogen activator inhibitor type 1udantigen release was reduced in the SRT2104 arm versusudplacebo (mean difference=−38.89 ng/100mL tissue/udmin, (95%CI −75.47, to –2.305, p=0.038)). There wereudno differences in other plasma fibrinolytic factors (p>0.05udfor all). After 28 days, SRT2104 exposure was associatedudwith weight reduction (−0.93 kg (95% CI −1.72 to −0.15),udp=0.0236), and a rise in glycated haemoglobin (5 mmol/udmol or 0.48% (0.26 to 0.70), p=0.004)udConclusions: In people with T2DM, SRT2104 hadudinconsistent, predominantly neutral effects on endothelialudand fibrinolytic function, and no discernible effect on lipidsudor platelet function. In contrast, weight loss was inducedudalong with deterioration in glycaemic control, suggestive ofudpotentially important metabolic effects.udClinical trial registration: NCT01031108; Results.