Bilirubin may confer cardiovascular protection because of its strong antioxidative properties. Both thyroid dysfunction and the diabetic state affect bilirubin metabolism. Here we tested whether low-normal thyroid function affects serum bilirubin among euthyroid subjects with and without type 2 diabetes mellitus (T2DM).
Methods:
Serum total bilirubin, thyrotropin and free thyroxine (free T4), transaminases, insulin sensitivity (homeostasis model assessment), and lipids were measured in 74 T2DM and 82 nondiabetic subjects with thyrotropin and free T4 levels within the euthyroid range.
Results:
Bilirubin was positively related to free T4 in T2DM subjects (r=0.370, p<0.001), but not in nondiabetic subjects (r=0.047, p=0.68). In age- and sex-adjusted multiple linear regression analysis, free T4 was found to interact positively with the presence of T2DM on serum bilirubin (interaction term: β=0.251, p=0.024). This interaction remained present after additional adjustment for alcohol intake, aspartate aminotransferase and insulin sensitivity (interaction term: β=0.222, p=0.043), or alternatively for cholesterol and triglycerides (interaction term: β=0.203, p=0.057).
Conclusions:
Lower free T4 levels within the euthyroid range confer decreased bilirubin in T2DM. Low-normal thyroid function could enhance atherosclerosis susceptibility in T2DM by decreasing serum bilirubin.
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References
1.
StockerR, YamamotoY, McDonaghAF, GlazerAN, AmesBN. 1987. Bilirubin is an antioxidant of possible physiological importance. Science, 235:1043–1046.
2.
NeuzilJ, StockerR. 1994. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem, 269:16712–16719.
3.
NovotnyL, VitekL. 2003. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med (Maywood), 228:568–571.
4.
AjjaR, LeeDC, SuiX, ChurchTS, StevenNB. 2011. Usefulness of serum bilirubin and cardiorespiratory fitness as predictors of mortality in men. Am J Cardiol, 108:1438–1442.
5.
VitekL, NovotnyL, SperlM, HolajR, SpacilJ. 2006. The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis, 21:408–414.
6.
DullaartRP, KappellePJ, de VriesR. 2012. Lower carotid intima media thickness is predicted by higher serum bilirubin in both non-diabetic and type 2 diabetic subjects. Clin Chim Acta, 414:161–165.
7.
CappolaAR, FriedLP, ArnoldAM, DaneseMD, KullerLH, BurkeGL, TracyRP, LadensonPW. 2006. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA, 295:1033–1041.
8.
OchsN, AuerR, BauerDC, NanchenD, GusseklooJ, CornuzJ, RodondiN. 2008. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med, 148:832–845.
9.
RodondiN, den ElzenWP, BauerDC, CappolaAR, RazviS, WalshJP, AsvoldBO, IervasiG, ImaizumiM, ColletTH, BremnerA, MaisonneuveP, SgarbiJA, KhawKT, VanderpumpMP, NewmanAB, CornuzJ, FranklynJA, WestendorpRG, VittinghoffE, GusseklooJ. Thyroid Studies Collaboration. 2010. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA, 304:1365–1374.
10.
AsvoldBO, BjoroT, PlatouC, VattenLJ. 2012. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT study in Norway. Clin Endocrinol (Oxf ), 77:911–917.
11.
GaoN, ZhangW, ZhangYZ, YangQ, ChenSH. 2013. Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis, 227:18–25.
12.
DullaartRP, de VriesR, RoozendaalC, KoboldAC, SluiterWJ. 2007. Carotid artery intima media thickness is inversely related to serum free thyroxine in euthyroid subjects. Clin Endocrinol (Oxf ), 67:668–673.
13.
TakamuraN, AkilzhanovaA, HayashidaN, KadotaK, YamasakiH, UsaT, NakazatoM, MaedaT, OzonoY, AoyagiK. 2009. Thyroid function is associated with carotid intima-media thickness in euthyroid subjects. Atherosclerosis, 204:e77–e81.
14.
IttermannT, BaumeisterSE, VolzkeH, WasnerC, SchminkeU, WallaschofskiH, NauckM, LudemannJ. 2012. Are serum TSH levels associated with oxidized low-density lipoprotein? Results from the Study of Health in Pomerania. Clin Endocrinol (Oxf ), 76:526–532.
15.
TorunAN, KulaksizogluS, KulaksizogluM, PamukBO, IsbilenE, TutuncuNB. 2009. Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clin Endocrinol (Oxf ), 70:469–474.
16.
SmithTJ, DrummondGS. 1991. Retinoic acid can enhance the stimulation by thyroid hormone of heme oxygenase activity in the liver of thyroidectomized rats. Biochim Biophys Acta, 1075:119–122.
17.
LiF, LuS, ZhuR, ZhouZ, MaL, CaiL, LiuZ. 2011. Heme oxygenase-1 is induced by thyroid hormone and involved in thyroid hormone preconditioning-induced protection against renal warm ischemia in rat. Mol Cell Endocrinol, 339:54–62.
18.
GartnerLM, AriasIM. 1972. Hormonal control of hepatic bilirubin transport and conjugation. Am J Physiol, 222:1091–1099.
19.
Van SteenbergenW, FeveryJ, De VosR, LeytenR, HeirweghKP, De GrooteJ. 1989. Thyroid hormones and the hepatic handling of bilirubin. I. Effects of hypothyroidism and hyperthyroidism on the hepatic transport of bilirubin mono- and diconjugates in the Wistar rat. Hepatology, 9:314–321.
20.
FeveryJ, MuracaM, MesaV, Van SteenbergenW, BlanckaertN. 1987. Plasma bilirubin pigments in health and disease. Mol Aspects Med, 9:391–404.
21.
DekkerD, DorresteijnMJ, PijnenburgM, HeemskerkS, Rasing-HoogveldA, BurgerDM, WagenerFA, SmitsP. 2011. The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol, 31:458–463.
22.
StehouwerCD, LambertJ, DonkerAJ, van HinsberghVW. 1997. Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res, 34:55–68.
23.
CerielloA. 2006. Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes. Curr Opin Lipidol, 17:510–518.
24.
NobecourtE, JacqueminetS, HanselB, ChantepieS, GrimaldiA, ChapmanMJ, KontushA. 2005. Defective antioxidative activity of small dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and hyperglycaemia. Diabetologia, 48:529–538.
25.
KappellePJ, de BoerJF, PertonFG, AnnemaW, de VriesR, DullaartRP, TietgeUJ. 2012. Increased LCAT activity and hyperglycaemia decrease the antioxidative functionality of HDL. Eur J Clin Invest, 42:487–495.
26.
VitekL. 2012. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol, 3:55.
27.
AbrahamNG, TsenovoyPL, McClungJ, DrummondGS. 2008. Heme oxygenase: a target gene for anti-diabetic and obesity. Curr Pharm Des, 14:412–421.
28.
BaoW, SongF, LiX, RongS, YangW, ZhangM, YaoP, HaoL, YangN, HuFB, LiuL. 2010. Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus. PLoS One, 5:e12371.
29.
Dutch College of General Practitioners. 2006. Standaard diabetes mellitus type 2. Huisarts en Wetenschap, 3:137–152.
30.
TisdaleWA, KlatskinG, KinsellaED. 1959. The significance of the direct-reacting fraction of serum bilirubin in hemolytic jaundice. Am J Med, 26:214–227.
31.
ZelleDM, DeetmanN, AlkhalafA, NavisG, BakkerSJ. 2011. Support for a protective effect of bilirubin on diabetic nephropathy in humans. Kidney Int, 79:686author reply 686–687.
32.
KatsikiN, KaragiannisA, MikhailidisDP. 2013. Diabetes, bilirubin and amputations: is there a link?Diabetologia, 56:683–685.
33.
DeetmanPE, ZelleDM, Homan van der HeideJJ, NavisGJ, GansRO, BakkerSJ. 2012. Plasma bilirubin and late graft failure in renal transplant recipients. Transpl Int, 25:876–881.
34.
SelvinS. 1996. Statistical Analysis of Epidemiological Data. Oxford University Press: New York.
35.
LuM, LydenPD, BrottTG, HamiltonS, BroderickJP, GrottaJC. 2005. Beyond subgroup analysis: improving the clinical interpretation of treatment effects in stroke research. J Neurosci Methods, 143:209–216.
36.
LambadiariV, MitrouP, MaratouE, RaptisAE, TountasN, RaptisSA, DimitriadisG. 2011. Thyroid hormones are positively associated with insulin resistance early in the development of type 2 diabetes. Endocrine, 39:28–32.
37.
KabadiUM. 1984. Impaired pituitary thyrotroph function in uncontrolled type II diabetes mellitus: normalization on recovery. J Clin Endocrinol Metab, 59:521–525.
38.
YehSY, DoupisJ, RahangdaleS, HorrS, MalhotraA, VevesA. 2009. Total serum bilirubin does not affect vascular reactivity in patients with diabetes. Vasc Med, 14:129–136.
39.
OdaE. 2010. Bilirubin is negatively associated with A1C independently of fasting plasma glucose, age, obesity, inflammation, hemoglobin, and iron in apparently healthy Japanese men and women. Diabetes Care, 33:e131.
40.
ClarkJM, BrancatiFL, DiehlAM. 2003. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol, 98:960–967.
41.
DullaartRP, de VriesR, Dallinga-ThieGM, SluiterWJ, van TolA. 2008. Phospholipid transfer protein activity is determined by type 2 diabetes mellitus and metabolic syndrome, and is positively associated with serum transaminases. Clin Endocrinol (Oxf ), 68:375–381.
42.
WassenFW, MoeringsEP, van ToorH, HennemannG, EvertsME. 2000. Thyroid hormone uptake in cultured rat anterior pituitary cells: effects of energy status and bilirubin. J Endocrinol, 165:599–606.
43.
OngKL, WuBJ, CheungBM, BarterPJ, RyeKA. 2011. Association of lower total bilirubin level with statin usage: the United States National Health and Nutrition Examination Survey 1999–2008. Atherosclerosis, 219:728–733.
