Low normal thyroid function enhances plasma cholesteryl ester transfer in Type 2 diabetes mellitus


      • Plasma cholesteryl ester transfer (CET) is elevated in T2DM and hypothyroidism.
      • We tested whether CET is related to thyroid function in euthyroid T2DM subjects.
      • CET was correlated positively with TSH in T2DM but not in non-diabetic subjects.
      • Plasma triglycerides also interacted positively with TSH on plasma CET in T2DM.
      • Low normal thyroid function confers increased CET in the context of hyperglycemia.



      Plasma cholesteryl ester transfer (CET), reflecting endogenous transfer of cholesteryl esters from HDL to very low and low density lipoproteins, is elevated in Type 2 diabetes mellitus (T2DM), and may predict (subclinical) cardiovascular disease. Low normal thyroid function may adversely affect lipoprotein metabolism and atherosclerosis development. We tested whether plasma CET is related to thyroid function in euthyroid T2DM and non-diabetic subjects.

      Subjects and methods

      Plasma CET was measured in 74 T2DM and 82 non-diabetic subjects with thyroid-stimulating hormone (TSH) and free thyroxine levels within the reference range.


      Plasma CET was 20% higher in T2DM (P = 0.003) coinciding higher cholesteryl ester transfer protein (CETP) mass (P = 0.009) and triglycerides (P = 0.02). In univariate analysis, plasma CET was correlated positively with TSH in T2DM only (r = 0.330, P = 0.004). Multiple linear regression analysis revealed a positive interaction between the presence of T2DM and TSH on plasma CET after controlling for age, sex, body mass index, non-HDL cholesterol, triglycerides and CETP mass (β = 0.167, P = 0.030). The relationship of plasma CET with TSH was also positively modified by plasma glucose and HbA1c (interaction terms: β = 0.119, P = 0.036, β = 0.170, P = 0.001, respectively). Additionally, plasma triglycerides interacted positively with TSH on plasma CET in T2DM (β = 0.198, P = 0.011).


      Low normal thyroid function, as inferred from higher TSH, confers increased plasma CET in the context of chronic hyperglycemia. Effects of thyroid function on plasma CET may be particularly relevant in hypertriglyceridemic T2DM. Low normal thyroid function could influence atherosclerosis susceptibility in T2DM by affecting the plasma cholesteryl ester transfer process.


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        • Duntas L.H.
        • Wartofsky L.
        Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence?.
        Thyroid. 2007; 17: 1075-1084
        • Hak A.E.
        • Pols H.A.
        • Visser T.J.
        • Drexhage H.A.
        • Hofman A.
        • Witteman J.C.
        Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.
        Ann Intern Med. 2000; 132: 270-278
        • Cappola A.R.
        • Fried L.P.
        • Arnold A.M.
        • et al.
        Thyroid status, cardiovascular risk, and mortality in older adults.
        J Am Med Assoc. 2006; 295: 1033-1041
        • Ochs N.
        • Auer R.
        • Bauer D.C.
        • et al.
        Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality.
        Ann Intern Med. 2008; 148: 832-845
        • Rodondi N.
        • den Elzen W.P.
        • Bauer D.C.
        • et al.
        Subclinical hypothyroidism and the risk of coronary heart disease and mortality.
        J Am Med Assoc. 2010; 304: 1365-1374
        • Asvold B.O.
        • Bjøro T.
        • Platou C.
        • Vatten L.J.
        Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT Study in Norway.
        Clin Endocrinol (Oxf). 2012; 77: 911-917
        • Dullaart R.P.F.
        • de Vries R.
        • Roozendaal C.
        • Kobold A.C.
        • Sluiter W.J.
        Carotid artery intima media thickness is inversely related to serum free thyroxine in euthyroid subjects.
        Clin Endocrinol (Oxf). 2007; 67: 668-673
        • Takamura N.
        • Akilzhanova A.
        • Hayashida N.
        • et al.
        Thyroid function is associated with carotid intima-media thickness in euthyroid subjects.
        Atherosclerosis. 2009; 204: e77-e81
        • Asvold B.O.
        • Vatten L.J.
        • Nilsen T.I.
        • Bjøro T.
        The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study.
        Eur J Endocrinol. 2007; 156: 181-186
        • Garduño-Garcia J de Jesus
        • Alvirde-Garcia U.
        • López-Carrasco G.
        • et al.
        TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects.
        Eur J Endocrinol. 2010; 163: 273-278
        • Wang F.
        • Tan Y.
        • Wang C.
        • et al.
        Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones.
        J Clin Endocrinol Metab. 2012; 97: 2724-2731
        • Ittermann T.
        • Baumeister S.E.
        • Völzke H.
        • et al.
        Are serum TSH levels associated with oxidized low-density lipoprotein? Results from the Study of Health in Pomerania.
        Clin Endocrinol (Oxf). 2012; 76: 526-532
        • Dallinga-Thie G.M.
        • Dullaart R.P.F.
        • van Tol A.
        Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins.
        Curr Opin Lipidol. 2007; 18: 251-257
        • de Vries R.
        • Perton F.G.
        • Dallinga-Thie G.M.
        • et al.
        Plasma cholesteryl ester transfer is a determinant of intima-media thickness in type 2 diabetic and nondiabetic subjects: role of CETP and triglycerides.
        Diabetes. 2005; 54: 3554-3559
        • Kappelle P.J.W.H.
        • Perton F.
        • Hillege H.L.
        • Dallinga-Thie G.M.
        • Dullaart R.P.F.
        High plasma cholesteryl ester transfer but not CETP mass predicts incident cardiovascular disease: a nested case-control study.
        Atherosclerosis. 2011; 217: 249-252
        • Zeller M.
        • Masson D.
        • Farnier M.
        • et al.
        High serum cholesteryl ester transfer rates and small high-density lipoproteins are associated with young age in patients with acute myocardial infarction.
        J Am Coll Cardiol. 2007; 50: 1948-1955
        • Pearce E.N.
        Update in lipid alterations in subclinical hypothyroidism.
        J Clin Endocrinol Metab. 2012; 97: 326-333
        • Ritter M.C.
        • Kannan C.R.
        • Bagdade J.D.
        The effects of hypothyroidism and replacement therapy on cholesteryl ester transfer.
        J Clin Endocrinol Metab. 1996; 81: 797-800
        • Dullaart R.P.F.
        • Hoogenberg K.
        • Groener J.E.
        • Dikkeschei L.D.
        • Erkelens D.W.
        • Doorenbos H.
        The activity of cholesteryl ester transfer protein is decreased in hypothyroidism: a possible contribution to alterations in high-density lipoproteins.
        Eur J Clin Invest. 1990; 20: 581-587
        • Bagdade J.D.
        • Lane J.T.
        • Subbaiah P.V.
        • Otto M.E.
        • Ritter M.C.
        Accelerated cholesterylester transfer in noninsulin-dependent diabetes mellitus.
        Atherosclerosis. 1993; 104: 69-77
        • Riemens S.
        • van Tol A.
        • Sluiter W.
        • Dullaart R.P.F.
        Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein.
        Atherosclerosis. 1998; 140: 71-79
        • Sutherland W.H.
        • Walker R.J.
        • Lewis-Barned N.J.
        • et al.
        Plasma cholesteryl ester transfer in patients with non-insulin dependent diabetes mellitus.
        Clin Chim Acta. 1994; 231: 29-38
        • Grundy S.M.
        • Cleeman J.I.
        • Daniels S.R.
        • et al.
        Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.
        Circulation. 2005; 112: 2735-2752
        • van Venrooij F.V.
        • Stolk R.P.
        • Banga J.D.
        • et al.
        Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes.
        Diabetes Care. 2003; 26: 1216-1223
        • Dullaart R.P.F.
        • de Vries R.
        • Scheek L.
        • et al.
        Type 2 diabetes mellitus is associated with differential effects on plasma cholesteryl ester transfer protein and phospholipid transfer protein activities and concentrations.
        Scand J Clin Lab Invest. 2004; 64: 205-215
        • Lu M.
        • Lyden P.D.
        • Brott T.G.
        • Hamilton S.
        • Broderick J.P.
        • Grotta J.C.
        Beyond subgroup analysis: improving the clinical interpretation of treatment effects in stroke research.
        J Neurosci Methods. 2005; 143: 209-216
        • Kabadi U.M.
        Impaired pituitary thyrotroph function in uncontrolled type II diabetes mellitus: normalization on recovery.
        J Clin Endocrinol Metab. 1984; 59: 521-525
        • Lambadiari V.
        • Mitrou P.
        • Maratou E.
        • et al.
        Thyroid hormones are positively associated with insulin resistance early in the development of type 2 diabetes.
        Endocrine. 2011; 39: 28-32
        • Passarelli M.
        • Catanozi S.
        • Nakandakare E.R.
        • et al.
        Plasma lipoproteins from patients with poorly controlled diabetes mellitus and “in vitro” glycation of lipoproteins enhance the transfer rate of cholesteryl ester from HDL to apo-B-containing lipoproteins.
        Diabetologia. 1997; 40: 1085-1093
        • Ceriello A.
        Controlling oxidative stress as a novel molecular approach to protecting the vascular wall in diabetes.
        Curr Opin Lipidol. 2006; 17: 510-518
        • Lagrost L.
        Regulation of cholesteryl ester transfer protein (CETP) activity: review of in vitro and in vivo studies.
        Biochim Biophys Acta. 1994; 1215: 209-226
        • Dullaart R.P.F.
        • Constantinides A.
        • Perton F.G.
        • et al.
        Plasma cholesteryl ester transfer, but not cholesterol esterification, is related to lipoprotein-associated phospholipase A2: possible contribution to an atherogenic lipoprotein profile.
        J Clin Endocrinol Metab. 2011; 96: 1077-1084
        • Diekman M.J.
        • Anghelescu N.
        • Endert E.
        • Bakker O.
        • Wiersinga W.M.
        Changes in plasma low-density lipoprotein (LDL)- and high-density lipoprotein cholesterol in hypo- and hyperthyroid patients are related to changes in free thyroxine, not to polymorphisms in LDL receptor or cholesterol ester transfer protein genes.
        J Clin Endocrinol Metab. 2000; 85: 1857-1862
        • de Vries R.
        • Dikkeschei B.D.
        • Sluiter W.J.
        • Dallinga-Thie G.M.
        • van Tol A.
        • Dullaart R.P.F.
        Statin and fibrate combination does not additionally lower plasma cholesteryl ester transfer in type 2 diabetes mellitus.
        Clin Lab. 2012; 58: 1231-1239