Atherosclerosis and Lipoproteins |
From the Department of Medicine, University of Kuopio, Kuopio, Finland.
Correspondence to Markku Laakso, MD, Professor and Chair, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail markku.laakso{at}uku.fi
| Abstract |
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7.7 mmol/L), in 22 with
hypertriglyceridemia (total
triglycerides
2.4 mmol/L in men 2.4 mmol/L in
women), and in 14 with combined hyperlipidemia. During
the hyperinsulinemic clamp, FCHL family members had
higher free fatty acid levels than did controls (0.06±0.06
[mean±SD] in controls versus 0.16±0.11 in relatives without
dyslipidemia versus 0.15±0.07 in
hypercholesterolemic patients versus 0.29±0.14 in
hypertriglyceridemic patients versus
0.27±0.17 mmol/L in patients with combined
hyperlipidemia; P<0.001 after
adjustment for age, sex, and body mass index). Relatives without
dyslipidemia (16.4±4.4 µmol ·
kg-1 · min-1, P=0.001)
and patients with hypertriglyceridemia
(12.8±3.8 µmol · kg-1 ·
min-1, P<0.001) and with combined
hyperlipidemia (13.7±3.1 µmol ·
kg-1 · min-1, P<0.001)
had lower rates of insulin-stimulated glucose oxidation than did
controls (19.4±4.7 µmol · kg-1 ·
min-1). Also, the rates of nonoxidative glucose disposal
were lower in patients with
hypertriglyceridemia
(P=0.001) and combined hyperlipidemia
(P=0.011) than in controls. In contrast, subjects with
hypercholesterolemia and control subjects had
similar rates of insulin-stimulated glucose uptake. We conclude that a
defect in free fatty acid suppression during
hyperinsulinemia, probably located in adipose
tissue, is characteristic for all FCHL patients with varying types of
dyslipidemia, whereas insulin resistance in skeletal muscle
is observed only in FCHL patients with elevated triglyceride
levels.
Key Words: familial combined hyperlipidemia insulin resistance insulin free fatty acids
| Introduction |
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Recent studies have indicated that insulin resistance is a central part of FCHL.10 11 12 Obese FCHL patients are more resistant to insulin than are nonobese patients,13 but even lean FCHL patients seem to have low rates of insulin-stimulated glucose uptake.11 12 13 This observation indicates that overweight is only a modifying factor for insulin sensitivity in FCHL.14 A defect in insulin action in adipose tissue is likely to play a significant role in FCHL because insulins suppressive effect on free fatty acid (FFA) levels is impaired in FCHL patients.10 12 15 High FFA levels may in turn lead to both a decrease in insulin-stimulated glucose uptake in adipose tissue and skeletal muscle, according to the scheme proposed by Randle et al,16 and to an increase in the synthesis of lipoproteins in the liver.17
Whether low insulin sensitivity is a characteristic feature for all FCHL patients or only a subgroup of FCHL patients, depending on the type of dyslipidemia, has not been investigated with direct measurements of insulin sensitivity. Furthermore, it is not known whether insulins impaired action on FFA suppression10 12 is a typical finding for all FCHL patients or only for a certain dyslipidemic phenotype. To address these questions, we measured the rates of whole-body glucose uptake (WBGU) and FFA levels during the hyperinsulinemic clamp in 110 control subjects and in 105 FCHL family members with varying dyslipidemias.
| Methods |
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90% of all cases of familial
hypercholesterolemia in this
area.19 Altogether, 33 families with FCHL and their 335
family members met the criteria and were included in this
study. All nondiabetic family members with dyslipidemia and a random sample of relatives without dyslipidemia, after exclusion of subjects <30 years of age and those with severe chronic disease, were invited for the hyperinsulinemic, euglycemic clamp. Results on the first 58 family members (30 without dyslipidemia and 28 with FCHL) have been previously reported.12 The final study population consisted of 105 family members, which allowed us to divide them into subgroups: 50 relatives without dyslipidemia (29 men, 21 women), 19 with hypercholesterolemia (14 men, 5 women), 22 with hypertriglyceridemia (16 men, 6 women), and 14 with combined hyperlipidemia (8 men, 6 women).
Control subjects were 110 healthy, unrelated subjects from our previous
population studies, members of the control families in the myocardial
infarction survivor study, or offspring of subjects who had a
repeatedly normal glucose tolerance during 10-year
follow-up.18 20 21 22 All controls and FCHL family members
had normal glucose tolerance according to the World Health Organization
criteria23 ; normal liver, kidney, and thyroid function
tests; no history of excessive alcohol intake; and no severe chronic
disease. In addition, control subjects did not have hypertension,
symptoms or signs of coronary heart disease, or continuous drug
treatment. Clinical characteristics of the study groups according to
the phenotypes of dyslipidemia are shown in
Table 1
.
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Informed consent was obtained from all subjects after the purpose and potential risks of the study were explained to them. The protocol was approved by the Ethics Committee of the University of Kuopio and was in accordance with the Declaration of Helsinki.
Metabolic Studies
The degree of insulin resistance was evaluated with the
euglycemic clamp technique24 after a 12-hour
fast as previously described.20 After a baseline blood
draw, a priming dose of insulin (Actrapid 100 IU/mL, Novo
Nordisk) was administered during the initial 10 minutes to raise
insulin concentration quickly to the desired level, where it was
maintained by a continuous insulin infusion of 480
pmol/m2 per minute. Under these study conditions,
hepatic glucose production is completely suppressed in
nondiabetic subjects.25 Blood glucose was clamped at
5.0 mmol/L for the next 180 minutes by the infusion of 20%
glucose at varying rates according to blood glucose measurements
performed at 5-minute intervals. The mean value for the last hour was
used to calculate the rates of insulin-stimulated WBGU.
Indirect calorimetry was performed with a computerized flow-through canopy gas analyzer system (Deltatrac, Datex) as previously described.26 27 Gas exchange was measured for 30 minutes after a 12-hour fast and during the last 30 minutes of the euglycemic clamp. The first 10 minutes of each measurement were discarded, and the mean value of the last 20 minutes was used in calculations. The rates of glucose oxidation were calculated according to Ferrannini28 (determined by indirect calorimetry in the last 20 minutes of the euglycemic clamp). The rates of nonoxidative glucose disposal during the euglycemic clamp were estimated by subtracting the carbohydrate oxidation rate from the rates of WBGU.
Analytical Methods
Plasma glucose levels in the fasting state and after an oral
glucose load, as well as blood glucose and plasma lactate levels during
the euglycemic clamp, were measured by the glucose oxidase
method (2300 Stat Plus, Yellow Springs Instrument Co, Inc). For the
determination of plasma insulin, blood was collected in EDTA-containing
tubes, and after centrifugation the plasma was stored
at -20°C until the analysis. Plasma insulin concentration
was determined by a commercial double-antibody, solid-phase
radioimmunoassay (Phadeseph Insulin RIA 100, Pharmacia
Diagnostics AB). Lipoprotein fractionation was performed by
ultracentrifugation and selective
precipitation29 as previously described.30
Cholesterol and triglyceride levels from whole
serum and lipoprotein fractions were assayed by automated enzymatic
methods (Boehringer-Mannheim). ApoB and apoA1 levels were
determined by a commercial immunoturbidimetric method (Kone
Instruments) and serum FFAs from fresh-frozen samples by an enzymatic
method (Wako Chemicals GmbH). Nonprotein urinary nitrogen was measured
by an automated Kjeldahl method.31
Statistical Analysis
All calculations were done with the SPSS/Win programs (version
7.5, SPSS Inc). The differences in insulin sensitivity among the 3
study groups were tested by ANCOVA, with age, sex, and body mass index
(BMI) as covariates. If the difference was statistically significant
(P<0.05), pairwise comparisons between the study groups
were done with ANCOVA, adjusting for confounding factors. Correlations
between the variables were determined as Pearson correlations with
2-sided tests. VLDL cholesterol, total
triglycerides, all subfractions of
triglycerides, insulin, and FFA levels were logarithmically
transformed to obtain normal distributions before statistical
analyses. Probability value <0.05 were considered
statistically significant. All data are presented as
mean±SD.
| Results |
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FFA Levels and Rates of Glucose Oxidation and Glucose Nonoxidation
During the Hyperinsulinemic, Euglycemic Clamp
Glucose and insulin infusions during the clamp resulted in similar
levels of glucose (5.0±0.1 [mean±SD] in control subjects, 5.0±0.1
in relatives without dyslipidemia, 5.0±0.1 in patients
with hypercholesterolemia, 5.0±0.1 in patients
with hypertriglyceridemia, and
5.0±0.2 mmol/L in patients with combined
hyperlipidemia), insulin (1073±215 versus 941±169
versus 990±185 versus 1008±201 versus 1004±190 pmol/L,
respectively), and lactate (1.15±0.27 versus 1.19±0.27 versus
1.17±0.25 versus 1.18±0.30 versus1.13±0.23 mmol/L) in the study
groups. During the clamp, all FCHL family members with or without
dyslipidemia had higher levels of FFAs (Table 2
and the
Figure
; P<0.001 after
adjustment for age, sex, and BMI) and the rates of lipid oxidation
(P<0.001) than did the controls. FFA levels and the rates
of lipid oxidation did not differ between subjects without
dyslipidemia and patients with
hypercholesterolemia, but patients with
hypertriglyceridemia (P<0.001)
and combined hyperlipidemia (P=0.027) had
even higher levels of FFAs than did the relatives without
dyslipidemia. The rates of insulin-stimulated WBGU were
lower in patients with hypertriglyceridemia
and combined hyperlipidemia than in control subjects
(P<0.001). No difference in the rates of WBGU were observed
between controls and relatives without dyslipidemia or
patients with hypercholesterolemia (Table 2
). The rates of insulin-stimulated glucose oxidation were lower
in relatives without dyslipidemia (P=0.001) and
patients with hypertriglyceridemia
(P<0.001) and combined hyperlipidemia
(P<0.001) compared with controls, whereas patients with
hypercholesterolemia did not differ from
controls (Table 2
and the Figure
). Similar to FFA levels,
patients with hypertriglyceridemia and
combined hyperlipidemia had even lower rates of glucose
oxidation than did relatives without dyslipidemia
(P<0.001 and P=0.022). The rates of nonoxidative
glucose disposal were lower in subjects with
hypertriglyceridemia (P=0.001)
and combined hyperlipidemia (P=0.011) than
in control subjects. No difference in the rates of glucose nonoxidation
was observed when relatives without dyslipidemia and
patients with hypercholesterolemia were
compared with controls (Table 2
and the Figure
).
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Correlations Between FFA Levels During the
Hyperinsulinemic Clamp and Serum Lipids and
Lipoproteins
Because FFA levels could serve as a link between insulin
resistance and dyslipidemias, their correlations with the
levels of serum lipids and lipoproteins were calculated in control
subjects, relatives without dyslipidemia, and FCHL patients
separately (Table 3
). FFA levels were
correlated positively with VLDL cholesterol in controls
(r=0.308, P=0.005; after controlling for age,
sex, and BMI) and positively with total triglyceride levels
in all study groups (r=0.261 to 0.338; P<0.01 in
all groups) but not with total, LDL, and HDL cholesterol
levels and apoB levels in any of the study groups.
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| Discussion |
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Originally, FCHL was suggested to be a dominantly inherited, monogenic disease,1 but polygenic inheritance is more likely.2 8 Segregation analyses have indicated a major locus for apoB32 33 ; small, dense LDL34 35 ; and triglyceride levels.36 However, so far only gene defects with a modifying, but not a major, effect on lipid and lipoprotein levels have been found in the lipoprotein lipase gene,37 38 in the intestinal fatty acidbinding protein 2 gene,39 and in the apoE gene.40 In addition, the apoAI-CIII-AIV gene complex has been implicated in the etiology of FCHL,41 42 but negative results have also been published.43 44 The locus in 1q21-q23 is a promising locus for FCHL9 because the identical locus has been linked with dyslipidemias in mice.45 However, it is doubtful that this locus could totally explain the etiology of FCHL, as linkage with hypercholesterolemia was not found in humans.9
Low rates of insulin-stimulated glucose uptake are typical for patients with FCHL.10 11 12 This is the first study to indicate that insulins action on glucose metabolism is selectively impaired only in hypertriglyceridemic FCHL patients. The latter result is in accordance with previous studies, which have demonstrated that total triglycerides, but not total cholesterol levels, are correlated with insulin sensitivity13 or fasting insulin levels14 in FCHL families. In contrast, FFA levels during hyperinsulinemia were poorly suppressed in all FCHL patients with varying dyslipidemias and not only in patients with high triglyceride levels. This defect seems to be specific for FCHL, because by utilizing an identical methodology and laboratory determinations, we have previously shown that the suppression of FFA levels during hyperinsulinemia is normal in familial and nonfamilial hypercholesterolemia,46 in nonfamilial combined hyperlipidemia,47 and in patients with isolated low HDL cholesterol levels without hypertriglyceridemia.48
Why are FFA levels poorly suppressed by insulin in patients with FCHL? FFAs are released into the plasma either by lipoprotein lipase from triglyceride-rich lipoproteins in adipocyte capillaries or from adipocyte triglyceride storage by hormone-sensitive lipase (HSL).49 On the other hand, FCHL is characterized by low7 or normal50 lipoprotein lipase activity and low HSL activity.50 Therefore, impaired uptake of FFAs into fat cells rather than increased lipolysis has been suggested to explain high serum FFA levels in FCHL.50 51 At least 3 mechanisms could explain the combination of low HSL activity and impaired uptake of FFAs into fat cells. First, although no linkage of the HSL gene with FCHL was found in the Finnish population,52 defects in the HSL gene are possible in this disorder. This hypothesis is supported by novel findings suggesting an association between a polymorphic marker in this gene and the metabolic syndrome53 and an association between a polymorphism in the promoter region of this gene and reporter gene activity in vitro.54 Second, low HSL activity could be secondary to impaired uptake of FFAs into fat cells by fatty acid transporter proteins.55 Third, low rates of triglyceride synthesis and consequent low uptake of FFAs from plasma could explain these findings.56
The defect in FFA suppression was partly dependent on the type of
dyslipidemia, because it was greater in FCHL patients with
high triglyceride levels
(hypertriglyceridemia or combined
hyperlipidemia) than in patients with pure
hypercholesterolemia. The difference is not
likely to be explained by obesity in patients with
hypertriglyceridemia, because the
difference was statistically significant after adjustment for BMI.
Higher FFA levels in patients with
hypertriglyceridemia may explain, at least
in part, the simultaneous occurrence of impaired glucose
oxidation via increased lipid oxidation and consequently, an increase
in intracellular acyl-CoA/CoA and NADH/NAD+
ratios, which inhibit pyruvate dehydrogenase, as suggested by Randle et
al.16 However, the rates of nonoxidative glucose
metabolism were also impaired in
hypertriglyceridemic FCHL patients. Because
80% of insulin-stimulated glucose uptake occurs in skeletal muscle,
this finding indicates a defect in skeletal muscle cells proximal to
the phosphorylation of glucose or separate defects in
both oxidative and nonoxidative glucose metabolism. A
defect in the translocation of glucose transporters to the plasma
membrane or in the phosphorylation of glucose could be
caused not only by defects in the insulin-signaling pathway (eg, by
defects in the genes coding for the insulin receptor substrates
phosphatidylinositol-3-kinase or hexokinase II) but also by an
increased supply of inhibitory mediators released from
adipose tissue, such as tumor necrosis factor-
57 or
FFAs.58 The possibility of 2 separate defects also cannot
be excluded: 1 in adipose tissue, causing impaired FFA suppression
during hyperinsulinemia, eg, by defects in the HSL
gene,50 leading to decreased rates of glucose oxidation in
skeletal muscle, and another in skeletal muscle due to impaired
insulin-stimulated glycogen synthesis.
Because we used a rather high cutoff point for total cholesterol (7.70 mmol/L), one could ask whether family members with lower cholesterol values were truly unaffected. Therefore, we formed a new group of family members with cholesterol levels <6 mmol/L and triglyceride levels <2 mmol/L. These normolipidemic FCHL family members (n=21; 12 men, 9 women) also had higher levels of FFAs (0.12±0.08 versus 0.06±0.06 mmol/L; P=0.003 after adjustment for age, sex, and BMI) and lower levels of glucose oxidation (17.2±4.1 versus 19.4±4.7 µmol · kg-1 · min-1; P=0.041) than did the control subjects. Although there were proportionally more women in FCHL family members without FCHL than in controls, it is unlikely that this explains our findings, since we adjusted for sex. Therefore, we think that impaired FFA suppression and glucose oxidation during hyperinsulinemia are characteristic findings also in relatives at risk to develop FCHL, as proposed in our previous study.12
High apoB levels are characteristic of FCHL patients with different types of dyslipidemia.59 This finding could be explained by impaired insulin-mediated FFA suppression, since FFAs also stimulate apoB and VLDL production in the liver.60 61 However, in the present study, FFA levels during hyperinsulinemia did not correlate with fasting apoB levels in FCHL patients, suggesting that mechanisms other than insulin resistance are needed to explain the high apoB levels in FCHL. Because no difference was observed in the rates of insulin-stimulated WBGU between relatives without dyslipidemia and patients with hypercholesterolemia, mechanisms independent of insulin action are likely to determine high levels of VLDL and LDL cholesterol in FCHL patients. However, FFA levels may partly determine the lipid content of VLDL particles by stimulating triglyceride synthesis in the liver independently of apoB synthesis.17
Some of our FCHL family members were relatives, and therefore we analyzed our results by including family status as a covariate. This additional analysis did not change the results. We did not apply a family-based analysis (segregation or linkage studies) because direct measurement of insulin sensitivity with the hyperinsulinemic, euglycemic clamp technique is possible only in healthy adults and not in very old or very young people. Therefore, studies that apply indirect measurements of insulin sensitivity, such as fasting or postprandial insulin levels, in young and old people are needed to demonstrate whether a common locus determines insulin resistance and dyslipidemias in FCHL.
In conclusion, the impaired effect of insulin in adipose tissue to suppress FFA levels during hyperinsulinemia is likely to be 1 of the primary metabolic disorders in FCHL because it occurred in all of our FCHL patients. In addition, FCHL patients with hypertriglyceridemia have a separate defect in skeletal muscle glucose uptake. Identification of these defects in adipose tissue, in skeletal muscle, or in the mediators that regulate these target tissues is needed to fully explain varying phenotypes in FCHL.
| Acknowledgments |
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Received February 23, 1999; accepted June 28, 1999.
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