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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 3903-3906
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Fasting Remnant Lipoprotein Cholesterol and Triglyceride Concentrations Are Elevated in Nondiabetic, Insulin-Resistant, Female Volunteers1

Fahim Abbasi, Tracey McLaughlin, Cindy Lamendola, Helen Yeni-Komshian, Akira Tanaka, Tao Wang, Katsuyuki Nakajima and Gerald M. Reaven

Stanford University School of Medicine, Stanford, California 94305; Tokyo Medical Dental University, Tokyo 113-8519, Japan; and Otsuka America Pharmaceutical, Inc., Rockville, Maryland 20850

Address all correspondence and requests for reprints to: G. M. Reaven, M.D., 213 East Grand Avenue, South San Francisco, California 94080. E-mail: greaven{at}shaman.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
This study was initiated to test the hypothesis that plasma concentrations of remnant lipoproteins would be higher after an overnight fast in insulin-resistant compared to insulin-sensitive volunteers. Forty-three healthy nonobese women were studied, divided into insulin-resistant (n = 21) and insulin-sensitive (n = 22) groups on the basis of their steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide acetate, insulin, and glucose. Under these conditions, steady state plasma insulin concentrations are similar in all subjects (~60 µU/mL), and the higher the SSPG concentrations, the more insulin resistant the individual. By selection, mean (±SEM) SSPG concentrations were significantly higher (P < 0.001) in the insulin-resistant group (210 ± 7 vs. 78 ± 3 mg/dL). In addition, the insulin-resistant group had higher triglycerides (198 ± 27 vs. 101 ± 12 mg/dL; P < 0.005) and lower high density lipoprotein cholesterol (48 ± 4 vs. 60 ± 4 mg/dL; P < 0.05) concentrations. Finally, insulin resistance was associated with higher remnant lipoprotein particle concentrations of cholesterol (7.2 ± 0.8 vs. 4.4 ± 0.3; P < 0.005) and triglycerides (22.2 ± 3.4 vs. 8.5 ± 1.0; P < 0.001). All of these differences were seen despite the fact that the two groups were similar in terms of age and body mass index. These results identify additional abnormalities in lipoprotein metabolism that may contribute to the increased risk of coronary heart disease seen in insulin-resistant, nondiabetic subjects (syndrome X).


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE IMPORTANCE of remnant lipoproteins as a risk factor for coronary heart disease (CHD) was first emphasized by Zilversmit (1), who suggested that atherogenesis was a postprandial phenomenon. More recently, several reports have concluded that CHD was significantly related to the degree of postprandial lipemia (2, 3, 4, 5). Our research group has been interested in the possibility that the increased risk of CHD associated with enhancement of postprandial lipemia might be related to a defect in insulin-mediated glucose disposal. In this context, we have shown that the postprandial accumulation of triglyceride (TG)-rich lipoproteins of endogenous and exogenous origins was significantly related to degree of insulin resistance and/or hyperinsulinemia in patients with type 2 diabetes (6), postmenopausal women (7), and healthy volunteers (8).

Our ability to evaluate the atherogenic potential of TG-rich lipoproteins has increased with the introduction of an assay method for quantifying apolipoprotein E (apoE)-rich lipoproteins (density, <1.006 g/mL) using an immunoaffinity gel mixture of anti apoB-100 and apoA-1 antibodies coupled to Sepharose (9, 10). Characterization of the unbound lipoproteins isolated in this manner indicated that they represent chylomicron and very low density lipoprotein remnants, collectively called remnant lipoprotein particles (RLP). Using this technique, evidence has recently been published (11) showing that RLP cholesterol (C) and RLP-TG concentrations were significantly higher after an overnight fast in subjects with type 2 diabetes and impaired glucose tolerance (IGT) than in subjects with either normal glucose tolerance or impaired fasting plasma glucose as defined by the American Diabetes Association (12). As patients with impaired fasting plasma glucose and IGT are relatively similar in terms of insulin resistance and hyperinsulinemia (13), the results of this recent study suggested that the increases in RLP-C and RLP-TG were more a function of increases in the degree of glycemia than either insulin resistance or hyperinsulinemia.

Given the great possibility that plasma concentrations of RLPs are important risk factors for CHD, we believed it important to further evaluate the impact of differences in insulin resistance, plasma glucose concentration, and plasma insulin concentration on the fasting plasma concentration of RLP-C and RLP-TG. For this purpose, we have compared the concentrations of these two variables in healthy, normal glucose-tolerant volunteers, defined as being either insulin resistant or sensitive, but matched for all other relevant variables.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Forty-three healthy, nondiabetic, women were selected for this study. They were recruited from a larger group who responded to a newspaper advertisement indicating our interest in studying the relationship between insulin resistance and risk factors for CHD. To enter the study, women had to be in good general health, with a body mass index between 19–30 kg/m2, a normal medical history and physical examination, normal values on a routine hematological survey and chemical screening battery, and normal glucose tolerance on the basis of at least two fasting plasma glucose concentrations less than 110 mg/dL (12). The population was subdivided into two groups, insulin sensitive and insulin resistant, on the basis of the results of their insulin suppression tests as described below.

Patients were admitted to the General Clinical Research Center of Stanford Medical Center after informed consent had been obtained. Insulin-mediated glucose disposal was evaluated by a modification (14) of the insulin suppression test as initially described by our laboratory (15, 16). Briefly, an iv catheter was placed in each of the patients’ arms. Blood was sampled from 1 arm for measurement of plasma glucose and insulin concentrations, and the contralateral arm was used for administration of test substances. Sandostatin (octreotide acetate) was administered at the rate of 0.27 µg/m2·min to suppress endogenous insulin secretion. Simultaneously, insulin and glucose were infused at rates of 32 mU/m2·min and 267 mg/m2·min, respectively. Blood was sampled every 30 min until 150 min into the study and then every 10 min until 180 min had elapsed. The four values obtained from 150–180 min were averaged and considered to represent the steady state plasma glucose (SSPG) and insulin concentrations achieved during the infusion. Because steady state plasma insulin concentrations are comparable in all individuals, SSPG concentrations provide a direct estimate of insulin-mediated glucose disposal in each individual: the lower the SSPG, the more insulin sensitive the individual. Volunteers with SSPG concentration values below 100 mg/dL were called insulin sensitive, and those with SSPG values above 160 mg/dL were insulin resistant. This somewhat arbitrary cut-off value was chosen based on unpublished data showing that one third of about 400 healthy volunteers will have an SSPG concentration greater than 160 mg/dL. Volunteers with SSPG concentrations between 100–160 mg/dL were excluded from further study. In this manner we were able to compare 2 groups dichotomous for insulin resistance.

Plasma was separated from blood samples obtained after an overnight fast the morning of the insulin suppression test, immediately frozen, and maintained at -70° until all the samples could be measured in one assay. Concentrations of TG, C, and high density lipoprotein (HDL)-C were determined as described previously (6, 7, 8). Chylomicron and VLDL remnant lipoprotein particles were isolated by an immunoseparation method (9, 10), using monoclonal antibodies to apoA-1 and apoB-100 that recognize TG-rich lipoproteins containing apoB-48 and a population of apoB-100 enriched in apoE. Briefly, plasma is added to an immunoaffinity gel suspension containing the two monoclonal antibodies, and the reaction mixture was shaken for 60 min at room temperature, then left to stand for 10 min. Aliquots of the supernatant were then taken for the measurement of RLP-C and RLP-TG concentrations.

Results are expressed as the mean ± SEM. Statistical analyses were conducted using Systat 7.0 package for Windows (Systat, Evanston, IL). Means of two groups were compared with Student’s nonpaired t test, and Kruskal-Wallis test. A logistic regression analysis was performed to evaluate the relationship between insulin resistance (SSPG), and RLP-TG and RLP-C concentrations. Insulin-resistant and -sensitive groups were dummy-coded and used as the dependent variable. Fasting TG, HDL-C, RLP-TG, and RLP-C were entered into the regression model as independent variables.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The baseline characteristics of the insulin-sensitive and -resistant groups are given in Table 1Go. By selection, the mean SSPG concentration in the insulin-resistant group was approximately 3 times higher than that in the insulin-sensitive group. In addition, the mean fasting insulin concentration was higher in the insulin-resistant individuals. However, the two groups were identical in terms of age, body mass index, and fasting glucose concentration.


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  		Table 1. Baseline characteristics of the insulin-sensitive and resistant groups

 
Figure 1Go compares the plasma TG, C, and HDL-C concentrations of the two groups. These data again demonstrate that insulin-resistant individuals have higher plasma TG and lower HDL-C concentrations than insulin-sensitive subjects (17).



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  		Figure 1. Plasma TG, cholesterol, and HDL-C in the insulin-sensitive ({blacksquare}) and insulin-resistant () groups.

 
Values for concentrations of RLP-C and RLP-TG in the two groups are shown in Fig. 2Go. These results show that the insulin-resistant group had significantly higher concentrations of both RLP-C (P < 0.005) and RLP-TG (P < 0.001) compared to the insulin-sensitive individuals.



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  		Figure 2. Plasma RLP, cholesterol (C), and TG in the insulin-sensitive ({blacksquare}) and insulin-resistant () groups.

 
A logistic regression analysis was performed to evaluate the relationship between insulin resistance and RLP-TG and RLP-C concentrations, adjusting for TG and HDL-C concentrations. Insulin-resistant and -sensitive groups were used as the dependent variable, and fasting TG, HDL-C, RLP-TG, and RLP-C concentrations were used as dependent variables. We first entered both TG and HDL-C into the model, and the results in Table 1Go, panel 1, showed that TG significantly predicted insulin resistance (P = 0.02), whereas HDL-C concentration was significant at the level of 0.12. The {chi}2 value for the model was 14.3 (P = 0.0008). We then added RLP-TG to TG and HDL-C (panel 2), and it was seen that RLP-TG predicted insulin resistance independent of TG and HDL-C (P = 0.05). The {chi}2 value for the model with the three variables together was 19.4 (P = 0.0002). When RLP-TG was replaced with RLP-C in the same model (panel 3), none of the three variables had P < 0.05. However, the {chi}2 value for this model was 17.3 (P = 0.0006). The P values for all three variables were borderline small, and RLP-C was the most significant (P = 0.12) variable.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study demonstrate that RLP concentrations (measured as RLP-C and RLP-TG) are significantly higher in insulin-resistant, healthy volunteers. All of the women studied were considered to be normal glucose tolerant on the basis of a fasting plasma glucose concentration less than 110 mg/dL, and the mean fasting plasma glucose concentration of the insulin-sensitive and insulin-resistant groups were essentially identical. However, the two groups were dichotomous with regard to their degree of insulin resistance; the SSPG values were almost 3 times higher in the insulin-resistant group, and there was no overlap between the two groups. As the population was discontinuous with regard to their degree of insulin resistance, we cannot anticipate at what degree of insulin resistance RLP concentrations will begin to increase.

Our results are quite different from the findings of Watanabe et al. (11), in that an increase in RLP-C and RLP-TG concentrations was not dependent upon the presence of states of abnormal glucose tolerance. However, the conclusion that increases in RLP-C and RLP-TG are not a simple function of elevated plasma glucose concentrations is also implicit in the report by Watanabe and associates (11). They reported essentially identical values for the two variables in patients with IGT and type 2 diabetes despite the fact that the glycosylated hemoglobin concentration was 1.7% higher in those with type 2 diabetes. Their report contains further evidence that hyperglycemia per se is unlikely to be an important modular of remnant lipoproteins, in that the hemoglobin A1c concentrations were quite similar in the normal and IGT groups (4.8% vs. 5.0%), yet those with IGT had significantly higher concentrations of RLP-C and RLP-TG.

Based upon our results as well as those of Watanabe et al. (11), it seems most likely that insulin resistance and/or hypertriglyceridemia are the major determinants of whether there will be an increase in the concentrations of plasma remnant lipoproteins after an overnight fast. This conclusion is based upon the following considerations: 1) insulin resistance is characteristic of patients with IGT and type 2 diabetes (16, 17, 18, 19) and was the selection criterion for the group in our study with the high RLP-C and RLP-TG concentrations; 2) plasma TG concentrations were increased in those groups with elevated concentrations of remnant lipoproteins in both studies; 3) RLP-C and RLP-TG concentrations can be elevated in the absence of increases in plasma glucose concentration; and 4) plasma insulin concentrations are elevated in insulin-resistant, nondiabetic volunteers (20, 21), and individuals with IGT (22), but not in patients with type 2 diabetes (23, 24).

The suggestion that insulin resistance is the major determinant of increases in plasma concentrations of remnant lipoproteins is consistent with a recent study of ours (7) documenting a highly significant relationship between insulin resistance and magnitude of postprandial lipemia. More specifically, we were able to demonstrate in 37 healthy, nondiabetic volunteers the presence of highly significant correlations between the magnitude of insulin resistance and the postprandial lipemic response to meals, whether assessed by the plasma concentration of all TG-rich lipoproteins or only those of intestinal origin. Furthermore, by ultracentrifugation analysis, it was apparent that this relationship involved VLDL, chylomicrons, and their remnants. Although the experimental protocol and the method of quantifying remnant lipoprotein particles were different in the current study and our previous publication (7), the results of both support the idea that the accumulation of remnant lipoproteins in plasma is closely associated with insulin resistance. Furthermore, the results of the logistic regression analysis shown in Table 2Go demonstrated that the relationship between insulin resistance and RLP-TG was independent of plasma TG and HDL-C concentrations. The relationship between SSPG and RLP-C was less powerful, consistent with the view that insulin resistance affects the catabolism of the TG in the RLP.


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  		Table 2. Logistive regression analysis of the relationship between insulin resistance (SSPG) and TG, HDL cholesterol, RLP-TG, and RLP-C concentrations

 
Before discussing the clinical significance of these results, it seems reasonable to briefly address the method we used to quantify remnant lipoproteins. As initially described by Campos et al. (9), and further defined by Nakajima et al. (10), a monoclonal antibody to apoB-100 is used to separate a population of TG-rich lipoproteins from plasma. The antibody does not recognize an apoE rich population of VLDL containing both apoA-100 and apoB-48. When combined with an anti-apoA-1 antibody, it was possible to isolate a preparation that appeared to consist of chylomicron and VLDL remnants, containing more molecules of apoE and cholesteryl ester per particle compared to the TG-rich lipoproteins that were recognized by the antibodies.

The availability of a technique that permits measurement of remnant lipoproteins provides another approach to assessing the importance of TG-rich lipoproteins as risk factors for CHD. It is a story that began approximately 40 yr ago with the publication by Albrink and Man of the association between CHD and hypertriglyceridemia (25). Although multiple publications have documented the presence of a univariate relationship between high plasma TG concentrations and CHD, the importance of hypertriglyceridemia as a CHD risk factor has been discounted on the basis of the difficulty of defining an independent relationship between hypertriglyceridemia and CHD with the use of multiple variate analysis (26). The appropriateness of this approach has been questioned by Austin (26), who also recently pointed out that an independent relationship between CHD and hypertriglyceridemia can be discerned (27).

More recently, attention has shifted from the idea that an increase in the plasma TG concentration is the cause of CHD to the view that it is only a surrogate marker. In this context, there is evidence that subjects with an increase in fasting plasma TG concentrations have smaller and denser LDL particles (28) and an enhanced degree of postprandial lipemia (29). Both of these changes have also been identified as CHD risk factors (2, 3, 4, 5, 28) and offer alternative explanations to account for the association of hypertriglyceridemia and CHD. Finally, attention has recently focused on the possibility that chylomicron and VLDL remnants are the atherogenic lipoproteins in patients with hypertriglyceridemia (10, 30).

In conclusion, results have been presented demonstrating that RLP-C and RLP-TG concentrations are increased in insulin-resistant individuals with normal glucose tolerance. These data permit us to add this abnormality of lipoprotein metabolism to the previously documented relationship between insulin resistance and 1) fasting hypertriglyceridemia (31), 2) lower HDL-C concentrations (17), 3) smaller and denser LDL particles (32), and 4) an accentuated degree of postprandial lipemia (7). All of these changes have been identified as risk factors for CHD (2, 3, 4, 5, 25, 26, 27, 28, 30, 33, 34). Although the details of the relationships between these various forms of dyslipidemia and insulin resistance remain to be understood, their existence strongly supports the view that a defect in insulin-mediated glucose disposal plays a major role in increasing risk of CHD.


   Footnotes
 
1 This work was supported by Research Grants HL-08506 and RR-00070 from the NIH. Back

Received April 8, 1999.

Revised June 14, 1999.

Accepted July 2, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  2. Simpson HS, Williamson CM, Olivecrona T, et al. 1990 Postprandial lipemia, fenofibrate and coronary artery disease. Atherosclerosis. 85:193–202.[CrossRef][Medline]
  3. Groot PH, van Stiphout WA, Krauss XH, et al. 1991 Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease. Arterioscler Thromb. 11:653–662.[Abstract/Free Full Text]
  4. Patsch JR, Miesenbock G, Hopferwieser T, et al. 1992 Relation of triglyceride metabolism and coronary artery disease studies in the postprandial state. Arterioscler Thromb. 12:1336–1345.[Abstract/Free Full Text]
  5. Karpe F, Bard JM, Steiner G, Carlson LA, Fruchart JC, Hamsten A. 1993 HDLs, and alimentary lipemia: studies in men with previous myocardial infarction at young age. Arterioscler Thromb. 13:11–22.[Abstract/Free Full Text]
  6. Chen Y-DI, Swami S, Skowronski R, Coulston A, Reaven GM. 1993 Differences in postprandial lipemia between patients with normal glucose tolerance and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 76:347–351.[Abstract]
  7. Jeppesen J, Hollenbeck CB, Zhou M-Y, Coulston AM, Jones C, Chen Y-DI, Reaven GM. 1995 Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia. Arterioscler Thromb Vasc Biol. 15:320–324.[Abstract/Free Full Text]
  8. Jeppesen J, Schaaf P, Jones C, Zhou M-Y, Chen Y-DI, Reaven GM. 1997 Effects of low-fat, high-carbohydrate diets on risk factors for ischemic heart disease in postmenopausal women. Am J Clin Nutr. 65:1027–1033.[Abstract/Free Full Text]
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