Hyperlipidemias: Ferrannini E

Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, Cosentino F, Jönsson B, Laakso M, Malmberg K, Priori S, Ostergren J, Tuomilehto J, Thrainsdottir I, Vanhorebeek I, Stramba-Badiale M, Lindgren P, Qiao Q, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL, Deckers JW, Bertrand M, Charbonnel B, Erdmann E, Ferrannini E, Flyvbjerg A, Gohlke H, Juanatey JR, Graham I, Monteiro PF, Parhofer K, Pyörälä K, Raz I, Schernthaner G, Volpe M, Wood D, Anonymous00256, Anonymous00257. · Department of Cardiology, Karolinska University Hospital, Sweden. · Eur Heart J. · Pubmed #17220161 links to  free full text

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Ferrannini E, Tuomilehto J. · University of Pisa, Italy. · Int J Clin Pract Suppl. · Pubmed #14649697 No free full text.

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Santini E, Madec S, Corretti V, Ferrannini E, Solini A. · Department of Internal Medicine, University of Pisa, I-56100 Pisa, Italy. · J Endocrinol Invest. · Pubmed #18787388 No free full text.

Abstract: Hypercholesterolemia and Type 2 diabetes are well-recognized risk factors for cardiovascular disease, promoted by a condition of subclinical inflammation and a hypercoagulable state. Soluble CD40 ligand (sCD40L), a marker of vascular inflammation, seems to predict vascular damage in patients with Type 2 diabetes. Beside the lipid-lowering effect, statins seem to slow the progression of atherosclerosis through a series of anti-inflammatory effects, including a reduction of sCD40L levels. This study compared the effect of a short-term (12 weeks) treatment with rosuvastatin or simvastatin on some markers of inflammation in 36 patients with Type 2 diabetes and moderate hypercholesterolemia. As expected, both drugs significantly modified lipid profile; moreover, rosuvastatin and simvastatin were both able to significantly reduce albumin excretion rate in these patients, without affecting urinary N-acetyl-beta-D-glucosaminidase. Serum homocysteine was not influenced by the treatment, as interleukin-6 levels, while C reactive protein diminished; moreover, rosuvastatin, but not simvastatin, was able to significantly reduce sCD40L. The only clinical parameter related with the variations in sCD40L was systolic blood pressure. In hypercholesterolemic Type 2 diabetic patients, sCD40L, a factor playing a pivotal role in the pathogenesis of atherosclerosis and associated with more rupture-prone lesions, is reduced by short-term treatment with rosuvastatin.

Solini A, Santini E, Ferrannini E. · Metabolism Section, Department of Internal Medicine University of Pisa, School of Medicine, Pisa, Italy. · J Hypertens. · Pubmed #15662225 No free full text.

Abstract: OBJECTIVE: Familial hypercholesterolemia (FH) is characterized by a high incidence of coronary heart disease. Evidence suggests an important role for angiotensin II (AngII) in the fibrotic response to tissue injury, and in promoting myocardial hypertrophy via paracrine mechanisms mediated by fibroblasts. We sought to determine whether AngII promotes proliferative and pro-atherogenic responses in FH patients. METHODS: We used primary fibroblasts -- from five patients with heterozygous FH and five control subjects (C) -- to study AngII-induced cell growth, intracellular calcium fluxes, and expression/release of matrix components and pro-inflammatory peptides [transforming growth factor-beta1 (TGFbeta1) and endothelin-1 (ET-1)] and metalloproteinases involved in plaque remodeling and vulnerability. RESULTS: AngII stimulated cell replication (5.1 +/- 0.03 versus 3.2 +/- 0.04 cells/50 cells per well, P < 0.001), and induced a larger increase in intracellular calcium content in FH cells than in C cells, in a dose-dependent fashion (mean difference = 76 nmol/l, P < 0.001). Similarly, TGFbeta1 and ET-1 expression and release were potentiated (after 24-h incubation with 1 micromol/l AngII: TGFbeta1 was 190 +/- 12 in C and 376 +/- 9 pg/ml per 10(6) cells in FH, and ET-1 was 93 +/- 5 in C and 192 +/- 7 pmol/ml per 10(6) cells in FH; P < 0.001 for both). AngII-induced release of the metalloproteinases MMP-1 and MMP-2 was also increased in FH versus C cells (0.52 +/- 0.04 versus 0.36 +/- 0.05 and 24 +/- 4 versus 13 +/- 3 ng/mg protein with 1 micromol/l AngII). These enhanced responses were likely due to an increased angiotensin receptor 1 (AT1) expression in cells from FH patients induced by AngII, and were prevented by pretreating cells with the selective AT1 antagonist irbesartan. CONCLUSIONS: These findings show that some AngII-mediated pathways are enhanced in FH subjects irrespective of the presence of low-density lipoprotein (LDL), thus contributing to the development and progression of atherosclerosis in these patients.

Solini A, Passaro A, Fioretto P, Nannipieri M, Ferrannini E. · Department of Internal Medicine, University of Pisa, Pisa, Italy. · J Intern Med. · Pubmed #15189363 No free full text.

Abstract: OBJECTIVE: Recent prospective studies have identified hyperlipidaemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants of the LPL, HindIII has been associated with coronary heart disease and, more recently, with microalbuminuria in type 2 diabetes. We evaluated the progression of renal disease in hypercholesterolaemic type 2 diabetic patients in relation to this polymorphism. DESIGN AND SUBJECTS: We followed up for 4 years 65 consecutively enrolled microalbuminuric patients with type 2 diabetes; of whom 28 had hypercholesterolaemia (6.62 +/- 0.9 mmol L(-1), group A) and 37 were normocholesterolaemic (4.68 +/- 0.5 mmol L(-1), group B). MAIN OUTCOME MEASURES: After performing the genetic analyses, albumin excretion rate (AER) and estimated glomerular filtration rate (GFR), calculated by the simplified equation of the MDRD Study Group, were repeated every year. RESULTS: In group A, AER increased more (deltaAER: 11 [38] vs. 4 [18] microg min(-1) per year in group B, P < 0.0001) while GFR declined faster (-3.5 +/- 2.1 vs. -2.0 +/- 1.4 mL min(-1) per year, P < 0.02). Patients homozygous for the allele + of HindIII showed a significantly faster decline of GFR and a higher increase of AER (both P = 0.0001) even after adjustment for cholesterol levels and anthropometric variables. CONCLUSIONS: In hypercholesterolaemic type 2 diabetic patients with microalbuminuria, the renal disease has an accelerated course, particularly in those carrying the H+/H+ genotype of the HindIII polymorphism at the LPL locus.

Franzoni F, Quiñones-Galvan A, Regoli F, Ferrannini E, Galetta F. · Department of Internal Medicine, University of Pisa School of Medicine, Via Roma, 67, 56100 Pisa, Italy. · Int J Cardiol. · Pubmed #12957768 No free full text.

Abstract: BACKGROUND: Treatment of hypercholesterolemia with statins is remarkably effective in cardiovascular prevention. This has led to the hypothesis that these drugs may act on the atherosclerotic plaque by mechanism(s) independent of the reduction of serum cholesterol levels. The aim of this study was to assess the total antioxidant activity of the most prescribed statins: fluvastatin, atorvastatin, pravastatin and simvastatin. METHODS: We measured the in vitro antioxidant activity of statins as their ability to antagonize the oxidation of alpha-keto-gamma-methiolbutyric acid by both hydroxyl and peroxyl radicals. The results are expressed as Total Oxyradical Scavenging Capacity (TOSC) units. Uric acid and Trolox were used as the reference antioxidants. RESULTS: The scavenging capacity towards hydroxyl radicals was highest for simvastatin (3375+/-112 U/mg), a value 270.2% higher (P<0.0001) compared to uric acid (reference antioxidant vs. hydroxyl radicals, 1249+/-71 U/mg). Among the tested statins, fluvastatin exhibited the highest anti-peroxyl radical antioxidant capacity (8755+/-187 U/mg) which appeared 50% lower (P<0.0001) compared to Trolox (reference antioxidant vs. peroxyl radicals, 17460+/-379 U/mg). CONCLUSIONS: All the statins tested have intrinsic antioxidant activity with both anti-hydroxyl and peroxyl radical activity. Simvastatin was the most effective as an anti-hydroxyl radical antioxidant and fluvastatin as an anti-peroxyl radical antioxidant.

Ferrannini E. · CNR Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Italy. · Lancet. · Pubmed #10881887 No free full text.

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Mingrone G, Henriksen FL, Greco AV, Krogh LN, Capristo E, Gastaldelli A, Castagneto M, Ferrannini E, Gasbarrini G, Beck-Nielsen H. · Department of Internal Medicine, Catholic University, Rome, Italy. · Diabetes. · Pubmed #10342813 links to  free full text

Abstract: Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA) concentrations are thought to play a role in the pathogenesis of insulin-resistant diabetes. We report on two sisters with extreme hypertriglyceridemia and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In all of the family members (parents, two affected sisters, ages 18 and 15 years, and an 11-year-old unaffected sister), we measured oral glucose tolerance, insulin sensitivity (by the euglycemic-hyperinsulinemic clamp technique), substrate oxidation (indirect calorimetry), endogenous glucose production (by the [6,6-2H2]glucose technique), and postheparin plasma lipoprotein lipase (LPL) activity. In addition, GC-clamped polymerase chain reaction-amplified DNA from the promoter region and the 10 coding LPL gene exons were screened for nucleotide substitution. Two silent mutations were found in the father's exon 4 (Glu118 Glu) and in the mother's exon 8 (Thr361 Thr), while a nonsense mutation (Ser447 Ter) was detected in the mother's exon 9. Mutations in exons 4 and 8 were inherited by the two affected girls. At 1-2 years after the appearance of hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin resistance. Because medical therapy (including high-dose insulin) failed to reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced by a modified biliopancreatic diversion. Within 3 weeks of surgery, plasma TGs and NEFA and cholesterol levels were drastically lowered. Concurrently, fasting plasma glucose levels fell from 17 to 5 mmol/l (with no therapy), while insulin-stimulated glucose uptake, oxidation, and storage were all markedly improved. Throughout the observation period, plasma TG levels were closely correlated with both plasma glucose and insulin concentrations, as measured during the oral glucose tolerance test. These cases provide evidence that insulin-resistant diabetes can be caused by extremely high levels of TGs.