© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia
From the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington (J.Q.P., J.D.B.), and the Seattle VA Puget Sound Health Care System (S.E.K.), Seattle, Wash, and the Department of Gerontology and Geriatric Medicine, University of Colorado (R.S.S.), Denver.
Correspondence to Jonathan Q. Purnell, MD, Oregon Health Sciences University, Division of Endocrinology, Diabetes, and Clinical Nutrition, Mailbox L607, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. E-mail purnellj{at}ohsu.edu
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Abstract—Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age- and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.
Key Words: obesity • insulin resistance • hyperlipidemia • visceral fat • apolipoproteins
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Introduction |
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Familial combined hyperlipidemia (FCHL) was first described in families of myocardial survivors when elevations in triglycerides, total cholesterol, or both were found in affected relatives.1 Subsequent reports confirmed these findings and the association of FCHL with premature coronary artery disease.2 3 4 Compared with normal control subjects, subjects with FCHL characteristically have elevations in apoB levels and an increased amount of small dense LDL particles, which persist even after reduction of triglyceride levels with gemfibrozil.5 6 7 8 Kinetic studies have suggested that 1 mechanism for the elevated apoB levels in FCHL subjects is through an increased production rate of apoB-containing lipoprotein particles.9 10 11
Although initially described as a monogenic disorder,1 inheritance of the lipid phenotype has been shown to be more complex. Segregation and linkage analysis have provided evidence of the influence of major gene effects on the elevation in apoB levels12 and the presence of small dense LDL particles in FCHL families.13 14 Further evidence of genetic heterogeneity is derived from studies showing that 36% of subjects with FCHL have reduced postheparin lipoprotein lipase (LpL) activity.15 FCHL subjects with this diminished LpL activity have higher triglyceride levels than do FCHL subjects with normal LpL activity,15 and by DNA sequencing, several mutations of the apoA-IV gene16 and regulatory elements of the LpL gene17 that could contribute to the diminished LpL activity and variable hyperlipidemia in this group have been described. In addition, several groups have shown polymorphisms of the LpL gene to be associated with higher lipid levels, specifically triglyceride levels, in FCHL subjects who carry these mutations than in noncarriers (for review, see Aouizerat el al18 ).
In the general population, small dense LDL particles are common, with an estimated prevalence rate of 30%.19 20 Subjects with small dense LDL have a number of other lipid abnormalities in common with FCHL subjects, including elevated triglyceride levels, apoB production rates, and apoB levels.21 22 23 Insulin resistance has also been reported in subjects with small dense LDL particles,24 25 and recent studies have shown that subjects with FCHL are also insulin resistant.26 27 28 29 30 31 32
Given these similarities in metabolic phenotype, it has been hypothesized that insulin resistance is a major determinant of the hyperlipidemia phenotype in FCHL, including elevated apoB levels.27 31 33 However, whether the increased apoB levels in FCHL can be entirely accounted for by the finding of insulin resistance in this population remains to be determined. In a study of FCHL families, Jarvik et al34 suggested that mechanisms resulting in the dense LDL phenotype (such as insulin resistance) may contribute to the lipid phenotype of FCHL, but they do not fully explain the elevated apoB levels in this disorder. Therefore, the present study sought to examine the relationship between insulin resistance and apoB levels in subjects with FCHL. In addition, the relationship of visceral fat (intra-abdominal fat [IAF]) accumulation, an important determinant of insulin resistance in the general population,24 35 36 to the expression of insulin resistance in FCHL subjects is described.
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Methods |
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Subjects With FCHL
Eleven affected subjects from families with FCHL were recruited for the present study. A family was defined as having FCHL if elevated levels of total cholesterol and triglyceride greater than the 90 percentile of age- and sex-matched controls (as reported in the Lipid Research Clinic data set37 ) were present in the proband and at least 2 other first-degree relatives. Participating subjects were screened with a history and physical examination, and all medications affecting lipid levels were stopped 4 weeks before the study. All other medications were continued, and thyroid status was confirmed to be normal if subjects were diagnosed with hypothyroidism and were taking replacement doses of hormones.
Control Subjects
Fifteen and 22 subjects recruited for other studies
of weight loss or hormonal supplementation at the University of
Washington served as the age-matched and the age- and weight-matched
control groups, respectively. Men and women participating in these
studies were considered to be healthy nonsmokers and nonexercisers and
to be free of chronic diseases such as cancer, cardiac disease, lung
disease, and kidney disease. Data obtained at the baseline visit before
the intervention were used for the present study. Informed consent
was obtained in all subjects before they entered the study, and the
Human Subjects Committee of the University of Washington approved all
procedures.
Lipids and Apolipoproteins
After a 12- to 16-hour overnight fast, blood was
collected in 0.1% EDTA and immediately centrifuged at 4°C at
3000 rpm for 15 minutes, and measurements were made on fresh plasma
within 2 days. Plasma total cholesterol,
triglycerides, HDL cholesterol, and apoB were
measured at the Northwest Lipid Research Laboratory as previously
described.38 39
Insulin Sensitivity
The tolbutamide-modified frequently sampled
intravenous glucose tolerance test was performed as
previously described40 : 3
basal samples were drawn for insulin and glucose at 5-minute intervals;
glucose (11.4 g/m2) was injected at time 0
as a bolus over 60 seconds; tolbutamide (125
mg/m2) was injected at the 20-minute time
point after the glucose injection over 30 seconds; and blood samples
for glucose and insulin measurements were drawn at 32 time points over
4 hours. Plasma glucose concentrations were measured in triplicate by
using the glucose oxidase method. Plasma insulin was measured in
duplicate by using a modification of a double-antibody
radioimmunoassay.41 Insulin
sensitivity (Si) was quantified by using the minimal model of glucose
kinetics of Bergman et
al.42
Body Composition and
Distribution
IAF and subcutaneous abdominal fat (SQF) depots were
manually separated and quantified by a blinded reader using single
abdominal CT images obtained on inspiration at the level of the
umbilicus. The CT image was analyzed for cross-sectional area
of fat by use of a density contour program available in the standard GE
computer software as described
previously.43 A single
blinded observer made all the CT measurements of IAF and SQF. The
coefficient of variation of reading the same scan is
<2%.
Statistical Methods
For comparisons between groups, the
t test was used unless the data
were nonnormally distributed, in which case the rank sum test was used.
Correlations were tested by linear regression. The independence of
linear relationships was tested by multiple linear
regression.
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Results |
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All groups were matched for age (Table 1
). In the FCHL group, no effect of sex on lipid
levels, IAF, or Si was found (data not shown). Compared with the
age-matched group, the FCHL group and the age- and weight-matched group
had higher body mass index (BMI), IAF, and SQF, but the FCHL and age-
and weight-matched group values were not different from each other
(Table 1).
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FCHL subjects had significantly higher levels of total
cholesterol, triglycerides, VLDL
cholesterol, LDL cholesterol, and apoB compared
with both control groups
(Table 2). Except for a lower HDL cholesterol
level in the age- and weight-matched control group compared with the
age-matched control group, lipid levels were similar between these 2
groups
(Table 2).
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Fasting glucose levels were similar in all groups
(Table 3). Insulin levels were significantly elevated in the
age- and weight-matched control group compared with the age-matched
control group and slightly higher than levels in the FCHL group. Si was
lower (the subjects were more insulin resistant) in the FCHL
group compared with the age-matched control group, but Si was not
different in the FCHL group compared with the age- and weight-matched
group
(Table 3). Finally, acute insulin response to glucose was
not different between groups, although results tended to be lower for
the more insulin-resistant FCHL group and age- and
weight-matched group compared with the age-matched group
(Table 3).
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When the relationship between Si and body composition
was tested in the FCHL group, Si was inversely associated with IAF
(r=-0.668,
P<0.05) and BMI
(r=- 0.642,
P<0.05) but not SQF
(r=- 0.443,
P=0.17). After all groups were
combined, Si was inversely related to BMI
(r=-0.521,
P<0.001), SQF
(r=-0.407,
P=0.005), and IAF
(r=-0.582,
P<0.001;
Figure 1). Multiple linear regression analysis of Si
as the dependent variable in the combined groups showed that only
IAF remained significantly related to Si as an independent variable
after the addition of BMI and SQF
(Table 4).
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To explore the relationships between the Si or IAF
accumulation and apoB levels in the FCHL group, scatterplots were
generated with a line to indicate the 90th percentile for apoB levels
in the combined control groups
(Figure 2). Nine of 11 subjects with FCHL had apoB levels at
or above the 90th percentile of the control groups at any level of Si
(Figure 2) and IAF
(Figure 3). ApoB levels were not related to Si in the FCHL
group alone (r=0.201,
P=0.553), in the combined
control groups alone (r=0.203,
P=0.236), or in the FCHL and
control groups combined
(r=0.165,
P=0.16). Similarly, apoB levels
were not related to IAF in the FCHL subjects
(r=0.236,
P=0.484) or in the FCHL and
control groups combined
(r=0.157,
P=0.285); however, a
nonsignificant trend between apoB levels and IAF was found in the
combined control groups
(r=0.301,
P=0.07).
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Discussion |
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A number of studies have demonstrated greater insulin resistance in subjects with FCHL than in control groups and unaffected family members. Elevated fasting insulin levels, a marker of insulin resistance, were found in FCHL subjects compared with normolipidemic control subjects.26 33 Castro Cabezas et al33 found that FCHL subjects with the highest triglyceride and cholesterol levels also had significantly higher insulin and nonesterified fatty acid levels compared with FCHL subjects with lesser degrees of hyperlipidemia. In these studies, BMI tended to be higher in the FCHL subjects with elevated insulin levels, but no measurements of abdominal fat were made. From these early studies, impaired suppression of fatty acid levels in FCHL subjects was proposed as a mechanism to explain the insulin resistance and the lipid phenotype.33
Using the euglycemic hyperinsulinemic clamp, Aitman et al27 demonstrated reduced Si and higher steady-state free fatty acid levels in FCHL subjects than in control subjects. The FCHL subjects in that study were slightly heavier (although not significantly) and had significantly greater waist fat, as measured by DEXA scan, than did the control subjects. Similar findings using the frequently sampled intravenous glucose tolerance test were reported by Ascaso and colleagues.29 30 Subsequent studies using the clamp technique confirmed that whole-body glucose uptake is reduced in FCHL subjects compared with control subjects.28 31 32 When the FCHL subjects in these studies were subdivided by lipid phenotype (high cholesterol, high triglycerides, or combined hyperlipidemia), Si was found to be reduced only in those subjects with hypertriglyceridemia or combined hyperlipidemia.32 33 In addition, when the FCHL subjects were separated by degree of adiposity (as measured by BMI) and abdominal obesity (as measured by waist-to-hip ratios), those with the highest BMIs and waist-to-hip ratios were found to be the most insulin resistant.30 32 33 In FCHL family members, also reported were significant correlations of free fatty acid levels during the clamp with triglyceride levels but not with apoB levels.31 32
Visceral adiposity has been associated with a number of metabolic abnormalities, including insulin resistance, increased triglyceride levels, lower HDL2 cholesterol, more cholesterol in small dense LDL particles,24 25 increased apoB production rates,44 and increased apoB levels.45 46 To determine whether accumulation of IAF is similarly associated with insulin resistance and dyslipidemia in FCHL, subjects in the present study underwent measurement of IAF and SQF by CT scan. Consistent with previous reports, FCHL subjects in the present study were more insulin resistant than were the age-matched control subjects. When FHCL subjects were compared with control subjects matched for age, BMI, and amount of IAF, however, Si was not different. Indeed, Si was inversely related to the amount of IAF but not to the amount of SQF in the FCHL subjects, and when the FCHL and control groups were combined, only IAF remained correlated with insulin resistance after including SQF and BMI on multiple regression analysis. So although the present study confirms the presence of insulin resistance in subjects with FCHL, it extends previous observations to show that FCHL subjects are viscerally obese and that their insulin resistance is appropriate for their degree of visceral adiposity. Although this conclusion may appear at odds with the report of reduced Si in nonobese FCHL subjects by Bredie et al,28 a study by Fujimoto et al24 has demonstrated that even in a nonobese population, IAF levels measured by CT scan can vary up to 10-fold and are a major determinant of insulin resistance. However, confirmation of this would require measurement of Si and IAF by CT in nonobese FCHL and control subjects.
One potential confounder in the present study is the predominance of men in the age- and weight-matched control group compared with the FCHL group. Men are known to have a greater amount of IAF and higher triglyceride and lower HDL cholesterol levels on average compared with age-matched women, and this may have introduced a bias, making some differences with the FCHL group more difficult to detect (ie, lipid levels) or other differences more pronounced (ie, IAF). In fact, neither of these was found in the present study. Lipid levels (and apoB) were still higher, and IAF was no different between these groups. With the added analysis showing no sex differences in the FCHL group for levels of lipids and IAF, it is unlikely that bias introduced by having a greater proportion of men in one control group is important in this analysis.
An important observation from the present study is that although increased production of apoB particles and elevated levels of apoB have been described in viscerally obese subjects, neither the amount of IAF nor insulin resistance could fully account for the elevation in apoB levels reported in the FCHL subjects in the present study. In >80% of the FCHL subjects, apoB levels were higher than the 90th percentile of controls at any level of Si or amount of IAF. These data provide support for genetic models describing a major, but separate, gene(s) for elevated apoB34 distinct from genes with effects on triglyceride and small dense LDL13 14 47 48 in subjects with FCHL. To date, no candidate genes, including the apoB gene,49 50 have been found to account for the increased apoB in FCHL. On the other hand, many genes seem to contribute to the increase in triglyceride and other lipid levels in FCHL.48
In summary, subjects with FCHL are viscerally obese and insulin resistant compared with the age-matched control subjects. However, when compared with age-, weight-, and IAF-matched control subjects, their insulin resistance is appropriate for their degree of visceral obesity. Levels of apoB are higher in FCHL subjects at any level of Si and IAF accumulation compared with levels in control subjects. Taken together, the present study suggests that the visceral obesity/insulin resistance syndrome contributes to the FCHL lipid phenotype but that a separate genetic regulator(s) likely controls the increased apoB levels above those found in the control subjects.
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Acknowledgments |
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This work was conducted at the University of Washington General Clinical Research Center (M01-RR-00037) and supported by Clinical Nutrition Research grant 5P30 DK-35816, Diabetes Endocrinology Research Center grant DK-17047, and National Institutes of Health grants RO1 AG-08673, PO-1 DK-02456, PO-1 HL-30086, and K-24-DK-02654.
Received July 20, 2000; accepted December 20, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease, II: genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544–1568.
2. Rose HG, Kranz P, Weinstock M, Juliano J, Haft JI. Inheritance of combined hyperlipoproteinemia: evidence for a new lipoprotein phenotype. Am J Med. 1973;54:148–160.[Medline] [Order article via Infotrieve]
3. Nikkila EA, Aro A. Family study of serum lipids and lipoproteins in coronary heart-disease. Lancet. 1973;1:954–959.[Medline] [Order article via Infotrieve]
4. Brunzell JD, Schrott HG, Motulsky AG, Bierman EL. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism. 1976;25:313–320.[Medline] [Order article via Infotrieve]
5.
Sniderman AD,
Shapiro S, Marpole D, Skinner B, Teng B, Kwiterovich PO Jr. Association
of coronary atherosclerosis with
hyperapobetalipoproteinemia [increased protein but normal
cholesterol levels in human plasma low density (ß)
lipoproteins]. Proc Natl Acad Sci
U S A. 1980;77:604–608.
6. Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J Lipid Res. 1983;24:147–155.[Abstract]
7.
Hokanson JE, Austin
MA, Zambon A, Brunzell JD. Plasma triglyceride and LDL
heterogeneity in familial combined
hyperlipidemia.
Arterioscler Thromb. 1993;13:427–434.
8.
Hokanson JE, Krauss
RM, Albers JJ, Austin MA, Brunzell JD. LDL physical and chemical
properties in familial combined hyperlipidemia.
Arterioscler Thromb Vasc Biol. 1995;15:452–459.
9. Chait A, Albers JJ, Brunzell JD. Very low density lipoprotein overproduction in genetic forms of hypertriglyceridemia. Eur J Clin Invest. 1980;10:17–22.[Medline] [Order article via Infotrieve]
10. Janus ED, Nicoll AM, Turner PR, Magill P, Lewis B. Kinetic bases of the primary hyperlipidemias: studies of apolipoprotein B turnover in genetically defined subjects. Eur J Clin Invest. 1980;10:161–172.[Medline] [Order article via Infotrieve]
11. Kissebah AH, Alfarsi S, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. Metabolism. 1981;30:856–868.[Medline] [Order article via Infotrieve]
12. Pairitz G, Davignon J, Mailloux H, Sing CF. Sources of inter-individual variation in the quantitative levels of apolipoprotein B in pedigrees ascertained through a lipid clinic. Am J Hum Genet. 1988;43:311–321.[Medline] [Order article via Infotrieve]
13. Austin MA, Wijsman E, Guo SW, Krauss RM, Brunzell JD, Deeb S. Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia. Genet Epidemiol. 1991;8:287–297.[Medline] [Order article via Infotrieve]
14. Austin MA, Horowitz H, Wijsman E, Krauss RM, Brunzell J. Bimodality of plasma apolipoprotein B levels in familial combined hyperlipidemia. Atherosclerosis. 1992;92:67–77.[Medline] [Order article via Infotrieve]
15. Babirak SP, Brown BG, Brunzell JD. Familial combined hyperlipidemia and abnormal lipoprotein lipase. Arterioscler Thromb. 1992;12:1176–1183.[Abstract]
16. Deeb SS, Nevin DN, Iwasaki L, Brunzell JD. Two novel apolipoprotein A-IV variants in individuals with familial combined hyperlipidemia and diminished levels of lipoprotein lipase activity. Hum Mutat. 1996;8:319–325.[Medline] [Order article via Infotrieve]
17. Yang WS, Nevin DN, Iwasaki L, Peng R, Brown BG, Brunzell JD, Deeb SS. Regulatory mutations in the human lipoprotein lipase gene in patients with familial combined hyperlipidemia and coronary artery disease. J Lipid Res. 1996;37:2627–2637.[Abstract]
18.
Aouizerat BE,
Allayee H, Cantor RM, Dallinga-Thie GM, Lanning CD, de Bruin TW, Lusis
AJ, Rotter JI. Linkage of a candidate gene locus to familial combined
hyperlipidemia: lecithin:cholesterol
acyltransferase on 16q. Arterioscler
Thromb Vasc Biol. 1999;19:2730–2736.
19. Austin MA, King M-C, Vranizan KM, Newman B, Krauss RM. Inheritance of low-density lipoprotein subclass patterns: results of complex segregation analysis. Am J Hum Genet. 1988;43:838–846.[Medline] [Order article via Infotrieve]
20.
Campos H,
Blijlevens E, McNamara JR, Ordovas JM, Posner BM, Wilson PW, Castelli
WP, Schaefer EJ. LDL particle size distribution: results from the
Framingham Offspring Study. Arterioscler
Thromb. 1992;12:1410–1419.
21.
McNamara JR,
Campos H, Ordovas JM, Peterson J, Wilson PW, Schaefer EJ. Effect of
gender, age, and lipid status on low density lipoprotein subfraction
distribution: results from the Framingham Offspring study.
Arteriosclerosis. 1987;7:483–490.
22.
Austin MA, Breslow
JA, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low density
lipoprotein subclass pattern and risk of myocardial infarction.
JAMA. 1988;260:1917–1921.
23.
Packard CJ, Demant
T, Stewart JP, Bedford D, Caslake MJ, Schwertfeger G, Bedynek A,
Shepherd J, Seidel D. Apolipoprotein B metabolism and the
distribution of VLDL and LDL subfractions.
J Lipid Res. 2000;41:305–318.
24. Fujimoto WY, Abbate SL, Kahn SE, Hokanson JE, Brunzell JD. The visceral adiposity syndrome in Japanese-American men. Obes Res. 1994;2:364–371.[Medline] [Order article via Infotrieve]
25. Tchernof A, Lamarche B, Prud’Homme D, Nadeau A, Moorjani S, Labrie F, Lupien PJ, Despres J-P. The dense LDL phenotype: association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men. Diabetes Care. 1996;19:629–637.[Abstract]
26.
Hunt SC, Wu
LL, Hopkins PN, Stults BM, Kuida H, Ramirez ME, Lalouel J-M, Williams
RR. Apolipoprotein, LDL subfraction, and insulin associations with
familial combined hyperlipidemia in Utah patients with
familial dyslipidemic hypertension.
Arteriosclerosis. 1989;9:335–344.
27.
Aitman TJ,
Godsland IF, Farren B, Crook D, Wong HJ, Scott J. Defects of insulin
action on fatty acid and carbohydrate metabolism in
familial combined hyperlipidemia.
Arterioscler Thromb Vasc Biol. 1997;17:748–754.
28. Bredie SJ, Tack CJ, Smits P, Stalenhoef AF. Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives. Arterioscler Thromb Vasc Biol. 1997;17:1465–1471.
29. Ascaso JF, Lorente R, Merchante A, Real JT, Priego A, Carmena R. Insulin resistance in patients with familial combined hyperlipidemia and coronary artery disease. Am J Cardiol. 1997;80:1484–1487.[Medline] [Order article via Infotrieve]
30. Ascaso JF, Merchante A, Lorente RI, Real JT, Martinez-Valls J, Carmena R. A study of insulin resistance using the minimal model in nondiabetic familial combined hyperlipidemic patients. Metabolism. 1998;47:508–513.[Medline] [Order article via Infotrieve]
31.
Karjalainen L,
Pihlajamaki J, Karhapaa P, Laakso M. Impaired insulin-stimulated
glucose oxidation and free fatty acid suppression in patients with
familial combined hyperlipidemia: a precursor defect
for dyslipidemia? Arterioscler
Thromb Vasc Biol. 1998;18:1548–1553.
32.
Pihlajamaki J,
Karjalainen L, Karhapaa P, Vauhkonen I, Laakso M. Impaired free fatty
acid suppression during hyperinsulinemia is a
characteristic finding in familial combined
hyperlipidemia, but insulin resistance is observed only
in hypertriglyceridemic patients.
Arterioscler Thromb Vasc Biol. 2000;20:164–170.
33. Castro Cabezas M, de Bruin TW, de Valk HW, Shoulders CC, Jansen H, Willem Erkelens D. Impaired fatty acid metabolism in familial combined hyperlipidemia: a mechanism associating hepatic apolipoprotein B overproduction and insulin resistance. J Clin Invest. 1993;92:160–168.
34.
Jarvik GP,
Brunzell JD, Austin MA, Krauss RM, Motulsky AG, Wijsman E. Genetic
predictors of FCHL in four large pedigrees: influence of apoB level
major locus predicted genotype and LDL subclass
phenotype. Arterioscler
Thromb. 1994;14:1687–1694.
35. Park KS, Rhee BD, Lee KU, Kim SY, Lee HK, Koh CS, Min HK. Intra-abdominal fat is associated with decreased insulin sensitivity in healthy young men. Metabolism. 1991;40:600–603.[Medline] [Order article via Infotrieve]
36. Marcus MA, Murphy L, Pi-Sunyer FX, Albu JB. Insulin sensitivity and serum triglyceride level in obese white and black women: relationship to visceral and truncal subcutaneous fat. Metabolism. 1999;48:194–199.[Medline] [Order article via Infotrieve]
37. National Institutes of Health. The lipid research clinics population studies data book. Vol 1. The prevalence study. NIH Publication No. 80-1527. Bethesda, Md: DHHS Government Printing Office, 1980.
38. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, Zhao X-Q, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289–1298.[Abstract]
39.
Capell WH, Zambon
A, Austin MA, Brunzell JD, Hokanson JE. Compositional differences of
LDL particles in normal subjects with LDL subclass phenotype A
and LDL subclass phenotype B.
Arterioscler Thromb Vasc Biol. 1996;16:1040–1046.
40. Beard JC, Bergman RN, Ward WK, Porte D Jr. The insulin sensitivity index in man: correlation between clamp-derived and IVGTT-derived values. Diabetes. 1986;35:362–369.[Abstract]
41. Morgan CR, Lazarow A. Immunoassay of insulin: two antibody systems. Diabetes. 1963;12:115–126.
42.
Bergman RN, Ider
YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin
sensitivity. Am J Physiol. 1979;236:E667–E677.
43. Shuman WP, Newell-Morris LL, Leonetti DL, Wahl PW, Moceri VM, Moss AA, Fujimoto WY. Abnormal body fat distribution detected by computed tomography in diabetic men. Invest Radiol. 1986;21:483–487.[Medline] [Order article via Infotrieve]
44. Riches FM, Watts GF, Naoumova RP, Kelly JM, Croft KD, Thompson GR. Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity. Int J Obes Relat Metab Disord. 1998;22:414–423.[Medline] [Order article via Infotrieve]
45.
Zamboni M,
Armellini F, Cominacini L, Turcato E, Todesco T, Bissoli L, Micciolo R,
Bergamo-Andreis IA, Bossello O. Obesity and regional body-fat
distribution in men: separate and joint relationships to glucose
tolerance and plasma lipoproteins. Am
J Clin Nutr. 1994;60:682–687.
46. Fujimoto WY, Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW. Metabolic and adipose risk factors for NIDDM and coronary disease in third-generation Japanese-American men and women with impaired glucose tolerance. Diabetologia. 1994;37:524–532.[Medline] [Order article via Infotrieve]
47.
Austin MA,
Brunzell JD, Fitch WL, Krauss RM. Inheritance of low density
lipoprotein subclass patterns in familial combined
hyperlipidemia.
Arteriosclerosis. 1990;10:520–530.
48. Aouizerat BE, Allayee H, Bodnar J, Krass KL, Peltonen L, de Bruin TW, Rotter JI, Lusis AJ. Novel genes for familial combined hyperlipidemia. Curr Opin Lipidol. 1999;10:113–122.[Medline] [Order article via Infotrieve]
49. Rauh G, Schuster H, Muller B, Schewe S, Keller C, Wolfram G, Zollner N. Genetic evidence from seven families that the apolipoprotein B gene is not involved in familial combined hyperlipidemia. Atherosclerosis. 1990;83:81–87.[Medline] [Order article via Infotrieve]
50. Coresh J, Beaty TH, Kwiterovich PO, Antonarakis SE. Pedigree and sib-pain linkage analysis suggest the apo B gene is not the major gene influencing plasma apolipoprotein B levels. Am J Hum Genet. 1992;50:1038–1045. [Medline] [Order article via Infotrieve]
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  M De Michele, A Iannuzzi, A Salvato, P Pauciullo, M Gentile, G Iannuzzo, S Panico, A Pujia, G M Bond, and P Rubba Impaired endothelium-dependent vascular reactivity in patients with familial combined hyperlipidaemia Heart, January 1, 2007; 93(1): 78 - 81. [Abstract] [Full Text] [PDF]
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 G. M Reaven The metabolic syndrome: is this diagnosis necessary? Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1237 - 1247. [Abstract] [Full Text] [PDF]
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 G. Reaven All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 105 - 112. [Abstract] [PDF]
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 M.J. Veerkamp, J. de Graaf, and A.F.H. Stalenhoef Role of Insulin Resistance in Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 1026 - 1031. [Abstract] [Full Text] [PDF]
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 M. C. Carr and J. D. Brunzell Abdominal Obesity and Dyslipidemia in the Metabolic Syndrome: Importance of Type 2 Diabetes and Familial Combined Hyperlipidemia in Coronary Artery Disease Risk J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2601 - 2607. [Abstract] [Full Text] [PDF]
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A.M. Georgieva, M.M.J. van Greevenbroek, R.M. Krauss, M.C.G.J. Brouwers, V.M.M.-J. Vermeulen, M.G. Robertus-Teunissen, C.J.H. van der Kallen, and T.W.A. de Bruin Subclasses of Low-Density Lipoprotein and Very Low-Density Lipoprotein in Familial Combined Hyperlipidemia: Relationship to Multiple Lipoprotein Phenotype Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 744 - 749. [Abstract] [Full Text] [PDF]
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 T. Ueno, J. Tremblay, J. Kunes, J. Zicha, Z. Dobesova, Z. Pausova, A. Y. Deng, Y.-L. Sun, H. J. Jacob, and P. Hamet Rat model of familial combined hyperlipidemia as a result of comparative mapping Physiol Genomics, March 12, 2004; 17(1): 38 - 47. [Abstract] [Full Text] [PDF]
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 C. Verseyden, S. Meijssen, H. van Dijk, H. Jansen, and M. C. Cabezas Effects of atorvastatin on fasting and postprandial complement component 3 response in familial combined hyperlipidemia J. Lipid Res., November 1, 2003; 44(11): 2100 - 2108. [Abstract] [Full Text] [PDF]
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R. P. Naoumova, S. A. Bonney, S. Eichenbaum-Voline, H. N. Patel, B. Jones, E. L. Jones, J. Amey, S. Colilla, C. K.Y. Neuwirth, R. Allotey, et al. Confirmed Locus on Chromosome 11p and Candidate Loci on 6q and 8p for the Triglyceride and Cholesterol Traits of Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2070 - 2077. [Abstract] [Full Text] [PDF]
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C.J.M. Halkes, H. van Dijk, C. Verseyden, P.P.Th. de Jaegere, H.W.M Plokker, S. Meijssen, D.W. Erkelens, and M. C. Cabezas Gender Differences in Postprandial Ketone Bodies in Normolipidemic Subjects and in Untreated Patients With Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1875 - 1880. [Abstract] [Full Text] [PDF]
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 P. N. Hopkins, G. Heiss, R. C. Ellison, M. A. Province, J. S. Pankow, J. H. Eckfeldt, and S. C. Hunt Coronary Artery Disease Risk in Familial Combined Hyperlipidemia and Familial Hypertriglyceridemia: A Case-Control Comparison From the National Heart, Lung, and Blood Institute Family Heart Study Circulation, August 5, 2003; 108(5): 519 - 523. [Abstract] [Full Text] [PDF]
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A. F. Ayyobi, S. H. McGladdery, M. J. McNeely, M. A. Austin, A. G. Motulsky, and J. D. Brunzell Small, Dense LDL and Elevated Apolipoprotein B Are the Common Characteristics for the Three Major Lipid Phenotypes of Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1289 - 1294. [Abstract] [Full Text] [PDF]
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P. M. H. Eurlings, C. J. H. van der Kallen, J. M. W. Geurts, P. Kouwenberg, W. D. Boeckx, and T. W. A. de Bruin Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia J. Lipid Res., June 1, 2002; 43(6): 930 - 935. [Abstract] [Full Text] [PDF]
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J. Vakkilainen, M. Jauhiainen, K. Ylitalo, I. O. Nuotio, J. S. A. Viikari, C. Ehnholm, and M.-R. Taskinen LDL particle size in familial combined hyperlipidemia: effects of serum lipids, lipoprotein-modifying enzymes, and lipid transfer proteins J. Lipid Res., April 1, 2002; 43(4): 598 - 603. [Abstract] [Full Text] [PDF]
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