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

Radzi M Noh, Sowmya Venkatasubramanian, Shruti Daga, Jeremy Langrish, Nicholas L Mills, Ninian N Lang, Ethan Hoffmann, Brian Waterhouse, David E Newby, Brian M Frier, Radzi M Noh, Sowmya Venkatasubramanian, Shruti Daga, Jeremy Langrish, Nicholas L Mills, Ninian N Lang, Ethan Hoffmann, Brian Waterhouse, David E Newby, Brian M Frier

Abstract

Background: The cardiometabolic effects of SRT2104, a novel SIRT1 activator, were investigated in people with type 2 diabetes mellitus (T2DM).

Methods: Fifteen adults with T2DM underwent a randomised, double-blind, placebo-controlled cross-over trial and received 28 days of oral SRT2104 (2.0 g/day) or placebo. Forearm vasodilatation (measured during intrabrachial bradykinin, acetylcholine and sodium nitroprusside infusions) as well as markers of glycaemic control, lipid profile, plasma fibrinolytic factors, and markers of platelet-monocyte activation, were measured at baseline and at the end of each treatment period.

Results: Lipid profile and platelet-monocyte activation were similar in both treatment arms (p>0.05 for all). Forearm vasodilatation was similar on exposure to acetylcholine and sodium nitroprusside (p>0.05, respectively). Bradykinin-induced vasodilatation was less during treatment with SRT2104 versus placebo (7.753vs9.044, respectively, mean difference=-1.291,(95% CI -2.296 to -0.285, p=0.012)). Estimated net plasminogen activator inhibitor type 1 antigen release was reduced in the SRT2104 arm versus placebo (mean difference=-38.89 ng/100 mL tissue/min, (95% CI -75.47, to -2.305, p=0.038)). There were no differences in other plasma fibrinolytic factors (p>0.05 for all). After 28 days, SRT2104 exposure was associated with weight reduction (-0.93 kg (95% CI -1.72 to -0.15), p=0.0236), and a rise in glycated haemoglobin (5 mmol/mol or 0.48% (0.26 to 0.70), p=0.004).

Conclusions: In people with T2DM, SRT2104 had inconsistent, predominantly neutral effects on endothelial and fibrinolytic function, and no discernible effect on lipids or platelet function. In contrast, weight loss was induced along with deterioration in glycaemic control, suggestive of potentially important metabolic effects.

Clinical trial registration: NCT01031108; Results.

Keywords: SIRT-1 activator; cardiovascular risk; endothelial dysfunction; lipids; platelet activation; sirtuins; type 2 diabetes mellitus; weight loss.

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Study design: schematic representation of study design. PK, pharmacokinetic; SCR, screening.
Figure 2
Figure 2
CONSORT flow diagram of randomisation.
Figure 3
Figure 3
Effect of bradykinin (100 pmol/min, 300 pmol/min, 1000 pmol/min), acetylcholine (5 µg/min, 10 µg/min, 20 µg/min) and sodium nitroprusside (2 µg/min, 4 µg/min, 8 µg/min) on absolute forearm blood flow. Blue, placebo; red, SRT2104; closed circle and square, infused forearm blood flow; open circle and square, non-infused forearm blood flow. Data are presented as mean ±95% CI.
Figure 4
Figure 4
Effect of SRT2104 on markers of platelet and monocyte activation. Data are presented as mean±SD. PMA, platelet-monocyte aggregate; CD11b, CD 11b/macrophage-1 antigen; sCD40L, soluble CD40 ligand.

References

    1. Barrows CH, Kokkonen GC, Moment GB, Dietary restriction and life extension, biological mechanisms. USA: CRC Press Boca Raton; 1982.
    1. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000;289:2126–8.10.1126/science.289.5487.2126
    1. Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, Illinois: Charles C Thomas, 1988.
    1. Ingram DK, Anson RM, de Cabo R, et al. . Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci 2004;1019:412–23.10.1196/annals.1297.074
    1. Roth GS, Mattison JA, Ottinger MA, et al. . Aging in rhesus monkeys: relevance to human health interventions. Science 2004;305:1423–6.10.1126/science.1102541
    1. Bordone L, Guarente L, Restriction C. SIRT1 and Metabolism. Understanding Longevity. Nature Reviews Molecular Cell Biology 2005;6:298–305.
    1. Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 1999;260:273–9.10.1006/bbrc.1999.0897
    1. Brunet A, Sweeney LB, Sturgill JF, et al. . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011–5.10.1126/science.1094637
    1. Motta MC, Divecha N, Lemieux M, et al. . Mammalian SIRT1 represses forkhead transcription factors. Cell 2004;116:551–63.10.1016/S0092-8674(04)00126-6
    1. Rodgers JT, Lerin C, Haas W, et al. . Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113–8.10.1038/nature03354
    1. Elliot P Jirousek M. Sirtuins: novel targets for metabolic disease. Curr Opin Investig Drugs 2008;9:371–8.
    1. Yu BP, Masoro EJ, McMahan CA. Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics. J Gerontol 1985;40:657–70.
    1. Maeda H, Gleiser CA, Masoro EJ, et al. . Nutritional influences on aging of Fischer 344 rats: II. Pathology. J Gerontol 1985;40:671–88.10.1093/geronj/40.6.671
    1. Ahmet I, Wan R, Mattson MP, et al. . Cardioprotection by intermittent fasting in rats. Circulation 2005;112:3115–21.10.1161/CIRCULATIONAHA.105.563817
    1. Breitenstein A, Stein S, Holy EW, et al. . SIRT1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells. Cardiovasc Res 2011;89:464–72.10.1093/cvr/cvq339
    1. Stein S, Lohmann C, Schäfer N, et al. . SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis. Eur Heart J 2010;31:2301–9.10.1093/eurheartj/ehq107
    1. Mattagajasingh I, Kim CS, Naqvi A, et al. . SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 2007;104:14855–60.10.1073/pnas.0704329104
    1. Wild S, Roglic G, Green A, et al. . Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047–53.10.2337/diacare.27.5.1047
    1. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care 2013;36:1033–46.10.2337/dc12-2625
    1. van Sloten TT, Henry RM, Dekker JM, et al. . Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes: the Hoorn study. Hypertension 2014;64:1299–305.10.1161/HYPERTENSIONAHA.114.04221
    1. Venkatasubramanian S, Noh RM, Daga S, et al. . Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers. J Am Heart Assoc 2013;2:e00004210.1161/JAHA.113.000042
    1. Mills NL, Törnqvist H, Gonzalez MC, et al. . Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease. N Engl J Med 2007;357:1075–82.10.1056/NEJMoa066314
    1. Labinjoh C, Newby DE, Pellegrini MP, et al. . Potentiation of bradykinin-induced tissue plasminogen activator release by angiotensin-converting enzyme inhibition. J Am Coll Cardiol 2001;38:1402–8.10.1016/S0735-1097(01)01562-5
    1. Harding SA, Sommerfield AJ, Sarma J, et al. . Increased CD40 ligand and platelet-monocyte aggregates in patients with type 1 diabetes mellitus. Atherosclerosis 2004;176:321–5.10.1016/j.atherosclerosis.2004.05.008
    1. Newby DE, Wright RA, Ludlam CA, et al. . An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium. Thromb Haemost 1997;78:1242–8.
    1. Sarma J, Laan CA, Alam S, et al. . Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 2002;105:2166–71.10.1161/01.CIR.0000015700.27754.6F
    1. Hoffmann E, Wald J, Lavu S, et al. . Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man. Br J Clin Pharmacol 2013;75:186–96.10.1111/j.1365-2125.2012.04340.x
    1. Baksi A, Kraydashenko O, Zalevkaya A, et al. . A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes. Br J Clin Pharmacol 2014;78:69–77.10.1111/bcp.12327
    1. Picard F, Kurtev M, Chung N, et al. . Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004;429:771–6.10.1038/nature02583
    1. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 2011;60:2441–9.10.2337/db11-0425
    1. Sims EA, Horton ES. Endocrine and metabolic adaptation to obesity and starvation. Am J Clin Nutr 1968;21:1455–70.

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