Hypertriglyceridemia is associated with increased insulin resistance in subjects with normal glucose tolerance: evaluation in a large cohort of subjects assessed with the 1999 World Health Organization criteria for the classification of diabetes.

The current study retrospectively examined the association between insulin resistance and plasma triglycerides (TG) in a group of subjects with normal glucose tolerance. Among 1,434 subjects consecutively undergoing a standard oral glucose tolerance test (OGTT) between 1993 and 1998, 567 (age, 15 to 78 years) were classified as having a normal glucose tolerance according to the 1999 World Health Organization (WHO) criteria and were selected for the study. Serum insulin was measured by radioimmunoassay (INSI-CTK, Dia Sorin, Saluggia, Italy). Intra-assay and interassay coefficients of variation for the method were less than 4% and less than 8.5%, respectively. Insulin resistance was calculated by a homeostasis model assessment (HOMA(IR) = fasting serum insulin [mU/mL] x fasting blood glucose [mmol/L]/22.5). A very significant correlation was found between HOMA(IR) and plasma TG (r = 0.27, P < 1.02E(-10)). Multiple regression analyses confirmed plasma TG as independent variables explicative of HOMA(IR). When subjects were evaluated according to tertiles of TG, those in the upper two tertiles were older (P <.001) and presented higher body mass index (BMI) values (P <.0001) in comparison to subjects in the lower tertile. A positive trend (analysis of variance [ANOVA]) was found in regard to systolic (P <.05) and diastolic blood pressure (P <.0001), fasting blood glucose (P <.01), fasting serum insulin (P <.0001), and total cholesterol (P <.0001), while a negative trend was found in regard to high-density lipoprotein cholesterol (HDL-C) (P <.0001). Insulin resistance, calculated as HOMA(IR), was higher in the upper two tertiles of TG in comparison to the lower tertile (P <.001 and P <.0001, respectively), with a statistically significant trend for the entire group (first tertile, 1.85 +/- 0.94; second tertile, 2.28 +/- 1.10; third tertile, 2.65 +/- 1.71; ANOVA: P <.0001). In conclusion, this study shows an association between high levels of circulating TG and insulin resistance in patients with normal glucose tolerance seen in an atherosclerosis prevention clinic. This association is also present at levels of plasma TG considered to be normal and is associated with a cluster of cardiovascular risk factors.

Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL(-).

A subpopulation of low-density lipoproteins (LDL) is present in human plasma that contains lipid hydroperoxides and is more negatively charged (LDL(-)) than normal native LDL. By circular dichroism and tryptophan lifetime measurements we found that apoB-100 secondary structure is markedly decreased and its conformation is severely altered in LDL(-). The low tryptophan fluorescence intensity confirms the oxidative degradation of the lipoprotein, and the very long lifetime value of one of its decay components indicates a low polarity environment for the remaining unbleached residues. Either a peculiar folding or, most likely, a sinking of the apoB-100 into the lipid core can account for the observed long lifetime component. Oxidation in vitro produces a similar unfolding of the apolipoprotein but the lifetime of tryptophan fluorescence is shifted to lower values, indicating that the denatured apoprotein remains at the hydrophilic surface of the lipoprotein particle. A disordering and an increased polarity of the LDL(-) surface lipids was demonstrated by measuring the generalized polarization of 2-dimethylamino-6-lauroylnaphthalene (Laurdan). The looser monolayer packing apparently favors the new conformation of apoB-100 and its sinking into a more hydrophobic environment, possibly accounting for it reduced receptor binding properties.

Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients.

In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome, a multicenter double-blind placebo controlled, parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance. These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion. Gemfibrozil reduced plasma triglyceride levels (P<0.001), whereas it increased free fatty acids (P<0.05) and high density lipoprotein cholesterol levels (P<0.05). In those patients reaching normalization of plasma triglyceride levels (triglyceride reduction > or =50%) (n=15), insulin levels (P<0.05) as well as the insulin resistance index were reduced by gemfibrozil treatment, suggesting an improvement of the insulin resistance index in this patient subgroup. Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels, despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization.

Fish intake, independent of apo(a) size, accounts for lower plasma lipoprotein(a) levels in Bantu fishermen of Tanzania: The Lugalawa Study.

Plasma lipoprotein(a) [Lp(a)] levels are largely genetically determined by sequences linked to the gene encoding apolipoprotein(a) [apo(a)], the distinct protein component of Lp(a). Apo(a) is highly polymorphic in length due to variation in the numbers of a sequence encoding the apo(a) kringle 4 domain, and plasma levels of Lp(a) are inversely correlated with apo(a) size. In 2 racially homogeneous Bantu populations from Tanzania differing in their dietary habits, we found that median plasma levels of Lp(a) were 48% lower in those living on a fish diet than in those living on a vegetarian diet. Considering the relationship between apo(a) size and Lp(a) plasma concentration, we have extensively evaluated apo(a) isoform distribution in the 2 populations to determine the impact of apo(a) size in the determination of Lp(a) values. The majority of individuals (82% of the fishermen and 80% of the vegetarians) had 2 expressed apo(a) alleles. Additionally, the fishermen had a high frequency of large apo(a) isoforms, whereas a higher frequency of small isoforms was found in the vegetarians. When subjects from the 2 groups were matched for apo(a) phenotype, the median Lp(a) value was 40% lower in Bantus on the fish diet than in those on the vegetarian diet. A significant inverse relationship was also found between plasma n-3 polyunsaturated fatty acids and Lp(a) levels (r=-0.24, P=0.01). The results of this study are consistent with the concept that a diet rich in n-3 polyunsaturated fatty acids, and not genetic differences, is responsible for the lower plasma levels of Lp(a) in the fish-eating Bantus and strongly suggest that a sustained fish-based diet is able to lower plasma levels of Lp(a).

Analytical capillary isotachophoresis of total plasma lipoproteins: a new tool to identify atherogenic low density lipoproteins.

Plasma low density lipoproteins from 20 patients were separated by capillary isotachophoresis (ITP). In each patient the apparent diameter of the predominant LDL peak on whole plasma was also determined by nondenaturing gradient gel electrophoresis. Furthermore the concentration of the more electronegatively charged in vivo oxidized LDL- was accomplished using anion exchange high pressure liquid chromatography. By analytical capillary ITP of whole plasma lipoproteins, prestained with a lipophilic dye, LDL were separated into four subfractions. Usually, the predominant subfraction was the slow migrating LDL4, followed by LDL3, and then by the faster LDL2 and LDL1. Slow migrating LDL4 correlated negatively with plasma triglycerides and LDL- and positively with plasma high density lipoprotein (HDL) cholesterol and with the LDL diameter, while the faster LDL1 showed an inverse behavior. The LDL1 + LDL2 to LDL3 + LDL4 ratio showed a strong positive correlation with LDL- concentration (r = 0.87; P < 0.001) and a highly significant inverse correlation with the LDL particle diameter (r = -0.74; P < 0.001). At least three highly atherogenic LDL that could be found in human plasma, namely oxidized, glycated and small-dense, are characterized by a greater electric charge. The LDL profile from capillary ITP and the relative prevalence of faster or slower migrating LDL fractions could indicate the presence of more atherogenic LDL.

Electronegative low density lipoprotein subform (LDL-) is increased in type 2 (non-insulin-dependent) microalbuminuric diabetic patients and is closely associated with LDL susceptibility to oxidation.

There is increasing evidence that diabetes mellitus is characterized by an enhanced lipoprotein oxidation. We have therefore investigated whether a relationship exists between LDL oxidation and microalbuminuria, which is considered an early marker of vascular involvement in type 2 diabetic patients. We selected 12 microalbuminuric and 12 normoalbuminuric type 2 diabetic patients, and 12 control subjects comparable for age, sex and blood pressure values. Oxidatively modified plasma LDL, referred as LDL-, were measured by ion-exchange HPLC. In vitro susceptibility to oxidation of LDL was evaluated by following the kinetics of conjugated diene formation in the presence of Cu++ ions (lag-phase time). Microalbuminuric diabetic patients had a less satisfactory metabolic control and showed a higher plasma triglyceride concentration than both normoalbuminuric diabetic patients (2.211+/-1.01 vs 1.15+/-0.39 mmol/l, P<0.O1) and controls (1.18+/-0.61 mmol/l, P<0.01 ). The percentage of LDL- in plasma was significantly increased in microalbuminuric diabetic patients in comparison with both normoalbuminuric diabetic patients (5.24+/-1.67 vs 3.13+/-1.22%, P<0.01) and controls (2.34+/-1.03%, P<0.001). LDL isolated from microalbuminuric diabetic patients had a significantly shorter lag-phase time in comparison with normoalbuminuric diabetic patients (79+/-11 vs 97+/-10 min, P<0.05) and controls (120+/-24 min. P<0.001). In diabetic patients a significant linear correlation was observed between the percentage of LDL and amount of fructosamine (r=0.45, P<0.05), HbA1c (r=0.41, P<0.05), and triglycerides (r=0.65, P<0.001). An inverse correlation was found between lag-phase time and fructosamine (r=-0.5, P<0.01) and triglycerides (r=-0.59, P<0.001). This study shows that microalbuminuric type 2 diabetic patients had evidence of increased LDL oxidation, which seems to be mainly due to a poor metabolic control and a more atherogenic lipid profile.

Effect of thyroid function on LDL oxidation.

In this study, the effect of different levels of thyroid hormone and metabolic activity on low density lipoprotein (LDL) oxidation was investigated. Thus, in 16 patients with hyperthyroidism, 16 with hypothyroidism, and 16 age- and sex-matched healthy normolipidemic control subjects, the native LDL content in lipid peroxides, vitamin E, beta-carotene, and lycopene, as well as the susceptibility of these particles to undergo lipid peroxidation, was assessed. Hyperthyroidism was associated with significantly higher lipid peroxidation, as characterized by a higher native LDL content in lipid peroxides, a lower lag phase, and a higher oxidation rate than in the other two groups. This elevated lipid peroxidation was associated with a lower LDL antioxidant concentration. Interestingly, hypothyroid patients showed an intermediate behavior. In fact, in hypothyroidism, LDL oxidation was significantly lower than in hyperthyroidism but higher than in the control group. Hypothyroidism was also characterized by the highest beta-carotene LDL content, whereas vitamin E was significantly lower than in control subjects. In hyperthyroidism but not in the other two groups, LDL oxidation was strongly influenced by free thyroxine blood content. In fact in this group, the native LDL lipid peroxide content and the lag phase were directly and indirectly, respectively, related to free thyroxine blood levels. On the contrary, in hypothyroidism LDL oxidation was strongly and significantly related to serum lipids. In conclusion, both hypothyroidism and hyperthyroidism are characterized by higher levels of LDL oxidation when compared with normolipidemic control subjects. In hyperthyroid patients, the increased lipid peroxidation was strictly related to free thyroxine levels, whereas in hypothyroidism it was strongly influenced by serum lipids.

Increased levels of soluble P-selectin in hypercholesterolemic patients.

BACKGROUND: Hypercholesterolemia is considered a major risk factor for the development of atherosclerosis. Enhanced lipid peroxidation and persistent platelet activation can be observed in vivo in hypercholesterolemic patients and may have pathophysiological implications in the occurrence of cardiovascular events. P-selectin may play an important role in the pathogenesis of multicellular events, including atherosclerosis. We studied the impact of hypercholesterolemia and oxidative stress on plasma levels of P-selectin. METHODS AND RESULTS: Plasma levels of P-selectin were measured by means of an enzyme immunoassay in 20 hypercholesterolemic patients with no clinical evidence of cardiovascular disease and in 20 sex- and age-matched normocholesterolemic subjects. Hypercholesterolemic patients had higher levels of P-selectin compared with that of control subjects (98+/-61 versus 56+/-14 ng/mL; P=.001). They also displayed increased von Willebrand Factor (vWF) levels (176+/-22 versus 119+/-12%; P=.0001). A direct correlation was observed between P-selectin and LDL cholesterol levels (p=.453). Administration of vitamin E (600 mg/d for 2 weeks) to hypercholesterolemic patients significantly reduced plasma P-selectin (40%), and an inverse correlation was observed between vitamin E and P-selectin plasma levels (p=-.446). CONCLUSIONS: Hypercholesterolemia is associated with elevated plasmatic P-selectin. Altered oxidative processes leading to endothelial dysfunction and persistent platelet activation may contribute to increased soluble P-selectin levels. P-selectin may be proposed as a marker of endothelial dysfunction in hypercholesterolemic patients.

LDL- is a lipid hydroperoxide-enriched circulating lipoprotein.

A subclass of LDL described on the basis of its greater electronegativity and oxidative status is further characterized using a new, highly sensitive single photon counting technique to measure lipid hydroperoxides. We describe in this report that these particles, which we refer to as LDL-, are enriched in lipid peroxides and other peroxidation products as compared to the bulk of the unmodified, normal LDL (nLDL) recovered from human plasma. This chemiluminescence-based, single photon counting technique has unique advantages in that analyses are performed on whole LDL, thus avoiding artifactual lipid peroxidation during lipid extraction. Evidence for increased amounts of lipid hydroperoxides in LDL- versus nLDL are in agreement with other analytical methods such as measurement of conjugated dienes as well as cholesterol oxidation products. LDL- also has lower proportions of polyunsaturated fatty acids than nLDL. Analysis of the amino acid composition of apoB-100 and fatty acid composition of total LDL lipids also revealed major differences between nLDL and LDL- consistent with an oxidative modification of the latter. Thus, LDL- has significantly lower proportions of the oxidizable amino acids histidine and lysine, and marked differences in other neutral and acidic amino acids. The deficit in specific amino acids is in agreement with a reduced TNBS reactivity and increased relative electrophoretic mobility of LDL-. We postulate that LDL- is a major carrier of lipid hydroperoxides associated with plasma LDL and may arise from oxidative events in the vasculature and/ or by ingestion of peroxide-enriched meals.

Blood pressure and atherogenic lipoprotein profiles of fish-diet and vegetarian villagers in Tanzania: the Lugalawa study.

BACKGROUND: There is evidence that populations with a high intake of fish, and specifically fish oils, are at reduced risk of cardiovascular disease. To explore the effect of fish intake, we compared two groups of Bantu villagers in Tanzania; one group live on the shores of Lake Nyasa and their diet includes large amounts of freshwater fish; the other group live in the nearby hills and have a vegetarian diet. METHODS: We carried out a cross-sectional study of 622 fish-consuming villagers and 686 vegetarian villagers. 618 (99.4%) and 645 (94.0%), respectively, agreed to take part. Anthropometric and self-reported medical history data were collected by one local physician and a medical assistant, who also measured blood pressure and took blood samples for measurement of plasma lipids. A dietary questionnaire was administered to 25 families (about 15% of the study population) in each village. FINDINGS: After adjustment for age, sex, and alcohol intake the fish-consuming group had lower mean blood pressure than the vegetarian group (123/72 vs 133/76 mm Hg, p < 0.001). The frequencies of definite and borderline hypertension (by WHO criteria) were lower in the fish-consuming than in the vegetarian group (2.8 vs 16.4%; 9.7 vs 22.3%, respectively). Plasma concentrations of total cholesterol (mean 3.53 [SD 1.04] vs 4.10 [1.04] mmol/L), triglycerides (0.92 [0.64] vs 1.31 [0.64] mmol/L), and lipoprotein(a) (201 [213] vs 321 [212] mg/L), were all lower (p < 0.0001) in the fish-consuming group than in the vegetarian group. The proportions of n-3 polyunsaturated fatty acids in plasma lipids were higher (p < 0.0001) in the fish-consuming group than in the vegetarian group (eicosapentaenoic acid 2.3 [1.3] vs 0.7 [0.2]%; docosapentaenoic acid 1.1 [0.4] vs 0.6 [0.3]%; docosahexaenoic acid 5.7 [1.6] vs 1.5 [1.1]%). INTERPRETATION: In these villagers, consumption of freshwater fish (300-600 g daily) was associated with raised plasma concentrations of n-3 polyunsaturated fatty acids, lower blood pressure, and lower plasma lipid concentrations.

Contribution of an in vivo oxidized LDL to LDL oxidation and its association with dense LDL subpopulations.

Oxidative modification of LDL is thought to be a radical-mediated process involving lipid peroxides. The small dense LDL subpopulations are particularly susceptible to oxidation, and individuals with high proportions of dense LDL are at a greater risk for atherosclerosis. An oxidatively modified plasma LDL, referred to as LDL-, is found largely among the dense LDL fractions. LDL- and dense LDL particles also contain much greater amounts of lipid peroxides compared with total LDL or the more buoyant LDL fractions. The content of LDL- in dense LDL particles appears to be related to copper- or heme-induced oxidative susceptibility, which may be attributable to peroxide levels. The rate of lipid peroxidation during the antioxidant-protected phase (lag period) and the length of the antioxidant-protected phase (lag time) are correlated with the LDL- content of total LDL. Once LDL oxidation enters the propagation phase, there is no relationship to the initial LDL- content or total LDL lipid peroxide or vitamin E levels. Beyond a threshold LDL- content of approximately 2%, there is a significant increase in the oxidative susceptibility of nLDL particles (ie, purified LDL that is free of LDL-), and this susceptibility becomes more pronounced as the LDL- content increases. nLDL is resistant to copper- or heme-induced oxidation. The oxidative susceptibility is not influenced by vitamin E content in LDL but is strongly inhibited by ascorbic acid in the medium. Involvement of LDL(-)-associated peroxides during the stimulated oxidation of LDL is suggested by the inhibition of nLDL oxidation when LDL- is treated with ebselen prior to its addition to nLDL. Populations of LDL enriched with LDL- appear to contain peroxides at levels approaching the threshold required for progressive radical propagation reactions. We postulate that elevated LDL- may constitute a pro-oxidant state that facilitates oxidative reactions in vascular components.

Blood pressure, serum lipids, and fatty acids in populations on a lake-fish diet or on a vegetarian diet in Tanzania.

Major risk factors for coronary heart disease were assessed in two populations of Tanzania, one on a fish diet (FD) living along the coast of Lake Nyasa, and the other, mainly on a vegetarian diet (VD), living in a farming area. Lower blood pressure values were found in the FD subjects (n = 618) vs. VD (n = 618) (systolic blood pressure, SBP, 120 +/- 15 vs. 135 +/- 20, P < 0.01; diastolic blood pressure, DBP, 70 +/- 9 vs. 78 +/- 11, P < 0.01, respectively). In an FD subgroup (n = 61), total cholesterol (TC) (122 vs. 136 mg/dL, P < 0.01); triglycerides (TG) (82 vs. 105 mg/dL, P < 0.01); and lipoprotein (a) [Lp(a)] (19.9 +/- 18.4 vs. 32.3 +/- 22.4, P < 0.001) were lower than in a VD subgroup (n = 55). Serum fatty acids (FA) in the FD subgroup were as follows: eicosapentaenoic acid (EPA) (20:5) 2.48 vs. 0.72%, docosahexaenoic acid (DHA) (22:6) 5.93 vs. 1.49%, vs. the VD, respectively. Arachidonic acid (AA) (20:4n-6) also was higher in the FD vs. the VD group (9.85 vs. 8.30%, P < 0.05), whereas 18:2n-6 was about double (23.97 and 14.85%) in VD vs. FD. The peculiar serum FA pattern in FD reflected the FA of dietary fish. In fact, in four main species of lake fish, DHA was 8-19%, higher than EPA (1.8-4.2%), in contrast with the situation in cold-water fish, and AA was 5.8-8%, higher than in cold-water fish. The data, obtained in populations strictly on natural, unprocessed, low-fat diets, show that a diet based on freshwater fish results in lower BP, serum TC, TG, and Lp(a), and suggests that serum AA is not reduced when the major dietary n-3 is DNA rather than EPA.

[Lipid peroxidation and LDL modifications in nondiabetic patients with ischemic heart disease: the role of insulin action]. / Perossidazione lipidica e modificazioni delle LDL in pazienti non diabetici con cardiopatia ischemica: il ruolo dell'azione insulinica.

BACKGROUND: Nondiabetic patients with advanced coronary artery disease (CAD) were assessed for lipid peroxidation, LDL modifications and insulin action. Twenty-four patients and 10 normal controls were studied. METHODS: Insulin tolerance test (Kitt), glucose, insulin lipoproteins, electronegatively charged, modified, low density lipoproteins (LDL-) and the thiobarbituric acid reactivity (TBARS), as an index of lipid peroxidation, were determined. RESULTS: No difference was observed in insulin action (determined by insulin tolerance test) between patients with CAD (3.31 +/- 0.28%/min; range 0.73-6.13) and normal controls (3.59 +/- 0.42; range 1.76-6.06). The percentage of modified, electronegative LDL (LDL -) was higher in patients with CAD (0.5 +/- 0.48%; range 1.3-9.2) than that of controls (2.80 +/- 0.33; range 1.00-4.00; p = 0.013). TBARS were significantly (P = 0.043) higher in CAD patients (3.49 +/- 0.17 nmol/ml; range 2.4-5.5) than normal controls (1.47 +/- 0.12; range 1.07-2.10). A significantly negative correlation was observed between Kitt and TBARS (r= - 0.48; p = 0.016), and a significant (r = 0.46; p = 0.022) positive correlation was observed between plasma glucose and TBARS. On the contrary no correlation has been observed between LDL- and TBARS. CONCLUSIONS: We conclude that in patients with advanced coronary artery disease: A) there are increased circulating levels of modified low density lipoprotein; B) there is evidence of increased lipid peroxidation. This latter process is significantly influenced by the degree of insulin action.

'Normolipidemic' tendinous and tuberous xanthomatosis.

BACKGROUND: Multiple tendinous and tuberous xanthomas are characteristically associated with hyperlipidemic states. However, normolipidemic tendinous and tuberous xanthomas have been reported in the literature, with normal levels of cholesterol, cholestanol and plant sterols. OBJECTIVE AND METHOD: To delineate the disorder and to suggest its likely origin, a case of apparently normolipidemic severe tuberous and tendinous xanthomatosis was studied. Several lipoprotein and lipid analyses, clinical tests and histological studies were performed over a period of 5 years in the propositus and his family. RESULTS: At the first lipid analysis, no quantitative or qualitative alterations of the lipoprotein fractions or of the apoproteins AI, B, CII, CIII, E were detected in the propositus and xanthomatosis was classified as normolipidemic. During the follow-up, the patient showed a nonconstant hypertriglyceridemia and/or hypercholesterolemia associated with the presence of small and dense VLDL and LDL. An increase in apo-B was observed. There was an unusual quantity of conjugated dienes of arachidonic acid in the plasma and in the LDLs of the patient, present only in small traces in the control population. The family study and the long follow-up of the lipid analysis of the propositus were compatible with the diagnosis of familial combined hyperlipidemia. CONCLUSION: Our data highlight the importance of a critical review of studies regarding normolipidemic xanthomatosis, since only after an extensive follow-up and sequential analyses of lipoprotein fractions is it possible to exclude the presence of time variables and complex lipoprotein abnormalities.

Naturally occurring modified low density lipoproteins are similar if not identical: more electronegative and desialylated lipoprotein subfractions.

Previous studies demonstrated that more electronegative low density lipoprotein (LDL) isolated from human blood by ion exchange chromatography has a chemical composition and physical properties similar to desialylated LDL obtained by lectin chromatography (Avogaro et al., 1988; Orekhov et al., 1989). In this study, sialic acid content and percentage of desialylated LDL in the electronegative LDL (LDL-) subfraction have been investigated. The sialic acid content of the LDL- was 2- to 6-fold lower than that of native LDL and close to that of desialylated LDL. In the native LDL subfraction, 83% of lipoprotein particles did not bind to the Ricinus communis agglutinin, indicating lack of terminal galactose, presumably appearing as a result of desialylation of LDL carbohydrate chains. By contrast, a major proportion of human LDL- (81%) was bound to the lectin. It was also found that the desialylated LDL subfraction consists of 88% LDL-. Native LDL did not affect the contents of free and esterified cholesterol in intimal cells cultured from grossly normal human aorta, while LDL- and desialylated LDL induced a 1.5- to 3-fold increase in the intracellular content of cholesteryl esters. Thus, LDL- is desialylated LDL which induces lipid accumulation in intimal cells. Our findings suggest that the LDL- particle is similar if not identical to the desialylated LDL particle.

[Decrease of insulin resistance after splenectomy in a diabetic patient with liver cirrhosis and portal hypertension. Physiopathologic evaluation]. / Riduzione del fabbisogno di insulina dopo splenectomia in un paziente diabetico con cirrosi epatica ed ipertensione portale. Valutazioni fisiopatologiche.

Liver cirrhosis is characterized by an increased incidence of glucose intolerance, diabetes and insulin resistance. We report a cirrhotic man (41 years old) who developed glucose intolerance and diabetes with insulin resistance over a period of six years. This patient suffered from severe portal hypertension with oesophageal varices and a enormously increased spleen volume. The subject underwent prophylactic endoscopic sclerotherapy of oesophageal varices. Splenectomy was performed because of severe piastrinopenia with recurrent nose bleeding. During laparotomy, multiple liver biopsies confirmed diagnosis of liver cirrhosis. Intra-operatory exploration revealed a splenic vein thrombosis. For this reason the planned spleno-renal shunting was not performed and the patient was only submitted to splenectomy. Liver function improved in the month following splenectomy and concomitant decrease of insulin resistance was observed (with a reduction in daily insulin dosage from 126 to 10 I.U.). We propose the following explanations of this event: 1) A decrease of portal and pancreatic vein pressure may have induced a proportional decrease (as already reported) of glucagon secretion. 2) The ameliorated liver function may have induced an improvement of liver glucose, insulin and glucagon metabolism. 3) A reduction of insulin circulating level (proved by a decrease of C Peptide value) may have lessened the insulin receptor down-regulation.

Probucol protects low-density lipoproteins from in vitro and in vivo oxidation.

Twelve patients with primary hypercholesterolemia were treated for 12 weeks with probucol (500 mg b.i.d.). For each patient low density lipoproteins (LDL), isolated by ultracentrifugation were subfractionated by ion exchange high resolution chromatography in order to evaluate the content of a more electronegatively charged LDL (LDL-), a small subfraction that probably represent a circulating oxidatively modified lipoprotein. The treatment induced a 17% reduction of total LDL and 43% reduction of LDL-. By thin layer chromatography the probucol content in LDL- was a quarter of that in normally charged LDL. Under basal conditions, native LDL incubated for 24 h with 3 microM copper sulphate shows a net increase in electrophoretic mobility, an increase in relative fluorescence intensity and a reduction in vitamin E content, thus indicating peroxidative damage. After treatment with probucol, no significant changes of electrophoretic mobility, fluorescence and vitamin E content are detectable. LDL isolated from patients treated with probucol thus become resistant to oxidation by copper ions. The observed reduction of LDL- after treatment with probucol, confirms in vivo the antioxidant role of the drug and support the hypothesis that circulating LDL- may be linked to an oxidative process occurring in vivo.

Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low density lipoprotein (LDL-).

Using ion exchange high pressure liquid chromatography, total plasma low density lipoprotein (LDL) from 30 hypercholesterolemic and 10 normocholesterolemic cynomolgus monkeys was subfractionated into unmodified LDL (n-LDL) and more negatively charged LDL (LDL-). In hypercholesterolemic monkeys, the absolute LDL-cholesterol level was 16.54 +/- 2.82 mg/dl (mean +/- SE) whereas in normocholesterolemic monkeys it was 2.39 +/- 0.12 mg/dl (P < 0.0001); the percentage of LDL- was 5.2 +/- 0.71% and 4.9 +/- 0.19% of the total LDL for hypercholesterolemic versus normocholesterolemic monkeys, respectively. LDL- averaged 5% and n-LDL 95% of the total plasma LDL cholesterol. To confirm and further elucidate the oxidative nature of LDL-, cholesterol and cholesterol oxide contents of LDL- and n-LDL were determined by capillary gas chromatography; 53.98 +/- 2.24% (mean +/- SE) of the LDL- cholesterol was oxidized whereas in n-LDL only 10.70 +/- 1.06% of the cholesterol was oxidized (P < 0.00001). The spectrum of oxysterols identified, which was similar for LDL- and n-LDL, suggested a free radical-mediated process for cholesterol oxidation. The principal oxysterols identified were: cholest-5-ene-3 beta, 7 alpha-diol, cholesta-3,5-diene-7-one, cholest-5-ene-3 beta, 7 beta-diol, 5,6 beta-epoxy-5 beta-cholestan-3 beta-ol, 5,6 alpha-epoxy-5 alpha-cholestan-3 beta-ol, 5 alpha-cholestan-3 beta,5,6 beta-triol, 3 beta-hydroxycholest-5-ene-7-one, and cholest-5-ene-3 beta,25-diol. To model one of the steps in the possible mechanism of atherogenesis, the cytotoxicity of LDL- was demonstrated to be greater against subconfluent than confluent aortic endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic liver radionuclide scanning in the evaluation of liver failure and portal hypertension in cirrhotic patients.

Dynamic liver radionuclide scanning was performed in cirrhotic patients to correlate three parameters derived by this technique to the severity of liver function impairment and clinical-endoscopic signs of portal hypertension. We found a close association between the severity of liver failure (Child-Pugh criteria) and both the relative blood flow (p < 0.05) and the shape (shifting to the left) of the early flow curve (p < 0.01). A significant association between the presence of portal hypertension and shifting to the left of the flow curve was demonstrated in all cases in which tense ascites was associated with varices (p < 0.05). Finally, a statistically significant association (p < 0.05) was found between the degree of esophageal varices (Beppu's criteria) and the liver-to-spleen uptake ratio. These data suggest that dynamic isotope liver scanning could be an important tool in the diagnostic evaluation of liver function impairment and portal hypertension.

Relationship of triglycerides and HDL cholesterol in hypertriglyceridemia.

Hypoalphalipoproteinemia (plasma HDL-cholesterol concentration at or below 35 mg/dl as reported in the National Cholesterol Education Program Guidelines) is a well known risk factor for premature coronary artery disease (CAD). In hypertriglyceridemic patients, hypoalphalipoproteinemia is commonly believed to be linked to the derangement of triglyceride metabolism. In this study the occurrence of primary hypoalphalipoproteinemia has been investigated in a cohort of hypertriglyceridemic patients whose plasma triglyceride concentration had been normalized either through diet or diet plus drug treatment. Following the initial visit, 115 hypertriglyceridemic patients received dietary advice and returned for the second visit four months later. Diet reduced plasma triglycerides in all the patients. HDL-cholesterol increased in 76 patients whereas in the others, it remained unchanged or even decreased. Plasma triglyceride concentration was normalized (less than 200 mg/dl) in 54 patients by diet alone, but among these 11 remained hypoalphalipoproteinemics. Patients in whom, despite dietary restrictions, triglycerides exceeded 200 mg/dl, were considered for pharmacological treatment with Bezafibrate (300 mg t.i.d.) for 4 months. Thirty-nine concluded the study. Treatment significantly decreased plasma triglyceride concentration in all the subjects. Normalization was achieved in 32 patients. Four of them, however, remained hypoalphalipoproteinemic. These results indicate that a subgroup of hypertriglyceridemic patients remained hypoalphalipoproteinemic even after normalization of triglyceride levels. In these patients hypertriglyceridemia and hypoalphalipoproteinemia may occur as expression of two distinct primary metabolic defects.