© 1997 American Heart Association, Inc.
Articles |
Relationship of LDL Size to Insulin Sensitivity in Normoglycemic Men
From the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio (L.M., S.M.H., H.M.) and Department of Genetics, Southwest Foundation for Biomedical Research (D.L.R.), San Antonio, Tex; and the Department of Medicine, University of Kuopio, Finland (P.K., M.L.).
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract A preponderance of small, dense LDL has been suggested to be more atherogenic than larger, more buoyant LDL. Although several studies have suggested associations of small, dense LDL with hyperinsulinemia, few data are available on the relation of small, dense LDL to insulin resistance. We examined the association of LDL particle size determined by gradient gel electrophoresis with the rates of whole-body glu-cose uptake (WBGU) as determined by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 87 Finnish normoglycemic men. LDL size was significantly positively correlated with the rates of WBGU (overall, r=.31, P<.01; oxidative, r=.23, P<.05; and nonoxidative, r=.31, P<.01). Rates of WBGU were also significantly lower in subjects with small LDL particles (
26.0 nm)
compared with those in sub-jects with larger LDL particles (>26.0
nm). This relation was not explained by obesity. Serum
triglyceride concentrations were found to significantly
affect the relationship of LDL particle size to WBGU. Specifically, LDL
size was correlated with the rates of WBGU in men with mildly elevated
triglyceride levels but not in men with low
triglyceride levels. Serum VLDL triglyceride
concentration was a substantially stronger determinant of LDL size than
were the rates of WBGU. WBGU was not significantly related to LDL size
when adjusted for triglycerides. We conclude that a
preponderance of small, dense LDL particles is associated with insulin
resistance and that serum triglyceride concentration
modifies this relationship.
Key Words: LDL size • insulin sensitivity • triglyceride
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
An increased concentration of LDL cholesterol is widely recognized as a risk factor for coronary heart disease.1 2 There is considerable heterogeneity in the size and density of LDL particles.3 4 Austin et al5 found that most individuals can be assigned to one of two LDL subclass patterns (A or B). Small, dense LDL particles (pattern B) are thought to be more atherogenic than larger LDL particles.5 6 7
Recently, several clinical and epidemiological studies have shown an association between insulin concentrations and various metabolic and physiological abnormalities, including glucose intolerance, dyslipidemia (specifically, increased serum triglyceride and decreased HDL cholesterol concentrations), and hypertension.8 9 10 11 These disorders are also associated with insulin resistance.12 13 14 15 16 17 18 In two prospective studies, several metabolic disorders related to insulin resistance syndrome have been found to cluster together.19 20
Small, dense LDL has been associated with most individual components of insulin resistance syndrome, including hypertriglyceridemia,4 5 6 7 21 22 23 24 25 low serum HDL cholesterol concentration,21 22 23 24 25 hypertension,22 23 25 diabetes,22 23 24 25 26 and hyperinsulinemia.21 22 23 25 Nevertheless, information about the association between LDL particle size and the degree of insulin resistance is limited. Reaven et al27 showed that subjects with a preponderance of small, dense LDL particles (pattern B) were more insulin resistant and had higher triglyceride concentrations than subjects with larger LDL particles (pattern A). However, they did not examine which of the two, the degree of insulin resistance or triglyceride concentration, was a stronger determinant of LDL particle size. Three studies28 29 30 examined the relation of small, dense LDL particles and insulin resistance in mildly hypertriglyceridemic subjects with NIDDM28 29 or in a combined group of subjects with and without NIDDM30 and gave contradictory results: one study29 did and two studies28 30 did not find a positive correlation between small, dense LDL and insulin resistance.
In the present study, we examined the association between insulin resistance and LDL particle size determined by gradient gel electrophoresis in normoglycemic middle-aged men. We used euglycemic clamp with indirect calorimetry to assess oxidative and nonoxidative glucose disposal. In addition to insulin resistance, we investigated the role of triglyceride and FFA concentrations as determinants of LDL particle size.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The subjects for this study were randomly selected from a population-based study from eastern Finland aiming to investigate the relationship of insulin resistance with asymptomatic atherosclerosis in middle-aged, healthy men.31 Descriptive data, including measures of insulin resistance and body fat distribution, have been published previously.32 None of the 87 subjects had any chronic disease, any drug treatment that could influence carbohydrate metabolism, any abnormality in an oral glucose tolerance test (impaired glucose tolerance or diabetes according to the criteria of the World Health Organization),33 or hypertension (use of antihypertensive drugs or systolic/diastolic blood pressure >160/95 mm Hg). Furthermore, liver, kidney, and thyroid function tests were normal in every subject. Informed consent was obtained from all subjects. The protocol was approved by the Ethics Committee of the University of Kuopio.
Weight and height were measured in light clothing without shoes. BMI was calculated as weight (kg) divided by height (m) squared and was used as an index of overall adiposity. Waist circumference was measured at the level of the umbilicus with the subject standing and breathing normally. Hip circumference was measured at the level of greatest hip girth. The WHR was used as a measure of body fat distribution.
The subjects selected for the study were admitted to the metabolic ward for 2 days. On day 1, an oral glucose tolerance test (75 g glucose) was performed and samples for blood glucose and plasma insulin were obtained at 0 and 2 hours to exclude those with impaired glucose tolerance or diabetes. On day 2, the euglycemic clamp and indirect calorimetry were performed.
Metabolic Studies
The degree of insulin resistance was evaluated by the
euglycemic clamp technique as previously
reported.34 After baseline blood collection and
measurement of gas exchange (see next paragraph), a priming dose of
insulin (Velosulin Human, Novo Nordisk) was administered during the
initial 10 minutes in a logarithmically decreasing manner to raise
serum insulin immediately to the desired level, where it was maintained
by a continuous insulin infusion at a rate of 480 pmol (80
mU)·m2 body surface
area-1·min-1. The
mean insulin during the last hour of the clamp study was 1.080 pmol/L.
Blood glucose was clamped at 5 mmol/L for the next 180 minutes by
20% glucose infused at various rates according to blood glucose
measurements performed at 5-minute intervals. The data were calculated
for each 20-minute interval during hour 3 of the euglycemic
clamp. FFA concentration during the clamp was calculated as the mean of
three measurements over 20-minute intervals during hour 3 of the
euglycemic clamp.
Indirect calorimetry was performed with a computerized flow-through canopy gas analyzer system (Deltatrac, TM Datex)35 as previously described in detail.36 On the day of the experiment, gas exchange (O2 consumption and CO2 production) was measured in the fasting state and for the last 20 minutes of the euglycemic clamp. Protein, glucose, and lipid oxidation were calculated according to Ferrannini.37 The fraction of carbohydrate nonoxidation during glucose clamp studies was estimated by subtraction of the carbohydrate oxidation rate (determined by indirect calorimetry) from the glucose infusion rate (determined by the euglycemic clamp).
Analytical Methods
Blood glucose in the fasting state and during glucose
clamp studies was measured by the glucose oxidase method (Glucose Auto
and Stat HGA-1120 analyzer, Daiichi Co). For the determination
of plasma insulin, blood was collected in chilled tubes (with EDTA).
After centrifugation, the plasma was stored at -70°C
until the analysis. Plasma insulin was determined by a
radioimmunoassay (Pharmacia Diagnostics AB). Nonprotein
urinary nitrogen excretion was measured by an automated Kjeldahl
method.38 Serum lipid and lipoprotein levels were
determined from fresh serum samples drawn after a 12-hour overnight
fast as previously described.31 Serum FFA concentrations
in the fasting state and during the clamp were determined by an
enzymatic method (Wako Chemicals GmbH).
Aliquots of fasting serum specimens were saved as contingency samples and were frozen at -70°C. The analyses for LDL particle size were done an average of 4 years later. Several studies have suggested that freezing samples does not alter their LDL phenotype.39 40 41 Nondenaturing 3% to 18% polyacrylamide gradient gels (LDL gels) were cast on the basis of a modification42 of published protocols.43 Gels were calibrated by use of (1) thyroglobulin (17.0 nm in diameter, Pharmacia); (2) carboxylated polystyrene microspheres (38.0 nm, Duke Scientific); and (3) two bands of LDL in a lyophilized plasma sample, with diameters of 27.5 and 26.6 nm.42 Samples (4 µL) were subjected to electrophoresis in TBE buffer (90 mmol/L boric acid, 81.5 mmol/L Tris, and 2.5 mmol/L EDTA, pH 8.35) for 3000 V·h. After electrophoresis was completed, LDL cholesterol was stained with Sudan black B39 and the standard proteins with Coomassie brilliant blue R-250 (Sigma).44 After destaining was completed, gels were soaked in the TBE buffer to restore gel size and shape before scanning.
The gels were subjected to densitometric scanning with an LKB-Ultroscan XL laser densitometer with GelScan XL software. Gels were calibrated for size by use of migration distance of each standard relative to thyroglobulin; a quadratic equation in relative migration distance was fitted to the natural logarithms of the diameters of the standards.45 We used a computer program developed in-house that automatically calibrated each gel, subtracted the baseline, and calculated particle diameter for the predominant peak in each sample lane. Samples were assayed at least twice, and mean values were used for analyses; the average coefficient of variation for replicated samples was 0.43% (range, 0% to 1.32%).
For some analyses, we used a cut point of LDL size of 26.0 nm to dichotomize LDL patterns into small, dense and large, buoyant LDLs. This cut point was used rather than 25.5 nm46 because this point best separates the two modes of the LDL size distribution in this group of normoglycemic subjects.47 Small, dense LDLs in this study would therefore include LDL subclass types B and I (intermediate).46 The fact that in this study the LDL size distribution was bimodal with a nadir >25.5 nm suggests that the population sample in the present study was different from earlier studies42 46 ; the previous studies had subjects with a high risk of developing diabetes.
Statistical Analyses
All calculations were performed with the SPSS/PC+ programs (SPSS
Inc) and SAS (version 6.09). Data are presented as mean±SEM.
The following statistical tests were done: Student's t test
(Table 2
), Spearman correlation (nonparametric) (Table 4),
and multiple linear regression (Tables 3 and 5). We also used multiple
linear regression in which ranks were substituted for actual LDL sizes
as an alternative to traditional linear regression
("semiparametric linear regression").48
Insulin and triglyceride were logarithmically transformed
(natural logarithm) for statistical testing to improve their skewness
and kurtosis. These variables are presented in their
natural units in the tables. Because LDL size in this population was
bimodal and could not be successfully transformed to a normal
distribution, we emphasized nonparametric methods in this
report.
|
|
|
|
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clinical and metabolic characteristics of the overall population are shown in Table 1
. LDL size was
significantly inversely correlated with BMI (Spearman correlation
coefficient, r=-.24, P<.05), WHR
(r=-.30, P<.01), plasma 2-hour insulin
concentration (r=-.27, P<.05), and FFA
concentration during clamp (r=-.24, P<.05) and
positively correlated with the rates of WBGU (overall,
r=.31, P<.01; oxidative, r=.23,
P<.05; and nonoxidative, r=.31,
P<.01). LDL size was also significantly inversely
correlated with serum VLDL triglyceride concentration
(r=-.60, P<.001) and positively correlated with
HDL cholesterol concentration (r=.40,
P<.001).
|
LDL cholesterol level was not related to LDL size or WBGU. HDL cholesterol concentration was significantly positively correlated with LDL size and inversely correlated with WHR (r=-.28, P<.01) but was not related to WBGU. VLDL triglyceride concentration was inversely correlated with LDL size and WBGU (overall, r=-.27, P<.05 and nonoxidative, r=-.26, P<.05) and positively correlated with WHR (r=.25, P<.05) and FFA concentration during clamp (r=.50, P<.001). Fasting FFA concentration did not correlate significantly with LDL size or WBGU (overall, r=-.19; oxidative, r=-.14; nonoxidative, r=-.19; P=NS). Lipid oxidation during clamp was not related to LDL size. There was an inverse association between lipid oxidation and oxidative glucose disposal during clamp (r=-.59, P<.001) but no relationship between lipid oxidation during clamp and overall (r=-.10, P=NS) or nonoxidative (r=-.19, P=NS) glucose disposal. FFA concentration during clamp correlated inversely with LDL size and overall (r=-.26, P=.020) and nonoxidative (r=-.30, P=.007) glucose disposal but not with oxidative glucose disposal (r=-.02, P=NS). We have previously reported significant correlations between BMI and WBGU (overall, r=-.30; oxidative, r=-.21; nonoxidative, r=-.25) and between WHR and WBGU (overall, r=-.54; oxidative, r=-.23; nonoxidative, r=-.50).32
In Table 2
, we show metabolic
characteristics of subjects with different LDL sizes. Subjects with a
preponderance of small, dense LDL (predominant LDL peak 26.0 nm) had
higher VLDL cholesterol and total, LDL, and VLDL
triglyceride concentrations and lower HDL
cholesterol concentrations than did subjects with larger
LDL particles (predominant LDL peak >26.0 nm). In addition, subjects
with small LDL particles had lower total, oxidative, and nonoxidative
glucose uptake than did subjects with larger LDL particles. However,
subjects with small LDL particles did not differ from subjects with
larger LDL particles in relation to fasting FFA concentration or lipid
oxidation and FFA suppression during clamp. It is noteworthy that
subjects with smaller and larger LDL particles did not differ in regard
to obesity (BMI) or body fat distribution (WHR).
We did stepwise multiple linear regression analyses to
investigate whether WBGU was an independent determinant of LDL size in
the overall study population (Table 3). In model 1, with
VLDL triglyceride (natural logarithm) and WBGU as
independent variables, the association of WBGU with LDL size was
only borderline significant (P=.056) and WBGU independently
explained merely 2% of the variance in LDL size. We also did the
multiple regression analyses including all the variables
associated with LDL size in univariate analyses,
ie, VLDL triglyceride level, WBGU, FFA concentration during
clamp, WHR, and HDL cholesterol level, as independent
variables; then VLDL triglyceride and HDL
cholesterol concentrations were independent determinants of
LDL size (model 2). In contrast, WBGU was not independently related to
LDL size after the effects of VLDL triglyceride and HDL
cholesterol levels were accounted for. VLDL
triglyceride concentration was overwhelmingly the strongest
determinant of LDL particle size, explaining 
47% of the variance of
LDL size in both linear regression models. The results for traditional
and semiparametric multiple linear regression analyses
were very similar.
We found an almost significant interaction (P=.059) between
total triglyceride concentration (dichotomized as below or
above the median, ie, 1.3 mmol/L) and WBGU when the dependent
variable was LDL size in multiple linear regression
analyses. Therefore, we also investigated the relationship
between LDL size and WBGU, plasma insulin concentration, and serum VLDL
triglyceride and HDL cholesterol concentrations
by calculating Spearman correlation coefficients separately in men with
serum triglyceride concentrations below the median
(<1.3 mmol/L; group with low triglyceride levels) and
those with serum triglyceride concentrations above the
median (
1.3 mmol/L; group with mildly elevated
triglyceride levels) (Table 4). There was no
relation between LDL particle size and WBGU and plasma insulin
concentration in men with low triglyceride levels. However,
VLDL triglyceride concentration was inversely associated
with LDL size in men with low triglyceride levels. In
contrast, there was a positive correlation between LDL size and overall
and nonoxidative glucose disposal (r=.42, P<.01)
in men with mildly elevated triglyceride levels.
Furthermore, LDL size correlated inversely with VLDL
triglyceride concentration and positively with HDL
cholesterol concentration in men with mildly elevated
triglyceride levels.
We also repeated the multiple linear regression analyses
separately in subjects with low and those with mildly elevated
triglyceride levels (Table 5). Again, VLDL
triglyceride level was the strongest determinant of LDL
particle size. However, in subjects with triglyceride
levels above the median (1.3 mmol/L), WBGU was associated with
LDL particle size independently of VLDL triglyceride and
HDL cholesterol concentrations.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this report, we have shown an association of insulin resistance with the preponderance of small, dense LDL particles in normoglycemic middle-aged men. Men with small, dense LDL particles had decreased rates of oxidative and nonoxidative glucose disposal compared with men with larger LDL particles. However, this relationship was markedly dependent on serum triglyceride concentration. Insulin resistance was a substantially stronger determinant of LDL size in men with mildly elevated triglyceride levels than in men with low triglyceride levels.
Our results are in accordance with findings of Reaven et al,27 who previously showed that nondiabetic subjects with LDL subclass pattern B are insulin resistant, as measured by the steady-state plasma glucose technique. Previous results on the relation of small, dense LDL particles and insulin sensitivity in mildly hypertriglyceridemic subjects with NIDDM have been contradictory; one study29 showed an association between insulin resistance and small, dense LDL, whereas two studies did not.28 30 This may be due to differences in the methodology to determine LDL subfractions (density gradient ultracentrifugation versus gradient gel electrophoresis) and to the degree of hypertriglyceridemia among the study subjects. Subjects with NIDDM have a preponderance of small, dense LDL particles, particularly if they are hypertriglyceridemic.29 30 42 Furthermore, one of the previous studies30 used 24-hour rather than fasting triglyceride levels.
LDL particle size was inversely related to fasting VLDL
triglyceride concentration, which, on the other hand, was
associated with insulin resistance. Thus, the relationship between LDL
size and insulin resistance could be due to the connection with VLDL
triglyceride level. Indeed, VLDL triglyceride
concentration was a substantially stronger independent predictor of LDL
size than WBGU in these normoglycemic middle-aged men (Table 3).
Interestingly, there was a positive correlation between LDL size and
WBGU in men with mildly elevated triglyceride
concentrations (1.3 mmol/L) but not in men with low
triglyceride concentrations (<1.3 mmol/L) (Table 4).
Previous studies have shown that serum triglyceride
concentration and hepatic lipase activity are major determinants of
small, dense LDL particles in mildly
hypertriglyceridemic diabetic and
nondiabetic subjects.29 30 Even mild elevations of
triglyceride levels have previously been shown to be
associated with insulin resistance.49 In
insulin-resistant states, the suppression of hepatic VLDL
secretion by insulin is impaired, and this leads to an increase in the
number of triglyceride-rich VLDL particles in the
circulation.50 51 High levels of VLDL
triglyceride may increase neutral lipid exchange between
VLDL and LDL, resulting in triglyceride-enriched
cholesteryl ester–depleted LDL species.52 53 These LDL
species are susceptible to the action of hepatic lipase, which
hydrolyzes LDL triglycerides, resulting in the formation of
small, dense LDL particles.54
LDL particle size was also inversely related to plasma FFA concentration during clamp, indicating impaired suppression of FFA by insulin and insulin resistance in adipose tissue in subjects with small, dense LDL particles. Elevated plasma FFA levels provide substrate to hepatic VLDL triglyceride synthesis. Furthermore, elevated plasma FFA levels can lead to increased lipid oxidation, which in turn leads to decreased glucose oxidation and insulin resistance via substrate competition.55 56 The association of FFA concentration during clamp and total and nonoxidative glucose disposal rate in the present study is probably due to its association with VLDL triglyceride concentration. In line with this view, the correlation between FFA concentration during clamp and fasting VLDL triglyceride concentration was substantially stronger than correlations between FFA concentration and WBGU. Furthermore, in multiple linear regression analysis in the overall study population, VLDL triglyceride was an independent determinant of LDL particle size, but FFA concentration during clamp and WBGU were not.
LDL particle size was positively correlated with serum HDL cholesterol level. Actually, HDL cholesterol concentration was the next strongest determinant of LDL size in this study. This can be partly explained by the close inverse relationship between HDL cholesterol and VLDL triglyceride concentrations. However, HDL cholesterol concentration was also associated with LDL size independently of VLDL triglyceride levels both in the overall study population and in men with mildly elevated triglyceride levels, which confirms findings in previous studies.24 29 42 This can be related at least in part to hepatic lipase activity. Hepatic lipase modulates both LDL particle composition, resulting in formation of small, dense LDL species,54 and remodeling of HDL particles.57
In conclusion, we have shown that normoglycemic subjects with small, dense LDL particles are insulin resistant. However, the association of LDL size and insulin sensitivity was strongly modified by triglyceride level.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by grants from the Medical Research Council of the Finnish Academy and grants R01-HL-24799, R37-HL-36820, and P01-HL-45522 from the National Heart, Lung, and Blood Institute. The authors gratefully acknowledge the technical assistance of Mahmood Poushesh, Wendy R. Shelledy, and Susan H. Slifer.
|
Footnotes |
|---|
Reprint requests to Leena Mykkänen, MD, Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873.
Received August 29, 1996; accepted November 18, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel W. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Heart Study. JAMA. 1986;256:2835-2838.
2. Kannel W, Castelli WP, Gordon T, McNamara PM. Serum cholesterol, lipoproteins and the risk of coronary heart disease: the Framingham Study. Ann Intern Med. 1971;74:1-12.
3. Shen MMS, Krauss RM, Lindgren FT, Forte TM. Heterogeneity of serum low density lipoproteins in normal human subjects. J Lipid Res. 1981;22:236-244.[Abstract]
4. Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982;23:97-104.[Abstract]
5.
Austin MA, Breslow JL, Hennekens CH, Buring JE,
Willett WC, Krauss RM. Low density lipoprotein subclass patterns
and risk of myocardial infarction. JAMA. 1988;260:1917-1921.
6. Crouse JR, Parks JS, Schey HM, Kahl FT. Studies of low density lipoprotein molecular weight in human beings with coronary artery disease. J Lipid Res. 1985;26:566-574.[Abstract]
7.
Campos H, Genest JJ, Blijlevens E, McNamara JR, Jenner
JL, Ordovas JM, Wilson PWF, Schaefer EJ. Low density lipoprotein
particle size and coronary artery disease.
Arteriosclerosis. 1992;12:187-195.
8. Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, Shitrit A, Fuchs Z. Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest. 1985;75:809-817.
9. Zavaroni I, Bonora E, Pagliara M, Dall'Aglio E, Luchetti L, Buonanno G, Bonati PA, Berganzani M, Gnudi L, Passeri M, Reaven G. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med. 1989;320:702-706.[Abstract]
10.
Orchard TJ, Becker DJ, Bates M, Kuller LH, Drash
AL. Plasma insulin and lipoprotein concentrations: an
atherogenic association? Am J Epidemiol. 1983;118:326-337.
11. Haffner SM, Fong D, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics. Metabolism. 1988;37:338-345.[Medline] [Order article via Infotrieve]
12. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-357.[Abstract]
13. Abbott WGH, Lillioja S, Young AA, Zawadzki JK, Yki-Jarvinen H, Christin L, Howard BV. Relationship between plasma lipoprotein concentrations and insulin concentrations and insulin action in an obese hyperinsulinemic population. Diabetes. 1987;36:897-904.[Abstract]
14. Garg A, Gelderman JH, Koffler M, Ayuso R, Rosenstock J, Raskin P. Relationship between lipoprotein levels and in vivo insulin action in normal white men. Metabolism. 1988;37:982-987.[Medline] [Order article via Infotrieve]
15.
Laakso M, Sarlund H, Mykkänen L. Insulin
resistance is associated with lipid and lipoprotein abnormalities in
subjects with varying degrees of glucose tolerance.
Arteriosclerosis. 1990;10:223-231.
16.
Godsland IF, Crook D, Walton C, Wynn V, Oliver
MF. Influence of insulin resistance, secretion, and clearance on
serum cholesterol, triglycerides, lipoprotein
cholesterol, and blood pressure in healthy men.
Arterioscler Thromb. 1992;12:1030-1035.
17.
Karhapää P, Voutilainen E, Malkki M, Laakso
M. Obese men with type IIB hyperlipidemia are
insulin resistant. Arterioscler Thromb Vasc
Biol. 1996;13:1469-1475.
18.
Falkner B, Kushner H, Tulenko T, Sumner AE, Marsh
JB. Insulin sensitivity, lipids, and blood pressure in young
American blacks. Arterioscler Thromb Vasc Biol. 1995;15:1798-1804.
19. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analyses of the insulin resistance syndrome (syndrome X). Diabetes. 1992;41:715-722.[Abstract]
20. Mykkänen L, Kuusisto J, Pyörälä K, Laakso M. Cardiovascular risk factors as predictors of type II (non-insulin-dependent) diabetes mellitus in elderly subjects. Diabetologia. 1993;36:553-559.[Medline] [Order article via Infotrieve]
21.
Haffner SM, Mykkänen L, Valdez RA, Paidi M, Stern
MP, Howard BV. Low density lipoprotein size and subclass
patterns in a biethnic population. Arterioscler
Thromb. 1993;13:1623-1630.
22.
Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP,
Mayer EJ, Krauss RM. LDL subclass phenotypes and the insulin
resistance syndrome in women. Circulation. 1993;88:381-387.
23. Barakat HA, Carpenter JW, McLendon VD, Khazanie P, Leggett N, Heath J, Marks R. Influence of obesity, impaired glucose tolerance, and NIDDM on LDL structure and composition: possible link between hyperinsulinemia and atherosclerosis. Diabetes. 1990;39:1527-1533.[Abstract]
24.
Feingold KR, Grunfeld C, Coerrier W, Krauss RM.
LDL subclass phenotypes and triglyceride
metabolism in non-insulin dependent diabetes.
Arterioscler Thromb. 1992;12:1496-1502.
25. Haffner SM, Mykkänen L, Robbins D, Valdez R, Miettinen H, Howard BV, Stern MP, Bowsher R. A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects. Diabetologia. 1995;38:1328-1336.[Medline] [Order article via Infotrieve]
26. Haffner SM, Mykkänen L, Stern MP, Paidi M, Howard BV. Greater effect of diabetes on LDL size in women than in men. Diabetes Care. 1994;17:1164-1171.[Abstract]
27. Reaven GM, Chen YDI, Jeppesen J, Mabeux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small dense low density lipoprotein particles. J Clin Invest. 1993;92:141-146.
28.
Stewart MW, Laker MF, Dyer RG, Game F, Mitcheson J,
Winocour PH, Alberti KGMM. Lipoprotein compositional
abnormalities and insulin resistance in type II diabetic patients with
mild hyperlipidemia. Arterioscler
Thromb. 1993;13:1046-1052.
29. Tan KCB, Cooper MB, Ling KLE, Griffin BA, Freeman DJ, Packard CJ, Shepherd J, Hales CN, Betteridge DJ. Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridemia: the involvement of insulin, insulin precursor species and insulin resistance. Atherosclerosis. 1995;113:273-287.[Medline] [Order article via Infotrieve]
30. Lahdenperä S, Sane T, Vuorinen-Markkola H, Knudsen P, Taskinen M-R. LDL particle size in mildly hypertriglyceridemic subjects: no relation to insulin resistance or diabetes. Atherosclerosis. 1995;113:227-236.[Medline] [Order article via Infotrieve]
31.
Laakso M, Sarlund H, Salonen R, Salonen M,
Pyörälä K, Salonen JT, Karhapää P.
Asymptomatic atherosclerosis and insulin
resistance. Arterioscler Thromb. 1991;11:1068-1078.
32. Haffner SM, Karhapää P, Mykkänen L, Laakso M. Insulin resistance, body fat distribution and sex hormones in men. Diabetes. 1994;43:212-219.[Abstract]
33. World Health Organization. Diabetes Mellitus: Report of a WHO Study Group. Geneva, Switzerland: World Health Organization; 1985 (Tech Rep Ser 727).
34.
DeFronzo RA, Tobin JE, Andres R. Glucose clamp
techniques: a method for quantifying insulin secretion and
resistance. Am J Physiol. 1979;237:E214-E223.
35. Takala J, Keinänen O, Väisänen P, Kari A. Measurement of gas exchange in intensive care: laboratory and clinical validation of a new device. Crit Care Med. 1989;17:1041-1047.[Medline] [Order article via Infotrieve]
36. Laakso M, Uusitupa M, Takala J, Majamder H, Reijonen T, Penttilä I. Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects. Metabolism. 1988;37:1092-1100.[Medline] [Order article via Infotrieve]
37. Ferrannini E. The theoretical basis of indirect calorimetry. Metabolism. 1988;37:287-301.[Medline] [Order article via Infotrieve]
38. Hawk PB, Oser BL, Summerson WH. Practical Physiological Chemistry. 12th ed. Toronto, Ont: Blakiston; 1957:814-822.
39. McNamara JR, Campos H, Ordovas JM, Wilson PWF, Schaefer EJ. Gradient gel electrophoretic analysis of low density lipoproteins. Am Biotech Lab. 1988;6:28-33.
40.
Dormans TPJ, Swinkels DW, De Graaf J, Hendriks JCM,
Stalenhoef AFP, Demacker PNM. Single-spin density-gradient
ultracentrifugation vs. gradient gel electrophoresis:
two methods for detecting low-density-lipoprotein
heterogeneity compared. Clin Chem. 1991;37:853-858.
41.
Hokanson JE, Austin MA, Zambon A, Brunzell JD.
Plasma triglyceride and LDL heterogeneity
in familial combined hyperlipidemia.
Arterioscler Thromb. 1993;13:427-434.
42.
Singh ATK, Rainwater DL, Haffner SM, VandeBerg JL,
Shelledy WR, Moore PH Jr, Dyer TD. Effect of diabetes on
lipoprotein size. Arterioscler Thromb Vasc Biol. 1995;15:1805-1811.
43. Rainwater DL, Andres DW, Ford AL, Lowe WF, Blanche PJ, Krauss RM. Production of polyacrylamide gradient gels for the electrophoretic resolution of lipoproteins. J Lipid Res. 1992;33:1876-1881.[Abstract]
44. Nichols AV, Krauss RM, Musliner TA. Nondenaturing polyacrylamide gradient gel electrophoresis. In: Segrest JP, Albers JJ, eds. Methods in Enzymology: Plasma Lipoproteins. New York, NY: Academic Press; 1986:417-431.
45. Williams PT, Krauss RM, Nichols AV, Vranizan KM, Wood PDS. Identifying the predominant peak diameter of high-density and low-density lipoproteins by electrophoresis. J Lipid Res. 1990;31:1131-1139.[Abstract]
46.
Austin MA, Mykkänen L, Kuusisto J, Edwards KL,
Nelson L, Haffner SM, Pyörälä K, Laakso M.
Prospective study of small LDLs as a risk factor for non-insulin
dependent diabetes mellitus in elderly men and women.
Circulation. 1993;92:1770-1778.
47. Haffner SM, Laakso M, Miettinen H, Mykkänen L, Karhapää P, Rainwater DL. Low levels of sex hormone-binding globulin and testosterone are associated with smaller, denser low density lipoprotein in normoglycemic men. J Clin Endocrinol Metab. 1996;81:3697-3701.[Abstract]
48. Marascuilo LA, McSweeney M. Nonparametric and Distribution-Free Methods for Social Sciences. Monterey, Calif: Brooks/Cole; 1977.
49. Taskinen M-R. Insulin resistance and lipoprotein metabolism. Curr Opin Lipidol. 1995;6:153-160.[Medline] [Order article via Infotrieve]
50. Howard BV, Abbott WGH, Eglissa G, Taskinen M-R. Co-ordination of very low density lipoprotein triglyceride and apolipoprotein B metabolism in humans: effect of obesity and non-insulin-dependent diabetes mellitus. Am Heart J. 1987;113:522-526.[Medline] [Order article via Infotrieve]
51. Fisher RM, Coppack SW, Gibbons GF, Frayn KN. Post-prandial VLDL subfraction metabolism in normal and obese subjects. Int J Obes. 1993;17:263-269.
52.
Deckelbaum RJ, Granot E, Oschry Y, Rose L, Eisenberg
S. Plasma triglyceride determines
structure-composition in low and high density lipoproteins.
Arterioscler Thromb. 1984;4:225-231.
53. Caslake MJ, Packard CJ, Series JJ, Yip B, Dagen MM, Shepherd J. Plasma triglyceride and low density lipoprotein metabolism. Eur J Clin Invest. 1992;22:96-104.[Medline] [Order article via Infotrieve]
54.
Zambon A, Austin MA, Brown BG, Hokanson JE, Brunzell
JD. Effect of hepatic lipase on LDL in normal men and those with
coronary heart disease. Arterioscler Thromb. 1993;13:147-153.
55. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785-789.[Medline] [Order article via Infotrieve]
56. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983;72:1737-1747.
57. Kuusi T, Saarinen P, Nikkilä EA. Evidence for the role of hepatic endothelial lipase in the metabolism of plasma high density lipoprotein2 in man. Atherosclerosis. 1980;36:589-593.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  Y. Jang, J. H. Lee, J. S. Chae, O. Y. Kim, S. J. Koh, J. Y. Kim, H. Cho, J. E. Lee, and J. M Ordovas Association of the 276G->T polymorphism of the adiponectin gene with cardiovascular disease risk factors in nondiabetic Koreans Am. J. Clinical Nutrition, October 1, 2005; 82(4): 760 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Stan, E. Levy, E. E. Delvin, J. A. Hanley, B. Lamarche, J. O'Loughlin, G. Paradis, and M. Lambert Distribution of LDL Particle Size in a Population-Based Sample of Children and Adolescents and Relationship with Other Cardiovascular Risk Factors Clin. Chem., July 1, 2005; 51(7): 1192 - 1200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Festa, K. Williams, A. J.G. Hanley, J. D. Otvos, D. C. Goff, L. E. Wagenknecht, and S. M. Haffner Nuclear Magnetic Resonance Lipoprotein Abnormalities in Prediabetic Subjects in the Insulin Resistance Atherosclerosis Study Circulation, June 28, 2005; 111(25): 3465 - 3472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wakatsuki, Y. Okatani, N. Ikenoue, K. Shinohara, K. Watanabe, and T. Fukaya Effect of Lower Dose of Oral Conjugated Equine Estrogen on Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Postmenopausal Women Circulation, August 19, 2003; 108(7): 808 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wakatsuki, Y. Okatani, N. Ikenoue, and T. Fukaya Different Effects of Oral Conjugated Equine Estrogen and Transdermal Estrogen Replacement Therapy on Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Postmenopausal Women Circulation, October 1, 2002; 106(14): 1771 - 1776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Berneis and R. M. Krauss Metabolic origins and clinical significance of LDL heterogeneity J. Lipid Res., September 1, 2002; 43(9): 1363 - 1379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wakatsuki, Y. Ogawa, T. Saibara, Y. Okatani, and T. Fukaya Size and Oxidative Susceptibility of Low-Density Lipoprotein Particles in Breast Cancer Patients with Tamoxifen-Induced Fatty Liver J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3676 - 3681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hulthe, L. Bokemark, J. Wikstrand, and B. Fagerberg The Metabolic Syndrome, LDL Particle Size, and Atherosclerosis : The Atherosclerosis and Insulin Resistance (AIR) Study Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2140 - 2147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bioletto, A. Golay, R. Munger, B. Kalix, and R. W James Acute hyperinsulinemia and very-low-density and low-density lipoprotein subfractions in obese subjects1 Am. J. Clinical Nutrition, February 1, 2000; 71(2): 443 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Mykkanen, J. Kuusisto, S. M. Haffner, M. Laakso, and M. A. Austin LDL Size and Risk of Coronary Heart Disease in Elderly Men and Women Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2742 - 2748. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||