Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women

MacLean, Paul S.; Vadlamudi, Satyaprasad; MacDonald, Kenneth G.; Pories, Walter J.; Houmard, Joseph A.; Barakat, Hisham A.

doi:10.1016/s0026-0495(00)80002-5

Cited by 25 publications

(19 citation statements)

References 51 publications

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“…Fasting plasma CETP activity was approximately 3 times higher (Ϸ250 nmol/mL per h) in CETP and db/CETP mice than is normally found in humans, 5,25 whereas the activity in db mice was negligible. After being fed the atherogenic diet for 16 weeks, the animals were killed and examined for oil red O-positive intimal plaque lesions and intramural fat deposition (Table).…”

Section: Resultsmentioning

confidence: 69%

Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice

MacLean

Bower

Vadlamudi

et al. 2003

ATVB

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Objective-Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity. Methods and Results-Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098Ϯ7486 m 2 . No lesions greater than 1000 m 2 were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL. Key Words: cholesterol Ⅲ FPLC Ⅲ VLDL Ⅲ LDL Ⅲ HDL obesity C holesteryl ester transfer protein (CETP) is a glycoprotein that catalyzes the transfer of neutral lipids between the plasma lipoproteins. In this respect, this enzyme is involved in at least one arm of reverse cholesterol transport (RCT), an antiatherogenic process by which cholesterol is cleared from peripheral tissues. 1 Even so, the atherogenic nature of CETP has been the subject of much debate because both increased and decreased CETP expression have been linked to elevated risk and incidence of vascular disease. 2 Thus, the atherogenic nature of CETP is thought to depend on the metabolic context in which it influences lipoprotein metabolism. Conclusions-TheObesity is a metabolic condition afflicting more than one third of the population of the United States. 3 Obesity is accompanied by both a mild increase in vascular disease complications 4 as well as elevated plasma CETP activity. [5][6][7][8][9] It is unclear whether this perturbation in CETP activity contributes to altered lipoprotein profiles and elevated vascular disease risk or is a normal consequence of elevated cholesterol levels observed in these patients. 5,10 Interestingly, obese patients with type 2 diabetes have a higher risk of vascular disease complications, 11 higher circulating cholesterol levels, 5,10 and depressed levels of plasma CETP concentrations 5,12 compared with obese nondiabetic controls. This suppressive effect of diabetes on plasma CETP is not apparent in nonobese individuals. [13][14][15][16] We have hypothesized that depressed plasma CETP levels in obese patients with diabetes may hinder the clearance of the high levels of peripheral cholesterol that accompany obesity and contribute to elevated atherosclerosis in these patients.The purpose of this study was to examine the effects of overexpressing CETP...

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Section: Resultsmentioning

confidence: 69%

Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice

MacLean

Bower

Vadlamudi

et al. 2003

ATVB

Self Cite

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“…The relation of these 2 lipoprotein particle measures to incident diabetes was independent of metabolic covariates, including insulin resistance. This is potentially important because in previous reports, both VLDL size and small HDL particles 21 or HDL size (inversely) 3,21 have been related to increased insulin resistance. Additionally, these and other NMR-identified lipoprotein abnormalities, which were prevalent in patients with type 2 diabetes, have been attributed to the underlying increased insulin resistance in these patients rather than the diabetic state itself.…”

Section: Discussionmentioning

confidence: 94%

“…Dyslipidemia in individuals with diabetes or insulin resistance is characterized by high levels of triglycerides, low levels of HDL cholesterol, and a preponderance of small dense LDL particles, as well as a relative increase of large VLDL particles and small HDL particles. [1][2][3] Previous work has suggested that elevated insulin resistance, blood pressure, and triglycerides and lower HDL cholesterol precede the onset of type 2 diabetes. 4 -7 In one report, small dense LDL predicted the incidence of type 2 diabetes.…”

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confidence: 99%

Nuclear Magnetic Resonance Lipoprotein Abnormalities in Prediabetic Subjects in the Insulin Resistance Atherosclerosis Study

et al. 2005

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Background-Subjects with type 2 diabetes have smaller LDL and HDL particles in addition to higher levels of triglycerides and lower HDL cholesterol. Elevated insulin resistance, blood pressure, and dyslipidemia (including small dense LDL) predicted incident diabetes. In the Insulin Resistance Atherosclerosis Study (IRAS) we studied nuclear magnetic resonance (NMR) lipoprotein particle measures in prediabetic individuals, considering potentially modifying covariates, including insulin resistance, as directly measured using a frequently sampled intravenous glucose tolerance test. Methods and Results-Of

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“…One previous study has addressed the relationship between insulin resistance and the NMR lipoprotein subclass profile. MacLean et al (22) assessed insulin sensitivity using the frequently sampled intravenous glucose tolerance test and found no difference in the NMR lipoprotein subclass profile between lean IS and lean IR women. This is in contrast to the current results: we observed significant relationships between VLDL, LDL, and HDL size and subclass particle concentrations independent of BMI or sex.…”

Section: Fig 1 Correlations Between Gdr (Insulin Sensitivitymentioning

confidence: 99%

“…For example, in the general population, increased levels of small, dense LDL (5-7) and a preponderance of the small subfraction of HDL (8 -10) have been shown to be associated with increased risk for atherosclerosis. The IRS has been most extensively studied for its effects on LDL particle subclasses (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) and is known to be associated with smaller, denser LDL particles that may be more atherogenic. Less information is known regarding the effects of insulin resistance on VLDL and HDL subclasses.…”

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confidence: 99%

Effects of Insulin Resistance and Type 2 Diabetes on Lipoprotein Subclass Particle Size and Concentration Determined by Nuclear Magnetic Resonance

et al. 2003

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The insulin resistance syndrome (IRS) is associated with dyslipidemia and increased cardiovascular disease risk. A novel method for detailed analyses of lipoprotein subclass sizes and particle concentrations that uses nuclear magnetic resonance (NMR) of whole sera has become available. To define the effects of insulin resistance, we measured dyslipidemia using both NMR lipoprotein subclass analysis and conventional lipid panel, and insulin sensitivity as the maximal glucose disposal rate (GDR) during hyperinsulinemic clamps in 56 insulin sensitive (IS; mean ؎ SD: GDR 15.8 ؎ 2.0 mg ⅐ kg ؊1 ⅐ min ؊1 , fasting blood glucose [FBG] 4.7 ؎ 0.3 mmol/l, BMI 26 ؎ 5), 46 insulin resistant (IR; GDR 10.2 ؎ 1.9, FBG 4.9 ؎ 0.5, BMI 29 ؎ 5), and 46 untreated subjects with type 2 diabetes (GDR 7.4 ؎ 2.8, FBG 10.8 ؎ 3.7, BMI 30 ؎ 5). In the group as a whole, regression analyses with GDR showed that progressive insulin resistance was associated with an increase in VLDL size (r ‫؍‬ ؊0.40) and an increase in large VLDL particle concentrations (r ‫؍‬ ؊0.42), a decrease in LDL size (r ‫؍‬ 0.42) as a result of a marked increase in small LDL particles (r ‫؍‬ ؊0.34) and reduced large LDL (r ‫؍‬ 0.34), an overall increase in the number of LDL particles (r ‫؍‬ ؊0.44), and a decrease in HDL size (r ‫؍‬ 0.41) as a result of depletion of large HDL particles (r ‫؍‬ 0.38) and a modest increase in small HDL (r ‫؍‬ ؊0.21; all P < 0.01). These correlations were also evident when only normoglycemic individuals were included in the analyses (i.e., IS ؉ IR but no diabetes), and persisted in multiple regression analyses adjusting for age, BMI, sex, and race. Discontinuous analyses were also performed. When compared with IS, the IR and diabetes subgroups exhibited a two-to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel. It will be important to study whether NMR lipoprotein subclass parameters can be used to manage risk more effectively and prevent cardiovascular disease in patients with the IRS. Diabetes 52:453-462, ...

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Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women

Cited by 25 publications

References 51 publications

Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice

Cholesteryl Ester Transfer Protein Expression Prevents Diet-Induced Atherosclerotic Lesions in Male db/db Mice

Nuclear Magnetic Resonance Lipoprotein Abnormalities in Prediabetic Subjects in the Insulin Resistance Atherosclerosis Study

Effects of Insulin Resistance and Type 2 Diabetes on Lipoprotein Subclass Particle Size and Concentration Determined by Nuclear Magnetic Resonance

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