The Relationship of Lipoprotein Lipase Activity and LDL size Is Dependent on Glucose Metabolism in an Elderly Population The Hoorn Study GRI ¨ ET BOS, MSC 1 PETER G. SCHEFFER, PHD 2 DELFINA VIEIRA, PHD 3 JACQUELINE M. DEKKER, PHD 1 GIEL NIJPELS, PHD 1 MICHAELA DIAMANT, PHD 2 TOM TEERLINK, PHD 2 COEN D.A. STEHOUWER, PHD 1,2 LEX M. BOUTER, PHD 1 ROBERT J. HEINE, PHD 1,2 HANS JANSEN, PHD 3 S mall LDL size is common in patients with type 2 diabetes and is associ- ated with an increased risk of car- diovascular disease (1). LDL size is determined by various constituents of lipoprotein metabolism, such as lipo- protein lipase (LPL) and hepatic lipase (HL) activities, cholesteryl ester transfer protein (CETP), as well as triglyceride concentrations (2– 4). Although abnor- malities in LPL, HL, and CETP levels are associated with a diabetic lipoprotein pro- file, a relation to insulin resistance has been found only with lipase activities (5–7) but not with CETP (8,9). In this cross-sectional study, we investigated the relationship of LPL and HL activities and CETP mass with LDL size in 426 subjects with normal and impaired glucose metab- olism or type 2 diabetes. RESEARCH DESIGN AND METHODS — The Hoorn Study is a population-based cohort study of glucose metabolism and cardiovascular risk fac- tors among 2,484 inhabitants of the mu- nicipality of Hoorn, which started in 1989. In 2000 –2001, a follow-up was conducted in selected subjects then aged 60 – 87 years, as previously described (10). We invited all surviving subjects with type 2 diabetes (n  176) and ran- dom samples of individuals with normal glucose metabolism ( n  705) or impaired glucose metabolism ( n  193) based on their glucose metabo- lism status (World Health Organiza- tion 1999 criteria) at the previous examination in 1996 –1998 (11). Of the 1,074 individuals invited, 648 (60.3%) subjects participated. At the follow-up ex- amination, a sample of 566 participated in the postheparin test. The Ethical Re- view Committee of the VU University Medical Center approved the study. Writ- ten informed consent was obtained from all participants. LDL size was measured by high-performance gel-filtration chro- matography (12). CETP mass was deter- mined using a two-antibody sandwich immunoassay (13). LPL and HL activities were measured in plasma collected 20 min after contralateral intravenous ad- ministration of heparin, using an immu- nochemical method (14). One hundred and seven samples were excluded from analyses because very low activities of LPL and HL in postheparin plasma indicated insufficient heparin delivery. Activities were considered as very low if LPL activity was 50 units/l and if HL activity was 72 units/l. The contribution of HDL cholesterol, triglycerides, insulin, LPL, HL, and CETP to LDL size was analyzed in univariate and multivariate linear regres- sion models in categories of glucose me- tabolism, with LDL size as the dependent variable with adjustment for sex. RESULTS — Mean LDL size (in nano- meters) was 21.6  0.4, 21.5  0.4, and 21.2  0.5 in subjects with normal, im- paired glucose metabolism, and diabetes, respectively. Mean LPL activity (in units per liter) was 150  51, 147  51, and 135  42, respectively. There were no differences in HL activity (mean 372  135 units/l) and CETP mass (1.87  0.56 mg/l) between the three glucose metabo- lism categories. In this elderly population, we ob- served a stronger positive association be- tween LPL activity and LDL size in subjects with impaired glucose metabo- lism and type 2 diabetes than in subjects with normal glucose metabolism, even af- ter adjustment for triglyceride concentra- tion, which was the most important independent determinant of LDL size in all glucose metabolism categories. A test for interaction between LPL activity and glucose metabolism was significant (P  0.03), indicating that glucose metabolism is an effect modifier in the relationship between LPL activity and LDL size (Ta- ble). Thus, higher LPL activity might pro- tect against the development of small LDL size, especially in subjects with type 2 di- abetes, who have increased triglyceride concentrations. Mechanisms responsible for the pres- ence of smaller LDL size in diabetic sub- jects compared with nondiabetic subjects are not fully understood. Lower LPL ac- tivity contributes to an impaired removal ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam, the Netherlands; the 2 Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; and the 3 Departments of Internal Medicine and Clinical Chemistry, Erasmus MC, Rotterdam, the Netherlands. Address correspondence and reprint requests to Grie ¨t Bos, MSc, Institute for Research in Extramural Medicine, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands. E-mail: g.bos.emgo@med.vu.nl. Received and accepted for publication 11 November 2002. Abbreviations: CETP, cholesteryl ester transfer protein; HL, hepatic lipase; LPL, lipoprotein lipase. © 2004 by the American Diabetes Association. BRIEF REPORT 796 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004