Obesity, overweight, and weight gain over adult life are main determinants of elevated hs-CRP in a cohort of Mediterranean women.

BACKGROUND/OBJECTIVES: Body mass index (BMI), waist circumference (WC), body weight modification, and rate of weight increase over 10 years were evaluated in relation to high-sensitive C-reactive protein (hs-CRP) to assess the association of cross-sectional or longitudinal estimates of obesity/overweight with levels of circulating CRP, a well established and standardized marker of low-grade inflammation, in relation to cardiovascular risk. SUBJECTS: This study included a subgroup of 390 menopausal women participating in a large currently ongoing epidemiological study (Progetto Atena; N=5062). RESULTS: At the final visit, women in the third tertile of BMI, compared with those in the first tertile, showed the following odds ratio (OR) of having high hs-CRP values: III vs I tertile OR, 3.55; 95% confidence interval, 1.94-6.49, P<0.001, adjusted for age, and metabolic syndrome. Similar results were obtained when we evaluated women in the third tertile of WC, or those in the highest group of estimated weight increase, relative to their weight at age 20 years or in the group of highest rate of weight increase over 10 years of observation (weight at the final visit-weight at the baseline visit divided by time in months between visits). CONCLUSIONS: The independent relations between different markers of overweight/obesity and elevated hs-CRP consistently indicate that high (above 1.5 mg l(-1), median) hs-CRP is a major biochemical counterpart of cross-sectional or longitudinal estimates of increased adipose tissue mass.

Impaired endothelium-dependent vascular reactivity in patients with familial combined hyperlipidaemia.

BACKGROUND: Familial combined hyperlipidaemia (FCHL) is associated with a markedly increased risk of premature coronary artery disease. This study was designed to evaluate whether preclinical atherosclerotic functional abnormalities are detectable in the arteries of patients with FCHL. METHODS: 60 subjects were recruited for the study: 30 probands of families with FCHL (mean (standard deviation (SD)) age 48 (10) years, 77% men), defined by fasting total plasma cholesterol or triglyceride concentration >250 mg/dl (>6.5 mmol/l cholesterol, >2.8 mmol/l triglyceride) and by the occurrence of multiple lipoprotein phenotypes within a family, and 30 age-matched and sex-matched healthy controls. All subjects underwent high-resolution B-mode ultrasound examination and the brachial arterial reactivity, a marker of endothelial function, was measured by a semiautomated computerised program. Lipid profile, resting blood pressure, body mass index (BMI), smoking status, insulin and homocysteine levels were also determined. RESULTS: Compared with controls, patients with FCHL had significantly higher BMI, diastolic blood pressure and insulin levels. No difference was observed in baseline brachial diameter between the two groups (mean (SD) 3.45 (0.51) mm for FCHL v 3.60 (0.63) mm for controls; p = 0.17). In response to flow increase, the arteries of the controls dilated (mean (SD) 8.9% (4.9%), range 2.3-20.8%), whereas in the patients with FCHL, brachial arterial reactivity was significantly impaired (5.5% (2.5%), range 0-10.1%; p = 0.002). In multivariate linear regression analysis, apolipoprotein B and BMI were independent determinants of brachial artery response to reactive hyperaemia. CONCLUSIONS: The findings of our study suggest that vascular reactivity is impaired in the arteries of patients with FCHL.

L-arginine improves post-ischemic vasodilation in coronary heart disease patients taking vasodilating drugs.

BACKGROUND: The hypothesis that intravenous L-arginine infusion improves the vasodilatory response to ischemia in the resistance vessels of human lower limbs in relatively young coronary heart disease patients taking vasodilating drugs was tested. METHODS: Twenty patients with onset of symptoms of coronary artery disease before age 50, operated for aortocoronary bypass and taking vasodilating drugs, were compared with 20 control subjects of comparable age and gender; neither group included heavy smokers (>10 cigarettes/day). Blood flow in the lower limbs was measured noninvasively with strain-gauge plethysmography, both at rest and during a reactive hyperemia test. Intravenous infusion of L-arginine was performed in nine coronary heart disease patients and in nine control subjects. RESULTS: Resting blood flow to the lower limbs was 2.3 mL/min/100 mL in control subjects vs 3.4 mL/min/100 mL in patients (difference not statistically significant). Peak blood flow measured after a 3-minute arterial occlusion was 24.0 mL/min/100 mL in control subjects vs 20.3 mL/min/100 mL in coronary heart disease patients (P<0.05). Peripheral minimal vascular resistances were 4.28 and 5.46 peripheral resistances units (p.r.u.) in control subjects and patients, respectively (P<0.05). Intravenous infusion of L-arginine was followed by increased resting blood flow in cases and controls (P=0.009), with a parallel reduction in peripheral resting vascular resistances (P=0.009). Coronary heart disease patients showed increased peak blood flow (P=0.04) and reduced minimal vascular resistances (P=0.02), whereas no statistically significant changes in these parameters were detectable in control subjects. Intravenous glucose infusion, leading to increased serum insulin concentration, did not modify any hemodynamic parameter. CONCLUSIONS: Hemodynamic responses in the skeletal muscle are impaired during a reactive hyperemia test in relatively young coronary heart disease patients taking vasodilating drugs. Intravenous L-arginine infusion corrects the impaired vasodilatory response of the lower limbs to an acute increase in flow following a cuff thigh occlusion.

LDL receptor cDNA sequence analysis in familial hypercholesterolemia patients: 5 novel mutations with high prevalence in families originating from southern Italy.

We screened a group of patients from southern Italy with clinically diagnosed familial hypercholesterolemia (FH) for mutations of the LDL receptor (LDLR) gene. RNA from each proband was analysed by RT-PCR followed by complete cDNA sequencing. Among 51 unrelated FH families we detected 17 mutations affecting the coding region of the LDLR gene. Five of these mutations, designated R395P, L783fsinsG, IVS15-3C>A, IVS3+5G>A, and 1698-1704delCACCCTAinsGCCCAAT (ITL545MPN), have not yet been reported in the literature. Interestingly, the novel IVS15-3C>A splicing mutation was detected in 20% of our unrelated FH families, suggesting an unusually high prevalence in our local population. Hum Mutat 17:433, 2001.

Comparison of the efficacy and tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: a randomized trial.

BACKGROUND: A new extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia. OBJECTIVE: The purpose of this study was to compare the lipid-lowering efficacy and tolerability of fluvastatin ER (80 mg once daily) versus fluvastatin immediate-release (IR) (40 mg once or twice daily). METHODS: Following a 4-week placebo/dietary run-in period, patients with primary hypercholesterolemia type IIa or IIb (low-density lipoprotein cholesterol ILDL-C] > or = 160 mg/dL and triglycerides [TG] < or = 400 mg/dL) were randomized (2:1:1) to receive fluvastatin ER 80 mg once daily at bedtime (QPM), fluvastatin IR 40 mg QPM, or fluvastatin IR 40 mg BID for 24 weeks. Patients who had homozygous familial hypercholesterolemia; type I, III, IV, V, or secondary hyperlipoproteinemia; diabetes; or evidence of liver or renal impairment were excluded. At weeks 0, 2, 4, 8, 12, 16, 20, and 24 of the active-treatment period, levels of LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) were measured. RESULTS: Of the 1183 patients enrolled, 695 were randomly assigned to treatment--346 to fluvastatin ER 80 mg QPM, 174 to fluvastatin IR 40 mg QPM, and 175 to fluvastatin IR 40 mg BID. Patients were well matched between groups, with a mean age of approximately 56 years and body mass index of 27 kg/m2; 56.0% of patients (389/695) were female and 97.7% (679/695) were white. Fluvastatin ER 80 mg QPM lowered LDL-C levels significantly more than did fluvastatin IR 40 mg QPM (33.7% vs 24.4%; P < 0.001) and as effectively as fluvastatin IR 40 mg BID (33.9%). More than half of the patients administered fluvastatin ER 80 mg QPM and IR 40 mg BID achieved reductions in LDL-C levels of > or = 35%; more than half of those administered fluvastatin IR 40 mg QPM experienced reductions in LDL-C levels of > or = 25%. The mean reductions in LDL:HDL ratio, TC, and apolipoprotein B levels in the fluvastatin ER 80 mg QPM group were significantly greater than the reductions in the IR 40 mg QPM group (P < 0.001). In patients with mixed dyslipidemia, fluvastatin ER 80 mg reduced triglycerides by 21.8% (median 28%) and increased HDL-C by 14.5%. Fluvastatin ER 80 mg QPM was well tolerated, with incidences of clinically notable elevations in alanine aminotransferase, aspartate aminotransferase, and creatine kinase levels and musculoskeletal adverse events comparable to those in the IR 40 mg QPM group. CONCLUSION: The ER 80-mg formulation of fluvastatin is effective and well tolerated as a once-daily starting and maintenance treatment for primary hypercholesterolemia.

Non-invasive vascular detection of early signs of atherosclerosis in hypercholesterolemic children: why and how.

Atherosclerosis is a lifelong disease process that begins in childhood and may lead to cardiovascular disease in middle age or later. Non-invasive methods for vascular diagnosis help identify hypercholesterolemic children to treat with dietary or pharmacological intervention on the basis of anatomical or functional markers of arterial pathology. It would be unethical to assess these markers using angiographic or other invasive procedures (such as intravascular ultrasound), but the measurement of intermediate vascular end-points using non-invasive techniques is feasible. We here review the methods and procedures of non-invasive vascular examination that have been demonstrated to be feasible and informative with regard to arterial pathology in hypercholesterolemic children. These include measuring carotid intima-media thickness (IMT) by means of B-mode imaging, Doppler evaluation of the transvalvular aortic pressure gradient, measuring coronary calcium by means of computed tomography, studying the elastic properties of arteries, detecting impaired vasodilation, and measuring arterial remodelling. Suggested operative guidelines could be to measure carotid IMT in all hypercholesterolemic children aged > 10 years. The measurement should be repeated each year if the IMT is in the upper tertile of distribution for that age. A progression in IMT or the development of new lesions during the study could be an indication for more aggressive treatment.

Left ventricular geometry and arterial function in hypercholesterolemia.

AIMS: To investigate the effect of hypercholesterolemia on total arterial compliance and left ventricular (LV) geometry in the absence of arterial hypertension and diabetes. METHODS: One hundred and fifty-two normotensive, non-diabetic patients (109 men) aged 52 +/- 10 years with plasma cholesterol > 240 mg/100 mL, and 282 normotensive controls (154 men) aged 42 +/- 10 years (p < 0.0001) with plasma cholesterol < 200 mg/100 mL were studied by means of echocardiography. The stroke volume/pulse pressure ratio as a percentage of the value predicted by individual age, body weight and heart rate was used as a prognostically-validated index of total arterial compliance. Central pulse pressure (PP) was estimated using a regression equation obtained in a non-overlapping population. RESULTS: Although within the "normal" range, systolic pressure, PP and estimated central PP were higher in the hypercholesterolemic patients even after controlling for differences in age, body mass index (BMI) and race (all p < 0.0001). After controlling for differences in systolic pressure, age, BMI and race, LV mass and the prevalence of hypertrophy were comparable between the two groups, whereas relative diastolic wall thickness was greater (0.36 + 0.06 vs 0.33 + 0.05) and percent SV/PP (stroke volume/PP) lower in the hypercholesterolemic patients (96 +/- 19% vs 102 +/- 18%; both p < 0.005). After considering the covariates, there was still an independent negative correlation between relative wall thickness and percent SV/PP (r = -0.37, p < 0.0001). CONCLUSIONS: Hypercholesterolemia in normotensive non-diabetic adults is independently associated with a mildly concentric LV geometry and a reduced index of total arterial compliance.

Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study).

Preliminary data suggest that fluvastatin may be safely combined with fibrates. The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia. A total of 333 patients were randomly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone (n=80), 400 mg bezafibrate (n=86), 20 mg fluvastatin+400 mg bezafibrate (n=85) or 40 mg fluvastatin+400 mg bezafibrate (n=82) for 24 weeks. Low-density lipoprotein (LDL)-cholesterol decreased >20% in all fluvastatin-containing regimens, with significantly greater decreases compared with bezafibrate alone (P<0.001). Bezafibrate alone and fluvastatin+bezafibrate combinations resulted in greater increases in high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides compared with fluvastatin alone (P<0.001). Fluvastatin (40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24%, a decrease in triglycerides of 38% and an increase in HDL-cholesterol of 22%. All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy, or between combination regimens. No clinically relevant liver (aspartate aminotransferase [ASAT] or alanine aminotransferase [ALAT]) greater than three times the upper limit of normal) or muscular (creatine phosphokinase (CPK) greater than four times the upper limit of normal) laboratory abnormalities were reported. This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia, and to be safe and well tolerated.

Stiffness of the aortic wall in hypercholesterolemic children.

Arterial stiffness may be an indicator of early vascular changes signaling the development of vascular disease, while hypercholesterolemia is a well-recognized promoter of atherogenesis. It has been shown that hypercholesterolemic children have a thicker intima-media in the carotid artery than children with normal cholesterol. The aim of this study was to assess the stiffness of the abdominal aorta in children with hypercholesterolemia. Noninvasive imaging evaluation of the aorta was performed in 85 outpatient children (age, 3 to 14 years) with and without high cholesterol levels ((and) 247 mg/dL [6.4 mmol/L], respectively). Ultrasound imaging of the abdominal aorta that allowed diameter measurements was available in 67 children. Using an image-processing workstation, the maximum and minimum internal diameter of the aorta was measured, and the following indices of elastic properties of the abdominal aorta were derived: arterial strain, pressure-strain elastic modulus, and stiffness. No statistical difference for aortic strain, stiffness, and elastic modulus was found in normocholesterolemic compared with hypercholesterolemic children. The effect of age on the elastic modulus was different in the two groups: in normal children, the elastic modulus increased linearly with age (y = -0.020+0.003 x age [months], P<.001), while the high-cholesterol group had a weak increase in this parameter with age (y = 0.118+0.0009 x age, P = .051). The slope of the regression equations (elastic modulus vage) was significantly different in the two groups (t = 2.45, P = .017). The behavior of arterial stiffness with respect to age was similar, y = 0.677+0.018 x age (P = .002) in normocholesterolemic children and y = 2.06+0.00198 x age (P = .66) in hypercholesterolemic children. The slope of the regression equations (stiffness v. age) was significantly different in the two groups (t = 2.37, P = .021). The present study demonstrates an influence of hypercholesterolemia on age-related modification in the elastic properties of the aorta. A remodeling of the aortic wall in hypercholesterolemic children (cholesterolemia >247 mg/dL) could explain the different age-dependent increase in aortic elastic modulus and stiffness.

Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic subjects with borderline hypertriglyceridemia.

BACKGROUND AND AIM: Impaired triglyceride-rich lipoprotein metabolism is most probably related to an enhanced cardiovascular risk, and may be associated with a pro-coagulant state. A double-blind, randomized study was undertaken to evaluate two widely utilized hypolipidemic drugs in the post-prandial phase and their impact on lipid, coagulation and fibrinolytic parameters. METHODS AND RESULTS: Thirty middle-aged men selected according to their low density lipoprotein-cholesterol (LDL-C) > or = 160 and < or = 240 mg/dl and borderline hypertriglyceridemia (110-220 mg/dl) after at least one month of a lipid-lowering diet received gemfibrozil (600 mg bid) or simvastatin (20 mg qd) and the corresponding placebo. On enrollment and after 2 months of drug treatment, they were tested with a standard oral fat load (OFL) (35 g fat/m2 body surface). On both occasions plasma total-cholesterol, LDL-C, HDL-C, triglycerides, lipoprotein[a] (Lp[a]), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (AT-III), plasminogen and fibrinogen were determined just before the meal (t0) and at times 2 hours, 4 h, 6 h, 8 h after it (t2-t8). A two-factor (time and visit) multivariate analysis for repeated measurements was performed to evaluate the data. Total cholesterol, and LDL-C were significantly diminished 2 months after both gemfibrozil and simvastatin, the latter being more active. Plasma triglycerides showed a marked reduction with gemfibrozil at all times, while simvastatin regimen yielded only minor modifications. HDL-C was only slightly increased by simvastatin; Lp[a] plasma levels were almost unaffected. Small fibrinogen (t0, t2, t6, t8), PAI-1 (t6) and AT III (t0-t8) increases were observed after gemfibrozil, while simvastatin did not significantly modify these parameters. CONCLUSIONS: In the post-prandial phase, gemfibrozil and simvastatin induce different metabolic effects that beneficially influence the lipid pattern, whereas fibrinolytic and coagulative parameters display minor variations of undetermined significance.

Familial combined hyperlipoproteinemia: experts panel position on diagnostic criteria for clinical practice. Committee of experts of the Atherosclerosis and Dysmetabolic Disorders Study Group.

The Atherosclerosis and Dysmetabolic Disorders Study Group, headed by Prof. Rodolfo Paoletti, decided in 1994 to compose a committee of experts to formulate a clear description of familial combined hyperlipoproteinemia (FCH), a disorder illustrated in the literature, but still unknown to most physicians in spite of its severity and relative diffusion. The Committee consists of experts from the Lipid Clinics of the Universities of Ancona, Bari, Bologna, Ferrara, Genoa, Milan, Naples, Padua, Palermo, Perugia, Rome, Sassari, Turin, Verona and Venice. It has held several meetings coordinated by the national secretary at the "Giancarlo Descovich" Atherosclerosis Centre of the University of Bologna. This paper summarizes its conclusions.

Treatment challenges in hypercholesterolemia.

Primary and secondary prevention trials in individuals with high plasma cholesterol levels have proven that cholesterol-lowering drug treatment significantly reduces the risk of coronary heart disease (CHD) morbidity and mortality, and prolongs life. The degree of clinical benefit derived from such treatment appears to be proportional to the percentage reduction in plasma cholesterol. Regression and reduced progression of atherosclerosis may partially account for the clinical gains derived from lipid-lowering drug therapy; however, other direct mechanisms may be operative, including reduced atherogenicity of macrophages, improved vascular vasodilation, and reduced thrombogenesis. Specific treatment is determined on the basis of LDL cholesterol levels and overall global risk for CHD, that is, the presence of CHD and/or other CHD risk factors. Angiographic and clinical data support intensive lipid-lowering therapy in all hypercholesterolemic patients with CHD and those with high CHD risk, particularly those with ultrasonographic evidence (but no symptoms) or clinical signs of extracoronary atherosclerosis. Selection criteria for monotherapy include LDL-cholesterol lowering efficacy, CHD morbidity/mortality and overall survival benefits, no adverse effect on concomitant metabolic diseases (e.g., diabetes), tolerability, long-term safety, simple dose schedule, and cost effectiveness. However, in refractory hypercholesterolemia combination therapy may be required. Secondary prevention and primary prevention in individuals at high CHD risk are cost effective.

Double-Blind Comparison of Apolipoprotein and Lipoprotein Particle Lowering Effects of Atorvastatin and Pravastatin Monotherapy in Patients With Primary Hypercholesterolemia.

METHODS AND RESULTS: A total of 305 subjects with primary hypercholesterolemia were randomized in a 3:1 ratio to receive either atorvastatin 10 mg daily or pravastatin 20 mg daily according to a 16-week double-blind comparative study of the effect on apolipoprotein and lipoprotein particle levels. All patients had low-density lipoprotein (LDL)-cholesterol levels between 4.2 and 6.6 mM and triglyceride concentrations below 4.5 mM at baseline. After 16 weeks of treatment, apoB (-27% and -16%; P <.001), apoE (-13.3% and -5.6%; P <.05) and the triglyceride-rich LpC-III:B particle (-33% and -26%; P <.05) levels were reduced to a significantly greater extent in the atorvastatin than in the pravastatin treatment group. Both atorvastatin and pravastatin increased apoA-I levels, an effect that was more pronounced in the pravastatin group (+7% and +11%; P <.002). The increased apoA-I levels predominated on LpA-I in the atorvastatin group (+11%) and on LpA-I:A-II in the pravastatin group (+13%). ApoA-II levels were decreased with atorvastatin to a greater extent than with pravastatin (-1% and +2.8%; P <.05). CONCLUSIONS: Although atorvastatin and pravastatin belong to the same therapeutic family, they produce different effects in apoliprotein concentrations in hypercholesterolemic patients. Atorvastatin, an agent of the new generation, appears to efficiently reduce apoB-containing lipoprotein particles containing apoC-III.

Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia.

Plasma cholesterol and other lipoproteins play a significant role in the development of atherosclerosis and subsequent coronary heart disease (CHD). This 1 year study was designed to confirm the efficacy and safety of atorvastatin (Lipitor) compared to pravastatin, a marketed agent for low density lipoprotein cholesterol (LDL-C) reduction in hypercholesterolemic patients. Patients were recruited at 26 centers in six European countries. After a 6 week placebo baseline phase, patients were randomized to receive atorvastatin 10 mg or pravastatin 20 mg daily. The dose could be doubled at week 16, if LDL-C levels remained > or = 3.4 mmol/l (135 mg/dl). Atorvastatin significantly lowered LDL-C from baseline by 35% compared with 23% for pravastatin (P < 0.05). A total of 72% of atorvastatin patients attained the LDL-C target level of < 3.4 mmol/l, compared to 26% of pravastatin patients. Atorvastatin also significantly reduced TC, TG and apo B (P < 0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for both treatment groups and neither treatment caused clinically relevant laboratory abnormalities. Atorvastatin 10 and 20 mg once daily is superior to pravastatin 20 and 40 mg once daily in treating patients with hypercholesterolemia.

Effect of dietary versus pharmacological correction of hypertriglyceridemia on red blood cell membrane sodium/lithium countertransport activity.

An elevated red blood cell Na/Li countertransport (Na/Li CT) is often associated with high blood pressure and metabolic abnormalities. Recent studies suggested that a reduction in serum TG levels is associated with a decrease in Na/Li CT activity. However, it is still unclear if this phenomenon could be originated from systemic metabolic alterations or from modifications of the membrane dynamic properties. Aim of the present study was to investigate whether dietary or pharmacological TG lowering therapy might have a different effect on Na/Li CT activity and related metabolic parameters. Twenty normotensive hyper-TG patients were recruited from the Lipid outpatient Clinic: they had a baseline Na/Li CT activity significantly higher compared with age- and BMI-matched normolipidemic controls (386+/-33 vs 274+/-39 umol/l RBC/h, p<0.05). The patients were randomly prescribed one of the following two-months treatment: Group 1)-triglyceride lowering diet; Group 2)-lipid lowering drug (Gemfibrozil 600 mg b.i.d.). Na/Li CT and metabolic and anthropometric variables were measured at baseline and after 1 and 2 months of treatment. At the end of intervention, there was in both groups a significant and comparable fall in plasma triglyceride (group 1: -2.61+/-0.73 mmol/l p<0.01; group 2: -4.29+/-1.20 mmol/l p<0.01). In the diet-treated group there were, in addition small but significant reductions in body weight (-3.7+/-0.8 kg p<0.01), fasting glucose (-0.36+/-0.14 mmol/l p<0.05) and insulin levels (-2.1+/-0.5 mU/l, p<0.01), while no such changes were observed in the fibrate treated patients. Na/Li CT activity was significantly and comparably reduced at the end of treatment in both groups (group 1: -97+/-28 umol/l cell/h, p<0.01; group 2: -89+/-30 umol/l cell/h, p<0.01). In conclusion, these results indicate that the decrease in Na/Li CT associated with both dietary and drug treatment of hypertriglyceridemia is to be traced to a direct effect of plasma TG concentration on this transport system (probably as a result of modification in the membrane lipid environment) rather than to changes in plasma insulin levels or insulin resistance.