© 1997 American Heart Association, Inc.
Articles |
Defects of Insulin Action on Fatty Acid and Carbohydrate Metabolism in Familial Combined Hyperlipidemia
From the Molecular Medicine Group, MRC Clinical Sciences Centre and Department of Medicine, Hammersmith Hospital (T.J.A., B.F., J.S.); the Wynn Division of Metabolic Medicine (National Heart and Lung Institute, Imperial College) (I.F.G., D.C.); and the Department of Chemical Pathology, Queen Mary's University Hospital (H.J.W.), London, England.
Correspondence to Dr T.J. Aitman, Molecular Medicine Group, MRC Clinical Sciences Centre and Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Road, London W12 0NN, UK. E-mail taitman{at}rpms.ac.u
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Abstract |
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Abstract Familial combined hyperlipidemia (FCHL) is a common cause of premature myocardial infarction, but its metabolic basis is unknown. Insulin resistance has been suggested in some patients by the presence of fasting hyperinsulinemia. We studied insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control subjects by a two-step euglycemic, hyperinsulinemic clamp. During low-dose insulin infusion, steady-state nonesterified fatty acids (NEFAs) were higher in patients than in control subjects (0.36 mmol/L [95% confidence limits, 0.19, 0.53] versus 0.19 mmol/L [0.10, 0.28]; P=.05). The ratio of steady-state to basal NEFAs was increased by 88% in patients compared with control subjects (P=.005). During high-dose insulin infusion, insulin sensitivity for peripheral glucose disposal was reduced by 60% in FCHL patients compared with control subjects (P=.03). Hepatic glucose production at baseline and during the clamp was similar in the two groups. In multiple regression analysis, increased upper-body fat in the patient group accounted for the impairment of insulin-mediated glucose disposal but did not influence the defect in insulin-mediated NEFA suppression in the FCHL patients. This defect in fatty acid metabolism may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of this disorder.
Key Words: insulin resistance • nonesterified fatty acids • hyperlipoproteinemia • hormone-sensitive lipase • glucose clamp technique
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Introduction |
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Familial combined hyperlipidemia is the most common inherited hyperlipidemia and is found in up to 10% of cases of premature myocardial infarction.1 The condition is characterized by the presence of multiple lipoprotein phenotypes, including mixed hyperlipidemia, in families at high risk of coronary disease.1 2 3 FCHL was originally proposed to have autosomal dominant inheritance1 but is now believed to have a more complex mode of inheritance, with major gene effects influencing levels of circulating triglyceride and apo B.4 5
Although the existence of FCHL has been questioned, the disease appears to be biochemically coherent, with consistent features being mixed hyperlipidemia accompanied by increased circulating apo B and hepatic overproduction of VLDL apo B.3 6 Other metabolic abnormalities include decreased activity of LPL7 and the presence in plasma of small dense LDL particles.8 The cause of these metabolic disturbances is presently unknown.
Reports of fasting hyperinsulinemia in some FCHL patients suggest the presence of insulin resistance.9 10 This is not a consistent finding, however,11 and fasting insulin is, in any case, an imprecise index of insulin sensitivity. Evidence for a putative role for insulin resistance in FCHL comes from the observed regulatory functions of insulin on the metabolism of triglyceride-rich, apo B–containing lipoproteins.12 13 14 Because insulin resistance may be a primary defect contributing to lipid abnormalities in FCHL, in this study we formally tested the hypothesis that insulin action is defective in FCHL patients.
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Methods |
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Patients
FCHL patients (26 to 59 years old) were unrelated, nonobese white men with normal fasting glucose and normal resting ECG and without cardiac, renal, or hepatic failure. Patients with combined hyperlipidemia (total cholesterol >95th and triglycerides >90th age-related percentile) from FCHL families were selected for this study. Both hypercholesterolemia and hypertriglyceridemia (similarly defined) were present in one or more of the patients' first-degree relatives (Fig 1
), and each FCHL family contained individuals with more than one lipoprotein phenotype.3 Patients or relatives with secondary hyperlipidemia or tendon xanthomata were excluded. Individuals taking any drug known to affect lipid or carbohydrate metabolism were excluded, as were individuals with a personal history of diabetes or history of diabetes in a first-degree relative.
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Control subjects were white men who were relatives of patients with combined hyperlipidemia with normal lipids on screening (n=6), or healthy volunteers without a family history of hyperlipidemia or diabetes from our own departments (n=2). Of the control subjects who were related to FCHL patients, 1 was related to a patient from this study (Fig 1
, family 2, member II 6), 4 were members of previously reported FCHL pedigrees,4 and 1 was from a new pedigree identified in family studies during 1994. The choice of family control subjects was designed to minimize genetic and environmental differences between patients and control subjects, aside from differences that result in hyperlipidemia. Differences in insulin action between patients and control subjects are therefore more likely to be causally related to hyperlipidemia than if all control subjects had been unrelated or had had no family history of FCHL.
Physical activity was measured on a three-point scale from no regular exercise to >2 hours per week of vigorous activity. Study subjects gave informed written consent, and the study protocol was approved by the relevant local hospital ethical committees.
Euglycemic Clamp Protocol
Studies were commenced at 8:30 AM after a 12-hour fast. A two-step euglycemic hyperinsulinemic clamp was used, derived from previous protocols.15 16 Insulin was infused for 150 minutes at 5 mU·m-2·min-1 and subsequently at 40 mU·m-2·min-1 for a further 150 minutes. Arterialized blood samples were withdrawn every 5 minutes during insulin infusions, and blood glucose was clamped at 5 mmol/L by administration of 20% dextrose. For estimation of hepatic glucose output, a priming injection of [6,6-2H2]glucose tracer (160 mg) was given 60 minutes before the start of the low-dose insulin infusion, followed by a constant infusion of [6,6-2H2]glucose, 1.8 mg/min, for the duration of the study. Blood glucose was estimated with a Yellow Springs YS2000 analyzer.
Laboratory Assays
All assays were performed blind with regard to affection status. Plasma glucose and insulin and levels of cholesterol and triglyceride (total serum and plasma lipoprotein fractions) were measured as described.17 Apo B concentrations were measured by immunoturbidimetry (coefficient of variation, 4.0% to 6.5%).18 NEFAs were measured by enzymatic colorimetric assay (WAKO NEFA-C kit, Alpha Laboratories; coefficient of variation, 2.2% at 0.36 mmol/L). VLDL, IDL, and LDL were isolated from fresh plasma by density-gradient ultracentrifugation. LDL subtype distribution was assessed by gradient gel electrophoresis19 with a Pharmacia GE 2/4 LS cell to run plasma samples on precast 3% to 13% gels (Gradipore). After gels were stained with Sudan black B, they were scanned with a laser densitometer (Personal Densitometer, Molecular Dynamics). LDL particle size was assessed against a pooled serum standard containing particles of known size, which were kindly provided and calibrated by Professor R.M. Krauss, University of California, Berkeley. Apo E phenotypes were determined by isoelectric focusing. Isotopic glucose enrichment was determined by mass spectrometry with selected ion monitoring of a glucose acetate boronate derivative.
Body Fat Distribution Measurement
Body composition was measured by dual-energy x-ray absorptiometry scan with a whole-body scanner (DPX, Lunar Radiation Corp). Regional fat mass in subscapular, waist, and thigh regions was defined with reference to anatomic bone landmarks as described.20 Coefficients of variation for repeated measures in a single individual were <5% for total and regional fat masses.
Data Analysis
Insulin action on total-body glucose disposal was assessed as the mean glucose infusion rate per kilogram body weight during the final 30 minutes of the high-dose clamp (the M value) and as the increment in glucose disposal rate (see below) divided by the product of the plasma glucose and increment in plasma insulin (Siclamp=
Rd/G·I).21 Insulin action on NEFAs was assessed as the ratio of the mean steady-state NEFA concentration during the final 30 minutes of the low-dose clamp to the basal NEFA concentration. Mean plasma [6,6-2H2]glucose enrichment (measured in the MRC Nutrition Unit, St Mary's Hospital, London) was derived from four estimates made at 10-minute intervals during the final 30 minutes of the equilibration period and the final 30 minutes of the low- and high-dose insulin infusions. Net glucose appearance rate, which at steady state equals the glucose disposal rate, was calculated from mean enrichment data.22 HGP was calculated by subtracting the mean glucose infusion rate from the glucose appearance rate.
Parametric statistics were used in this study because of the quantitative nature of the variables measured. Variables were tested for deviation from normality by the Shapiro and Francia W test with the program STATA. Analyses of triglycerides, insulin, and insulin-derived variables used log-transformed values because of deviation from normality before but not after log transformation. All other variables showed no deviation from normality except for systolic blood pressure (nonnormal both before and after transformation) and IDL cholesterol (nonnormal before but not after transformation). Testing of these variables with parametric and nonparametric statistics yielded identical results, and it was therefore concluded that the use of parametric statistics was reasonable for all variables. Differences between cases and control subjects were assessed by Student's t test. To test for possible effects of age, BMI, and fat distribution on differences in outcome variables between patients and control subjects, multiple regression analysis was performed with STATA, with age, BMI, and upper-body fat as covariates in the regression equations.
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Results |
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Patient Characteristics
Patients and control subjects did not differ significantly in age, BMI, blood pressure, physical activity, or smoking status (Table 1
). Upper-body fat mass (subscapular and waist) was higher in patients than in control subjects (P=.02) despite similar lower-body (thigh) fat mass. FCHL patients had higher total cholesterol (mean, 7.23 mmol/L; range, 6.09 to 9.82 mmol/L), triglycerides (mean, 4.10 mmol/L; range, 1.97 to 6.83 mmol/L), and apo B levels (mean, 105 mg/dL; range, 83 to 138 mg/dL) than control subjects.
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Euglycemic Clamp
Fasting concentrations of glucose, insulin, and NEFAs were similar in patients and control subjects (Table 1). No differences were observed in mean plasma glucose levels during the final 30 minutes of the low-dose or the high-dose clamp (Fig 2). Insulin concentrations throughout the low- and high-dose insulin infusion were slightly higher in patients than in control subjects, but this was not statistically significant (Fig 2).
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) and control subjects (
). Values are mean±SEM.
Glucose disposal. Glucose infusion rates during the low-dose insulin infusion were similar in patients and control subjects (Fig 2). During the final 30 minutes of the high-dose clamp, glucose infusion rates required to maintain euglycemia were 30% lower in FCHL patients than in control subjects (Fig 2; P=.02). Insulin sensitivity for peripheral glucose disposal (Siclamp) in patients was reduced by 60% compared with control subjects (Fig 3A; P=.03).
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Serum NEFAs. Steady-state NEFA concentrations during the final 30 minutes of the low-dose clamp were markedly higher in patients than in control subjects (P=.05; Fig 2). The ratio of steady-state to basal NEFAs in patients was 88% higher than that seen in control subjects (Fig 3B; P=.005). NEFA levels were completely and similarly suppressed during the high-dose insulin infusion in both groups (Fig 2).
Hepatic glucose production. Basal HGP was similar in patients and control subjects (13.5 [95% confidence limits, 12.3, 14.7] versus 14.4 [12.7, 16.1] mg·kg-1·min-1). During the final 30 minutes of the low-dose clamp, HGP was similar in patients and control subjects (Fig 3C). Mean glucose production during the high-dose clamp was estimated to be negative in both groups, probably reflecting limitations of the fixed-rate infusion technique in situations in which there is relatively high glucose turnover. Such negative values have conventionally been taken to indicate complete suppression of HGP. No significant differences in HGP were observed between patients and control subjects during the high-dose clamp.
Characterization of Lipids and Lipoproteins
HDL cholesterol concentration was reduced (P=.03), but cholesterol concentration was increased in VLDL and IDL (P=.0006 and P=.002) in the patient group. LDL cholesterol was similar in patients and control subjects. Triglyceride concentration was increased in all lipoprotein fractions in patients compared with control subjects (P<.005; Table 2), whereas lipoprotein triglyceride to cholesterol ratios were raised in HDL and LDL but reduced in VLDL and IDL (Table 2). The compositional abnormality in LDL was reflected in patients by a reduced LDL particle diameter (24.6 [95% confidence limits, 23.5, 25.7] versus 27.1 [26.0, 28.2] nm; P=.003). Apo E alleles were similarly distributed in patients and control subjects, but one patient was homozygous for apo E2 (Family 7, member II 2; Fig 1).
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Multiple Regression Analysis
Adjustment for age, BMI, and upper-body fat did not affect the significance of the differences between patients and control subjects in the ratio of steady-state to basal NEFAs (Table 3). Age adjustment had no effect on differences in peripheral glucose disposal, but adjustment for BMI reduced the significance of this result, and the significance was lost after adjustment for upper-body fat.
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Discussion |
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FCHL is a common cause of CHD, but the underlying pathogenesis is as yet unknown. In this study, we have investigated the basis of metabolic abnormalities seen in FCHL. Using a two-step euglycemic hyperinsulinemic clamp, we have demonstrated impaired insulin-mediated glucose uptake in peripheral tissues and impaired insulin-mediated suppression of serum NEFAs in FCHL patients compared with normolipidemic control subjects. Upper-body fat (subscapular and waist) was increased in patients compared with control subjects despite similar lower-body (thigh) fat. The impairment in insulin-mediated glucose disposal in FCHL cases was found in regression analysis to be dependent on increased upper-body fat, whereas impaired NEFA suppression was independent of BMI and fat distribution. These findings suggest that a defect in insulin-mediated NEFA suppression in patients with FCHL may play a primary part in the development of metabolic abnormalities in this disorder. Such a defect is likely to be localized in the adipocyte, because blood NEFA concentrations are determined primarily by the balance in adipocytes between the activity of hormone-sensitive lipase and the rate of triglyceride reesterification.23 24
Our finding of impaired insulin-mediated suppression of serum NEFA concentrations is consistent with the previous demonstration of elevated fasting and postprandial NEFAs in hypertriglyceridemic FCHL patients10 and with the hypothesis, based on epidemiological data, that reduced insulin-mediated NEFA suppression drives hepatic overproduction of triglycerides and apo B.25 Since it has been suggested that insulin resistance is associated with type IIb or type IV but not type IIa hyperlipidemia,26 the role of insulin resistance in FCHL subjects with high cholesterol in the absence of raised triglycerides remains to be determined.
Increased hepatic availability of NEFAs stimulates VLDL apo B and triglyceride production.12 27 28 A defect in insulin action at the level of the adipocyte could therefore result directly in elevated serum NEFAs, increased hepatic production of VLDL, and increased serum apo B, triglycerides, and cholesterol, as seen in FCHL. Although significantly raised NEFA levels were detected in our study only during physiological hyperinsulinemia, previous data have shown that NEFAs are elevated in FCHL patients for up to 14 hours postprandially.10 In addition, although the differences were not statistically significant, both our study and that of Castro Cabezas et al10 showed higher fasting NEFAs in FCHL patients. Plasma NEFAs may therefore be expected to be raised for much of the day in FCHL and could easily contribute to an aggregate increase in VLDL production in this disorder.
This interpretation is of interest in the light of other studies suggesting defects in catecholamine-mediated adipocyte lipolysis11 or in adipocyte triglyceride synthesis29 in FCHL patients. Defective insulin action in adipocytes could also lead to reduced LPL activity, as described in some FCHL patients,7 because insulin stimulates expression and activity of adipocyte LPL.13 14 In this regard, it is of note that mutations in the LPL gene are rare in this condition.30 31
Insulin resistance in FCHL has been previously suggested by the presence in some studies of fasting hyperinsulinemia in FCHL patients.9 10 11 Using the hyperinsulinemic clamp to measure insulin action directly, we demonstrated reduced insulin-mediated peripheral glucose disposal in our FCHL patients. In multivariate analysis, this characteristic was shown to be strongly dependent on accumulation of upper-body fat, consistent with the recognized association between upper-body obesity and insulin resistance.32
Because increased upper-body fat has been observed previously in FCHL,11 this may be an important feature of the disorder that contributes to the development of metabolic abnormalities. In this respect, it is noteworthy that both central obesity and the FCHL phenotype have a late age of onset, around the third decade.3 However, further studies are needed to confirm that upper-body fat accumulation is a consistent feature in FCHL.
Our finding of reduced LDL particle size in FCHL patients is in agreement with previous reports of small dense LDL in FCHL5 33 and in healthy volunteers with insulin resistance.34 The triglyceride concentration was increased in all lipoprotein fractions in our patients, and the cholesterol concentration was increased in VLDL and IDL. These changes are consistent with previously reported values in FCHL patients35 and similar to those in heterozygous LPL deficiency36 and other insulin-resistant states.34 37 The raised triglyceride-to-cholesterol ratios in LDL are consistent with the data of Hokanson et al,33 who showed that LDL particles in FCHL patients are depleted in cholesterol, cholesteryl ester, and phospholipid compared with control subjects. The low triglyceride-to-cholesterol ratios in VLDL and IDL suggest that they may be triglyceride-poor, reflecting their close metabolic link and the small particle size of VLDL in FCHL.35
Physical activity, smoking status, and apo E genotype may all affect insulin sensitivity, and our patients and control subjects were well matched for these variables. Since FCHL is an oligo/polygenic disorder, the sharing of genetic background between patients and control subjects, including possibly nonpenetrant genes for FCHL, is an important design feature of this type of study. The demonstration of differences in insulin action, even when most control subjects were from FCHL families, supports the view that shared genetic influences contribute to both impaired insulin action and hyperlipidemia in these FCHL patients. One patient was homozygous for the apo E2 allele, but his lipid levels were comparable to those of the patient group (total cholesterol, 9.82 mmol/L; triglycerides, 6.83 mmol/L; apo B, 83 mg/dL), and he had no clinical stigmata of type III hyperlipidemia. Although this individual had a broad ß-band, this does not exclude the diagnosis of FCHL, because additional metabolic and genetic influences besides the apo E gene are required to produce hyperlipidemia in apo E2 homozygotes, and concomitant diagnosis of FCHL and type III hyperlipidemia is well recognized.38
Segregation studies have demonstrated the influence of major genes in FCHL acting on triglyceride levels, apo B levels, and LDL subclass.4 5 8 Genetic linkage has been shown between FCHL and the apo A-I/C-III/A-IV locus on chromosome 11q,39 although this was not confirmed in a subsequent study.40 An association between polymorphisms of the same gene cluster and hypertriglyceridemia, however, has been shown in a number of studies.10 41 42 43 Genetic linkage has also been shown between the small dense LDL phenotype and the LDL receptor locus on chromosome 19.44
The present study raises the possibility that the polymorphisms or mutations underlying these associations may combine with genetic defects in insulin action to produce the hyperlipidemia phenotype seen in FCHL. For example, the apo C-III promoter contains a negative insulin response element.45 Polymorphisms in the insulin response element that are normally silent may, in the presence of defective insulin action or signaling, result in constitutive expression of apo C-III and increased plasma VLDL triglyceride through recognized effects of apo C-III on VLDL catabolism and synthesis.46 Alternatively, defective inhibitory influences by insulin on genes on separate chromosomes could contribute to hyperlipidemia, such as the known effects of insulin on the transcription of the microsomal triglyceride transfer protein gene,47 or secretion of apo B.48 Both of these gene products are essential for VLDL assembly and could potentially contribute to VLDL overproduction. Defects in insulin action may therefore be useful as intermediate phenotypes in further genetic studies of FCHL.
In summary, we have demonstrated impaired insulin action in FCHL patients, both on the suppression of serum NEFAs and on stimulation of glucose disposal. Impaired insulin-mediated glucose disposal appeared to be secondary to increased accumulation of upper-body fat, which may be an important and possibly consistent feature of FCHL. Impaired insulin-mediated NEFA suppression was independent of the increase in upper-body fat and may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of FCHL and may be relevant to the development of new treatment strategies for this disorder.
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Acknowledgments |
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We acknowledge financial support from the British Heart Foundation (grant PG/94016). Dr Aitman was supported by the Medical Research Council and Drs Godsland and Crook by the Cecil Rosen Foundation and Heart Disease and Diabetes Research Trust. We thank Mandeep Sidhu, Saro Niththyananthan, and Hazel Truman for technical support, Caroline Doré for statistical advice, and Drs Gil Thompson, Carol Shoulders, Jaspal Kooner, and Professor Chris Packard for constructive criticism of the manuscript.
Received February 6, 1996; accepted September 6, 1996.
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