RESUMEN

Context: Earlier nuclear magnetic resonance spectroscopy (NMR) studies of plasma lipoproteins estimated by size as small, medium, and large particles, demonstrated hypothyroidism was associated with increases in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and intermediate-density lipoprotein (IDL) subclass particle number but variable changes in the high-density lipoprotein (HDL) subclasses. These disparate changes in HDL might be explained by reduced activity of the thyroid hormone-dependent remodeling proteins whose subclass specificity may be obscured when the 5 HDL subclasses identified by NMR are combined by size. Objective: This work aimed to determine whether directional changes in particle number of individually measured HDL subclasses correlate with reduced activity of their thyroid hormone-dependent remodeling proteins in hypothyroid individuals. Methods: VLDL, LDL, IDL, and HDL subclasses were measured by NMR in 13 thyroidectomized individuals 1 month following thyroid hormone withdrawal and 3 months after replacement. Changes in particle numbers in each subclass were compared when expressed individually and by size. Results: Following thyroid hormone withdrawal, plasma lipids and VLDL, LDL, and IDL subclass particle number increased. HDL particle number nearly doubled in very small HDL-1 (P = .04), declined in small HDL-2 (P = .02), and increased 2-fold in HDL-5 (P = .0009). Conclusion: The increment in HDL-1 and decline in HDL-2 subclasses is consistent with their precursor-product relationship and reduced lecithin cholesterol acyltransferase activity while the almost 2-fold increase in large HDL-5 is indicative of diminished action of hepatic lipase, phospholipid transfer protein, and endothelial lipase. These findings are inapparent when the 5 subclasses are expressed conventionally by size. This linking of specific HDL subclasses with HDL remodeling protein function provides new details about the specificity of their interactions.

RESUMEN

BACKGROUND: Previous studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes. Since apoproteins are now known to have important roles in host defense, we have separated these subclasses according to their apoprotein content and characterized their changes during experimental endotoxemia in human volunteers. METHODS: We have studied apoB- and apoA containing lipoprotein subclasses in twelve healthy male volunteers before and for 8 h after a single dose of endotoxin (ET; 2 µg/kg) to stimulate inflammation. RESULTS: After endotoxin, TG, TC, apoB and the apoB-containing lipoprotein cholesterol-rich subclass LpB and two of the three triglyceride-rich subclasses (TGRLP: Lp:B:C, LpB:C:E+ LpB:E) all declined. In contrast, the third TGRLP, LpA-II:B:C:D:E ("complex particle"), after reaching a nadir at 4 h rose 49% above baseline, p = .006 at 8 h and became the dominant particle in the TGRLP pool. This increment exceeds the threshold of > 25% change required for designation as an acute phase protein. Simultaneous decreases in LpA-I:A-II and LpB:C:E + LpB:E suggest that these subclasses undergo post-translational modification and contribute to the formation of new LpA-II:B:C:D:E particles. CONCLUSIONS: We have identified a new acute phase lipoprotein whose apoprotein constituents have metabolic and immunoregulatory properties applicable to host defense that make it well constituted to engage in the APR.

Asunto(s)

RESUMEN

In the ILLUMINATE Trial, treatment with the cholesteryl ester transfer protein inhibitor torcetrapib resulted in a significant increase in both atherosclerotic cardiovascular disease events and total mortality which was not explained by changes in the routinely measured plasma lipids. To determine whether alterations in lipoproteins defined by their apoprotein content that are not estimated with conventional laboratory methods contributed to these unexpected events, we measured the apoB- and apoA-containing subclasses in a subgroup of ILLUMINATE participants. We find that torcetrapib treatment significantly increased the high-density lipoprotein subclasses LpA-I and LpA-I:A-II equally (p <0.0001) and the apoC-III content of high-density lipoprotein (p <0.001) without altering the apoB-containing subclasses. In conclusion, these findings provide further evidence that the untoward effects of torcetrapib were attributable to off-target effects and not related to disturbances in lipoprotein transport.

Asunto(s)

RESUMEN

AIMS: Accelerated cholesteryl ester transfer (CET) protein (CETP) activity is believed to promote macrovascular disease in patients with type 2 diabetes (T2D) by increasing the cholesterol burden of the apoB - containing triglyceride-rich lipoprotein (TGRLP) CE acceptors and promoting small dense LDL formation. While previous studies have shown that this same abnormality is present in patients with type 1 diabetes (T1D) and was normalized by the anti-oxidant drug probucol, its effects on CET in T2D are unknown. PATIENTS AND METHODS: The net mass transfer of CE from HDL to the apoB lipoproteins (VLDL+LDL) was studied in intact plasma from seven T2D patients before and two months after treatment with probucol (1g/day). RESULTS: Before treatment, CET was significantly greater than controls at 1 and 2h (p<.005). Recombination studies showed that this disturbance was attributable to dysfunction of VLDL and not due to altered behavior of HDL or CETP. Probucol treatment normalized CET in all subjects and significantly lowered plasma cholesterol (pre-Rx: 197±4.5 vs post-Rx: 162±27.1mg/dL; mean±S.D.; p<.025) and HDL-C (pre-Rx: 46.4±7.5 vs post-Rx: 39.1±4.0; p<.025) without changing glycemic control. CONCLUSIONS: By normalizing CET in T2D, probucol likely reduces the formation of atherogenic lipoproteins. This effect on CET is achieved through qualitative alterations in CETP's lipoprotein substrates and not through changes in CETP or HDL. Since probucol also has potent anti-oxidative and anti-inflammatory properties, it may have a new role to play in lipoprotein remodeling that reduce cardiovascular risk in T2D.

Asunto(s)

RESUMEN

OBJECTIVE: Accelerated cholesteryl ester transfer (CET) in patients with types 1 (T1D) and 2 diabetes enhances the atherogenicity of the apoB-containing CE acceptor lipoproteins. The study of lipoprotein density fractions cannot identify which of the five immunologically distinct apoB subclasses function as CE acceptors because they are heterogeneous and present in very low-, intermediate- and low density lipoproteins (VLDL, IDL and LDL, respectively). In order to design lipid-modifying therapies that specifically target these CE-enriched lipoprotein particles, it is necessary to first characterize their CE acceptor function. METHODS AND RESULTS: To identify the CE acceptors, we estimated CE net mass transfer to the apoB subclasses LpB:C, LpB:E + LpB:C:E, LpB and LpAII:B:C:D:E from changes in neutral lipids measured by gas chromatography following their separation by sequential immunoaffinity chromatography in the plasma of 12 patients with T1D and six control subjects. In both groups, CE was distributed equally to LpB:E + LpB:C:E and LpB:C. In the T1D CE acceptors, however, both the magnitude of the increase (18% vs. 10%; P < 0·01) and the per particle mass of CE transferred were significantly greater than in controls (T1D: 2·29 µmol ± 2·1 vs. control 0·43 ± 0·43/mg apoB; P < 0·047). CONCLUSION: While LpB:E + LpB:C:E and LpB:C functioned as CE acceptors in both groups, these subclasses increased their CE content to a greater degree and accrued more CE per particle in the patients with T1D. As this disturbance in lipoprotein remodelling may increase the cholesterol burden and potential atherogenicity of these apoB subclasses, it may be a previously unrecognized factor that increases cardiovascular risk in patients with T1D.

Asunto(s)

RESUMEN

IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6. Though plasma TG and apoB-containing particle number were unchanged by IL-6, the distribution of TG-rich subclasses was significantly altered. Compared to baseline values, LpB:E + LpB:C:E increased significantly at 0.5 h (p < 0.02) and were higher than saline-infused controls at 0.5 and 1 h (p < 0.05). At 0.5 h LpAII:B:C:D:E reciprocally declined from baseline (p < 0.01). While the pattern of change for total apoB showed an overall decline (p < 0.05), these changes in LpB:E + LpB:C:E and LpAII:B:C:D:E in IL-6 subjects differed from controls (p < 0.05; p < 0.01, respectively). These findings indicate that physiologic concentrations of IL-6 rapidly and selectively regulate the transport of apoB particles that contain apoE. Since apoE has immunomodulatory and host defense functions, these changes may be a previously unrecognized early step in the innate immune response.

Asunto(s)

RESUMEN

OBJECTIVE: Young women with T1D develop CHD without any apparent lipid related risk factor. To determine whether abnormalities in the five immunochemically defined apoB-containing lipoprotein subclasses might influence this risk, we have measured these subclasses in T1D subjects. RESEARCH DESIGN AND METHODS: ApoA- and B-containing lipoprotein subclasses were isolated immunochemically and quantitated in 37 young (mean age 31.8+/-12.7 years) otherwise healthy subjects (16 males; 21 females) with T1D (HbA1c=8.2+/-1.7%) treated conventionally with subcutaneous insulin. RESULTS: T1D women had significantly more cholesterol-rich Lp-B particles (T1D: 55.9+/-4.5 vs. control 46.8+/-11.1mg apoB/dL; p<.01) which were over-represented in the apolipoprotein B particle pool (apoB/Lp-B: T1D: 1.49+/-.19 vs. control: 1.67+/-.22; p<.01). HbA1c correlated with Lp-B (r=0.60; p<.001) and the mass of apoB subclasses containing apoC-III (r=0.69; p<.001). CONCLUSIONS: Women with T1D have a disturbance in the transport of Lp-B particles manifested by both an absolute and relative increase in their number that may result from portal hypoinsulinemia and reduced LDL B,E receptor activity. This pathway may enhance CHD risk in T1D women when of LDL and apoB levels are normal.

Asunto(s)

RESUMEN

OBJECTIVE: Few multiple lifestyle behavior change programs have been designed to reduce the risk of coronary heart disease in postmenopausal women with type 2 diabetes. This study tested the effectiveness of the Mediterranean Lifestyle Program (MLP), a comprehensive lifestyle self-management program (Mediterranean low-saturated fat diet, stress management training, exercise, group support, and smoking cessation), in reducing cardiovascular risk factors in postmenopausal women with type 2 diabetes. RESEARCH DESIGN AND METHODS: Postmenopausal women with type 2 diabetes (n = 279) were randomized to either usual care (control) or treatment (MLP) conditions. MLP participants took part in an initial 3-day retreat, followed by 6 months of weekly meetings, to learn and practice program components. Biological end points were changes in HbA(1c), lipid profiles, BMI, blood pressure, plasma fatty acids, and flexibility. Impact on quality of life was assessed. RESULTS: Multivariate ANCOVAs revealed significantly greater improvements in the MLP condition compared with the usual care group on HbA(1c), BMI, plasma fatty acids, and quality of life at the 6-month follow-up. Patterns favoring intervention were seen in lipids, blood pressure, and flexibility but did not reach statistical significance. CONCLUSIONS: These results demonstrate that postmenopausal women with type 2 diabetes can make comprehensive lifestyle changes that may lead to clinically significant improvements in glycemic control, some coronary heart disease risk factors, and quality of life.

Asunto(s)

RESUMEN

This paper describes a randomized study to evaluate the effects of a comprehensive lifestyle management intervention for 279 postmenopausal women with type 2 diabetes who are at elevated risk for coronary heart disease (CHD). The intervention, called the Mediterranean Lifestyle Trial, is focused on dietary factors, physical activity, social support and stress management. The Mediterranean Lifestyle Trial relies on a synthesis of Social Cognitive Theory and Social Ecologic Theory, as well as goal-systems theory, to explicitly inform the lifestyle intervention and to address maintenance. Thus, the trial should help illuminate the theoretical mechanisms responsible for lifestyle change. Primary outcome variables are dietary, stress management and physical activity behavior change, quality of life, and CHD-related biological risk factors. Hypothesized mediating variables include self-efficacy, coping, and social and environmental support. Following the initial 6-month intervention, participants in the intervention condition are randomized to one of two groups designed to enhance maintenance of effects: either a peer-led support group or a personalized multilevel community resources maintenance condition. Unlike the peer group, the personalized approach focuses on multiple levels of community resources to promote healthful lifestyle change. Because this research focuses on issues of generalization and translation to practice, the RE-AIM evaluation framework is being used to evaluate Reach, Effectiveness, Adoption, Implementation and Maintenance. This framework will help to translate research into practice by directing researchers' attention to important but seldom-investigated strategies for enhancing longer-term maintenance. Specifically, the study tests how long-term maintenance may be improved through the use of existing community resources, an intervention based on multiple environmental factors and multiple lifestyle behaviors, and lay leaders versus personalized professional support.

Asunto(s)

RESUMEN

This paper describes recruitment and participation of physicians and patients in a randomized study to evaluate the effects of a moderately intensive (2-year) lifestyle management intervention for post-menopausal women with type 2 diabetes at risk for coronary heart disease (CHD). The purpose of this report is to answer two practical public health questions: (1) "Will physicians refer their patients with type 2 diabetes to such an intensive lifestyle change program?" and, if so, (2) "Will these patients participate?" Results showed high (70%) acceptance among physicians. About 51% of eligible patients agreed to participate, which was encouraging given the substantial time commitment involved. Main reasons for refusal were lack of eligible patients (among physicians) and lack of time (among patients). Patient participants and non-participants did not differ significantly on age, body mass, and other demographic and medical variables. Based on these results, it appears that appropriate recruitment procedures will yield a representative sample of women willing to participate in intensive lifestyle management programs.

Asunto(s)