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Elevated LDL-Cholesterol Level Predicts Diabetes in Centrally Obese Women but Not Men Relative Roles of Insulin Resistance and Central Obesity

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Elevated LDL-Cholesterol Level Predicts Diabetes in Centrally Obese Women but Not Men Relative Roles of Insulin Resistance and Central Obesity Circ J 2007; 71: 1463–1467 Elevated LDL-Cholesterol Level Predicts Diabetes in Centrally Obese Women but Not Men Relative Roles of Insulin Resistance and Central Obesity · Altan Onat, MD*,**; Gülay Hergenç, PhD†; Ibrahim Sarı, MD††; Ahmet Karabulut, MD††; Günay Can, MD** Background The aim was to investigate the sex-specific effect of hypercholesterolemia interacting with ab- dominal obesity (AO) in predicting Type 2 diabetes mellitus (DM). The 3,048 participants (aged ≥28 years) were free of DM at baseline, a representative sample of Turkish adults and were evaluated prospectively. Methods and Results As cut-off points for AO were used ≥95cm in men and ≥91cm in women, and for hyper- cholesterolemia ≥5.2mmol/L. Diabetes was diagnosed using criteria of the American Diabetes Association. Four groups were formed at baseline: Group I subjects had neither AO nor hypercholesterolemia (33.3%), Group II subjects had AO only (27.6%), Group III subjects had hypercholesterolemia only (17.8%), and Group IV subjects had AO combined with hypercholesterolemia (21.3%). Over a mean of 5.9 years, DM developed in 103 women and 116 men. An age-adjusted relative risk (RR) by logistic regression for DM in the 4 groups, using AO as a reference group, disclosed an RR of 1.88 (95%confidence interval 1.14; 3.09) in women and an insignificant RR 1.29 in men (women were predicted to be 1.46 times more likely to develop DM). Hypercholesterolemia alone did not differ significantly from Group I in its ability to predict diabetes. An elevated level of low-density lipo- protein (LDL)-cholesterol (C) (≥3.4mmol/L) was delineated as the element associated with diabetes in hyper- cholesterolemia by multiple logistic regression. The identification of 48 participants with familial-combined hyperlipidemia phenotypes alone could not account for most of the centrally obese and hypercholesterolemic women developing DM. Conclusion It was suggested that a diminished effectiveness of insulin resistance in centrally obese Turkish women (but not men) might predispose them to an elevation in LDL concentrations, while other features of visceral adiposity still predispose them to DM. In summary, an elevated LDL-C level interacts with AO in Turkish women to enhance the development of diabetes. (Circ J 2007; 71: 1463–1467) Key Words: Abdominal obesity; Diabetes type 2; Familial-combined hyperlipidemia; Hypercholesterolemia; Insulin resistance; Sex difference ypertriglyceridemia, low high-density lipoprotein eridemia. FCH has been described as a subtype of MS with (HDL)-cholesterol (C) levels and small-dense higher apo B levels.7 H low-density lipoprotein (LDL) particles character- Genetic susceptibility to hyperlipidemia in FCH was ize the dyslipidemia associated with increased amounts of shown to interact with AO.8 In studying 618 FCH relatives visceral adipose tissue, metabolic syndrome (MS) and Type and 297 spouses, age- and gender-corrected odds for the 2 diabetes mellitus (DM). An elevated level of LDL-C is prevalence of hyper apoB and hypertriglyceridemia were not a feature of the dyslipidemia seen with abdominal obesi- dependent on (abdominal) obesity in FCH but not in hyper- ty (AO),1–3 but has been observed in some diabetic groups.4,5 cholesterolemia. Increments in measure of central obesity A higher prevalence of hypercholesterolemia has been were a determinant of the expression of hypertriglyceri- reported in upper compared with lower brackets of waist demia alone in FCH.8 circumference6 without elaborating specifically on this Possibly because of a higher prevalence of FCH among issue. The major link between hypercholesterolemia, AO Turks than in most Western populations, Turks have a and diabetes is familial-combined hyperlipidemia (FCH). higher prevalence also of MS, among whom hypercholes- Underlying this most common genetic form of hyperlipi- terolemia is significantly associated with AO. However, demia, is the overproduction of apolipoprotein (apo) B in there is an excess of this association in women than in men; lipoproteins, not observed in other forms of hypertriglyc- the underlying factor for which is unknown. Our hypo- thesis is that this association predicts the development of (Received January 22, 2007; revised manuscript received May 14, DM in Turkish women. 2007; accepted May 24, 2007) The aim of the study is to investigate prospectively the *Turkish Society of Cardiology, **Cerrahpas¸a Medical Faculty, Istanbul University, †Biology Department, Yıldız Technical Universi- association between hypercholesterolemia and abdominally ty, ††S. Ersek Cardiovascular Surgery Center, Istanbul, Turkey obese women in the prediction of Type 2 diabetes, in com- Mailing address: Altan Onat, MD, Nisbetiye cad. 37/24, Etiler 34335, parison with men, in a representative sample of Turkish Istanbul, Turkey. E-mail: [email protected] adults.9 Circulation Journal Vol.71, September 2007 1464 ONAT A et al. Table 1 Baseline Characteristics in Men and Women With AO (n=1,464) Men Women AO AO + H AO AO + H n p value n p value Mean SD Mean SD Mean SD Mean SD Age, years 733 49.6 11.1 49.8 11.1 0.7 731 50.8 11 51.3 11.2 0.5 WC, cm 733 101.5 3.7 102.7 4.1 0.2 731 99.5 3.8 100.4 4.1 0.15 Log f. insulin*, ml U/L 389 8.87 2.0 10.8 2.07 0.01 441 94.5 1.94 9.43 1.77 0.98 Log HOMA* 322 1.68 1.9 2.07 1.98 0.006 365 1.86 1.79 1.82 1.69 0.63 SBP, mmHg 733 130.7 21.1 137.4 25.7 0 731 137.6 25.3 143.5 26.9 0.003 DBP, mmHg 733 83.8 12.6 86.9 14.9 0 731 86.2 13.8 88.4 14.9 0.046 Fasting glucose, mmol/L 425 5.3 1.1 5.4 1.1 0.46 493 8.35 1.1 5.5 25.4 1.4 TC, mmol/L 733 4.26 0.6 5.93 0.6 0 731 4.4 0.55 6.0 0.68 0 F. triglyceride, mmol/L 577 1.67 0.95 2.58 1.4 0 611 1.45 1.0 2.0 1.1 0 LDL-C, mmol/L 602 2.66 0.6 3.72 0.7 0 638 2.7 0.6 3.9 0.78 0 HDL-C, mmol/L 723 0.89 0.25 0.98 0.29 0 709 1.1 0.32 1.22 0.33 0 *Geometric means. AO, abdominal obesity; H, hypercholesterolemia; WC, waist circumference; HOMA, homeostatic model assessment; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; LDL-C, low-density lipoprotein-cholesterol; HDL-C, high-density lipoprotein-cholesterol. a Reflotron apparatus (Roche Diagnostics, Mannheim, Methods Germany). External quality control was performed with a Population Sample reference laboratory in a random selection of 5–6% of par- Participants of the nationwide survey conducted in 1997/ ticipants. LDL-C values were computed according to the 1998 of the Turkish Adult Risk Factor Study were followed Friedewald formula. Blood samples were spun at 1,000g up until 2004/2005. This is a prospective survey on the pre- for 10min and also shipped within a few hours on cooled valence of cardiac disease and risk factors in a represen- gel packs at 2–5°C to Istanbul to be stored in deep-freeze at tative sample of adults in Turkey carried out periodically –75°C, until analyzed at a central laboratory. Concentra- almost biennially since 1990 in 59 communities scattered tions of insulin were determined by the chemiluminescent throughout all geographical regions of the country.9 Details immunometric method using Roche kits and an Elecsys of sampling were described previously.10 As the combined 1010 immunautoanalyzer (Roche Diagnostics, Mannheim, measurements of waist circumference, HDL-C and apo B Germany). A homeostatic model assessment (HOMA) was were first perfomed at the follow-up visit in 1997/1998, the calculated with the following formula:11 insulin (mIU/L)× latter examination formed the baseline. Participants were glucose (in mmol/L)/22.5. 28 years of age or older at baseline examination, and those with no missing values for serum total cholesterol and Definitions and Outcomes waist circumference numbered 3,229, of which 1,631 were Individuals with diabetes were diagnosed using criteria women. Of the survivors, 8% were examined up to the sur- from the American Diabetes Association,12 namely by vey period of 2001/2002, 14% up to 2003, and the remain- self report or when the plasma fasting glucose was der having been examined last in the survey period of ≥7.0mmol/L or when the 2-h postprandial glucose level 2004/2005. Exclusion of cases of diabetes limited the study was >11.1mmol/L. The same criteria were utilized for the sample to 1,509 men and 1,529 women. Individuals of the diagnosis of new diabetes that had developed over the cohort were visited at their addresses on the eve of the follow-up period. Hypercholesterolemia was defined as a examination and were requested to give written consent for serum total cholesterol level of ≥5.2mmol/L. AO was de- participation after having read an explanatory note, which fined in this study in terms of waist circumference in agree- was manifested by their voluntary participation the next ment with this anthropometric measure emerging as the morning. The survey conformed to the principles embodied most appropriate one to reflect visceral adiposity among in the Declaration of Helsinki. Data were obtained by histo- Turks;13 ≥95cm in males14 and ≥91cm in females were ry of the past years via a questionnaire, a physical examina- cut-off points selected for AO based on results of receiver tion of the cardiovascular system, sampling of blood and operating characteristics related to CHD, DM, and MS.
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