| The Relationship between Thyrotropin and Low Density Lipoprotein Cholesterol Is Modified by Insulin Sensitivity in Healthy Euthyroid Subjects Stephan J. L. Bakker, Jan C. ter Maaten, Corrie Popp-Snijders, Joris P. J. Slaets, Robert J. Heine and Rijk O. B. Gans The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3 1206-1211 Copyright © 2001 by The Endocrine Society Department of Internal Medicine, University Hospital Groningen (S.J.L.B., J.C.t.M., J.P.J. S., R.O.B.G.), 9700 RB Groningen; and Institute for Endocrinology, Reproduction and Metabolism (C.P.-S., R.J.H.) and Department of Clinical Chemistry (C.P.-S.), University Hospital Vrije Universiteit, 1007 MB Amsterdam, The Netherlands Abstract High levels of TSH are associated with an increased cardiovascular risk. Many cardiovascular risk factors cluster within the insulin resistance syndrome. It is not known whether levels of TSH cluster as well. We conducted this research to test the hypothesis that TSH, insulin sensitivity, and levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) are interdependent in euthyroid subjects. Levels of TSH, free thyroid hormone, and serum lipids were measured in fasting serum samples taken before performance of a hyperinsulinemic euglycemic clamp to assess insulin sensitivity in 46 healthy euthyroid subjects with a mean TSH of 1.8 ± 0.7 mU/L. Significant age- and sex-adjusted partial correlations of TSH with LDL-C (r = 0.48; P < 0.01) and HDL-C (r = -0.36; P < 0.05) were observed. TSH was not significantly correlated with insulin sensitivity or fasting triglyceride concentrations. In line with these results, we found the associations of TSH with LDL-C and HDL-C to be independent of insulin sensitivity. However, we observed significant effect-modification of the association of TSH with LDL-C by insulin sensitivity (P = 0.02). This effect-modification implies a range of associations of TSH with LDL-C that varies from absent in insulin-sensitive subjects to strongly positive in insulin-resistant subjects. We conclude that the increased cardiovascular risk associated with subclinical hypothyroidism seems to extend itself into the normal range of thyroid function. Importantly, the effect-modification of the association of TSH with LDL-C by insulin sensitivity suggests that insulin-resistant subjects are most susceptible to this increased risk. Introduction OVERT HYPOTHYROIDISM is associated with an elevated risk of cardiovascular disease and adverse changes in blood lipids (1, 2, 3). Subclinical hypothyroidism, an asymptomatic state characterized by normal serum concentrations of free T4 and slightly elevated serum concentrations of TSH, is also associated with an increased risk of cardiovascular disease (4, 5, 6, 7, 8, 9). This has potentially important healthcare implications, because about 10% of the elderly women have been reported to develop subclinical hypothyroidism (9, 10, 11, 12, 13). However, most cardiovascular events occur in subjects with normal thyroid function. Thus, the question of whether an association of TSH with cardiovascular disease also exists in the euthyroid range is important. One study that addressed this question indeed showed significantly higher TSH levels in patients with coronary heart disease compared with healthy controls matched for age, sex, and body mass index (14). Interestingly, this difference could not be explained by a higher incidence of subclinical hypothyroidism or thyroid autoantibodies (14). Therefore, the known associations of overt and subclinical hypothyroidism with hyperlipidemia and dyslipidemia may be extended into the normal range of thyroid function. However, differences in mean blood lipids between euthyroid subjects and subjects with overt or subclinical hypothyroidism seem too small to entirely explain an increased cardiovascular risk in subjects with high normal TSH levels (13, 14, 15). An association of high normal TSH levels with the many cardiovascular risk factors that cluster within the insulin resistance syndrome (16, 17, 18) may be an explanation. We therefore hypothesized that high normal TSH levels are associated with a greater degree of insulin resistance than low normal levels of TSH. A stimulation of the synthesis and activity of hepatic and peripheral low density lipoprotein (LDL) receptors, and a consequent increase in LDL cholesterol (LDL-C) clearance in combination with stimulation of high density lipoprotein (HDL) synthesis is known to play a role in the induction of changes in blood lipids by thyroid hormone (19, 20, 21, 22, 23, 24). It is also known that an increased production of hepatic cholesterol and very low density lipoproteins (VLDL), the precursor particles of LDL (25, 26, 27), and an increased HDL cholesterol (HDL-C) clearance (28) accompany insulin-resistant states. We therefore also considered the possibility that insulin resistance modifies the effect of TSH on LDL-C and HDL-C concentrations. The aim of this study was to explore these hypotheses by investigating the potential association of TSH with insulin sensitivity as assessed with the gold standard hyperinsulinemic euglycemic clamp technique (29) and of both TSH and insulin sensitivity with blood lipids in healthy euthyroid subjects. Moreover, we investigated the interaction of TSH and insulin sensitivity with each other in potential associations with LDL-C and HDL-C concentrations. Study subjects Forty-seven Caucasian subjects were recruited by advertisement. All were normoglycemic according to criteria of the American Diabetes Association (30). They were healthy, nonsmoking, and euthyroid as judged by medical history. All were normotensive (office blood pressure measurement on recruitment, <140/90 mm Hg), and none was taking medication. All subjects gave informed, written consent before participating in the project, and the hospital ethics committee approved the study. Protocol All subjects were studied in the morning after an overnight fast. Measurements were performed on the same day. Body weight, height, and waist and hip circumference were measured. Two polytetrafluoroethylene cannulas (Venflon, Viggo, Helsinborg, Sweden) were inserted for intermittent blood sampling and infusions as described previously (31). After a resting period of 30 min, blood pressure and heart rate were measured using a semicontinuous blood pressure-measuring device (Nippon Colin BP 103 N sphygmomanometer, Hayashi, Komaki City, Japan). The mean of five readings was used during evaluation of the results. Sensitivity to insulin-mediated glucose uptake was assessed by the euglycemic hyperinsulinemic clamp technique, as described previously (31). A volume of 0.5 mL insulin (600 pmol/L; Actrapid, Novo Nordisk, Bagsvaerd, Denmark) was diluted to 50 mL with 45 mL saline and 4.5 mL human albumin (200 g/L). It was infused in a primed continuous manner at a rate of 8.3 fmol/kg•s for 2 h. Normoglycemia was maintained by adjusting the rate of a D- glucose infusion (1.11 mol/L) as based on frequent plasma glucose measurements with an automated glucose oxidase method (YSI, Inc., Yellow Springs, OH). The whole body glucose uptake (M value) was calculated from the glucose infusion rate during the last 60 min and expressed per unit of plasma insulin concentration (M/I value), thereby correcting for differences in steady state plasma insulin levels. To calculate the M/I value, we used the average value of four plasma insulin concentrations obtained during the second hour of the clamp. Analytical methods Analyses were performed in the laboratories of clinical chemistry and endocrinology of the University Hospital at the Vrije Universiteit Amsterdam. TSH, free serum T4 (fT4) was measured using an ACS:180 system (Chiron Corp., Emeryville, CA), TSH by an immunometric assay, and fT4 by competitive immunoassays. Lower limits of detection were 0.05 mU/L for TSH and 3 pmol/L for fT4. Serum concentrations of HDL-C were measured with an enzymatic colorimetric method (CHOD-PAP, Roche Molecular Biochemicals, Mannheim, Germany). Fasting serum triglycerides and total cholesterol (TC) were measured using an enzymatic colorimetric method (CPO-PAP, Roche Molecular Biochemicals). LDL-C concentrations were calculated using the Friedewald formula (32). Non-HDL-C was calculated as TC minus HDL-C. Plasma glucose was measured with a glucose dehydrogenase method (Merck & Co., Inc., Darmstadt, Germany; interassay coefficient of variation, 1.4%). Serum urate was determined by standard laboratory methods. Plasma insulin concentrations were measured with an immunoradiometric assay (Medgenix Biosource Diagnostics, Fleurus, Belgium), which has no cross-reactivity for proinsulin or split proinsulin. Insulin clearance was calculated using the insulin infusion rate and achieved steady state serum insulin concentrations during the euglycemic hyperinsulinemic clamp, assuming that endogenous insulin production was completely suppressed during the clamp (33). Statistical analysis Data are reported as the mean ± SD. All correlation analyses were performed using partial correlation analyses to adjust for age and gender. Two-sided P < 0.05 was considered to indicate statistical significance. TSH, M/I value, and a product-term of both (TSH x M/I) were further investigated as determinants of LDL-C, TC, non-HDL-C, and HDL-C in multiple linear regression models. In all of these models, adjustments were made for age and gender. All multiple linear regression models were checked for linearity and their residuals to have a random distribution. Statistical analysis was performed on a personal computer using a statistical software package (SPSS version 9.0, SPSS, Inc., Chicago, IL). Results The characteristics of the study subjects are listed in Table 1 . One subject with a TSH of 5.5 mU/L was excluded from the study because of biochemical subclinical hypothyroidism. Exclusion of this subject did not affect the presented associations to a significant extent. During the hyperinsulinemic euglycemic clamps the average glucose concentration was maintained at 4.6 ± 0.4 mmol/L. The plasma insulin concentration attained averaged 432 ± 140 pmol/L. There were significant age- and gender-independent correlations of TSH with TC, LDL- C, non-HDL-C, HDL-C, and LDL-C/HDL-C ratio (Table 2 ). There were no correlations of TSH with the M/I value or any of the other assessed nonlipid insulin resistance syndrome-related phenomena, including concentrations of fasting insulin and the waist to hip ratio. Correlations of TSH with individual blood lipids persisted after further adjustment for M/I values and waist to hip ratio in additional partial correlation analyses (for LDL-C: r = 0.48; P = 0.001; for TC: r = 0.40; P = 0.008; for non-HDL-C: r = 0.52; P < 0.001; for HDL-C: r = -0.39; P = 0.011). Neither the M/I values nor the waist to hip ratio showed significant correlations with any of the blood lipids; only the correlation of the M/I value with the LDL-C/HDL-C ratio tended to be significant (P = 0.07). In line with the known associations in the insulin resistance syndrome, there were strong age- and gender-independent correlations of the M/I value and the waist to hip ratio with fasting insulin, systolic blood pressure, diastolic blood pressure, and heart rate (Table 2 ). Multiple linear regression models were used to determine slopes of associations of TSH with LDL-C, TC, non-HDL-C, and HDL-C and to determine whether the associations were either dependent on or modified by M/I values (Tables 3 and 4 ). The associations of TSH with LDL-C and TC appeared to be significantly modified by the M/I values. This is indicated by significant product-terms of TSH and M/I value (Table 3 , model 4; P = 0.02 for LDL-C, P = 0.006 for TC, and P = 0.008 for non-HDL-C; regression analyses for TC and non-HDL-C not shown). The regression equation in Table 3 , model 4, predicts an LDL-C of 2.03 mmol/L for a low normal TSH of 0.5 mU/L in a 40-yr-old insulin-resistant man with an M/I value of 0.5 mL/kg•s, whereas a high normal TSH of 3.5 mU/L would result in an LDL-C of 5.23 mmol/L. With an M/I value of 3.23 mL/kg•s, the equation would predict an LDL-C of 2.92 mmol/L for both a TSH of 0.5 mU/L and a TSH of 3.5 mU/L. Thus, the association of TSH with LDL-C is much steeper in insulin-resistant subjects. The regression equation is shown in Fig. 1A . Although M/I values seem to contribute little to the explained variance of LDL-C independently of TSH (adjusted r2 = 0.47 instead of 0.46 with TSH alone), it is important to note that the introduction of the product-term increases the adjusted r2 further, toward 0.52. Graphical representation of the interaction between the associations of TSH and insulin sensitivity (M/I value) with LDL-C (A) and the LDL-C/HDL-C ratio (B), derived from the multiple linear regression equations that included a product-term of TSH and M/I values. In insulin-sensitive subjects (i.e. an M/I value of 3.5), there is virtually no association of TSH with either LDL-C or the LDL-C/HDL-C ratio. In insulin-resistant subjects (i.e. an M/I value of 0.5), the association of TSH with both LDL-C and the LCL- C/HDL-C ratio is steep. With an increase in TSH levels, the association of M/I values with either LDL-C or the LDL-C/HDL-C ratio becomes positive. The regression equation for generation of B was: LDL-C/HDL-C = -0.31 + 0.043 x age - 0.046 x sex + 1.33 x TSH + 0.29 x M/I - 0.35 x TSH x M/I. TSH was also significantly and inversely associated with HDL-C, independently of the M/I value (Table 4 ). The best model seems to be the model with TSH alone, with an adjusted r2 of 0.18, whereas adjusted r2 values of all other models were lower. The regression equation with the LDL-C/HDL-C ratio, a prime epidemiological cardiovascular risk indicator, is shown in Fig. 1B . Discussion This study is, to our knowledge, the first that addresses the possible linkage among TSH, insulin resistance, and serum concentrations of LDL- and HDL-C in healthy euthyroid subjects. We found no association of TSH with insulin sensitivity as assessed with the gold standard hyperinsulinemic euglycemic clamp technique. However, there were significant positive associations of TSH with LDL-C, TC, and non- HDL-C and an inverse association with HDL-C. Interestingly, the associations of TSH with LDL-C, TC, non-HDL-C, but not that of TSH with HDL-C, were significantly modified by M/I values. Figure 1A shows a regression model consistent with a virtual absence of an association between TSH with LDL-C in very insulin-sensitive subjects, whereas in insulin-resistant subjects a steep association exists. Our regression models also suggest that at high values of TSH, there is an inverse association between M/I values and LDL-C concentrations. Thyroid hormone supplementation in the case of hypothyroidism results in a decrease in TC and LDL-C concentrations (19, 22) despite a concomitant stimulation of hepatic cholesterol synthesis by thyroid hormone (19, 34, 35, 36). Apparently, the increased cholesterol synthesis is overruled by an increase in LDL-C clearance that results from up-regulation of hepatic and peripheral LDL receptor synthesis and activity by thyroid hormone (19, 21, 22, 23, 24). Our results are consistent with unmasking by insulin resistance of an otherwise unnoticed difference in LDL-C clearance between subjects with high normal and subjects with low normal TSH levels. The known effects of insulin resistance on LDL metabolism can explain its unmasking properties. Insulin- resistant states are accompanied by an increased hepatic cholesterol synthesis, with overproduction of triglyceride-rich VLDL, the precursor particles of LDL (25, 37, 38). Despite the increased production of LDL particles, LDL-C concentrations remain essentially unchanged in insulin-resistant states because of a decrease in cholesterol content per LDL particle, resulting in higher concentrations of small dense LDL particles (38, 39). This decrease in cholesterol content per particle results from a stimulation of cholesteryl ester transfer from LDL to VLDL particles by triglycerides in the latter particles. The small dense LDL particles have a lower affinity for the LDL receptor, causing a delay in their clearance (40, 41). It is therefore conceivable that insulin resistance can unmask the effects of small changes in LDL receptor activity on LDL-C concentrations. The slightly stronger association for non-HDL-C than for LDL-C with TSH agrees with this concept, because the non-HDL-C concentration, derived by subtracting HDL-C from TC concentrations, represents the cholesterol content of VLDL particles, LDL particles, and their intermediates (42). All of these apolipoprotein B- containing particles have LDL receptor-binding capacity. Importantly, the use of non- HDL-C concentrations is gaining appreciation as a cardiovascular risk marker that can replace LDL-C when fasting triglyceride concentrations are above 4.5 mmol/L and thus too high to accurately calculate LDL-C concentrations by the Friedewald formula (42). Our results also indicate an inverse association between insulin sensitivity and LDL-C concentrations at high TSH concentrations. This is important, because it may explain why reports about associations of LDL-C with components of insulin resistance syndrome vary between absent and mildly inverse (38). TSH levels were also inversely associated with HDL-C concentrations. However, there was no effect-modification of this association by M/I values. As with LDL-C concentrations, there was no association of M/I values with HDL-C concentrations. Ratios of TC to HDL-C, and even more so those of LDL-C to HDL-C, have been demonstrated to be very strong indicators of cardiovascular risk. Our finding of a positive association of TSH with LDL-C in insulin-resistant subjects in combination with an inverse association of TSH with HDL-C ratio in all subjects explains an even stronger association of TSH with the LDL-C/HDL-C ratio, as shown in Fig. 1B . Thus, TSH seems to affect this important cardiovascular risk factor especially in subjects who are already at risk of developing cardiovascular disease because of their insulin- resistant state. Interestingly, this association already appears to exist in the euthyroid range. Our finding is important because it suggests that we should aim for low normal TSH concentrations in insulin-resistant subjects with cardiovascular disease or at high risk of developing cardiovascular disease, especially in those that already require T4 therapy. TSH levels below the normal range should be avoided, because these are known to be associated with an increased incidence of atrial fibrillation (43). A recent meta-analysis indicates that treatment of subclinical hypothyroidism to restore euthyroidism with thyroid hormone replacement therapy is accompanied by a small, but significant, decrease in serum TC concentrations, without a consistent effect on HDL-C concentrations (44). Differences between values of TC and LDL-C in groups of subjects with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism in cross-sectional studies are of comparable magnitude, without significant differences in HDL-C (2, 8, 13, 15, 45, 46, 47). The direction of the associations of TSH with TC, LDL-C, and non-HDL-C in our study is the same as that in the aforementioned studies. However, the strength of the associations that we found is greater than one might have expected. Notably, we investigated young, healthy, nonsmoking subjects without thyroid disease, whereaslongitudinal treatment studies and cross-sectional studies almost invariably investigated elderly subjects. In the latter studies there was no control for the effects of smoking (47). Another important consideration is that we investigated associations within a group of euthyroid subjects, whereas differences in mean values between groups were assessed in previously reported studies. Recently, subclinical hypothyroidism was identified as a risk factor for atherosclerosis and myocardial infarction in elderly women in a large population-based cross- sectional study in The Netherlands (9). This increased risk was found to be independent of TC and HDL-C concentrations. Because LDL-C levels were not available for analysis in this study, the researchers suggested a role for LDL-C levels instead of TC and HDL-C concentrations. However, our results are suggestive of an even closer relationship of the LDL-C/HDL-C ratio with development of atherosclerosis in subclinical hypothyroidism. The main limitation of our study is the relatively small size. When confirmed in a larger study, intervention studies will be warranted in patients at high risk of cardiovascular disease. Rather than aiming for a normal TSH level, it would imply targeting for the lowest TSH level within the euthyroid range. Another important consequence of the findings in this study is that TSH should be considered a confounder in future epidemiological studies on associations of serum lipids and insulin resistance. Footnotes 1 The work presented in this article has not previously been presented or published in whole or in part. This work was supported by Grant C95.1443 from the Dutch Kidney Foundation (Nier Stichting Nederland; to J.C.t.M.). No other sources of support were involved. Received August 1, 2000. Revised December 5, 2000. Accepted December 6, 2000. References 1. Becker C. 1985 Hypothyroidism and atherosclerotic heart disease: pathogenesis, medical management, and the role of coronary artery bypass surgery. Endocr Rev. 6:432–440.[Abstract/Free Full Text] 2. Kutty KM, Bryant DG, Farid NR. 1978 Serum lipids in hypothyroidism–a re- evaluation. J Clin Endocrinol Metab. 46:55–56.[Abstract/Free Full Text] 3. Bastenie PA. 1982 Hypothyroidism and coronary heart disease. Acta Cardiol. 37:365–373.[Medline] 4. Bastenie PA, Vanhaelst L, Bonnyns M, Neve P, Staquet M. 1971 Preclinical hypothyroidism: a risk factor for coronary heart-disease. Lancet. 1:203–204.[Medline] 5. Tieche M, Lupi GA, Gutzwiller F, Grob PJ, Studer H, Burgi H. 1981 Borderline low thyroid function and thyroid autoimmunity. Risk factors for coronary heart disease? Br Heart J. 46:202–206.[Abstract/Free Full Text] 6. Dean JW, Fowler PB. 1985 Exaggerated responsiveness to thyrotrophin releasing hormone: a risk factor in women with coronary artery disease. Br Med J. 290:1555–1561. 7. Caron P, Calazel C, Parra HJ, Hoff M, Louvet JP. 1990 Decreased HDL cholesterol in subclinical hypothyroidism: the effect of L-thyroxine therapy. Clin Endocrinol (Oxf). 33:519–523.[Medline] 8. Althaus BU, Staub JJ, Ryff-De Leche A, Oberhansli A, Stahelin HB. 1988 LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol (Oxf). 28:157–163.[Medline] 9. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. 2000 Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 132: 270–278.[Abstract/Free Full Text] 10. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. 1985 The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med. 145: 1386–1388.[Abstract/Free Full Text] 11. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. 1991 Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf). 34:77–83.[Medline] 12. Wang C, Crapo LM. 1997 The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am. 26:189–218.[CrossRef] [Medline] 13. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. 2000 The Colorado thyroid disease prevalence study. Arch Intern Med. 160:526–534.[Abstract/Free Full Text] 14. Miura S, Iitaka M, Suzuki S, et al. 1996 Decrease in serum levels of thyroid hormone in patients with coronary heart disease. Endocr J. 43:657–663.[Medline] 15. Bauer DC, Ettinger B, Browner WS. 1998 Thyroid functions and serum lipids in older women: a population-based study. Am J Med. 104:546–551.[CrossRef][Medline] 16. Reaven GM. 1988 Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 37:1595–1607.[Abstract] 17. Mykkanen L, Haffner SM, Ronnemaa T, Bergman RN, Laakso M. 1997 Low insulin sensitivity is associated with clustering of cardiovascular disease risk factors. Am J Epidemiol. 146:315–321.[Abstract/Free Full Text] 18. Genest Jr J, Cohn JS. 1995 Clustering of cardiovascular risk factors: targeting high-risk individuals. Am J Cardiol. 76:8A–20A. 19. Ness GC, Lopez D, Chambers CM, et al. 1998 Effects of L-triiodothyronine and the thyromimetic L-94901 on serum lipoprotein levels and hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and apo A-I gene expression. Biochem Pharmacol. 56:121–129.[CrossRef][Medline] 20. Hayashi H, Mizushima N, Yoshinaga H, et al. 1996 The relationship between lipoprotein(a) and low density lipoprotein receptors during the treatment of hyperthyroidism. Horm Metab Res. 28:384–387.[Medline] 21. Ness GC, Zhao Z. 1994 Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in hypophysectomized rats. Arch Biochem Biophys. 315:199–202. [CrossRef][Medline] 22. Wiseman SA, Powell JT, Humphries SE, Press M. 1993 The magnitude of the hypercholesterolemia of hypothyroidism is associated with variation in the low density lipoprotein receptor gene. J Clin Endocrinol Metab. 77:108–112.[Abstract] 23. Chait A, Bierman EL, Albers JJ. 1979 Regulatory role of triiodothyronine in the degradation of low density lipoprotein by cultured human skin fibroblasts. J Clin Endocrinol Metab. 48:887–889.[Abstract/Free Full Text] 24. Gross G, Sykes M, Arellano R, Fong B, Angel A. 1987 HDL clearance and receptor-mediated catabolism of LDL are reduced in hypothyroid rats. Atherosclerosis. 66:269–275.[CrossRef][Medline] 25. Egusa G, Beltz WF, Grundy SM, Howard BV. 1985 Influence of obesity on the metabolism of apolipoprotein B in humans. J Clin Invest. 76:596–603. 26. Ginsberg HN, Le NA, Gibson JC. 1985 Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss. J Clin Invest. 75:614–623. 27. Howard BV, Egusa G, Beltz WF, Kesaniemi YA, Grundy SM. 1986 Compensatory mechanisms governing the concentration of plasma low density lipoprotein. J Lipid Res. 27:11–20.[Abstract] 28. Ginsberg HN. 1996 Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. Diabetes. 45(Suppl 3): S27–S30. 29. Ferrannini E, Mari A. 1998 How to measure insulin sensitivity. J Hypertens. 16: 895–906.[CrossRef][Medline] 30. Anonymous. 1997 American Diabetes Association: clinical practice recommendations 1997. Diabetes Care. 20(Suppl 1):S1–S70. 31. ter Maaten JC, Voorburg A, Heine RJ, ter Wee PM, Donker AJ, Gans ROB. 1997 Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. Clin Sci. 92:51–58.[Medline] 32. Friedewald WT, Levy RI, Fredrickson DS. 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 18:499–502.[Abstract] 33. Ferranini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. 1997 Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest. 100:1166–1173.[Medline] 34. Ness GC, Chambers CM. 2000 Feedback and hormonal regulation of hepatic 3- hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med. 224:8–19.[Abstract/Free Full Text] 35. Choi JW, Choi HS. 2000 The regulatory effects of thyroid hormone on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Endocr Res. 26:1–21. [Medline] 36. Day R, Gebhard RL, Schwartz HL, et al. 1989 Time course of hepatic 3- hydroxy-3-methylglutaryl coenzyme A reductase activity and messenger ribonucleic acid, biliary lipid secretion, and hepatic cholesterol content in methimazole-treated hypothyroid and hypophysectomized rats after triiodothyronine administration: possible linkage of cholesterol synthesis to biliary secretion. Endocrinology. 125:459– 468.[CrossRef][Medline] 37. Cummings MH, Watts GF, Pal C, et al. 1995 Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in obesity: a stable isotope study. Clin Sci. 88:225–233.[Medline] 38. Howard BV. 1999 Insulin resistance and lipid metabolism. Am J Cardiol. 84: 28J–32J. 39. Syvanne M, Taskinen MR. 1997 Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes mellitus. Lancet. 350 Suppl 1:SI20–SI23. 40. Campos H, Arnold KS, Balestra ME, Innerarity TL, Krauss RM. 1996 Differences in receptor binding of LDL subfractions. Arterioscl Throm Vasc Biol. 16:794–801. [Abstract/Free Full Text] 41. Galeano NF, Milne R, Marcel YL, et al. 1994 Apoprotein B structure and receptor recognition of triglyceride-rich low density lipoprotein (LDL) is modified in small LDL but not in triglyceride-rich LDL of normal size. J Biol Chem. 269:511–519. [Abstract/Free Full Text] 42. Frost PH, Havel RJ. 1998 Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy. Am J Cardiol. 81:26B–31B. 43. Sawin CT, Geller A, Wolf PA, et al. 1994 Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 331:1249–1252. [Abstract/Free Full Text] 44. Tanis BC, Westendorp GJ, Smelt HM. 1996 Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol (Oxf). 44:643–649.[CrossRef][Medline] 45. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. 1992 Circulating lipids and minor abnormalities of thyroid function. Clin Endocrinol (Oxf). 37:411–414. [Medline] 46. Geul KW, van Sluisveld IL, Grobbee DE, et al. 1993 The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids. Clin Endocrinol (Oxf). 39:275–280.[Medline] 47. Muller B, Zulewski H, Huber P, Ratcliffe JG, Staub JJ. 1995 Impaired action of thyroid hormone associated with smoking in women with hypothyroidism. N Engl J Med. 333:964–969 Address all correspondence and requests for reprints to: S. J. L. Bakker, M.D., Department of Internal Medicine, University Hospital Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands. E-mail: s.j.l.bakker@int.azg.nl. |
| Aesthetic Medicine Today |
 | |  | |  | |  | |  | |  |
 | |  | |  | |  | |  | |  |