Significant improvement of apolipoprotein B-containing lipoprotein metabolism by insulin treatment in patients with non-insulin-dependent diabetes mellitus

Duvillard, Laurence; Pont, Frédéric; Florentin, E; Gambert, Philippe; Vergès, Bruno

doi:10.1007/s001250050004

Cited by 39 publications

(20 citation statements)

References 40 publications

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“…Since lipoproteins are metabolically active in the plasma compartment, we expressed the production rates adjusted to plasma volume instead of body weight, as previously reported. 10,11 Our results indicate that insulin resistance significantly influences HDL metabolism since the insulin resistance index (HOMA) was negatively correlated with HDL cholesterol levels. Furthermore, apoA-I fractional catabolic rate was positively correlated with clinical (waist -hip ratio, waist circumference) and biological markers of insulin resistance (plasma fasting and post-load insulin levels, HOMA).…”

Section: Discussionmentioning

confidence: 71%

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High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

et al. 2002

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AIMS=HYPOTHESIS:Mechanisms responsible for the decreased high-density lipoprotein (HDL) cholesterol level associated with insulin resistance in obese patients are not clearly understood. To determine the influence of insulin resistance at an early stage on HDL metabolism, we performed a stable isotope kinetic study of apolipoprotein (apo) A-I, in five obese insulin resistant women with normal fasting triglycerides and without impaired glucose tolerance, and in five age-matched control women. METHODS: Each subject received a 16 h constant infusion of L-[1-13 C]leucine at 0.7 mg=kg=h following a primed bolus of 0.7 mg=kg. RESULTS: ApoA-I fractional catabolic rate (FCR) was significantly increased in insulin-resistant women compared to controls (0.316 AE 0.056 vs 0.210 AE 0.040 per day, P < 0.01), indicating a significant 50% increase of apoA-I catabolism, leading to an important reduction of plasma apoA-I residence time (3.25 AE 0.59 vs 4.92 AE 1.11, P < 0.01). ApoA-I production rate tended to be higher in insulin resistant women than in controls (364 AE 77 vs 258 AE 60 mg=l=day, P ¼ 0.13), but the difference was not statistically significant. ApoA-I FCR was correlated with triglycerides during the fed state (r ¼ 0.69; P ¼ 0.026) and HDL triglycerides -esterified cholesterol ratio (r ¼ 0.73; P ¼ 0.016), suggesting that alteration of apoA-I metabolism in insulin resistance may be partly related to HDL enrichment in triglycerides. CONCLUSIONS: Our kinetic study shows that patients, at an early stage of insulin resistance (without impaired glucose tolerance nor fasting hypertriglyceridaemia), already have a significant alteration of apoA-I metabolism (increased apoA-I catabolism), which is consistent with the increased risk of atherosclerosis in this population.

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Section: Discussionmentioning

confidence: 71%

“…Thus, data were normalized to the plasma volume of each subject, as previously reported. 10,11 Analytical methods Apolipoprotein and lipid assays. Concentrations of apoA-I were determined by immunoturbidimetry 24 with anti-apoA-I antibodies purchased from Boeringer Mannheim.…”

Section: Modellingmentioning

confidence: 99%

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

et al. 2002

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“…The following day, kinetic study was performed in the fed state. Food intake, with a leucinepoor diet (1700 kcal/day, 55% carbohydrates, 39% fats, and 7% proteins), was fractionated in small portions that were provided every 2 h starting 6 h prior to the tracer infusion up to the end of the study to avoid important variations in apolipoprotein plasma concentration, as previously performed by our group (18,19) and others (20). The endogenous labeling of apoA-I was carried out by administration of L- [1][2][3][4][5][6][7][8][9][10][11][12][13] C] leucine (99 atom %, w/v; Eurisotop, Saint Aubin, France), dissolved in 0.9% (w/v) NaCl solution.…”

Section: Methodsmentioning

confidence: 99%

Rosuvastatin 20 mg restores normal HDL-apoA-I kinetics in type 2 diabetes

Vergès

Florentin

Baillot-Rudoni

et al. 2009

Journal of Lipid Research

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Catabolism of HDL particles is accelerated in type 2 diabetes, leading to a reduction in plasma residence time, which may be detrimental. Rosuvastatin is the most powerful statin to reduce LDL-cholesterol, but its effects on HDL metabolism in type 2 diabetes remain unknown. We performed a randomized double-blind cross-over trial of 6-week treatment period with placebo or rosuvastatin 20 mg in eight patients with type 2 diabetes. An in vivo kinetic study of HDL-apolipoprotein A-I (apoA-I) with 13 C leucine was performed at the end of each treatment period. Moreover, a similar kinetic study was carried out in eight nondiabetic normolipidemic controls. Rosuvastatin significantly reduced plasma LDL-cholesterol (251%), triglycerides (TGs) (238%), and HDL-TG (223%). HDL-apoA-I fractional catabolic rate (FCR) was decreased by rosuvastatin (0.25 6 0.06 vs. 0.32 6 0.07 pool/day, P 5 0.011), leading to an increase in plasma HDL-apoA-I residence time (4.21 6 1.02 vs. 3.30 6 0.73 day, P 5 0.011). Treatment with rosuvastatin was associated with a concomitant reduction of HDL-apoA-I production rate. The decrease in HDL-apoA-I FCR, induced by rosuvastatin, was correlated with the reduction of plasma TGs and HDL-TG. HDL apoA-I FCR and production rate values in diabetic patients on rosuvastatin were not different from those found in controls. Rosuvastatin is responsible for a 22% reduction of HDL-apoA-I FCR and restores to normal the increased HDL turnover observed in type 2 diabetes. These kinetic modifications may have beneficial effects by increasing HDL plasma residence time. Cardiovascular disease is the major cause of morbidity and mortality in patients with type 2 diabetes, and cardiovascular disease risk is 2-to 4-fold increased over nondiabetic subjects (1-4). Abnormalities of lipid metabolism, observed in type 2 diabetes, are one of the major factors contributing to vascular risk (5, 6). Diabetic dyslipidemia includes increased plasma triglycerides (TGs), decreased HDL-cholesterol levels, and qualitative lipoprotein abnormalities, such as TG enrichment of LDL and HDL particles (7, 8). Low HDL-cholesterol level, in patients with type 2 diabetes, has been shown to be due to increased catabolism of HDL lipoproteins by in vivo kinetic studies using radioisotopes (9) or stable isotopes (10). This increased catabolism of HDL particles leads automatically to significantly decrease their plasma residence time. The cardiovascular protective role of HDL is thought to be mainly due to its role in reverse cholesterol transport (11) and potentially to the antioxidative, anti-inflammatory, antithrombotic, and endothelium-dependent vasorelaxant effects of HDL particles (12). The increased catabolism of HDL lipoproteins is likely to reduce the cardioprotective effects of HDLs in patients with type 2 diabetes.Rosuvastatin is a statin that has been shown to reduce LDL-cholesterol more than the other statins at an equivalent dose (13). In addition, rosuvastatin significantly decreases plasma TG level with larger effect than prav...

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“…A slight increase of VLDL-apoB production likely contributes to the hyperlipidemia in 1 patient (BIII3). It is most likely the consequence of her diabetes mellitus rather than of Apoa5 truncation because her VLDL-apoB PR is as usually observed in type 2 diabetic patients (22,23). Accordingly, recent experimental studies indicated that Apoa5 does not modulate hepatic VLDL production (24) but induces an LPL-dependent acceleration of the catabolism of TG-rich lipoproteins (24)(25)(26).The increase in IDL pool despite the reduced VLDL catabolism is likely due to the 22-fold increase in VLDL pool leading to a residual conversion into LDL.…”

Section: Figurementioning

confidence: 99%

Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment

Marçais

Vergès²,

Charrière³

et al. 2005

Journal of Clinical Investigation

150

105

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While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia. IntroductionRaised plasma triglyceride (TG) levels are an independent risk factor for coronary artery disease (1) and are influenced by both genetic and environmental factors. Severe hypertriglyceridemia (HTG) is a general condition with a few well-documented genetic contributors, including lipoprotein lipase (LPL), APOC2, and APOE, as well as environmental factors such as diet and/or conditions such as pregnancy and diabetes (2-5). While genetic factors account for a large proportion of the rare type 1 hyperlipidemia, the complex interaction between genetics and environment is only partly understood in the more common type 5 hyperlipidemia.A strong candidate for severe HTG is the recently discovered human apolipoprotein A-V (APOA5) gene based on its profound modulation of plasma TG concentration. In mice, apoa5 overexpression lowered plasma TG concentration (6-8) whereas mice lacking Apoa5 had a 4-fold increase in plasma TG concentration (6). In humans, independent studies have demonstrated that variant haplotypes with either the S19W or the c.A-3G APOA5 polymorphisms are strong determinants of plasma TG

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Significant improvement of apolipoprotein B-containing lipoprotein metabolism by insulin treatment in patients with non-insulin-dependent diabetes mellitus

Cited by 39 publications

References 40 publications

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

Rosuvastatin 20 mg restores normal HDL-apoA-I kinetics in type 2 diabetes

Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment

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