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The effect of long-term (4 months) insulin deficiency on triglyceride turnover was examined using Triton WR1339 in rats. Triglyceride secretion rate was estimated in rats 2 weeks and 4 months after induction of diabetes with 40 mg/kg of streptozotocin. By the second week diabetic rats showed prominent hyperglycemia and the plasma insulin level was very low. In spite of a lower triglyceride secretion rate compared to non-diabetic control rats, diabetic rats showed normotriglyceridemia. Thus, the estimated fractional catabolic rate for plasma triglyceride was decreased in the diabetic rats of 2 weeks duration. By the fourth month diabetic rats still showed a suppressed triglyceride secretion rate but plasma triglyceride was markedly higher than in the non-diabetic control rats. Therefore, their estimated fractional catabolic rate for plasma triglyceride was severely suppressed. They also showed hyperglycemia and hypercholesterolemia. The triglyceride-rich lipoprotein particles obtained after Triton injection in long-term diabetic rats were significantly cholesterol-enriched and triglyceride-depleted compared to control rats. These changes were already present in 2-week diabetic rats but the magnitude was significantly smaller that those in long-term diabetic rats. All of these abnormalities (including triglyceride turnover and the particle composition) were almost normalized by 2 weeks of insulin treatment (6 units/day). Thus, it was concluded from the present data that duration of insulin deficiency is an important determinant of triglyceride removal rate from the circulation in rats. Further modification of lipid composition of triglyceride-rich lipoprotein particles by long-term insulin-deficiency could be one of the reasons for this removal defect. Furthermore, overproduction of triglyceride cannot be a cause of hypertriglyceridemia seen in long-term uncontrolled experimental diabetes.

Background: Oxidative stress and inflammation of the arterial wall are now recognized as important factors in the progression of atherosclerosis. C-reactive protein (CRP) has been defined as a sensitive but not specific marker of inflammation. Statin therapy has been reported to decrease plasma high-sensitivity CRP (hs-CRP) concentration in hypercholesterolemic patients. Objective: The aim of this study was to examine the effect of rosuvastatin on concentrations of plasma lipids, urine and plasma oxidative stress markers, and plasma hs-CRP in hypercholesterolemic patients with and without type 2 diabetes mellitus. Methods: Patients with hypercholesterolemia with and without type 2 diabetes mellitus were enrolled in this pilot study after written informed consent was given. At baseline and after 12 weeks of open-label treatment with rosuvastatin 2.5 mg/d, concentrations of plasma lipids, urine and plasma oxidative stress markers, and plasma hs-CRP were measured. Urine 8-iso-prostaglandin F2α (8-iso-PGF2α) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) concentrations were also measured to asess whole-body oxidative stress. Plasma free-radical generation was estimated using a total reactive oxygen species (TROS) assay system. Adverse effects were assessed at each study visit (4-week intervals) through patient interviews and laboratory testing. Results: Thirty-five patients were enrolled with 1 dropping out prior to study completion; therefore, 34 patients (19 women, 15 men; mean [SE] age, 55.4 [13.6] years; range, 30–78 years) completed the study. Compared with baseline, significant decreases were found in serum concentrations of total cholesterol (TC) (252.3 [39.3] vs 187.8 [30.1] mg/dL; P < 0.001; Δ = 24.5%), LDL-C (162.0 [44.3] vs 98.5 [31.9] mg/dL; P < 0.001; Δ = 38.7%), and triglycerides (TG) (157.2 [93.6] vs 124.4 [69.9] mg/dL; P < 0.05; Δ = 11.7%) after 12 weeks of treatment with rosuvastatin. Serum HDL-C concentration did not change significantly from baseline (59.7 [20.5] vs 63.7 [19.3] mg/dL; Δ = 9.4%). The plasma LDL-C/HDL-C ratio decreased significantly after rosuvastatin treatment (3.03 [1.33] vs 1.72 [0.83]; P < 0.001; Δ = 43.2%). Compared with baseline, significant decreases were observed in urine concentrations of the oxidative stress markers after 12 weeks of rosuvastatin treatment: 8-iso-PGF2α (342.8 [154.3] vs 300.6 [101.2] pg/mg; P < 0.05) and 8-OHdG (11.1 [4.53] vs 8.1 [2.7] ng/mg; P < 0.01). TROS decreased significantly (182.3 [29.0] vs 157.6 [17.3] U; P < 0.001), and plasma hs-CRP concentration also decreased significantly (0.107 [0.100] vs 0.054 [0.033] mg/dL; P < 0.05). When the patients' results were assessed according to the presence or absence of type 2 diabetes mellitus, urine 8-iso-PGF2α concentration was significantly decreased from baseline only in the nondiabetic group. No adverse events were reported or observed during the course of the study. Conclusion: Rosuvastatin treatment was associated with significant reductions in plasma concentrations of TC, LDL-C, and TG, urine and plasma oxidative stress markers, and plasma hs-CRP in these hypercholesterolemic patients.

Obesity and systemic oxidative stress are closely related. However data concerning the relationships between oxidative stress and body fat mass distribution are sparse. Anthropometric and metabolic profile was evaluated in 148 clinically healthy middle-aged women to assess the correlations between oxidative stress, fat mass distribution, adipokines, and inflammatory markers. Systemic oxidative stress was assessed by urinary creatinine-indexed 8-epi-prostaglandin F-(2alpha) (8-epi-PGF(2alpha)). Body fat mass distribution was examined by dual-energy X-ray absorptiometry (DXA). Lipid profile, adipokines and inflammatory markers including leptin, adiponectin, high sensitive C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNF-alpha) were determined. We found body mass index (BMI), waist circumference (WC), both central and peripheral DXA-derived regional fat mass (FM) accumulations were positively correlated with 8-epi-PGF(2alpha). Leptin, hsCRP and PAI-1also positively associated with 8-epi-PGF(2alpha). After adjustment for BMI and WC, lower-body FM, total FM and PAI-1 retained significant association with 8-epi-PGF(2alpha). Mutliple linear regression analyses indicated lower-body FM and PAI-1 were the two important predicators of 8-epi-PGF(2alpha). These results suggest that DXA-derived regional FM indices, especially low extremity adiposity, are more closely associated with systemic oxidative stress than indirect anthropometric indices. Positive associations between 8-epi-PGF(2alpha) and PAI-1, hsCRP, leptin support the notion that oxidative-stress-induced dysregulation of inflammation and adipokines may mediate the obesity-related metabolic derangement.

Sulfated sericin's influence on factors in the blood coagulation cascade was investigated to elucidate its anticoagulant mechanism. Prolongation of the prothrombin time (PT) and activated partial thromboplastin time (APTT) were observed in the presence of sulfated sericin. Fluorogenic peptide substrates on thrombin (factor IIa) and factor Xa were used to study the influence of sulfate sericin on their respective activities. Sulfated sericin inhibited neither thrombin nor factor Xa in the presence of antithrombin III (AT III). Gel electrophoresis was used to examine fibrinogen-fibrin conversion by thrombin in the presence of sulfated sericin. FPA and FPB release from fibrinogen by thrombin proceeded in the presence of sulfated sericin. The behavior of polymerization of fibrin monomer (FM) was affected by the presence of sulfated sericin. No initial lag time in the polymerization process was observed by addition of sulfated sericin to FM. This result means that sulfated sericin will interfere in the build-up of normal double-strand fibrils of FM during formation of fibrin fiber. Scanning electron microscopy (SEM) observations supported this inference. The anticoagulant mechanism of sulfated sericin is inferred to interfere with the initial polymerization process of FM.

Effects of dietary carbohydrate on the secretion rate and particle size of triglyceride-rich lipoproteins were examined in Zucker fatty rats fed fructose and glucose and were compared with those of Zucker lean rats. Carbohydrates were supplied as 10% drinking solutions for 14 days. As compared with lean rats, Zucker fatty rats had hyperinsulinemia and hypertriglyceridemia associated with an increased rate of triglyceride secretion into the circulation. Feeding fructose and glucose to fatty rats produced an increase in plasma glucose levels, whereas plasma insulin concentrations did not show significant changes. Neither fructose nor glucose supplementation produced significant changes in the rate of triglyceride secretion. Despite this, plasma triglyceride concentrations in fructose-fed fatty rats were twice as high as those in glucose-fed rats or those receiving no supplementary carbohydrate. Particle diameters of lipoproteins of density between 0.96 and 1.006 were larger in fructose-fed fatty rats than in those receiving no sugar. The results suggest that feeding fructose, but not glucose, into fatty rats is associated with an impairment of triglyceride removal and a resultant increase in plasma triglyceride concentration, the latter of which is accompanied by an increase in triglyceride contents in each particle.

The plasma enzyme, human lecithin-cholesterol acyltransferase(LCAT) is responsible for the majority of cholesterol ester formation in human plasma and is a key enzyme of the reverse transport of cholesterol from peripheral tissue to the liver. We sequenced genomic DNA of the LCAT gene from a Japanese male patient who was clinically and biochemically diagnosed as a familial LCAT deficiency. Analysis of all exons and exon-intron boundaries revealed only a single G to A transition within the sixth exon of both allele of the gene, leading to the substitution of methionine for isoleucinle at residue 293 of the mature enzyme. This mutation creates a new hexanucleotide recognition site for the restriction endonuclease Ndel. Familial study of Ndel digestion of the genomic DNA and determination of plasma LCAT activity established that the patient and his sister whose plasma LCAT activity were extremely reduced were homozygous and his children whose plasma LCAT activity were about half of normal controls were heterozygous for this mutation.

To see whether there are any lipoprotein abnormalities in diabetic patients without hyperlipidemia, lipoprotein composition was examined in 75 strictly normolipidemic diabetic patients. Their plasma cholesterol (chol) and triglyceride (TG) were limited to

Long-term effects of bezafibrate on in vivo production of VLDL-triglyceride were studied in the rat. Bezafibrate given at a daily dose of 30 mg/kg body weight for 14 days produced a decrease not only in triglyceride by 51% but in cholesterol by 28% and phospholipid by 18%. Despite a marked reduction in plasma triglyceride concentrations, there was no significant change in the rate of VLDL-triglyceride secretion from the liver into the circulation between bezafibrate-treated and control animals (1113 +/- 58 and 1234 +/- 63 micrograms/min, respectively). In addition, bezafibrate produced no change in lipid composition in VLDL. These results suggest that bezafibrate enhances triglyceride removal from the circulation, which leads to reduction in plasma triglyceride.

A 50-year-old woman was admitted to our hospital because of severe diarrhea, irritableness, and severe pitting edema of the legs. The patient had been well until 5 years before admission, when a tremor and tachycardia developed and a diagnosis of Graves' disease was made. Treatment with methimazole was effective in reducing her tremor and tachycardia; however, she was often nonadherent with her antithyroid medication because of improvement of her symptoms. On admission, a thyroid swelling, exophthalmos, a pleural effusion, and ascites were observed. The results of thyroid function tests (free triiodothyronine: 21.5 pg/mL; free thyroxine: 7.17 ng/dL; thyroid-stimulating hormone (TSH):0.01 microIU/mL; TSH receptor antibodies: 95.9%) were consistent with Graves' disease. Biochemical analysis of pleural and ascitic fluid was consistent with chylothorax and chylous ascites, respectively. Serum calcium, total protein, and albumin were very low. Her symptoms and signs except severe diarrhea, edema, pleural effusion, and ascites disappeared after receiving intravenous drip infusion of fluid replacement, and methimazole and iodine. Because of malnutrition, she was given a high-calorie intravenous infusion. Three months after admission, her pleural effusion and ascites began to improve, as did her diarrhea and hypoalbuminemia. An appropriate treatment of Graves' disease is crucial to avoid serious sequelae of longstanding, poorly controlled hyperthyroidism.

The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

Several studies have reported an association between markers of liver injury, including elevated concentrations of alanine aminotransferase (ALT) aspartate aminotransferase (AST), and prospective risk of type 2 diabetes. We therefore examined the relationship between ALT and AST on the one hand, and serum adiponectin and highly sensitive CRP on the other, both of which have been reported to be associated with prospective risk of type 2 diabetes; we also tested for variable components of metabolic syndrome in 198 male college students aged 18-20 years. ALT showed a positive relationship with percentage body fat (r = 0.19, p = 0.02), serum leptin (r = 0.21, p = 0.01), LDL cholesterol (r = 0.29, p = 0.0003), triglyceride (r = 0.28, p = 0.0004) and apolipoprotein B (r = 0.35, p < 0.0001) even after adjustment for body mass index (BMI). Although there was a significant relationship with serum insulin, adiponectin (inversely), homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure, HDL cholesterol (inversely) and LDL particle diameter in simple regression analysis, significance disappeared after adjustment for BMI. In contrast, CRP (r = 0.16, p = 0.04) was associated with ALT after adjustment for BMI, although simple regression analysis revealed no association between the two. Relationships were smaller for AST, and significance disappeared after adjustment for BMI. Multiple regression analysis excluding lipid variables revealed significant and independent associations of ALT with adiponectin and percentage body fat. In a model including lipid variables, apolipoprotein B emerged as an independent predictor of ALT in addition to adiponectin and percentage body fat. These variables explained 29 % of ALT variability. In conclusion, serum ALT levels were associated with leptin and CRP as well as many components of the insulin resistance syndrome in young healthy men. Adiponectin, apolipoprotein B and percentage body fat emerged as significant and independent predictors of ALT. Since adiponectin and chronic subclinical inflammation have been reported to predict the development of type 2 diabetes and since abnormalities in apolipoprotein B metabolism occur in the early course of insulin resistance, these findings may be compatible with the association between liver markers and risk of diabetes.

Heme oxygenase (HO) is a microsomal enzyme that catalyzes the degradation of heme into biliverdin, which is subsequently reduced to bilirubin, free iron and carbon monoxide (CO), and induction of heme oxygenase-1 (HO-1) is potentially associated with cellular protection, especially against oxidative insults. Using transgenic mice that overexpress HO-1 (HO-1 Tg) specifically in vascular smooth muscle cells, we investigated the organ-protective effects of HO-1 against angiotensin II (Ang II). Following administration of Ang II and a high- salt diet for 14 days, marked intimal hyperplasia as well as inflammatory changes were observed in coronary arteries of Ang II/salt-treated wild type (Wt) mice. In Wt mice, Ang II/salt loading increased urinary excretion of 8- hydroxydeoxyguanosine (8-OHdG) and 8-lso- Prostaglandin F2 alpha. Cardiac levels of MDA and 4-HAE, markers of lipid peroxidation, and GSSG/GSH were also increased in Wt. mice after Ang II/salt loading, but not in HO-1 Tg mice. Consistently, immunostaining for both 8-0HdG, a marker of oxidative DNA damage, and 3-nitrotyrosine, the metabolites of reactive oxygen species, were apparently increased in the Ang II/salt-treated heart of Wt. mice; however, no significant changes in these responses were detected in HO-1 Tg mice after Ang II/salt loading. These data suggest that increased oxidative stress might be involved in the coronary artery changes induced by Ang II/salt loading. The evidence presented in the current study indicates that vascular HO-1 exerts its protective effect against cardiovascular damage, possibly through the inhibition of oxidative stress.

Previously, we reported that intranasal (IN) ACTH(1-24) administration stimulates adrenocortical steroid secretion in normal subjects. To determine the efficiency of transmucosal absorption of ACTH into the adrenal medulla, we measured serum cortisol, aldosterone, epinephrine, norepinephrine and dopamine levels after IN vs. intravenous (IV) administration of 250 microg ACTH(1-24) in 7 healthy adult men (mean age 21.7 +/- 1.2 yr; range, 21 - 24 yr). Blood was collected at 0, 30, 60 and 120 min after administration of ACTH(1-24), and the levels of adrenocortical steroids and catecholamines were measured by specific RIA and HPLC methods, respectively. There were no side effects associated with IN or IV ACTH administration. Consistent with the previous study, serum cortisol and aldosterone increased after IN administration of ACTH(1-24), peaking 30 min after administration. Sixty minutes after IN and IV administration of ACTH, epinephrine levels increased by 41.9 +/- 13.1 % and 63.3 +/- 11.8 %, respectively, and remained elevated throughout the sampling period. Thirty minutes after IN or IV administration of ACTH(1-24), plasma norepinephrine levels increased by 55.9 +/- 13.4 % and 73.7 +/- 15.0 %, respectively, peaking 30 min after ACTH(1-24) administration, and decreasing to basal levels within 60 min. Plasma dopamine levels did not change after IN administration of ACTH(1-24). Adrenocortical steroid and catecholamine levels did not increase after IN administration of saline. These results demonstrate that IN administration of ACTH(1-24) not only stimulates adrenocortical steroids, but also epinephrine and norepinephrine.

Background: In 2001, the Committee on Standardization of Laboratory Testing Related to Diabetes Mellitus of the Japan Diabetes Society (JDS) prepared and certified a new reference material for haemoglobin A1c (HbA1c), Lot 2. The standardization programme for HbA1c measurement in Japan is currently based on Lot 2, although some laboratories still use the previous material (Lot 1). The values assigned to Lot 2 were based on the consensus values for Lot 1 and should give the same results. Therefore, there should be no difference in the measured values no matter which calibrators are used. The Committee conducted a domestic survey in order to confirm this relationship. Method: In November 2002, four samples for HbA1c assay were sent to 795 laboratories as part of a national survey in Japan. Assays were performed using the laboratories' routine clinical methods. The coefficients of variation (CVs) of the reported values from all laboratories for the samples were calculated in order to determine the current level of standardization in Japan. Results: The overall CVs in the measured values for the four samples ranged from 2.7% to 4.0%. Values from laboratories using calibrators based on Lots 1 and 2 were similar. Conclusion: The present state of standardization for the routine measurement of HbA1c in Japan, as indicated by the 2002 survey, is excellent. This should aid in the eventual conversion of Lot 2 to IFCC-based values from the results of the 2002 national HbA1c survey.

Dyslipidemia is an important risk factor for cardiovascular disease in patients with chronic renal failure (CRF). We evaluated the safety and efficacy of atorvastatin in patients with dyslipidemia associated with CRF who were undergoing hemodialysis (HD). Thirty-five patients who were receiving HD were given atorvastatin (10 mg/d) for 3 months. Chylomicron (CM), light and dense very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and light and dense low-density lipoprotein (LDL) were separated by ultracentrifugation. Apolipoprotein (apo) B was measured by electroimmunoassay. Mean LDL particle diameter was measured by gradient gel electrophoresis. Atorvastatin therapy reduced LDL-cholesterol (C) by 36% and remnant-like particle (RLP)-C by 58%. Atorvastatin significantly reduced apo B, apo CIII, and apo E in VLDL by 40% to 46% and IDL-apo B by 66%. Atorvastatin also significantly reduced cholesterol in CM, light VLDL, and dense VLDL without consistently affecting triglyceride (TG) in these lipoproteins. Atorvastatin similarly reduced both light and dense LDL-apo B by 38%. LDL particle size in the HD patients significantly increased during atorvastatin treatment from 25.7 +/- 0.4 to 26.2 +/- 0.6 nm. High sensitive C-reactive protein (HS-CRP) was halved by atorvastatin decreasing from 0.08 +/- 0.05 to 0.04 +/- 0.03 mg/dL. Atorvastatin treatment did not affect the creatinine kinase level, and no classical adverse effects were observed during the study. These results suggest that atorvastatin is safe and effective for the management of dyslipidemia in patients with CFR who are receiving HD, which may help to suppress the development of atherosclerosis.

We evaluated the immunological effects of a Kampo (Chinese) prescription Hochu-ekki-to (TJ-41) for 32 weeks and 1 week prophylactically in mice. The splenic natural killer cells (NK) of C57BL/6N mice prophylactically treated with TJ-41 for 32 weeks showed little enhanced cytotoxicity against NK-sensitive YAC-1 targets, but mice treated for 1 week showed significantly enhanced cytotoxicity. TJ-41 administration for 32 weeks increased the splenic NK cell population and CD4/CD8 significantly, but TJ-41 for 1 week was not affected. Further, there were no adverse effects of TJ-41 administration for 32 weeks. Whether or not that duration of administration can have the same beneficial effects on humans await further studies.

Small, dense LDL (S LDL) is regarded as a significant risk factor for coronary heart disease (CHD) and has also been reported its high appearance in type 2 diabetic patients. Although ultracentrifugation and electrophoresis based methods are currently used for the measurement of S LDL, such methods are either too laborious or expensive for clinical use. We have developed a simple method for quantification of S LDL. The new method consists of two steps; first to filter out large buoyant LDL and other apoB-containing lipoproteins by forming aggregates of these unintended lipoproteins with a heparin-manganese based reagent; and second to measure S LDL-cholesterol (S LDL-C) in the penetrate solution, the mixture of HDL and S LDL, on automated general chemistry analyzers. Comparison with the ultracentrifugation method yielded a correlation coefficient of 0.900 and an equation of y = 1.090x-1.8 (n = 146). Positive correlation was observed with total LDL-C level and also with triglyceride level (r = 0.782 and r = 0.526, respectively) while negative correlation was observed with LDL particle size (r = 0.658). As for the study with various types of hyperlipidemia sample, the highest level of S LDL-C was observed in combined hyperlipidemia patients. Patients with CHD had higher S LDL-C than control group (45.2 +/- 22.1 in the CHD vs. 36.7 +/- 16.9 in the control), however no difference was seen in total LDL-C level between the two groups (117.6 +/- 35.0 in the CHD vs. 115.7 +/- 30.1 in the control). Patients with type 2 diabetes also showed higher S LDL-C (54.0 +/- 22.7). S LDL-C/LDL-C ratios were also significantly higher in CHD patients and in type 2 diabetes patients than the control group (39.9 +/- 16.7 in the CHD, 37.6 +/- 13.0 in the type 2 diabetes and 31.0 +/- 9.9 in the control). Our findings suggest that this method can measure S LDL reliably with a simple procedure and that the analysis of S LDL-C can give a better index for the risk assessment of CHD than total LDL-C.

The chromosomal localization of adiponectin has been found to be mapped to human chromosome 1q21.4-1q23, a region that was identified as a susceptibility locus for familial combined hyperlipidemia and polygenic type 2 diabetes. As these 2 disorders are associated with low high-density lipoprotein (HDL)-cholesterol, high triglycerides, and insulin resistance (IR), we examined the relation of serum adiponectin concentrations to serum lipid and lipoprotein profiles as well as IR in young healthy men. Serum adiponectin levels were positively associated with HDL-cholesterol, apolipoprotein (apo) A1, and low-density lipoprotein (LDL) particle size, and negatively associated with triglycerides and apo B. Negative associations were also found between adiponectin and body mass index (BMI), percent body fat, and IR,as determined by homeostasis model assessment (HOMA). However, after adjustment for BMI, no significant associations were found between adiponectin and LDL particle size and apo B. In a multiple regression analysis including all variables that showed significant univariate associations with adiponectin, associations of adiponectin with HDL-cholesterol (beta = 0.079, P =.0009), percent body fat (beta = -0.165, P =.002), and serum leptin (beta = -0.291, P =.01) were statistically significant. HDL-cholesterol (beta = 0.077, P =.001), percent body fat (beta = -0.078, P =.03), and LDL size (beta = 0.092, P =.03) emerged as significant and independent determinants of adiponectin after HOMA IR, fasting glucose, triglycerides, and systolic blood pressure (BP) were taken into account. Together, these variables explained 19% of adiponectin variability in the 2 models. HOMA IR did not emerge as a determinant of adiponectin in both models. These findings suggest that in young healthy men hypoadiponectinemia is more closely related to adiposity and dyslipidemia than IR.

The effects of fluvastatin on levels of urinary 8-iso-prostaglandin F2alpha (iPF2alphaIII), a marker of oxidative stress, and low-density lipoprotein (LDL) particle size in serum were investigated in patients with hypercholesterolemia. After 6 months of fluvastatin therapy, levels of urinary iPF2alphaIII decreased from 1720.1 +/- 392.0 to 539.6 +/- 75.5 pg/mg (p < 0.01), and LDL particle size increased from 24.3 +/- 0.3 to 26.5 +/- 0.2 nm (p < 0.001). These changes from the treatment of fluvastatin were not correlated with those of the serum LDL cholesterol (LDL-C) levels. The results imply that fluvastatin, with its unique antioxidant property among statins, reduces oxidative stress and increases LDL particle size simultaneously in hyperlipidemic patients.

To determine which anthropometric, biochemical, and cardiovascular variables are associated with serum levels of C-reactive protein (CRP) in young, apparently healthy men, a cross-sectional study of 179 male college students aged 18 to 22 years was performed. Multiple regression analysis was used to derive models for serum CRP concentrations in terms of the other variables measured. Although CRP was positively correlated with body mass index (BMI), percent fat mass, and serum leptin, correlations with BMI (r = 0.15, P =.05) and percent body fat (r = 0.16, P =.003) were not as strong as the correlation with leptin (r = 0.28, P =.0002). CRP was also associated with resting heart rate (r = 0.14, P =.05), heart-rate corrected QT (QTc) interval (r = 0.22, P =.003) and several components of the insulin resistance (IR) syndrome. CRP showed a strong and negative association with high-density lipoprotein (HDL)-cholesterol (r = -0.26, P =.0005) and a marginal and positive association with triglyceride (r = 0.14, P =.05). Although CRP was associated with fasting insulin (r = 0.15, P =.04), it was not related to serum adiponectin or IR index estimated using homeostasis model assessment (HOMA). Multiple regression analysis indicated that serum CRP was positively related to serum leptin (P =.003) and QTc interval (P =.01), and negatively correlated with HDL-cholesterol (P =.01, R(2) = 0.15). In young, apparently healthy men, serum leptin but not BMI was independently associated with serum CRP, suggesting that amount of body fat may be the most significant predictor of CRP. Although low-grade inflammation was associated with long QTc interval and low HDL-cholesterol, the mechanism underlying these associations is an important question to be addressed.

Monocyte chemoattractant protein 1 (MCP-1) and the receptor for MCP-1, CCR2, play a pivotal role in the recruitment of monocytes to the subendothelium, which is the initial event in atherosclerosis. Heme oxygenase (HO) is a microsomal enzyme that catalyzes the degradation of heme into biliverdin, which is subsequently reduced to bilirubin, free iron, and carbon monoxide, and induction of HO-1 is potentially associated with cellular protection, especially against oxidative insults. The present study was designed to examine the role of HO-1 in monocytes in angiotensin II (Ang II)-induced chemotactic response. Ang II significantly stimulated superoxide formation in monocytes, as measured by nitro blue tetrazolium reduction assay, as well as the chemotactic response to MCP-1 with the increased expression of CCR2 determined by RT-PCR and western blotting analysis. Hemin-treated monocytes displayed an enhanced HO activity with the increased accumulation of bilirubin determined by immunostaining, when compared with control monocytes. The induction of HO-1 in monocytes suppresses not only Ang II-stimulated superoxide formation, but also Ang II-enhanced chemotactic activity. Exogenously applied bilirubin and carbon monoxide mimicked the inhibitory effect of HO-1 on the chemotactic response. These findings suggest that monocytic HO-1 might be a new therapeutic target for atherosclerosis.

To explore the relationship between microsomal triglyceride transfer protein (MTP) gene variation and diabetic dyslipidemia among Chinese.Using PCR restriction fragment length polymorphism (PCR-RFLP) analysis and gene sequencing, we studied the influence of a common MTP gene polymorphism in the promoter region on the apoB-containing lipoproteins in 44 Chinese type 2 diabetic subjects and 32 non-diabetic volunteers.A common functional G/T polymorphism in 493 bp upstream from the transcriptional start point was detected among native Chinese. There were 41 carriers (53.9%) of the MTP-493 G/G genotype, 28 (36.8%) of the MTP-493 G/T genotype and 7 (9.3%) of the MTP-493 T/T genotype. The allele frequency of MTP-493 T in the diabetic group was 0.30. The MTP-493 T/T diabetic group had significantly higher TG (P0.05), VLDL-CH (P0.05) and smaller LDL particle size (P0.001) than the MTP-493 common genotype group.Genetic variation in the MTP promoter is likely to be highly involved in the production of dyslipidemia in type 2 diabetic subjects.

The combination therapy of a Kampo formula and an analgesic- antipyretic agent is often used for the common cold in Japan. We investigated the effect of such a combination therapy, using the Ephedra herb, which is a common ingredient of Kakkon-to and Mao-to, and Loxoprofen, a nonsteroidal anti-inflammatory drug (NSAID), on fever induced in an experimental model of mice under strong stress. The combination therapy of Ephedra herb and Loxoprofen caused gastric mucosal lesions and loss of body weight. It is considered that this combination therapy should be avoided because of its adverse effects.

Patients with type 2 diabetes are known to have abnormalities in their remnant metabolism and low density lipoprotein (LDL) subfraction pattern, with a preponderance of small dense LDL. The effects of pitavastatin, a newly synthesized 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, on lipoprotein profiles in patients with type 2 diabetes were determined. Thirty-three patients were treated with pitavastatin with a daily dose of 2 mg for 8 weeks. After treatment, triglyceride, total and LDL cholesterol were significantly reduced by 28.7 +/- 36.7%, 25.2 +/- 14.3% and 36.1 +/- 14.3%, respectively. Remnant-like particle cholesterol (RLP-C), an independent risk factor for CAD which is known to be elevated in diabetic patients, was also significantly reduced (-30.9 +/- 30.5%) by the treatment and this decrease correlated well with the decrease in triglyceride level. The proportion of small dense LDL, which is known for its atherogenisity, decreased from 29.9 +/- 26.2% to 19.7 +/- 22.7% and the mean LDL particle size significantly increased from 26.36 +/- 1.13 nm to 27.10 +/- 1.36 nm. Pitavastatin, which is known to improve triglyceride levels and cholesterol levels, also improves RLP-C level and LDL subfraction profiles, and this in turn may reduce the cardiovascular risk in patients with type 2 diabetes and dyslipidemia.

Hyperlipidemia, especially hypercholesterolemia is one of the most important risk factors for coronary heart disease. Now it is well recognized that aggressive lipid-lowering drug treatment in high-risk individuals reduces coronary heart disease morbidity and mortality rates and increases overall survival. Hypertriglyceridemia has now been recognized as another important risk factor for coronary heart disease. Recently, much attention has been focused on the atherogenesis of small, dense LDL, remnant lipoprotein and isolated hypoalphalipoproteinemia. Hypertriglyceridemia is known to be deeply involved in the pathogenesis of all of these abnormal lipoprotein profiles. Therefore, treatment of hypertriglyceridemia as well as hypercholesterolemia must be fully discussed. In this issue, I will talk about new insights into treatment of dyslipidemia by changing the life style and/or by various hypolipidemic drugs.

The most common lipoprotein abnormality in type 2 diabetics is hypertriglyceridemia, which is known to be an independent risk factor for coronary artery disease (CAD) in diabetics. It is known that remnant lipoproteins, small, dense LDL, and isolated hypo-alphalipoproteinemia exist in diabetics even if they are apparently normolipidemic. Our previous observation revealed that type 2 diabetics had smaller LDL even if they were without hyperlipidemia. We also found that diabetics with microalbuminuria had smaller LDL than those with normoalbuminuria, indicating early nephrotoxicity of small, dense LDL. More than half of the Japanese type 2 diabetics associated with acute myocardial infarction (AMI) showed isolated hypo-alpha lipoproteinemia, indicating the clinical importance of suppressed HDL fraction without prominent hyperlipidemia in the diabetics. Finally, strict diet control and treatment of diabetics with dyslipidemias by acarbose, troglitazone, fibrates and/or statins were all successful in increasing LDL size.

Niceritrol, 750 to 1000 mg/day, produced and maintained a decrease in serum lipoprotein(a) [Lp(a)] levels over a 12-month treatment period. Reductions in Lp(a) were more prominent in patients who had pretreatment Lp(a) levels >30 mg/dl than in patients with initial Lp(a) levels

To elucidate the hypothesis that albuminuria in diabetic subjects reflects widespread vascular damage, plasma markers for vascular endothelial damage was measured in diabetic subjects with various degrees of albuminuria and compared to results in patients with primary renal disease. The groups consisted of 31 non-diabetic patient controls with normoalbuminuria, 109 type 2 diabetic patients with normo- micro- and macro-albuminuria, and 16 proteinuric patients with primary renal disease. Endothelial markers, plasma von Willebrand factor (vWF) and thrombomodulin (TM), were measured by enzyme-linked immunosolvent assay and enzyme immunoassay (EIA) methods, respectively. Plasma vWF levels were similar in controls (119+/-7%, mean+/-S.E.M.) and diabetic patients with normoalbuminuria (139+/-6), but significantly elevated in diabetic patients with microalbuminuria (174+/-11) and macroalbuminuria (204+/-17), while the level was not increased in patients with primary renal disease (124+/-11). Because plasma TM level was strongly affected by kidney function, TM index (TM (FU/ml)/serum creatinine (mg %)) was used as an endothelial marker. The TM index was substantially increased in diabetic patients with overt nephropathy compared with controls (5.29+/-2.98 vs. 2.35+/-0.85), whereas this was not observed in patients with primary renal disease (3.25+/-0.29). Both vWF and TM index were significantly higher in diabetic patients with retinopathy than in the patients without retinopathy. These results suggest that generalized vascular endothelial damage occurs in diabetic nephropathy including the microalbuminuric stage, which is not attributed to kidney damage per se.

According to the definition of the Lipid Research Clinic's protocol, low-density lipoprotein (LDL) refers to the lipoprotein of density (d)=1.006-1.063 g/ml which contains another atherogenic lipoprotein, IDL (d=1.006-1.019 g/ml). Because metabolic properties are largely different between LDL and IDL, LDL is now defined as the lipoprotein of d=1.019-1.063 g/ml. Recently direct LDL-cholesterol assay kits using novel surfactants (the homogeneous methods) have become commercially available and widely used in Japan. The aim of this study is to examine how three direct LDL-cholesterol assay kits, LDL-EX, Choletest-LDL and Determinor-L LDL, react with pure LDL (d=1. 019-1.063 g/ml) and IDL (1.006-1.019 g/ml) fractions isolated by ultracentrifugation. Thirty-one healthy subjects and one type III dysbetalipoproteinemic patient were enrolled in this study. All homogeneous methods highly correlated with LDL-cholesterol (r=0.95-0. 98), although the values for LDL-EX were closer to the values for ultracentrifugation than were those of the other two methods (95 vs. 86-87%, P0.0001). Cross-reactivity with IDL was 31, 47 and 64% for LDL-EX, Choletest-LDL, and Determinor-L LDL, respectively. Similar results were obtained in the IDL from a type III dysbetalipoproteinemic patient. These results suggest that LDL-cholesterol measured by LDL-EX better reflects pure LDL fraction with weaker cross-reaction with IDL than other homogeneous methods.

To examine the relationship between leptin and insulin serum levels and systolic and diastolic blood pressure in young men.Kobe University of Mercantile Marine, Kobe, Japan.One hundred and ninety-eight male students aged 18-20 years (comprising 100% of those eligible).A cross-sectional survey of a sample of male college students was performed, with measurements to include anthropometry, blood pressure and blood tests after overnight fasting.Compared with 90 men with an optimal blood pressure, 56 men with high-normal and high blood pressure had an increase in body mass index (23.7 +/- 5.2 versus 20.4 +/- 2.2 kg/m2), percentage body fat (21.7 +/- 8.0 versus 16.3 +/- 4.2%) and serum leptin (3.7 +/- 4.7 versus 1.5 +/- 0.8 ng/ml). In addition, they had greater serum insulin (59 +/- 31 versus 43 +/- 12 pmol/l) despite there being no differences in plasma glucose, resulting in a reduction of the ratio of glucose to insulin (x 10(6)) (107 +/- 43 versus 126 +/-, which is an estimate of insulin sensitivity in a nondiabetic population. Furthermore, the 56 men had higher serum triglyceride levels, although there was no difference in low density lipoprotein-cholesterol and high density lipoprotein-cholesterol between men with optimal and high-normal plus high blood pressure. Similar differences were found between men in a top versus low tertile of systolic and diastolic blood pressure. In multiple regression analysis, both log leptin and log insulin emerged as determinants for systolic blood pressure independent of body mass index and percentage body fat, but an association with diastolic blood pressure was only shown for log leptin.Hyperleptinemia and hyperinsulinemia may be regulators of arterial pressure, independent of body mass index or percentage body fat.

To determine whether high prevalence of small dense low-density lipoprotein (LDL) in non-insulin-dependent diabetes (NIDDM) with nephropathy is directly associated with kidney damage, we measured LDL particle size by non-denaturing 2-16% gradient polyacrylamide gel electrophoresis in non-diabetic patients with primary renal disease and compared the results to particle size in NIDDM patients with diabetic nephropathy. The average LDL particle diameter was significantly smaller in patients with diabetic nephropathy (245+/-3 A mean +/- SEM) compared to the controls (263+/-1 A), diabetics without nephropathy (257+/-2 A), patients with primary renal disease (254+/-2 A) or non-diabetic patients treated with hemodialysis (HD) (260+/-1 A). The incidence of small LDL (mean diameter isor =255 A) was remarkably increased in diabetic nephropathy (67%) compared to diabetes without nephropathy (27%), patients with renal disease (24%), HD patients (15%) and controls (10%). LDL size in patients with primary renal disease was significantly smaller than those in controls. However, because there was an excellent correlation between LDL size and plasma triglyceride (TG) levels, when hypertriglyceridemic subjects (TG1.7 mM) were excluded, no difference of LDL size was observed between the renal disease group (260+/-2 A) and the control group (264+/-1 A). On the other hand, even when hypertriglyceridemic subjects were excluded, LDL size was still smaller in diabetic nephropathy (250+/-4 A). We performed an oral fat load test in normotriglyceridemic subjects (fasting TG1.7 mM) of control, diabetes with and without nephropathy and primary renal disease. The TG responses in plasma and TG-rich-lipoprotein (TRL) (d1.006) after the oral fat load were significantly greater in NIDDMs with nephropathy compared to controls or NIDDMs without nephropathy, while such a marked postprandial lipemia was not observed in patients with primary renal disease. In these fasting normotriglyceridemic subjects, LDL size was significantly inversely correlated with postprandial TG responses, which is totally independent from fasting TG levels. These results suggest that high prevalence of small dense LDL in NIDDM patients with nephropathy is not directly associated with kidney damage. Postprandial lipemia may play an important role in reducing LDL particle size in these patients.

OBJECTIVE: To explore mechanisms for hypertriglyceridemia in diabetic patients with microalbuminuria, we examined an association between heparin-releasable lipoprotein lipase (LPL) and the von Willebrand factor (vWF), based on the hypothesis that LPL bound to endothelium is decreased by generalized endothelial damage. RESEARCH DESIGN AND METHODS: A total of 37 NIDDM patients with microalbuminuria and 69 patients with normoalbuminuria were studied. Plasma LPL mass in post-heparin plasma and plasma vWF antigen were quantified by sandwich-enzyme immunoassay and enzyme-linked immunosorbent assay, respectively. RESULTS: The NIDDM patients with microalbuminuria had higher plasma triglyceride (TG) and lower HDL cholesterol concentrations compared with the patients with normoalbuminuria. Heparin-releasable LPL mass was significantly lower in the microalbuminuric than in the normoalbuminuric subjects. Plasma level of vWF, a marker for endothelial damage, was significantly increased in microalbuminuric subjects compared with their normoalbuminuric counterparts. The LPL mass was inversely correlated with plasma vWF level at a high correlation coefficient value. The LPL mass was inversely related to TG and positively to HDL cholesterol concentrations. CONCLUSIONS: These results suggest that widespread endothelial damage occurred in NIDDM patients with microalbuminuria, thereby LPL moiety bound to the endothelium is decreased, which results in an impaired catabolism of TG-rich lipoproteins.

Angiotensin-converting enzyme (ACE) inhibitors have been used in several clinical trials to slow a progressive decline in glomerular function in patients with diabetic nephropathy independent of their effects on blood pressure. The purpose of this study was to clarify the mechanisms(s) through which an ACE inhibitor, captopril, exerts its protective effect on renal function using spontaneously hypertensive rats (SHR) with streptozotocin (STZ)-induced diabetes. Male SHRs were made diabetic by intravenous injection of STZ (45 mg/kg). One hundred or 25 mg/kg of captopril was administered daily for 4 weeks to them. Urine albumin excretion (UAE) rate was markedly increased in diabetic SHRs, while captopril treatment resulted in a significant suppression of UAE in diabetic SHRs, independent of both its daily dose and effects on blood pressure as well as glycemic control. Examination by electron microscope revealed that the number of anionic sites (AS) in the lamina rara externa per 1000 nm of glomerular basement membrane (GBM) was significantly decreased (22.9+/-0.2 to 16.1+/-0.3, p0.001), after induction of diabetes, whereas, significant recovery (18.2+/-0.1, p0.001) could be obtained even by the smaller dose (25 mg/kg) of captopril which did not exert either antihypertensive or antidiabetic effect on diabetic SHRs. Thus, we demonstrate here the direct evidence that captopril, an ACE inhibitor, can protect against damage on GBM of diabetic SHR without controlling blood pressure as well as blood glucose level.

The present study was conducted in order to examine the role of low-density lipoprotein (LDL)-receptor activity in very-low-density lipoprotein (VLDL) triglyceride metabolism in vivo. Fructose-feeding (10% in drinking water) for 2 weeks resulted in elevated plasma triglyceride in heterozygote of Watanabe heritable hyperlipidemic (WHHL) rabbit (WHHLH) associated with suppressed fractional catabolic rate (FCR) of plasma triglyceride, whereas Japanese white (JW) rabbit with normal LDL receptor activity showed no remarkable change in plasma triglyceride turnover after fructose-feeding, suggesting an involvement of LDL receptor activity on triglyceride metabolism. Thereafter, in order to stimulate cellular LDL receptor activity, fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitor, was administered orally (1.52±0.26 mg/kg) to fructose-fed WHHLH. Significant suppression of triglyceride secretion rate (TGSR) was observed after treatment. However, since plasma triglyceride level was markedly suppressed, FCR of plasma triglyceride was significantly elevated by fluvastatin. Thus, it is speculated from the present data that LDL receptor activity is significantly involved in VLDL triglyceride metabolism in rabbits.

Effects of dietary carbohydrates on triglyceride production and hepatic lipogenic enzyme activities were examined in Wistar fatty rats, an animal model of noninsulin dependent diabetes mellitus, fed fructose or glucose and were compared with those of Wistar lean rats. Carbohydrates were supplied in 10% drinking solutions for 21 days. As compared with lean rats, Wistar fatty rats were characterized by hyperglycemia, hyperinsulinemia and hypertriglyceridemia, the last of which was associated with an increased hepatic activity of fatty acid synthetase and an increased rate of triglyceride secretion from the liver to the circulation. Feeding fructose to genetically obese diabetic rats produced a threefold increase in the hepatic activity of fatty acid synthetase, a twofold increase in NADPH-generating enzymes (malic enzyme and glucose-6-phosphate dehydrogenase) and a 56% increase in the rate of triglyceride secretion, with a resultant 86% increase in plasma triglyceride concentrations. Feeding glucose produced a similar increase in the activity of NADPH-generating enzymes and triglyceride production in the fatty liver but it differed in producing no change in plasma triglyceride concentrations or hepatic fatty acid synthetase activity. Neither dietary fructose nor glucose changed glycemia or insulinemia. These results show that in genetically obese, diabetic rats feeding fructose and glucose is associated with an increase in hepatic lipogenic enzyme activities and triglyceride production, and suggest that fructose stimulates triglyceride production but impairs triglyceride removal, whereas glucose stimulates both of them.

We examined the effect of long-term (6 months) hyperinsulinemia on VLDL-triglyceride turnover in male Wistar rats. Hyperinsulinemia was induced in rats by daily s.c. injection of Ultralente insulin (6 U/day at 19:00). Fructose (F) or glucose (G) was supplied in the drinking water (10%) in order to prevent hypoglycemia. The rats were divided into 5 groups: (1) hyperinsulinemia with F water: group F + I; (2) hyperinsulinemia with G water: group G + I; (3) F water alone: group F; (4) G water alone: group G; and (5) control rats without sugar water group C. After 6 months of daily insulin injection triglyceride secretion rate (TGSR) was estimated using Triton WR1339 in all the rats. Groups F + I and G + I were obese and hypoglycemic compared to the other groups. Fasting plasma glucose level of group F was higher than any other group value. TGSR of group F + I was significantly higher than that of the control group, while that of group G + I was not, indicating that long-term hyperinsulinemia can stimulate hepatic triglyceride production when the rats were supplemented only with fructose. On the other hand, the rats in group G + I showed the lowest plasma free fatty acid level of all and their postheparin lipolytic activity was significantly elevated compared to that of the control rats. Moreover, they had suppressed plasma triglyceride levels and its fractional catabolic rate was significantly increased, suggesting that hyperinsulinemia can still stimulate triglyceride removal from the circulation of glucose supplemented rats even at month 6. In conclusion, exogenous hyperinsulinemia can stimulate hepatic triglyceride secretion even after 6 months duration when supplemented with fructose, while its stimulating effect on triglyceride removal from the circulation can be seen only with glucose supplementation. Thus, the effect of long-term hyperinsulinemia on plasma triglyceride turnover differs depending on the supplemented monosaccharides.

Patients with diabetes mellitus have a higher rate of mortality than the general population. This higher mortality may be attributed mainly to cardiovascular disease. A high prevalence of dyslipidemia in diabetics can be one of the reasons for this. The most commonly recognized lipid abnormality in non-insulin-dependent diabetics (NIDDM) is hypertriglyceridemia, which is known to be an independent risk factor for coronary heart disease in diabetics. Hypertriglyceridemia can be produced by two mechanisms, increased synthesis of very-low-density lipoprotein (VLDL) triglyceride and removal defect of plasma triglyceride. It has been a matter of debate whether insulin always stimulates hepatic VLDL secretion but it is generally accepted that insulin deficiency results in an impairment of plasma triglyceride clearance. Considerable attention has recently been focused on the atherogenecity of postprandial hyperlipidemia, remnant lipoproteins, small, dense LDL, lipoprotein (a) [Lp(a)] and isolated hypo-alphalipoproteinemia in NIDDM subjects. Several reports suggested that these atherogenic lipoprotein abnormalities are present in NIDDMs even if they are apparently normolipidemic. Association of visceral fat obesity, insulin resistance and nephropathy may aggravate the atherogenic lipoprotein profile. Therefore, we propose here that plasma lipid levels of diabetic subjects must be more strictly controlled than for the non-diabetic population in order to avoid an increased risk for coronary heart disease. If they are obese or associated with insulin resistance or nephropathy, these conditions should be carefully controlled.

To determine whether small-sized low density lipoprotein (LDL) is associated with a high incidence of coronary heart disease in diabetic nephropathy, we measured the LDL particle size in non-insulin-dependent diabetes mellitus (NIDDM) patients with various degrees of albuminuria (n = 95) and age-, weight-matched non-diabetic control subjects (n = 31). The diabetic subjects were divided into three groups, normoalbuminuric, microalbuminuric and macroalbuminuric NIDDM, based on the amount of albuminuria. The average diameter of LDL particles was determined by non-denaturing polyacrylamide gradient (2-16%) gel electrophoresis. The plasma lipid and lipoprotein concentrations were comparable between the non-diabetic controls and normoalbuminuric NIDDM, whereas the plasma triglyceride, very-low-density lipoprotein (VLDL) or LDL concentration was significantly increased in diabetic nephropathy. The mean LDL particle size was significantly smaller in microalbuminuric NIDDM compared with the controls or normoalbuminuric NIDDM, and the LDL size was further decreased in macroalbuminuric NIDDM. The incidence of small LDL (diameter < 255 A) was remarkably increased in microalbuminuric (58%) and macroalbuminuric NIDDM (67%) compared to the control (13%) and normoalbuminuric NIDDM (27%). Corresponding to the decreased LDL size, the cholesterol content of the LDL was significantly depleted in NIDDM with nephropathy. The high prevalence of small LDL in diabetic nephropathy was also observed even when hypertriglyceridemic or hypertensive subjects were excluded from each group. The increment in triglyceride-rich lipoprotein (d < 1.006) after oral fat-loading was increased, and postheparin lipoprotein lipase activity was decreased significantly in diabetic nephropathy. These abnormalities were significantly associated with LDL particle size. Multivariate regression analysis revealed that the amount of albuminuria was closely associated with the average LDL particle size, and this association was independent of the plasma triglyceride level. Neither insulin resistance nor glycemic control was directly associated with LDL particle diameter. The present study indicates that LDL particles become smaller in diabetic nephropathy, and this may be associated primarily with abnormal triglyceride metabolism. However, in addition to hypertriglyceridemia, other metabolic abnormalities caused by diabetic nephropathy may also be involved in the pathogenesis of small LDL particles.