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Introduction

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

In 2001, the National Cholesterol Education Program Adult Treatment Panel III guidelines defined a cluster of metabolic factors that increase the risk for atherosclerotic cardiovascular disease (ASCVD)1 (1). They called this cluster the “metabolic syndrome” and defined afflicted individuals by the presence of three of the following five characteristics: central obesity, hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, hypertension, and either impaired fasting glucose or type 2 diabetes (Table 1). An analysis of data from 8814 men and women in the Third National Health and Nutrition Examination Survey (1988 to 1994) that used the Adult Treatment Panel III definition of the metabolic syndrome indicates that the age-adjusted prevalence of the syndrome was 23.7% in the U.S. population ≥20 years of age (2). A recent update of National Health and Nutrition Examination Survey data (3) indicates increases in the prevalence of the metabolic syndrome in all age and both sex groups.

Table 1. . Clinical identification of the metabolic syndrome
Risk factorDefining level
  • Data from the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (1). TG, triglycerides; HDL, high-density lipoproteins.

  • *

    Some men have multiple metabolic risk factors when waist circumference is only marginally increased (e.g., 94 to 102 cm or 37 to 40 in). Such patients may have a strong genetic contribution to insulin resistance and should benefit from changes in life habits in a manner similar to men with a categorical increase in waist circumference.

Abdominal obesity— waist circumference 
 Men*>102 cm (>40 in)
 Women>88 cm (>35 in)
TG≥150 mg/dL
HDL-cholesterol 
 Men<40 mg/dL
 Women<50 mg/dL
Blood pressure≥130/≥85 mm Hg
Fasting glucose≥110 mg/dL

Although Reaven (4) popularized the concept of the clustering of insulin resistance, a dyslipidemia characterized by hypertriglyceridemia, low HDL-cholesterol, and hypertension, in his Banting Lecture of 1988, the initial observations of associations between components of the metabolic syndrome were published much earlier by Vague (5), Albrink and Meigs (6), and Reaven et al. (7). Furthermore, the World Health Organization defined a slightly different version of the metabolic syndrome in 1998 (8). However, the formal presentation of the metabolic syndrome by the Adult Treatment Panel III panel has made the metabolic syndrome into a major topic for medical discussion.

Metabolic Syndrome: Link to Atherosclerosis

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

The contribution of the metabolic syndrome to atherosclerotic disease can be illustrated, at least in part, by the more extensively examined relationship of diabetes to atherosclerotic disease. Atherosclerosis accounts for ∼80% of all diabetic mortality (9), with 75% attributed to coronary atherosclerosis and 25% to cerebral or peripheral vascular disease. Atherosclerosis also accounts for >75% of all hospitalizations for diabetic complications. It has been estimated that >50% of patients with newly diagnosed type 2 diabetes have coronary heart disease (CHD). Among 350, 977 non-diabetic and 5245 diabetic subjects screened for enrollment in the Multiple Risk Factor Intervention Trial (10), the risk of ASCVD mortality in both groups increased with an increasing number of classical risk factors, but ASCVD mortality was significantly increased in the diabetics at all levels of risk. In a study by Haffner et al. (11), the 7-year incidence rates of myocardial infarction (MI) among 1373 patients without diabetes were 3.5% in those without prior MI and 18.8% in those with prior MI. Among the 1059 diabetic patients, the MI rate in those without prior MI was 20.2% (comparable with that in non-diabetic patients with prior MI), whereas the rate was 45% in patients with prior MI. Data such as these led the Adult Treatment Panel III to designate diabetes as a CHD equivalent.

Although ∼80% to 90% of individuals with type 2 diabetes meet the criteria of the metabolic syndrome, it is important to look carefully at the risk for ASCVD in the group with metabolic syndrome but without diabetes. Epidemiological data indicate that impaired glucose tolerance increases risk for ASCVD mortality. In the 10-year Paris Prospective Study follow-up of >7000 men (12), CHD mortality rates were significantly increased by ∼2-fold in subjects with impaired glucose tolerance or with diabetes newly diagnosed on the basis of glucose tolerance testing. In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe study group analysis (13) of data from 10 European studies involving more than 22, 000 participants (15, 388 men and 7126 women) followed for a median of 8.8 years, impaired glucose tolerance was associated with multivariate-adjusted hazard ratios of 1.28 (95% CI, 1.02 to 1.59) for CHD death, 1.34 (95% CI, 1.14 to 1.57) for cardiovascular death, and 1.40 (95% CI, 1.27 to 1.54) for all-cause mortality. In an analysis of 3174 subjects in the U.S. Second National Health and Nutrition Examination Survey Mortality Study who underwent oral glucose tolerance testing and were followed from 1976–1980 through 1992 (14), impaired glucose tolerance was associated with multivariate-adjusted relative risks of 1.42 (95% CI, 1.08 to 1.87) for all-cause mortality and 1.15 (95% CI, 0.81 to 1.62) for cardiovascular mortality. All of these studies, however, predated the Adult Treatment Panel III publication defining the metabolic syndrome.

A number of recent studies have used the definition of the metabolic syndrome by either Adult Treatment Panel III or the World Health Organization to determine the impact of this syndrome on ASCVD or CHD. Isomaa et al. (15) assessed cardiovascular morbidity and mortality associated with the World Health Organization metabolic syndrome (defined as having type 2 diabetes or impaired fasting glucose/impaired glucose tolerance or insulin resistance and at least two other phenotypic characteristics, including obesity, hypertension, dyslipidemia, and microalbuminuria). During 6.9 years of follow-up, the investigators assessed cardiovascular mortality in 3606 men and women in the Botnia study who had insulin resistance with normal glucose tolerance, impaired fasting glucose/impaired glucose tolerance, or type 2 diabetes. The metabolic syndrome was seen in 10% of women and 15% of men with normal glucose tolerance; in 42% and 64% of women and men, respectively, with impaired fasting glucose/impaired glucose tolerance; and in 78% of women and 84% of men with type 2 diabetes. In patients with the metabolic syndrome, relative risk of CHD was 2.96 (95% CI, 2.36 to 3.72), and cardiovascular mortality was significantly increased to 12% compared with 2.2% in subjects without the metabolic syndrome. However, these investigators did not adjust for the components of the metabolic syndrome, although most of them were also predictors of increased morbidity and mortality. Several studies followed that, in some cases, supported the study by Isomaa et al. (16, 17, 18), but in others did not show that the definition of the metabolic syndrome added significantly to the usual predictors of cardiovascular events (18, 19, 20). Furthermore, even the studies showing an “independent” predictive power for the term metabolic syndrome showed only modest relative risks after adjustment for traditional risk factors. Importantly, none of these studies analyzed the risk associated with the metabolic syndrome after adjusting for the components; that would not really be a legitimate analysis, but the inability to separate the “syndrome” from its components analytically shows the difficulties inherent in conducting these studies.

One conclusion that can be drawn from the studies described above is that the increase in risk of ASCVD and CHD observed in patients with the metabolic syndrome may not be greater than that associated with the components of the syndrome. On the other hand, insulin resistance may be a risk factor itself or may impart additional risk through its effects on the components. In the latter instance, each of the traditional risk factors could be more atherogenic because they are driven by insulin resistance and have, therefore, a more atherogenic pathophysiology. In the former case, insulin resistance has proatherogenic effects beyond the risk factors included in the definition of the metabolic syndrome: inflammation and hypercoagulability are important atherogenic factors that are increased in the insulin-resistant patient but are not included in the definition of the metabolic syndrome. Thus, individuals with the metabolic syndrome who also have significant insulin resistance may have greater risk than simply the sum of the components of the syndrome would indicate.

In the remainder of this review, we will focus on the well-characterized interaction between insulin resistance and one of the components of the metabolic syndrome, dyslipidemia, with special reference to the increased atherogenicity produced by that interaction. We will also discuss new findings concerning the role of inflammation in the metabolic syndrome.

Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

The dyslipidemia of the metabolic syndrome is characterized by elevated levels of triglycerides (TGs), low HDL-cholesterol, and small, dense low-density lipoprotein (LDL) particles with normal or slightly elevated LDL-cholesterol levels. Data from the Framingham Offspring Study (21) showed the high prevalence of elevated TGs and low HDL-cholesterol in individuals with diabetes. Among men, HDL-cholesterol <35 mg/dL was present in 20.3% of non-diabetic controls and 43.9% of diabetic patients, TGs >250 mg/dL were present in 9.3% vs. 22.6% of participants, respectively, and their combination was present in 4.9% of controls vs. 11.7% of patients with diabetes. The prevalence of low HDL-cholesterol, high TGs, and elevations of both HDL-cholesterol and TG levels were 37.7%, 29.3%, and 23.4%, respectively, for women with diabetes and 9.3%, 3%, and 1% for controls. In addition, diabetic women were more likely to have elevated LDL-cholesterol and total cholesterol levels.

The triad of lipid abnormalities present in patients with type 2 diabetes is also present in non-diabetics who are insulin resistant. Indeed, the evidence is clear that insulin resistance is the major underlying abnormality that drives the dyslipidemia; there may be some exacerbation of each abnormality, and in particular, hypertriglyceridemia, when significant hyperglycemia is present, but in general, individuals with type 2 diabetes that is reasonably well controlled have the same dyslipidemia that is found in non-diabetics with only insulin resistance. Furthermore, although each of the components of the dyslipidemia may be affected by insulin resistance, there are convincing data that the effect of insulin resistance on the assembly and secretion of very-low-density lipoprotein (VLDL) apolipoprotein B (apo B) and TGs is central abnormality. Specifically, insulin resistance leads to increased assembly and secretion of VLDL, and the resulting hypertriglyceridemia leads, in turn, to lower HDL-cholesterol levels and smaller, cholesteryl ester depleted LDL. The basis for the interaction between insulin resistance and VLDL secretion is the complex post-translational regulation of apo B.

Regulation of the assembly and secretion of VLDLs by the liver has been under intense study for the past 25 years, and much as been learned (22, 23, 24). Of particular relevance to this review, there is significant post-transcriptional and post-translational regulation of the hepatic assembly of apo B100 (and in rodents apo B48) with lipids to form VLDLs. Thus, studies in cultured liver cells indicate that a significant proportion of newly synthesized apo B100 may be degraded before secretion and that this degradation is inhibited when hepatic lipids are abundant. Studies in rodents support the tissue culture data. There is also abundant evidence that microsomal triglyceride transfer protein is essential for the assembly and secretion of VLDLs (25). Once in the plasma, VLDL TG is hydrolyzed by lipoprotein lipase (LPL); this step can be modified by the ratio of apo CII to apo CIII. Apo CII is the necessary activator of LPL, whereas apo CIII can inhibit LPL activity. Lipolysis generates smaller and denser VLDLs, and, subsequently intermediate density lipoprotein (IDL). These small VLDLs, together with IDLs, are similar to chylomicron remnants in that the small VLDLs and IDLs can be removed by the liver. However, unlike chylomicron remnants, small VLDLs and IDLs can also undergo further catabolism to become LDLs. It also seems that apo E, hepatic lipase, and LDL receptors play important roles in this metabolic cascade that ends with the generation of LDLs. Thus, the levels of VLDL TGs in the blood will be determined by the rates of secretion of VLDL TGs and apo B100, rates of lipolysis of VLDL TGs by LPL, and the rates of both removal of small VLDLs from the circulation and conversion to IDLs. Each of these processes can be affected by insulin resistance. This review will focus on VLDL TGs and apo B100 secretion, but the other metabolic steps will be discussed as well.

Overproduction of VLDLs, with increased secretion of both TGs and apo B100, seems to be the central and most important etiology of increased plasma VLDL levels in patients with insulin resistance or type 2 diabetes (26). As noted above, the series of steps whereby apo B100 assembles with lipids and VLDL is secreted is regulated post-transcriptionally. Recent studies in cell culture, rodents, and humans have provided significant insights regarding the mechanisms whereby insulin resistance can drive increased VLDL secretion. First, the targeting of apo B100 for secretion as VLDLs is regulated significantly by the availability of its lipid ligands, particularly TGs. If hepatic lipids are unavailable for assembly into VLDLs, apo B can be degraded by the proteasome, after cotranslational ubiquitination (24). Limited lipid availability can also target apo B100 for post-translational degradation: some of that is in the endoplasmic reticulum and some distal to the endoplasmic reticulum. Insulin resistance is associated with increases in the three main sources of TGs for VLDLs assembly: fatty acid (FA) flux from adipose tissue to the liver, hepatic uptake of VLDLs, IDLs, and chylomicron remnants, and de novo lipogenesis (Figure 1).

image

Figure 1. There are three major sources of TGs, the main substrate regulating apoB secretion as VLDL. They are FAs from peripheral tissues, particularly adipose tissue; chylomicron and VLDL remnants; and de novo hepatic lipogenesis. In insulin resistance, FA flux through the plasma to the liver is increased, and peripheral removal (by lipolysis) of chylomicron and VLDL TGs is reduced, leaving TG-enriched remnants for hepatic uptake; de novo lipogenesis can be increased. All of these sources of TGs may contribute to the increased VLDL secretion present in insulin-resistant people.

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Increased FA levels in blood and increased fatty acid flux to the liver have been known to occur in humans with insulin resistance with and without type 2 diabetes for >30 years. It is also known that plasma albumin-bound FAs are a source of VLDL TGs (27, 28). More recently, Lewis (29) showed that acutely raising plasma FA levels could increase VLDL secretion in normal individuals. We confirmed the role of FAs in chronically catheterized normal mice; intravenous infusion of oleic acid bound to albumin over 6 hours doubled hepatic secretion of apo B100 (and apo B48, which is synthesized in both the liver and intestine in rodents) (30). We have also shown, in a mouse model of insulin resistance and increased secretion of VLDLs, that FA flux to the liver was modestly increased (31); similar findings were observed in a sucrose-fed hamster model of insulin resistance and increased VLDL secretion (32). In contrast, mice that lack hormone-sensitive lipase, one of the adipocyte enzymes needed to release FAs from cell TGs, have low levels of FAs in the blood and secrete less VLDL TGs (33).

The increased FA flux to the liver results from insulin resistance in adipocytes. It is not clear whether this insulin resistance occurs in only some adipose depots, such as intra-abdominal adipose tissue, or is present in all fat tissues in insulin-resistant individuals. Basu et al. (34) showed that release of free fatty acids was increased in diabetics from all fat tissue depots, including upper body, leg, and splanchnic sites. Adipocyte uptake and storage of FAs and TGs relies critically on insulin-mediated glucose uptake, because the latter is the necessary precursor of glycerol, the backbone of TGs. Reduction of glucose uptake caused by insulin resistance results in reduced trapping of FA in adipocytes. In addition, insulin inhibits hormone-sensitive lipase, the intracellular lipolytic enzyme; if the adipocyte is insulin resistant, hormone-sensitive lipase activity may be increased, resulting in greater intracellular lipolysis of stored TGs and increased release of FAs from adipocytes.

The causes of insulin resistance in the adipocyte (indeed, the underlying causes of insulin resistance syndrome per se) remain undefined, but probably involve numerous genetic factors, similar to other complex disorders (e.g., atherosclerosis and hypertension). Although candidate genes and factors have been identified in murine models, their importance in human insulin resistance has been difficult to show. The roles of such molecules as tumor necrosis factor-α (35), resistin (36), and adiponectin (37) in the adipocyte—hepatic axis and overproduction of VLDLs remain to be fully defined. Regardless of the molecular basis for insulin resistance, if FAs are not being stored normally in adipocytes, their levels in the circulation will increase, and this is associated with resistance to both insulin-mediated glucose uptake and metabolism in muscle and an increase in glucose production and release by the liver. Both result in hyperinsulinemia, because insulin secretion will be increased to compensate for the increased plasma glucose levels. In the liver, increased uptake of FAs from the bloodstream stimulates the synthesis of TGs and the assembly and secretion of VLDL particles. The additional roles of hyperinsulinemia in VLDL assembly and secretion will be discussed below.

Hepatic uptake of remnant lipoproteins plays an important role in regulating both postprandial and fasting levels of TGs in the blood. Postprandial hyperlipidemia is common in insulin-resistant individuals, and this is almost certainly associated with hepatic uptake of remnants that contain more TGs than do remnants in normal people. This will stimulate VLDL assembly and secretion, as the liver attempts to maintain homeostasis regarding its FA and TG content; delivery of excess remnant TG FAs will lead to increased VLDL secretion. This has been shown in cultured liver cells (38) and humans (39). Using the chronically catheterized normal mouse model described above, we showed that infusion of Intralipid (Pfizer, Inc., New York, NY), an emulsion of TGs and phospholipids, could stimulate both apo B and TG secretion (30). Of interest, we found that TG FAs delivered through remnant uptake were not as potent a stimulus for VLDL secretion as were FAs delivered by albumin. We are moving forward with studies to better understand these apparent qualitative difference in the effects of different sources of fatty acids on VLDL assembly and secretion.

The third source of TGs for assembly and secretion with apo B100 is de novo fatty acid synthesis (lipogenesis) in the liver. In rodents, lipogenesis is clearly an important source of VLDL TGs; data in humans are less abundant, but several recent papers have shown that lipogenesis does contribute significantly to VLDL TGs and is increased in individuals with obesity and insulin resistance (40, 41, 42). Horton et al. (43) defined in detail the regulation of hepatic lipogenesis by the transcription factor, sterol response element binding protein isoform 1 (SREBP1-c). Their work indicated that hepatic SREBP1-c gene expression was regulated by insulin, through another transcription factor, the liver-x-receptor; in hyperinsulinemic ob/ob mice, SREBP1-c gene expression was increased (44). Of note, in their studies with ob/ob mice, it seemed that, although insulin resistance might exist in the pathway regulating gluconeogenesis, this resistance did not extend to insulin's ability to stimulate lipogenesis (44).

In our recent studies (unpublished observations), we found that lipogenesis is increased in the apo B/BATless mouse, a model of moderate obesity, insulin resistance, and increased VLDL secretion (31), but that SREBP1-c expression or activity was not altered. On the other hand, the expression and activity of the peroxisome proliferators activated receptor γ (PPARγ) was increased in the livers of apo B/BATless mice, and that finding, together with published data indicating an important role of PPARγ in hepatic lipogenesis in other mouse models of obesity and insulin resistance (45), has led us to pursue this interesting and potentially clinically relevant finding.

Studies conducted over a number of years in cultured liver cells have indicated clearly that insulin not only stimulates lipogenesis but also plays a key role in determining whether apo B is targeted for secretion or degradation (46, 47). Insulin, acting through a phosphatidylinositol 3-kinase pathway, can target apo B for degradation. This degradation is post-translational and probably post-endoplasmic reticulum. In recent studies, Pan et al. (48) suggested that insulin's stimulation of apo B degradation in cultured liver cells may be linked to high levels of oxidant stress in insulin-treated cells. Results in cultured cells have been extended to in vivo studies in rodents and humans. In the latter, both Lewis et al. (49) and Malmstrom et al. (50) showed decreased VLDL secretion, both TGs and apo B, in normal subjects treated with large quantities of insulin and glucose (euglycemic clamps). Importantly, the effects of insulin on apo B degradation seemed to diminish significantly if insulin resistance was present; this is true in cultured cells (51), whole animals (52), and humans (49, 50). In ongoing studies in our laboratory (unpublished observations), we are looking at the extreme case of hepatic insulin resistance in mice that lack insulin receptors only in the liver (LIRKO mice). Our preliminary results indicate that, in the presence of decreased SREBP1-c and PPARγ gene expression and reduced TG secretion, the rates of secretion of apo B100 and apo B48 from the liver are either normal or increased. This dissociation of TG and apo B secretion supports a direct role of insulin; in the absence of insulin signaling, less apo B is degraded and more is secreted, even when hepatic lipid availability and secretion are reduced.

A potentially important and clinically relevant extension of the finding described above relates to the increasing prevalence of fatty livers in people with the metabolic syndrome (53). Although such individuals seem to be able to increase VLDL secretion as they attempt to maintain hepatic lipid homeostasis in the face of increased sources of TGs, they cannot “keep up,” and hepatic TG accumulates. It is possible that the relative degrees of both insulin resistance and hyperinsulinemia determine whether fatty liver will develop. Thus, if there is severe insulin resistance, despite increased uptake of albumin-bound FA- and TG-containing remnants and regardless of the level of lipogenesis, there may be enough apo B (because of reduced insulin-mediated degradation) to unload the TGs through VLDL secretion; if there is moderate insulin resistance and, in particular, there is adequate signaling through the insulin-mediated apo B degradation pathway, less VLDLs may be assembled and secreted, and a fatty liver may develop (Figure 2). This hypothesis requires further study.

image

Figure 2. Insulin regulates de novo hepatic lipogenesis, mainly through its ability to increase the gene expression of SREBP1-c, the major lipogenic transcription factor. Insulin also can target nascent apoB for degradation post-translationally. In an insulin-resistant liver, the relative effects of insulin to increase FA and TG synthesis and to reduce availability of apoB to secrete TGs from the liver will be a major determinant of both hepatic TG accumulation and plasma TG levels.

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The hypertriglyceridemia of the metabolic syndrome is not, however, completely driven by overproduction of VLDLs. Modest reductions in post-heparin LPL levels have been reported in some type 2 diabetics, and this may contribute significantly to elevated TG levels, particularly in severely hyperglycemic patients. Additionally, VLDLs and chylomicrons can compete for the same LPL-mediated pathway for TG removal from the circulation; because postprandial hyperlipidemia is more common in patients with the metabolic syndrome, the efficiency with which both chylomicrons and VLDLs are cleared from the circulation will be impaired. Finally, hepatic uptake of VLDL remnants is a complex process involving several parallel and yet interactive pathways. Insulin resistance might lead to reduced LDL receptors, limiting remnant removal. Hepatic lipase is increased in many individuals with diabetic dyslipidemia, and although high hepatic lipase activity may be important for the low HDL levels and the predominance of small dense LDLs characteristic of this lipid complex, the fact that it is usually elevated suggests that hepatic lipase—mediated TG hydrolysis of VLDL remnants is unimportant as a cause of elevated levels of either chylomicrons or VLDLs.

Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

In people with insulin resistance and type 2 diabetes, regulation of plasma levels of LDLs, like that of its precursor VLDLs, is complex. In the presence of hypertriglyceridemia, dense, cholesteryl ester-depleted, triglyceride-enriched LDLs are present. Thus, individuals with type 2 diabetes and mild to moderate hypertriglyceridemia may have the Pattern B profile of LDL described by Austin and Krauss (54). The increase in small dense LDLs in insulin resistance is derived in large part from the action of cholesteryl ester transfer protein. This protein, which is associated with lipoproteins in the blood, can mediate the exchange of VLDL (or chylomicron) TGs for LDL cholesteryl ester, thereby creating a TG-enriched, cholesteryl ester—depleted LDL particle. The TGs in LDL can be lipolyzed by LPL or hepatic lipase, generating the small, dense LDLs. The finding that small dense LDLs are present in insulin-resistant and type 2 diabetic patients even when they have relatively normal TG levels suggests other factors are at play. One factor is hepatic lipase, which, as noted earlier, is increased in insulin resistance and can, therefore, more effectively hydrolyze any TGs in LDLs. Higher levels of blood FAs have also been shown to stimulate exchange of cholesterol esters and TGs between LDLs (or HDLs) and VLDLs.

Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

HDL-cholesterol and apo AI levels are characteristically reduced in insulin-resistant people. Much of this derives, as in the case of small dense LDLs, from the action of cholesteryl ester transfer protein—mediated transfer of cholesteryl esters from HDLs to TG-rich lipoproteins (chylomicrons and VLDLs). A consistent finding is the inverse relationship between plasma insulin (or C-peptide) concentrations, which are measures of insulin resistance, and HDL-cholesterol levels. Fractional catabolism of apo AI is increased in type 2 diabetics with low HDLs as it is in non-diabetics with similar lipoprotein profiles (55). Although apo AI levels are reduced consistently, correction of hypertriglyceridemia does not usually normalize apo AI levels.

Studies have shown that apo AI may dissociate from TG-enriched HDLs and be cleared by the kidney (55). Increased hepatic lipase activity in insulin resistance, with increased hydrolysis of TGs and the generation of smaller HDLs, may also play a role in this scheme. Whether defective adenosine 5′-triphosphate-binding cassette transporter A1-mediated efflux of cellular free cholesterol, defective lecithin cholesterol acyltransferase activity, or increased selective delivery of HDL cholesteryl ester to hepatocytes is involved in the low HDL levels present in insulin resistance is under study. However, the fact the low HDL-cholesterol and apo AI are frequently present even when TG levels are relatively normal suggest non-cholesteryl ester transfer protein mechanisms are important.

Metabolic Syndrome: Link between Inflammation and Insulin Resistance

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

During the past 10 years, it has become increasingly clear that insulin-resistant states are associated with increases in several inflammatory markers such as C-reactive protein (56, 57). During that same time period, numerous studies have shown that adipose tissue is not simply a storage depot for excess energy, but rather, is an active endocrine organ that secretes a number of molecules that have been called, collectively, adipokines (58, 59). Among these are tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase, C-reactive protein, plasminogen activator inhibitor 1, monocyte chemoattractant protein-1, leptin, and adiponectin. Some of these are proinflammatory molecules that have been linked to alterations in insulin sensitivity. In particular, tumor necrosis factor-α has been shown to play an important role in mouse models of obesity and insulin resistance (60). Interleukin-6 has been shown to cause hypertriglyceridemia in rodents by increasing VLDL secretion (61). In two recent reports (62, 63), investigators showed that adipose tissue of obese mice and humans is infiltrated by bone marrow—derived macrophages and that these macrophages are the source of most of the tumor necrosis factor-α and significant proportions of the inducible nitric oxide synthase and interleukin-6 that enter the circulation from the adipose tissue. Whether inflammation, driven by these molecules, is the basis of insulin resistance or a response to other signals that induce insulin resistance, i.e., increased FA release from adipocytes, remains to be clarified. However, these new data make it clear that reductions in adipose tissue mass will be associated with changes not only in energy balance, but with secretion of active molecules that are integral to the insulin resistance or metabolic syndrome.

Summary

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References

The metabolic syndrome, which is closely linked in most instances to insulin resistance, is a growing problem throughout the world and will impact negatively on both the incidence of type 2 diabetes and ASCVD. Understanding the links between insulin resistance and the components of the metabolic syndrome will enable physicians and scientists to approach the phenotypic problems (hypertension, diabetes, dyslipidemia, obesity) in a more rational and mechanism-based manner. In this review, we have detailed the complex interactions between insulin resistance and dyslipidemia, with a particular focus on the regulation of the assembly and secretion of VLDLs and the resultant hypertriglyceridemia. New treatments leading to lower plasma TG levels, higher plasma HDL-cholesterol levels, and normalized LDL particle composition will have to be based, at least in part, on reducing VLDL secretion. Reducing adipose tissue mass is the most physiological approach to improving insulin sensitivity and thereby reducing VLDL secretion.

Footnotes
  • 1

    Nonstandard abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL, high-density lipoprotein; CHD, coronary heart disease; MI, myocardial infarction; TG, triglyceride; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; apo, apolipoprotein; LPL, lipoprotein lipase; IDL, intermediate density lipoprotein; FA, fatty acid; SREBP1-c, sterol response element binding protein isoform 1; PPARγ, peroxisome proliferators activated receptor γ.

References

  1. Top of page
  2. Introduction
  3. Metabolic Syndrome: Link to Atherosclerosis
  4. Metabolic Syndrome: Link between Insulin Resistance and Dyslipidemia
  5. Metabolic Syndrome: Link between Insulin Resistance and Small Dense LDL
  6. Metabolic Syndrome: Link between Insulin Resistance and Low Levels of HDL-cholesterol
  7. Metabolic Syndrome: Link between Inflammation and Insulin Resistance
  8. Summary
  9. Acknowledgement
  10. References
  • 1
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